Dr. med.

Volker Herold
Senior Physician of the Clinic for Internal Medicine I
Caritas Hospital St. Josef
Landshuter Straße 65
93053 Regensburg
E-Mail: volker-herold@gmx.de

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The "Deutsche Bibliothek" lists this publication in the German national biography; detailed bibliographic data
is available on the internet at http://dnb.ddb.de.

10th edition 2020 (1st Englisch edition); Internal Intensive Care Medicine
598 figures
120 tables

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Printed in Germany

Planning: Dr. V. Herold, Regensburg

Design: Printgallery, Regensburg
Set: Printgallery, Regensburg
Print: Friedrich Pustet KG, Regensburg
Translation: Nina Peinthor, Dr. Florian Eisner (Graz, Austria)

ISBN 978-3-00-066099-3
 Dedicated to my wife Claudia
and my children Leonie, Lukas, Lena and Luis
 Preface

Intensive Care Medicine was born in the year 1952: During the polio epidemic in Denmark the Danish an-
esthetist Björn Ibsen (1915-2007), who is meanwhile considered as the founder of intensive care medicine,
ventilated for the first time a 12 years old girl with a severe poliomyelitis by positive pressure ventilation for
a longer time, so that the first intensive care unit was founded in Kopenhagen 1952. The internal intensive
care medicine has progressed rapidly since that time in the last few years like hardly any other medical field.
On the basis of numerous studies new diagnostic and therapeutic approaches are continuously developed
for the treatment of critically ill patients. The book "Internal intensive care medicine" has its origin in the
"Compact course internal intensive care medicine": This highly popular nationwide course is attended by
colleagues from all over Germany, Austria and Switzerland for several years now. This course was primarily
intended as an introduction for new staff in the intensive care unit, but it now comprises the entire internal
intensive care medicine and is therefore also attended by a number of "old hands".
The special internal intensive care medicine is a challenge for everyone, not least because the mortality
of internal intensive care patients is about three times as high as the mortality of surgical intensive care
patients. About three quarters of all ventilated internal intensive care patients die! In Germany there is no
interdisciplinary intensive care medicine. Only area-specific additional qualifications can be acquired (e.g.
operational, internal or neurological intensive care medicine). De iure herefore it should be considered cri-
tically if it is reasonable that anaesthesiologists (e.g. with an additional qualification in operational intensive
care medicine) assume the complette responsibility alone for the intensive care treatment of internal intensi-
ve care patients. In the case of a medical error the physician may be accused of contributory negligence and
the hospital may be held liable for organizational faults (i.a. joint statement of the German Society for Internal
Intensive Care Medicine [DGIIN] and the German Society for Internal Medicine (DGIM]: On the organization
of internal intensive medicine at university clinics and hospitals). De facto, however, in my experience, it is
already the case that the colleagues of anethesiology can very well take care of internist intensive care pati-
ents and do so (and sometimes even better than some internists). Especially in an interdisciplinary intensive
care unit is is suitable to work together: Perhaps the anesthetist can occasionally support the internist with
complex ventilation on the one hand, and on the other hand the internist may be helpful for the anesthesio-
logist in the management of complex cardiac arrhythmias. In about 50% of the cases a cardial disease leads
to the admission of the patient to the intensive care unit and about 30% of all internal intensive care patients
have a relevant cardial accompanying disease, so that often a cardiologist is appointed as head of an inten-
sive care unit. Since 2014, the complex intensive care treatment (OPS-code 8-980) may only be accounted
in the DRG-system (Diagnosis-Related System) by hospitals with the required structural requirements: This
includes the continuous presence (24h) of a physician in the intensive care unit. The additional supervision
of the intensive care unit by the doctor on duty who is also in charge of the emergency department and the
peripheral units is not possible! Furthermore, the head of the intensive care unit has to have the additional
qualification "intensive care". The amount of the daily effort points (SAPS II, TISS 10) must also be deter-
mined. Since 2016, an in-house cardiac catheterization laboratory with 24h standby is also a prerequisite,
which is a major problem for many clinics. Curiously enough this applies for the accounting of all diagnoses
- not only for the cardiological ones. The reasons for this regulation are difficult to understand: One has to
raise the question why a cardiac catheter is required for the treatment and therefore also for the accounting
of, for example, a severe pneumonia or pancreatitis. Since 2020 the hold up ECMO is also a prerequisite.

Moreover, the acquisition of relevant skills is essential in the internal intensive care medicine. In a small (to
medium-sized) clinic, where there are usually only three to four consultants for internal medicine, an internist
should, at the latest when he becomes a consultant, fully master the relevant techniques and skills. The
acquisition of an additional qualification is certainly very pleasant and graces the homepage of the hospital:
Nevertheless, the consultant for internal medicine with the additional qualification "cardiology" is also expec-
ted to conduct an emergency gastroscopy with endoscopic haemostasis or an emergency-ERCP in case of
a jammed concrement with cholangiogenic sepsis as well as the consultant for internal medicine with the
additional designation "gastroenterology" is expected to master the attachment of a temporary pacemaker
or the TEE.
In a small clinic it is not possible to employ eight consultants for internal medicine with the respective addi-
tional qualification (cardiology, gastroenterology, pulmology, haematology etc.) which will then also have to
do background tasks. All these tasks have to be performed by a single internist, because there is no other
possibility. On the other hand, if you work in a large clinic ("center"), where there is a gastroenterologist for
the endoscopic treatment of esophageal variceal bleeding , a cardiologist for the attachment of a temporary
pacemaker, a pulmonologist for emergency bronchoscopy, a neurologist for the treatment of strokes or for
the performance of lumbar punctures in case of suspected meningitis, a haematologist for the bone marrow
puncture in case of suspected acute leukemia, an endocrinologist for the management of a ketoacidotic
coma, an Addisonian crisis or a thyrotoxic crisis, an angiologist for emergency angiography, a radiologist for
the assessment of an x-ray image etc., this is not absolutely necessary. Then it could be very useful to have
at least the most important telephone numbers at hand and to complete the konsilzettel correctly. It should
be noted that most of the physicians do not work in centers and the majority of intensive care patients is not
treated in centers (94% of all patients are not treated in university clinics).

This book is an attempt to present all aspects of internal intensive care medicine in a clear and concise
manner. The content of this book is practice-oriented and intended primarily for clinicians. True to the motto
"a picture is worth a thousand words", an attempt was made to illustrate the topics with numerous pictures.
This book can certainly not replace the practical training in intensive care units, but sometimes it can make
it a little easier. Almost all of the treatment recommendations are based on studies so the reader should
not be deprived of them (the knowledge of fundamental studies is also important for the examination of
the optional internal intensive care training!). However, they are listed in separate boxes, so that they can
be read by interested readers, but they are not absolutely necessary for the understanding of the text. An
attempt was also made to implement the current guidelines (annotation to the zur S-Classification of guideli-
nes [usual in Germany]: S1 [only recommendations of expert groups; lowest status]; S2e [evidence-based],
S2k [consensus-based], S3 [evidence- and consensus-based; highest status]) and recommendations of the
respective expert associations. The text is consciously and deliberately written in the nominal style since, in
my personal opinion, learning is easier in the nominal style than in the verbal style.

I hope that this book will facilitate the often difficult everyday life for many colleagues on the intensive care
unit. At this point I would like to thank my faithful "allies" in the compact course on internal intensive care
medicine, Dr. Josef Zach, Dr. Uli Tausch, Ulrich Follmann, Dr. Peter Roch, Dr. Franziska Rothfritz-Deutsch,
Dr. Werner Kargl, Dr. Stefan Großmann (also sincere thanks to him for the kind permission to use his won-
derful schemata and drawings on the topic of ventilation), Dr. Carmen Großmann, Dr. Horst Schleicher, Dr.
Robert Dengler, Prof. Dr. Roland Büttner and Mr. Alois Philipp and Mr. Peter Reiser for the provision of many
images. A very special word of thanks goes to my clinical teachers of many years, Dr. Johannes Bumes,
Ulrich Follmann, Dr. Josef Kraus and Dr. Bernhard Schießl, my two instructors for cardiac catheterization PD
Dr. Markus Resch and Prof. Dr. Dierk Endemann as well as to my parents.

In Germany meanwhile the 10th edition of the book was published. The translation into English was started in
March 2020 and is expected to be completed by the end of this year (still ongoing). The complete book has
about 1600 pages. The translation of the general part and the chapters cardiology, angiology, pulmonology,
endocrinology, nephrology, infectiology and hematologyhave now (01.12.2020) been completed, which has
now been published and is available here.

Regensburg, June, 2020 Volker Herold

Table of Contents

GENERAL PART
Accesses
Venous Accesses...................................................................................................................................22
Arterial Accesses ...................................................................................................................................36
Airway Management ................................................................................................................42
Mechanical Ventilation (basics, types).....................................................................................77
Non-invasive ventilation (NIV) ...............................................................................................127
Weaning.................................................................................................................................141
Tracheotomy...........................................................................................................................154
Analgosedation.......................................................................................................................164
Hemodynamic monitoring ......................................................................................................186
Circulatory therapy
Volume therapy ....................................................................................................................................230
Catecholamine therapy ........................................................................................................................239
Shock.....................................................................................................................................245
Nutrition of critically ill patients ..............................................................................................254
Resuscitation
Resuscitation of children .....................................................................................................................283
Resuscitation of adults ........................................................................................................................295

SPECIAL PART
Cardiology
Acute coronary syndrome (ACS)............................................................................................342
Cardiogenic shock..................................................................................................................398
Cardiac arrhythmias...............................................................................................................430
Inflammatory heart diseases
Endocarditis..........................................................................................................................................494
Myocarditis...........................................................................................................................................518
Pericarditis............................................................................................................................................524
Hypertensive crisis.................................................................................................................536

Angiology
Acute pulmonary embolism....................................................................................................544
Acute aortic syndrome............................................................................................................596

PULMONOLOGY
ARDS.....................................................................................................................................614
Pulmonary Hypertension........................................................................................................667
Acute right heart failure..........................................................................................................682
Obstructive lung diseases
Status asthmaticus...............................................................................................................................689
Exacerbated COPD..............................................................................................................................693
Interstitial lung diseases.........................................................................................................712
Bronchial hemorrhage............................................................................................................720
EndoCrinologY
Endocrinological emergencies
Diabetic coma.......................................................................................................................................728
Lactic acidosis......................................................................................................................................731
Thyreotoxic crisis..................................................................................................................................734
Myxedema coma..................................................................................................................................738
Addison crisis.......................................................................................................................................739
Hypopituitarism (i.a. pituitary coma).....................................................................................................744
Acute intermittent porphyria (AIP)........................................................................................................747
Disorders of electrolytes
Disorders of sodium..............................................................................................................................752
Disorders of potassium.........................................................................................................................763
Disorders of calcium.............................................................................................................................767
Disorders of magnesiums.....................................................................................................................774
Disorders of phosphate........................................................................................................................776
Disorders of acid-base balance
Acidoses...............................................................................................................................................780
Alkaloses................................................................................................................................................................ 785

Nephrology
Acute kidney failure................................................................................................................790
Renal replacement therapy....................................................................................................801

Infectiology
Sepsis.....................................................................................................................................820
Pneumonia
Community aquired pneumonia
gerneral...................................................................................................................................................................877
special (special forms)
Legionella pneumonia.................................................................................................................................................................... 909
Swine flu (H1N1)............................................................................................................................................................................ 911
COVID-19 (SARS-CoV-2).............................................................................................................................................................. 914
Hospital aquired pneumonia.................................................................................................................940
Multi-drug resistant organisms (MDRO).................................................................................953
Skin and soft tissue infections (SSTI).....................................................................................973
Fungal infections (mycoses)...................................................................................................979
Malaria....................................................................................................................................990

HEmatologY
Disseminated intravascular coagulation (DIC).....................................................................1004
Hyperfibrinolysis...................................................................................................................1008
Blood products.....................................................................................................................1010
Heparin-induced thrombocytopenia (HIT)............................................................................1040
Idiopathic thrombocytopenic purpura (ITP)..........................................................................1047
Thrombolic microangiopathies (TMA)
TTP (thrombotic thrombocytopenic purpura)......................................................................................1051
HUS (hemolytic uremic syndrome).....................................................................................................1054
HELLP syndrome................................................................................................................................1057

Appendix 1060
 ABBREVIATIONS

A Ampere tion rance

AA amino acids AHF acute heart failure ARDS acute respiratory distress
AAA abdominal aortic aneu- aHUS atypical hemolytic uremic syndrome
rysm syndrome ARF acute kidney failure
ABG arterial blood gas AIDP acute inflammatory de- ARI acute respiratory insuffici-
AaDO2 alveolar-arterial oxygen myelinating polyneuropa- ency
gradient thie ARNI Angiotensin-receptor-
AAE acquired angioedema AIHA autoimmune hemolytic neprilysine-inhibitor
ABPH allergic bronchopulmona- anemia ARR absolute risk reduction
ry aspergillosis AIP acute intermittent por- ARRVD arrhythmogenic right ven-
ABS Antibiotic-Stewardship phyria tricular dysplasia
ACCP American College of AIP acute interstitiell pneu- ARF acute kidney failure
Chest Physicians monia As Arsenic
ACE Angiotensin-Converting- AIP autoimmune pancreatitis ASA American Society of
Enzyme AIPO acute intestinal pseudo- Anesthesiology
ACI Arteria carotis interna obstruction ASA anti sarcolemmal
(internal carotid artery) AKI(N) acute kidney injury antibodies
ACLF acute on chronic liver fai- ALA aminolevulinic acid ASA acetyl salicylic acid
lure ALF acute liver failure ASA atrial septum aneurysm
ACP advanced care planing ALFA automated low-flow asci- ASB amnesic shellfish poiso-
ACP afterload-related cardiac tes ning
performance ALFSG acute liver failure study ASB assisted spontaneous
ACP Amplatzer Cardiac Plug group breathing
ACPO acute colonic pseudoob- ALS amyotrophic lateral scle- ASH alcoholic steatohepatitis
struction rosis ASI Antibody-specificity-Index
ACR American College of Ra- ALI acute lung injury ASV adaptive support ventila-
diology ALS advanced life support on
ACS acute coronary syndrome AMAN acute motor axonal neu- AT Antithrombin
ACT activated clotting time ropathy ATC acute traumatic coagulo-
ACTH adrenocorticotropic hor- AMI acute mesenteric ische- pathy
mone mia ATC automatic tube compen-
ACV assisted controlled venti- AMLA antimyolemmal antibo- sation
lation dies ATP anti-tachycardic pacing
ADA adenosine deaminase amp. ampoule ATR allergic transfusion
ADAMTS a disintegrin and metallo- AMSAN acute motor sensory reaction
proteinase with a throm- axonal neuropathy ATS American Thoracic Socie-
bospondin motifs AND allow natural death ty
ADD-RS Aortic Dissection Detec- annot. annotation ATS anti-tachycardic stimulation
tion Risk Score AOS Aneurysm-osteoarthritis- ATLS Advanced Trauma Life
ADEM acute disseminated syndrome Support
encephalomyelitis AP alkaline phosphatase ATN acute tubular necrosis
ADH alcohol dehydrogenase AP angina pectoris AUC area under the curve
ADH antidiuretic hormone APACHE acute physiology and AVDSF alveolar dead space frac-
AECOPD acute exacerbated COPD chronic health evaluation tion
AED automatic external APC activated Protein C AVNRT AV-nodal reentrant tachy-
defibrillator APC Argonplasmacoagulation cardia
AEP auditory evoked poten- APCC activated prothrombin AVRT AV reentrant tachycardia
tials complex concentrate (WPW-syndrome)
AFE amniotic fluid embolism APL acute promyelocytic leu- AV atrio-ventriculär
AFLP acute fatty liver of preg- kemia av-EC-
nancy APRV airway pressure release CO2-R arterio-venous extracor-
AG anion gap ventilation poreal carbon dioxide re-
AGE arterial gas embolism APTC activated prothrombin- moval
AGP aerosol-generating pro- complex aVL augmented-voltage left
cedures ARB Angiotensin-receptor-blo- AVR activation-velocity-ratio
AHA acquired haemophilia A cker aVR augmented-voltage right
AHA American Heart Associa- ARC augmented renal clea- avDO2 arterial-venous oxygen
 gradient CAS central anticholinergic syn- COP cryptogenic organizing
BAE bronchial artery embolizati- drome pneumonia
on CAT COPD Assessment Test COPD chronic obstructive pul-
BAFF B-cell activating factor of cath lab cardiac catheterization monary disease
the TNF family laboratory COVID coronavirus disease
BAL British Antilewisit (Dimer CAVH continuous arterio-venous CPAP continuous positive aiway
caprol) hemofiltration pressure
BAL bronchoalveolar lavage CBF cerebral blood flow CPB cardiopulmonary bypass
BBRT bundle-branch-reentrant CC chest compression CPFE combined pulmonary fib-
tachycardia CCMP cirrhotic cardiomyopathy rosis and emphysema
BCAA branched chain amino CCL cardiac catheterization CPE Carbapenemase-produ-
acids laboratory cing enterobacteriaceae
BCNIE blood culture-negative CCRV cardiac compression re- CPO cardiac power output
infective endocarditis lease velocity CPOT Critical-Care Pain Obser-
BE base-excess Cd Cadmium vation Tool
BER benign early repolarisation CDAD Clostridium-difficile-associ- CPP cerebral perfusion pres-
BGA blood gas analysis ated diarrhea sure
BIP bleomycin-induced CEA carotid thromboend- CPP coronary perfusion pres-
pneumonitis arterectomy sure
BIPAP biphasic positive airway CFA Cardio First Angel CPPV continuous positive pres-
pressure CFR case fatility rate sure ventilation
BIS bispectral index CFT clot formation time CPR cardiopulmonary resuscita-
BIVAD biventricular assist device CFU colony-forming units tion
BLS basic life support Ch Charriere (Charr.; 0.33mm; CPS cerebral performance
BLUE bedside lung ultrasound in syn.: French) scale
emergency CHE cholecystektomy CPU Chest Pain Unit
BMI body mass index CHE cholinesterase enzyme CPVT catecholaminergic poly-
BMS bare metal stent CHF chronic heart failure morphic ventricular tachy-
BMV bag mask ventilation CI cardiac index cardia
BNP brain natriuretic peptide CIBD chronic inflammatory bowel CRE Carbapenem-resistant
BOOP bronchiolitis obliterans disease enterobacteriaceae
organizing pneumonia CIC COVID-19 associated CRO Carbapenem-resistant
BP blood pressure coagulopathy organisms
BPA balloon pulmonary angio- CICV cannot intubate cannot CRP C-reactive protein
plasty ventilate CRPS complex regional pain
BPI blood pressure index CIM critical illness-myopathy syndrome
bpm beats per minute CIN contrast-induced CRT capillary refill time
BPS behavioral pain scale nephropathy CRT cardial resynchronisation
BSA body surface area CINMA critical illness neuromus- therapy
BSC blood sugar concentration cular abnormalitiies CRS cytokine release syndrome
BSR blood sedimentation rate CIP critical illness-polyneuro- CSA cross sectional area
BTVA bronchoscopic thermal pathy CSF cerebrospinal fluid
vapor ablation CIPO chronic intestinal pseudo- CSE Cholesterin-Synthesis-En-
BTX botulinum toxin obstruction zyme
BUN blood urea nitrogen CIRCI critical illness-related corti- CSM carotid sinus massage
BVM bag valve mask costeroid insufficiency cSSTI complicated skin and soft
BVS bioresorbable vascular CK creatine kinase tissue infections
scaffholds CL cycle length CSW cerebral salt wasting
bw body weight CLI clot lysis index CT clotting time
C Compliance CLRT continuous lateral rotation CT computed tomography
CABG coronary artery bypass therapy CTCAE Common Terminology Cri-
graft cMRSA community aquired MRSA teria for Adverse Events
CAD coronary artery disease CMV controlled mechanical ven- CTPA CT-pulmonalisangiogra-
CAM coma acidosis malaria tilation phy
CAM confusion assessment CMV cytomegaly-virus CTB call-to-balloon
method CNS central nervous system CTG cardiotocography
CAPA coronavirus-associated CO cardiac output CTSI CT-Severity-Index
pulmonary aspergillosis CO carbon monoxide CVC central venous catheter
CARS compensatory antiinflam- CO2 carbon dioxide CVID common variable immuno-
matory response syndro- COLD chronic obstructive lung deficiency
me disease CVP central venous pressure
CART cardiac arrest team CONS coagulase negative CVVH continuous veno-venous
CAS Carotid angioplasty and staphylococci hemofiltration
stenting COP colloid-osmotic pressure CVVHDFcontinuous veno-venous
 hemodiafiltration the Study of the Liver drome
D Dalton ECA ecarin chromogenic assay ERV expiratory reserve volume
DAD diffuse alveolar damage ECG electrocardiogram ESBL extended spectrum beta-
DAH diffuse alveolar hemorrha- ECPB extracorporeal cardiopul- lactamase
ge monary bypass ESO European Stroke Organi-
DAN Divers Alert Network ECLS extracorporeal life support sation
DAPT dual antiplatelet therapy ECMO extracorporeal membrane ESRD end-stage renal disease
DBP diastolic blood pressure oxygenation ESUS embolic stroke of undeter-
DCI decompression illness eCPR extracorporeal cardiopul- mined source
DCM dilated cardiomyopathy monary resuscitation ESWL extracorporeal shockwave
dCO2 central venous-arterial ECT ecarin clotting time therapy
pCO2-difference ED emergency department ESKD endstage kidney disease
DCS decompression sickness EDC epidural catheter esp. especially
DD differential diagnosis EDD esophagus detection de- ESS euthyroid sick syndrom
DES drug eluting stent vice ESV endsystolic volume
DFT defibrillation threshold EDV enddiastolic volume ET endotracheal tube
DHC decompressive hemicra- EELI end-expiratory lung impe- ETCO2 end-tidal CO2-concentrati-
niectomy dance on
DHC Ductus hepatocholedo- EELV endexspiratory lung volu- ETTI Eschmann tracheal tube
chus me introducer
DIC disseminated intravasal EF ejection fraction EUG extrauterine gravidity
coagulopathy e.g. exempli gratia (for examp- EUS endosonographic ultra-
DIDP chronic inflammatory de- le) sound
myelinating polyneuropathy EGD esophagogastroduodeno- EVD external ventricular draina-
DILD drug-induced lung disease scopy ge
DILI drug-induced liver injury EGPA eosinophilic granulomato- EVLW extravascular lung water
DIP desquamative interstitial sis with polyangiitis FATE focus assesed transthora-
pneumonia (Wegener’s disease) cic echocardiography
DKA diabetic ketoacidosis EHS exertional heat stroke- FDA Food and Drug Admini-
DLCO diffusion capacity of the Syndrom stration
lung for CO EIT electrical impedance FDI fibrillation detection interval
DMPA dimercaptopropanesulfonic tomography FEEL focused echocardiogra-
acid ELS emergency life support phy for life support
DMSA dimercaptosuccinic acid ELSO extracorporeal life support FEES fiberoptic endoscopic eva-
DNI do not intubate organization luation of swallowing
DNP Dinitrophenol ELT endless-loop-tachycardia FES fat embolism syndrome
DNR do not resuscitate EMA European Medicines FEV1 forced expiratory volume in
DNS delayed neurological se- Agency 1 second
quelae EMB endomyocardial biopsy FF filtration fraction
DO2 delivery of oxygen EMD electromechanical dissoci- FFB farfield blanking Zeit
DOAK direct oral anticoagulants ation FFP filtering face piece
DO-DI door-in to door-out-time EMG elektromyography FFP fresh frozen plasma
DOGA diffusion optimized gas EN enteral nutrition FFR fractional flow reserve
application ENG elektroneurography FHH familial hypocalciuric
DPDS disconnected pancreatic ENT ears, nose and throat hypercalcemia
duct syndrome EOL end of life Fig figure
DPG diphosphoglycrate EOS end of service FiO2 fraction of inspired oxygen
DRG diagnosis related groups EPP erythropoietic protoporphy- F, Fr French (0.33mm; syn.:
DSA digital subtraction angio- rin Charriere; 3F = 1mm, 6F =
graphy EPAP expiratory airway pressu- 2mm)
DSI daily desation interruption re Fe Ferrum (iron)
DSM Diagnostic Manual of EpCAM epithelial cell adhesion FEIBA Factor Eight Inhibitor By-
Mental Disorders molecule passing Activity
DSt down-slope time EPS extrapyramidal syndrome FES fat embolism syndrome
D-TTP differential time to positivi- ERA endothelin-receptor-anta- FEUrea fractional excretion of urea
ty gonist FHH benign familial hypo-
DVT deep vein thrombosis ERC European Resuscitation calcemia
EAA exogenous-allergic alveoli- Council FMC first medical contact
tis ERCP endoscopic retrograde FMF familial Mediterranean
EACTS European Association for cholangiopancreatography fever
Cardio-Thoracic Surgery ERI elective replacement indi- FMT fecal microbiota-transplan-
EAH exercise associated hypo- cation tation
natremia ERP effective refractory period FNCJ fine needle catheter jejuno-
EASL European Association for ERS early repolarisation syn- stomy
FNHTR febrile non-hemolytic trans- HE hepatic encephalopathy pulmonary aspergillosis
fusion reaction HES hydroxyethylic starch IBP invasive blood pressure
FNP fine needle puncture HF hemofiltration IBD inflammatory bowel
FOCUS focused cardiac ultra- H-FABP heart-fatty acid-binding disease
sound protein ICA International Club of Asci-
FPSA fractionated plasma sepa- HFNOT high-flow nasal oxygen tes
ration and adsorption therapy ICAAC Interscience Conference
FRC functional residual capacity HFOV high frequency oscillatory on Antimicrobial Agents
FSH follicular stimulating ventilation and Chemotherapy
hormone HFV high frequency ventilation ICD implantable cardioverter-
FST furosemide stress test HFPEF heart failure with preser- defibrillator
FVL Faktor V Leiden ved ejection fraction ICD International Classifica-
GABA gamma aminobutyric acid HFREF heart failure with reduced tion of Diseases
GAS genetic aortic syndromes ejection fraction ICG indocyanine green
GAS group A streptococci HFRS hemorrhagic fever with ICH intracerebral hemorrhage
GAVE gastric antral vascular renal syndrome ICH intracranial hypertension
ectasia Hg Hydrargyrum (mercury) ICM insertable cardiac monitor
GBL gamma butyrolactone HHS hyperglycemic hyper- ICP intracerebral pressure
GBS Glasgow Blatchford Score osmolar syndrome ICS inhaled corticosteroids
GBS Guillain-Barré-Strohl-syn- HIE hypoxic ischemic encepha- ICS intercostal space
drome lopathy ICU intensive care unit
GCS Glasgow Coma Scale HIET high-dose insulin euglyce- ICUAW ICU-acquired weakness
G-CSF granulozyte-colony stimu- mic therapy ID inner diameter
lating factor HIPA heparin-induced platelet IDA iron deficiency anemia
GEDV global enddiastolic activation iDCM inflammatory dilated
volume HIT heparin-induced thrombo- cardiomyopathy
GEV gastroesophageal varices cytopenia IDSA Infectious Diseases
GFR glomerular filtration rate Hkt hematocrit Society of America
GGO ground glass opacity HLA human leukocyte antigen IE infective endocarditis
GH growth hormon HLHS hemophagocytic lympho- i.a. inter altri (among others)
GHRH growth hormon releasing histiocytic syndrome i.e. id est (meaning)
hormon HLM heart lung machine IFA inspiratory flow assistance
GI gastrointestinal HME heat and moisture ex- IFR infection fatality rate
GIF gastrointestinal failure changer IGF insulin-like growth factor
GIST gastrointestinal stromal HMPAO hexamethylpropylene- IHD intermittent hemodialysis
tumor amine oxime IIP idiopathic interstitial pneu-
GLDH glutamine dehydrogenase HNA human neutrophil antigen monia
GN Glomerulonephritis HOCM hypertrophic obstructive IIT intensified insulin-therapy
GM galactomannan cardiomyopathy iLA interventional lung assist
GOLD global initiative for chronic HP Helicobacter pylori ILCOR International Liaison
obstructive lung diseases HPV hypoxic pulmonary vaso- Committee on Resuscita-
GPA granulomatosis with poly- constriction tion
angiitis (Wegener’s disea- HPS hemophagocytic syndrome ILD interstitial lung disease
se) HR heart rate ILMA intubation laryngeal mask
GRACE global registry of acute HR-CT high resolution computed ILR implantable loop recorder
coronary events tomography iLT intubation laryngeal tube
GRC German Resuscitation HRS hepatorenal syndrome IM intramuscular
Council HSCT hematopoietic stem-cell IMC intermediate care
GRV gastric residual volume transplantation incl. included
GUCH grown-up congenital heart hTIG human Tetanus-Immun- Ind indication
disease globulin INR international normalized
GvHD graft versus host disease HTR hemolytic transfusion reac- ratio
GWR grey-white-ratio tion IPAP inspiratory airway pres-
HAE hereditary angioedema HTX heart transplantation sure
HAP hospital aquired pneumo- HU Houncefield-Units IPC intermittent pneumatic
nia HUS hemolytic-uremic syndro- compression
Hb hemoglobin me IPF idiopathic pulmonary fibro-
HBO hyperbaric oxygenation i.a. inter altri (among others) sis
HCAP healthcare associated i.a. intraarterial IPMN intraductal papillary
pneumonia IABP intra-aortic balloon pump mucinous neoplasm
HCFC hydrochlorofluorocarbons IACS interposed abdominal IPPV intermittend positive pres-
Hct hematocrit counterpulsation sure ventilation
HD hemodialysis IAP intraabdominal pressure IPS inspiratory pressure sup-
HDF hemodiafiltration IAPA influenza-associated port
IRAD International Registry of cocci MEF minimal enteral feeding
Acute Aortic Dissection LRT lipid-rescue-therapy MEGX Monoethylglycinexylidide
IRDS infant respiratory distress LSD lysergic acid diethylamide MELD model for endstage liver
syndrome LTA light transmission aggrego- disease
IRV inverse ratio ventilation metry MEP motor evoked potentials
IRAD International Registry of LTOT long term oxygen therapy MFS Miller-Fisher-Syndrome
Acute Aortic Dissection LTX liver transplantation MGUS monoclonal gammopathy
ISB intermittent self-ventilation LVAD left ventricular assist de- of unknown significance
ISO International Organisation vice MH malignant hyperthermia
for Standardization LVED left ventricular assist de- MHE minimal hepatic encepha-
ISTH International Society on vice lopathy
Thrombosis and Haemo- LVEDAI left ventricular enddiasto- MI myocardial infarction
stasis lic area index MIC minimal inhibitory concent-
ISV intermittent self venti- LVEDD left-ventricular enddiastolic ration
lation diameter MICR minimal interruption of the
ITBV intrathoracic blood volume LVEDP left ventricular end- cardiopulmonary reanima-
ITGV intrathoracic gas volume diastolic pressure tion
ITR immunological transfusion LVEDV left ventricular end- MICU medical intensive care unit
reactions diastolic volume MILS manual in-line stabilisation
ITTV intrathoracic thermo LVR lung volume reduction MINCA myocardial infarction with
volume LVSWI left ventricular stroke work normal coronary arteries
IV intravenous index MINS manual in-line stabilizati-
IV invasive ventilation M morbus (disease) on of the cervical spine
IVC inferior vena cava mab monoclonal antibody ML maximum lysis
IVH intraventricular hemorrha- MAC minimal alveolar concen- MMH monomethyl hydrazine
ge tration MMI malignant media infarction
IVR idioventricular rhythm MACE major adverse cardiac MMV mandatory minute ventila-
IWI integrative weaning index events tion
J Joule MAHA microangiopathic hemolytic MODS multiple organ dysfunc-
JHW John William Huffmann anemia tion syndrome
KDIGO kidney disease improving MAD Mucosal Atomization De- MOF multiorgan failure
global outcomes vice MPAP mean pulmonal-arterial
KIU Kallikrein Inactivator Unit MALA Metformin-associated lactic pressure
KPC Klebsiella pneumoniae- acidosis mPAN microscopic panarteriitis
carbapenemase MAO monoamine oxidase nodosa
LAA left atrial appendage MAP mean arterial pressure MRA mineralocorticoid receptor
LABA long acting beta agonist MAPSE mitral annular plane systo- antagonist
LAD left anterior descending lic excursion MRE multiresistente Erreger
artery MARS molecular adsorbent MRI magnetic resonance ima-
LAM lymphangioleiomyomatosis recycling system ging
LAMA long acting muscarinic MAS macrophage activation MRSA methicillin-resistant sta-
antagonist syndrome phylococcus aureus
LBBB left bundle branch block MAS Morgagni-Adams-Stokes mRS modified ranking scale
LBM little brown mushrooms attack MRSE methicillin-resistant sta-
LCOS low cardiac output MAS meconium aspiration syn- phylococcus epidermidis
syndrome drome MSG major surface glycopro-
LFT liver function tests masl meters above sea level tein
LGE late gadolinium enhance- MASV mitral annular systolic velo- MSSA methicillin-sensitive sta-
ment city phylococcus aureus
LH luteinizing hormone MAV mitral annulus velocity MSCS malignant spinal compres-
LIP lower inflection point MBL Metallo-Beta-Lactamase sion syndrome
LIP lymphocytic interstitial MBP maximum barrier precau- mTOR mechanistic target of ra-
pneumonia tions pamycin
LIS Lung Injury Score MCF maximal clot firmness MTt mean transit time
LMA laryngeal mask airway MDAC multi-dose activated MUST malnutrition universal
LMCA left main coronary artery charcoal screening tool
LMWH low molecuar weight hepa- MDR multi-drug resistance MVO2 myocardial oxygen
rin MDRGN multidrug resistant gram consumption
LOLA L-ornithine-L-aspartate negative bacteria MW molecular weight
LPR lactate-pyruvate-ratio MDRO multi-drug resistant NAVA neurally adjusted ventila-
LPV lung protective ventilation organisms tory assist
LRSA Linezolid-resistant Staphy- MDS myelodysplastic syndrome NCS Nociception Coma Scale
lococcus aureus MECC minimal extracorporeal NCSE nonconvulsive status epi-
LRE Linezolid-resistant entero- circulation lepticus
NCT narrow complex tachycar- OPIDN organophosphate induced real lung assist
dia delayed neurotoxicity PEF peak expiratory flow
NDM New-Delhi-Carbapenema- OR operation room PEF post-extubation failure
se OSDS obesity supine death syn- PEEP positive endexpiratory
NEC necrotizing enterocolitis drome pressure
NHF nasal high-flow p.d. per definitionem PEP positive expiratory pres-
NIBP non-invasive blood pres- PAC premature atrial contrac- sure
sure tions PEF peak exspiratory flow
NIH national institutes of PAC pulmonary artery catheter PEG Paul-Ehrlich-Gesellschaft
health PACNS primary angiitis of the CNS PEG percutaneous endoscopic
NIHSS national institutes of PAE pulmonary artery embolism gastroenterostomy
health stroke scala PAD peripheral artery disease PEG polyethylene glycol
NIP non-invasive pressure PAD public access defibrillation PEP Post-ERCP-pancreatitis
NIV non-invasive ventilation PAF platelet-activating factor PEJ percutaneous endoscopic
NLS newborn life support PAH pulmonary-arterial hyper- jejunostomy
NLR neutrophil-lymphocyte ratio tension PELE post extubation laryngeal
NIRS near infrared spectroscopy PAI plasminogen-activator- edema
NISS Nosocomial Infection Sur- inhibitor PES post-extubation stridor
veillance System PAINAD pain assessment in advan- PFA platelet function assay
NITR non-immunological ced dementia PFO patent foramen ovale
transfusion reactions PAL physical activity index PH pulmonary hypertension
NMDA N-methyl-D-aspartate PAN Panarteriitis nodosa PHC permissive hypercapnia
NMM neuromuscular monitoring PAP pulmonal-arterial pressure PHG portal hypertensive gastro-
NMS neuroleptic malignant syn- PAU penetrating aortic ulcer pathy
drome PAV proportional assist venti- PHS polysaccharide hemostatic
NNT number needed to treat lation system
NO nitric oxide Pb Plumbum (lead) PIC pulmonary intravascular
NOAC non-vitamin K antagonist / PBGD Porphobilinogen-deamina- coagulopathy
novel /new oral anticoagu- se PICA posterior inferior cerebellar
lants PBM Patient Blood Manage- artery
NOMI non-occlusive mesenterial ment PICC peripher inserted central-
ischemia PBT pulmonary barotrauma venous catheter
NOTES natural orifice translumi- PBW predicted body weight PiCCO pulse invasive contour
nal endoscopic surgery PC platelet concentrate cardiac output
NPA nasopharyngeal airway PCA patient controlled analge- PIMS pediatric inflammatory mul-
NPO nil per os (keep fasted) sia tisystem syndrome
NRS numeric rating scale PCAS post-cardiac-arrest-syn- PIRRT prolonged intermittent re-
NRS Nutritional Risk Screening drome nal replacement therapy
NSAID non-steroidal anti-inflam- PCC prothrombin complex PICS post intensive care syn-
matory drugs concentrate drome
NSB neurotoxic shellfish poi- PCEA patient controlled epidural PJP Pneumocystis jirovecii-
soning analgesia pneumonia
NSE neuron specific enolase PCI percutaneous coronary PJRT permanent junctional reen-
NSF nephrogenic systemic intervention trant tachycardia
fibrosis pCO2 carbon dioxide partial pres- PLE protein losing enteropathy
NSIP non-specific interstitial sure PLS pediatric life support
pneumonia PCP Phencyclidine PLV pressure limited ventilation
NSTE non-ST-segment-elevati- PCP Pneumocystis-pneumonia PLVR polymeric lung volume
on PCR Polymerase chain reaction reduction
NSTEMI non-ST-elevation myocar- PCT Procalcitonin PMP polymethylpentene
dial infarction PCV pressure controlled venti- PMSC perimortem cesarean
NYHA New York Heart Associa- lation section
tion PCWP pulmonary capillary PMT pacemaker mediated ta-
O2 oxygen wedge pressure chycardia
O2 -ER oxygen extraction ratio PDA Periduralanästhesie PN parenteral nutrition
OBS organic brain syndrome PDE Phosphodiesterase PNH paroxysmal nocturnal
OCS oral corticosteroids PDMS patient data management hemoglobinuria
ODS osmotic demyelination syn- system PNS peripheral nervous system
drome PDT percutaneous dilational tra- PNS persistent neurological
OMI occlusive mesenterial cheostomy sequelae
ischemia PE pulmonary embolism PO per os
OOB out-of-bed PEA pulmonary endarterectomy pO2 oxygen partial pressure
OPA oropharyngeal airway PEA pulseless electrical activity POCT point of care testing
OPAL open albumin dialysis pECLA percutaneous extracorpo- POCUS point of care-ultrasound
POD physician on duty lation SBEM spontaneous bacterial
POI postoperative ileus RCA right coronary artery empyema
PONV postoperative nausea and RCC red cell concentrate SBP spontaneous bacterial
vomiting RCT randomized controlled trial peritonitis
POP pancreatitis outcome RCX Ramus circumflexus SBP systolic blood pressure
prediction RDT rapid diagnostic tests SBT spontaneous breathing
PPCD post-paracentesis circula- REBOA resuscitative endovascu- trial
tion dysfunction lar balloon occlusion of the SC sieving coefficient
PPE personal protective equip- aorta SC subcutan
ment resp. respectively SCCM Society of Critical Care
PPHN persistent pulmonary hy- RKI Robert Koch Institute Medicine
pertension of the newborn RIP remote ischemic precon- SC-CIP sclerosing cholangitis in
PPI proton pump inhibitor ditioning critically ill patients
ppm parts per million RIS rapid infusion system SCD sudden cardiac death
PPS proportional pressure RIVA Ramus interventricularis SCS subclavian crush syndrome
support anterior SCUF slow continuous ultrafiltra-
PPV pulse pressure variation RMV respiratory minute volume tion
PRAC Pharmacovigilance Risk RMVT repetitive monomorphic SD standard deviation
Assessment Committee ventricular tachycardia SDAD singe-dose activated
PRES posterior reversible ence- RER respiratory exchange ratio charcoal
phalopathy syndrome ROSC return of spontaneous cir- SDC suboccipital decompressi-
PSB paralytic shellfish poiso- culation ve craniectomy
ning ROTEM rotational thromboelasto- SDD selective decontamination
PSPG portosystemic pressure metry of the digestive tract
gradient RPGN rapid-progressive glomeru- SDH subdural hematoma
PSS Poisoning Severity Score lonephritis SEB Staphylococcus-enteroto-
PSS polystyrol sulfonate rpm revolutions per minute xin B
PTC percutaneous transhepatic RPP renal perfusion pressure SGA subjective global assess-
cholangiography Rq reflection quotient ment
PTCA percutaneous transluminal RQ respiratory quotient SHOC sonography in hypotension
coronary angioplasty RR respiratory rate and cardiac arrest
PTFE polytetrafluoroethylene RR systemic blood pressure SID selective intestinal
PTH parathyroid hormone according to Riva-Rocci decontamination
PTP Post-transfusion purpura RRR relative risk reduction SIB self inflating bulb
PTT partial thromboplastine RRT renal replacement therapy SIDS sudden infant death syn-
time RRT rapid responsive team drome
PTV pulmonal thermo-volume RSBI rapid shallow breathing SILI self-inflicted lung injury
PVAB post ventricular atrial index SIMV synchronized intermittend
blanking period RSS Ramsay-Sedation-Scale mandatory ventilation
PVARP post ventricular atrial RTA renal-tubular acidosis SIRS systemic inflammatoric
refractory period RTP renal tubulopathy response syndrome
PVC peripheral-venous catheter RTP reverse Trendelenburg SLE systemic lupus erythema-
PVC premature ventricular positioning tosus
contraction RV residual volume SLED slow extended dialysis,
PVI pleth variability index RVMI right ventricular myocardial sustainded low-efficiency
PVI pulmonary vein isolation infarction dialysis
PVPI pulmonary vascular perme- RVSWI right ventricular stroke SMI soft mist inhaler
ability index work index SNARE synaptosomal associated
PVR pulmonal vascular resi- SA sinu-atrial protein
stance SAAG serum/ascites-albumin- SNP sodium nitroprusside
qSOFA quick SOFA (sepsis rela- gradient SO2 saturation oxygen
ted failure assessment) SAB S. aureus-bacteremia SOD selective oral decontami-
R Resistance SAD supraglottic airway devices nation
RAP Respirator-associated SAH subarachnoid hemorrhage SOD sphincter-Oddi-dysfunction
pneumothorax SAPS simplified acute physiolo- SOFA Sepsis-related Organ Fai-
RASS Richmond-Agitation-Se- gy score lure Assessment
dation-Scale SAPF Sepsis-associated Purpura SOM sphincter-Oddi-manometry
rATG rabbit antithymocyte glo- fulminans SOS sinusoidal obstruction syn-
bulin SARI severe acute respiratory drome
RBBB right bundle branch block infections SPAD single pass albumin
RBF renal blood flow SARS severe respiratory distress dialysis
RB-ILD respiratory bronchiolitis syndrome SPE supplemental parenteral
interstitial lung disease SAT spontaneous awakening nutrition
RCA regional citrate anticoagu- trial SPN supplemental parenteral
 nutrition TCT transcatheter cardiovas- nagement
SRBA selective relaxant binding cular therapeutics TTP thrombotic-thrombocytope-
agent TDI tachycardia detection in- nic purpura
SSC Surviving Sepsis Cam- terval TUS thoracic ultrasound
paign TDI tissue Doppler imaging TV tidal volume
SSEP somatosensory evoked TDM therapeutic drug monito- ULBT upper lip bite test
potentials ring UFH unfractionated heparin
SSNRI selective serotonin-norad- TEE transesophageal echocar- UIP upper inflection point
renalin-reuptake-inhibitors diography UIP usual interstitial pneumo-
SSRI selective serotonin-reup- TEG thrombelastography nia
take-inhibitors TEM thrombelastometry ULN upper limit normal
SSSS staphylococcal scaled TEN toxic epidermal necrolysis UN urea nitrogen
skin syndrome TEVAR thoracic endovascular UPR urea production rate
SSTI skin and soft tissue infec- aortic repair USAT ultrasound-assisted ca-
tions TGA transient global amnesia theter directed thomboly-
STEC shigatoxigenic E. coli TGC tight glycaemic control sis
STEMI ST-elevation myocardial THAM tris hydroxymethyl amino- USCOM ultrasonic cardiac output
infarction methane monitor
STH somatotropin hormone TIA transient ischemic attack UUN urine urea nitrogen
SUDEP sudden unexpected death TIC tachycardia induced V Volt
in epilepsy cardiomyopathy VAD ventricular assist device
SV stroke volume TIC trauma induced coagulopa- Va/Q ventilations-perfusions-
SVA sinus valsalvae aneurysm thy quotient
SVC superior vena cava TICI thrombolysis in cerebral VALI ventilator associated lung
SVI stroke volume index infarction injury
SvO2 venous oxygen saturation TIMI thrombolysis in myocar- VAP ventilator-associated pneu-
ScvO2 central venous oxygen dial infarction monia
saturation TIPS transjugular intrahepatic VARPD video assisted retroperito-
SmvO2 mixed venous oxygen portosystemic shunt neal debridement
saturation TISS therapeutic intervention VAS visual analog scale
SVR small volume resuscita- scoring system VATS video assisted thoracosco-
tion Tl Thallium py
SVR systemic vascular resi- TLC total lung capacity VC vital capacity
stance TMA thrombotic microangiopa- VCD vocal cord dysfunction
SVT supraventricular tachycar- thy VCO2 carbon dioxide production
dia TMP transmembrane pressure VCV volume controlled ventila-
SVV stroke volume variation TOF train of four tion
SWI stroke work index TOR Termination of Resuscita- VDR Vitamin D-receptor
TAA Tachyarrhythmia absoluta tion Rules VES ventricular extrasystole
TAC temporary abdominal clo- TPE total parenteral nutrition VF ventricular fibrillation
sure TPMT thiopurine methyl trans- VFD ventilator free days
TACO transfusion associated ferase VFR visiting friends and relati-
circulatory overload TPN total parenteral nutrition ves
TAD transfusion associated TPTD transpulmonal thermodilu- VGCC voltage gated calcium
dyspnea tion channel
TAG Triglyceride TRALI transfusion-related acute VGE venous gas embolism
Ta-GvHDtransfusion associated lung injury VIDD ventilator-induced dia-
Graft-versus-Host-disease TRC tube resistance compen- phragmatic dysfunction
THA total artificial heart sation VIHE valproic acid-induced hy-
TAP tube-associated pneumo- TSH Thyroid-stimulating hormo- perammonemia with ence-
nia ne phalopathy
TAPSE tricupid annular plane TRCA trauma related cardiac VILI ventilator-induced lung
systolic excursion arrest injury
TASH transcoronary ablation of TRH thyreotropin releasing VIP vasoactive intestinal
septal hypertrophy hormon peptide
TAVI transcatheter aortic valve TRO triple rule out VKA Vitamin-K antagonists
implantation TSST toxic shock syndrome to- VO2 volume per time of oxy-
TBB transbronchial biopsy xin gen (Sauerstoffverbrauch)
TBI traumatic brain injury TTE transthoracic echocardio- VRE Vancomycin-resistant en-
TBW total body water graphy terococci
Tc Technetium TTI tension time index VSR ventricular septal rupture
TCA traumatic cardiac arrest TTI transfusion-transmitted in- VT tidal volume
TCA tricyclic antidepressant fections VT ventricular tachycardia
TCD transcranial doppler TTM targeted temperature ma- VTE venous thromboembolism
VTI velocity time integral
vv-EC-
CO2-R veno-venous extracorpo-
real carbon dioxide remo-
val
vWD von Willebrand disease
vWF von Willebrand factor
WCT wide complex tachycardia
WFNS World Federation of Neu-
rosurgical Societies
WHO World Health Organization
WHVPG wedged hepatic venous
pressure gradient
WIPO weaning-induced
pulmonary oedema
WOB work of breathing
WOP week of pregnancy
WPW Wolff-Parkinson-White
ZEEP zero endexpiratory
pres-sure

General Part
 Outside Flow rate ml/ Flow rate ml/
Accesses G Colour Diameter min water min blood
24 yellow 0.7 13 10
• venous accesses
22 blue 0.9 31 18
• arterial accesses
20 pink 1.1 54 31
18 green 1.3 80 45
venous accesses 17 white 1.4 125 76
16 grey 1.7 180 118
• peripher venous accesses
• central venous accesses 14 orange 2.0 270 172

Peripher venous accesses A white needle has the same flow rate
as a CVC!!
• synonyms: Braunula, Flexule, Viggo, PVC (peripheral
venous catheter)
• positioning
-- antecubital fossa
-- forearm
-- dorsum of the hand
-- Vena jugularis externa
• recommended for all monitored patients (unless there
is already a CVC)
• no programmed regular (e.g. every 3 days) replace-
ments (only in case of signs of inflammation)
• special cases:
-- dialysis patients: if possible, do not position in shunt
arm (at least not proximally; in cases of acute emer-
gency [i.e. reanimation], however, the shunt may be
punctured in dialysis patients in whom venous ac-
cess is often difficult due to the mostly poor vascular
status)
-- stroke patients: not in the paretic arm
• sizes (G: Gauge; see table)
• The achievable flow rate in a white Braunula (17 G)
is just as high as in a CVC (flow rate approx. 120 ml/
min), in a grey (16G) and orange (14G) Braunula even
Fig. 001  peripheral venous access - various sizes [8]
higher, so that in case of emergency one or more large
Braunula are completely adequate for a rapid volume
loading (above all, loss of time due to the positioning
of the CVC!).
• If a Braunula ist connected wirh an infusion, the Brau-
nula should be saved in addition to a Braunula plaster
with a cob rein, which is sticked over a 10cm long loop
of the infusion tube, in order to reduce the risk of dis-
location.
• advice: If the positioning of a Braunula is not possible,
an ultrasound device can be helpful (linear array) to
find a vein in the antecubital fossa or in the proximal
upper arm (medial). The puncture can then be perfor-
med under sonographic view.

Fig. 002  peripheral venous access - application via one-

way valve [8]

22 General Part
 Tip for extremely poor vein status in an
emergency: sonographically aided
positioning of the Braunula in antecubi-
tal fossa or proximal medial upper arm
vein
artery
artery
vein
Fig. 003  sonographically aided positioning of a Braunula
with the linear array probe in the proximal medial upper
arm: good emergency option in case of poor vein status
in the emergency room or in the intensive care unit (there
should always be an ultrasound device!)
Central venous access
Definition
• central venous catheter (CVC)
• catheter in the vena cava (superior or inferior)
• made of polyurethane, coating with hydromer
• flow rate: approx. 100-150 ml/min (note: Shaldon-ca-
theter: 300-400 ml/min)
• lumina:
-- A single catheter incorporates separate, noncommu-
nicating access lumens within its body.
-- CVCs may have a single or multiple lumens (one to
five lumens; meanwhile even CVCs with seven lu-
mens on the market).
-- In the intensive care medicine you should at least
use triple-lumen catheters. Especially in the inter-
nal intensive care medicine one should rather use
multi-lumen CVCs (preferrably five-lumen cathe-
ters) in case of doubt. It is not unusual that, after a
triple-lumen CVC has been positioned, the patient's
condition aggravates within the next few days and
additional lumens are needed for the administration
of catecholamines, for parenteral nutrition or for the
PiCCO techology. Then one must change to a five-
lumen CVC or in case of a lay time of > 48h the CVC
has to be positioned once again, which is extremely
annoying. A five-lumen CVC is not more expensive
than a triple-lumen CVC! However, it should be no-
ted, that the risk of infection increases with the num-
ber of lumina.
Fig. 004  central venous catheters (CVC): triple-lumen [8]
Fig. 005  central venous catheters (CVC): five-lumen [8]
General Part 23
Indications
• diagnostic:
-- measurement of central venous pressure (CVP) for
haemodynamic monitoring (note: A CVC should not
be placed only for the measurement of the CVP!)
-- measurement of the central venous oxygen saturati-
on (ScvO2; see page 191)
• therapeutic:
-- hyperosmolar solutions (p.d. > 900 mosmol/l)
◦◦ parenteral nutrition (note: Administration of fats,
amino acids and glucose up to a concentration
of G10% [from a concentration of G20% glucose
acts as "sclerosing agent"!] through peripheral ve-
nous access is allowed)
◦◦ electrolytes (e.g. KCl)
◦◦ sodium carbonate
◦◦ chemotherapy
-- catecholamine therapy
-- long term infusion therapy
-- impossibility to place a peripheral access due to
poor vascular status
the confluence of the coronary sinus
-- alignment of the position of the zero point with the
position of the right atrium (3/5 of the dorsoventral
diameter); the pressure transducer must be at the
height of the right atrium! If it is placed too high, a
too low CVP is measured, if it is placed too low, a
too high CVP is measured. The CVP changes by 1
cmH20 or 0.75 mmHg per cm of deviation from the
zero point.
-- only in spontaneously breathing patients (not in ven-
tilated patients: The method of water column is inac-
curate here, because the water column has too little
time to level off to an average between the ventilati-
on-induced pressure increase.)
• continuously (electrically via transducer; pressure ele-
ment; in ventilated patients)

Central Venous Pressure (CVP)

Definition
• medium pressure in the superior vena cava at the junc-
tion with the right atrium
• The CVP corresponds to the filling pressure in the right
ventricle.
• transmural pressure difference between the inside and
Fig. 006  thorax-caliper - theory [14]
the outside of the superior vena cava
• Only the pressure on the inside can be measured. For
the pressure on the outside the atmospheric pressu-
re is taken as a surrogate parameter, which is why a
zero adjustment must be made. This pressure can,
however, be increased by various disturbance varia-
bles (e.g. pleural effusion, increased intra-abdominal
pressure, mediastinal edema), so that the CVP only
inadequately correlates with the preload.
• Since the CVP depends on the intrathoracic pressu-
re fluctuations through respiration, the end-expiratory
pressure should be taken.
• meaning:
-- volume status
-- preload: The CVP is a measure for the right ventricu-
lar end-diastolic pressure (RVEDP; filling pressure of
the right ventricle) and thus a measure for the right
ventricular preload.
• standard value:
Fig. 007  thorax-caliper - practice
-- 8-12 cmH2O (discontinuous measurement)
-- 5-10 mmHg (continuous measurement 1 mmHg = Wave form
1.36 cmH2O) • waves (pressure increases in the right atrium):
-- a-wave: through contraction of the right atrium (a:
Measurement atrial)
• discontinuous (connection of central venous catheter ◦◦ high a-wave: pulmonary hypertension, tricuspid
to a special infusion set connected to a diameter water stenosis; even giant-/ cannon-a-waves: AV dis-
column [thorax-caliper]; Burri and Perren method) sociation (atrioventricular fusion: The right atrium
-- horizontal position contracts against the closed tricuspid valve, which
-- hydrostatic zero point: right atrium at the height of massively increases the pressure in the right at-

24 General Part
 rium.)
◦◦ several a-waves: atrial flutter Orientation based on ECG:
◦◦ missing a-wave: atrial fibrillation a-wave: after the P-wave
v-wave: after the T-wave
-- c-wave: contraction of the right ventricle (The con-
traction of the right ventricle leads to a systolic pro-
trusion of the leaflets of the tricuspid valve into the
right atrium, which increases the pressure in the

mmHg
right atrium.)
-- v-wave: passive filling of the right atrium with closed
tricuspid valve (influx of venous blood); high v-wave a a a
(the v-wave is usually smaller than the a-wave): se- 5 c v
vere tricuspid valve regurgitation (pressure increase
in the right atrium due to the influx of blood through
regurgitating tricuspid valve), acute right-sided heart
failure, pericardial tamponade y
• descents (pressure drop in the right atrium):
x
-- x-descent: pressure drop through downward move-
ment of the valvular plane (displacement of the val- Fig. 009  CVP pressure curve (RAP-pressure) in patient with
vular plane), relaxation of the right atrium (filling of atrial flutter: Several a-waves can be seen.
the right atrium)
◦◦ missing x-descent: atrial fibrillation

mmHg
◦◦ flattened x-descent: tricuspid valve regurgitation
(Müller's sign: ventricularization of the CVP cur-
ve upon inspiration, i.e. the pressure curve of the
CVP is similar to that of the right ventricle; typical
5 c v
for a severe tricuspid valve regurgitation; pressure
may also increase upon inspiration [Kussmaul's
sign])
-- y-descent: pressure drop through influx of blood
from the right atrium to the right ventricle (relaxation y
of the right ventricle)
◦◦ deep y-descent: right-sided heart attack, hypervo-
laemia, constrictive pericarditis, restrictive cardio-
myopathy Fig. 010  CVP pressure curve (RAP-pressure) in patient with
◦◦ flattened y-descent: pericardial tamponade, tri- atrial fibrillation: There is no a-wave and no x-descent.
cuspid valve stenosis
v
mmHg

5 a c

x
y

Fig. 011  CVP pressure curve (RAP-pressure) in patient with

severe tricuspid valve regurgitation (e.g. as a result of a
right ventricular load): The high v-wave is recognizable. It is
higher than the a-wave. The v-wave is usually smaller than
the a-wave. The x-descent is also reduced

Fig. 008  CVP pressure curve (pressure curve right atrium;

normal diagnosis)

General Part 25
 ◦◦ ventilation with PEEP (PEEP increases the CVP. A
mmHg a rule of thumb is: In order to calculate the true CVP,
half of the set PEEP has to be deducted from the
measured CVP [given a normal compliance and
resistance of the lung).
5 c v ◦◦ auto-PEEP (syn.: intrinsic-PEEP ; i.e. as a result of
hyperinflation in patients with obstructive pulmo-
nary disease)
◦◦ tension pneumothorax
y ◦◦ Trendelenburg positioning
x
Fig. 012  CVP pressure curve (RAP-pressure) in patient with No more use of CVP for haemodyna-
AV dissociation (e.g. AV-block III): The right atrium con- mic monitoring! Especially the
tracts against the closed tricuspid valve, which massively interpretation of an increased CVP is
increases the pressure in the right atrium. It results in a often completely unreliable!
higher a-wave-level (fusion wave; giant / cannon-a-wave).

Positioning
mmHg

CVC can be positioned in different places. The most

a to left vein at 18 cm); preferably use right internal jugu-
5 c v lar vein; disadvantage of the CVC-positioning via the
y ence of the left brachiocephalic vein into the superior
x cus may be injured.
Fig. 013  CVP pressure curve (RAP-pressure) in patient with
pericardial tamponade: It shows a reduction or a loss of the
y-descent (with maintained x-descent): Due to the increa-
sed intrapericardial pressure the right ventricle can no lon-
ger be filled during diastole. Consequently, no more blood
can flow from the right atrium into the right ventricle and
there is no loss of pressure in the right atrium.
From the analysis of the CVP pressure
waves on the monitor (if sufficiently
derivable) one can gain valuable
diagnostic information!!
Interpretation
• CVP ↓: Hypovolaemia (lack of volume); further rea-
sons: Venodilatation (e.g. as a result of a reduction
of the sympathetic tone [vegetative regulation], admi-
nistration of vasodilators), reduction of pressure in the
thorax (e.g. in case of forced inspiration, inspiratory
stridor)
• CVP ↑­:
-- Hypervolaemia
-- cardiac insufficiency
-- pulmonary embolism
-- pericardial tamponade (fluid resuscitation required
[in addition to pericardial puncture]!)
-- venous constriction (e.g. as a result of a vasopres-
sors like e.g. noradrenaline)
-- pressure increase in the thorax:
common places are:
• internal jugular vein (No. 1; sew to right vein at 15 cm,
left internal jugular vein: Due to the diagonal conflu-
vena cava the risk of perforating the wall of the vessel
is higher than on the right hand side. Furthermore, es-
pecially during proximal puncture the ductus thoraci-
• subclavian vein (No. 2; sew to right vein at 17 cm, to
left vein at 22 cm)
• femoral vein (caution: increased thrombosis and infec-
tion rate!)
• seldom:
-- cephalic vein
-- basilic vein
-- brachiocephalic vein (fixed on tissue → also open
during hypovolemic shock)
-- external jugular vein (fixed on tissue → also open
during hypovolemic shock)
PICC
• peripher inserted centralvenous catheter
• a central venous catheter with the top in the superior
vena cava, which is introduced via peripheral puncture
(mostly cubital, brachial)
• length 60 cm, 1-2 lumens, made of polyurethane or
silicone
• all types of infusions possible (including parenteral nu-
trition and chemotherapy)
• special form: midline catheter (shorter version of the
PICC: peripheral placement, the tip of the catheter is
only in the axillary and subclavian vein, but not in the
superior vena cava)

26 General Part

Fig. 014  PICC (C.R. Bard, Inc.) [37]
Procedure
• coagulation monitoring (thrombocytes > 50000/μl,
Quick > 50% or INR < 1.5; only optional: The positio-
ning of a CVC is definitely also possible in the case of
reduced coagulation, if necessary.)
• lowering of head (Trendelenburg positioning)
-- always necessary for prevention of air embolism
(note: This also applies to the removal of the CVC.
This must never be done while sitting, for example!)
-- but caution in spontaneously breathing obese pati-
ents: The apical relocation of fat mass in the Tren-
delenburg positioning may cause a reduction of the
lung volumes and quickly lead to acute respiratory
insufficiency (OSDS [obesity supine death syndro-
me]). Furthermore the lowering of the head is cont-
raindicated in patients with increased cerebral pres-
sure.
• sterile conditions (including hand disinfection, sterile
gloves, a sterile coat, cap, mouth protection)
• Disinfection of the puncture site
• ECG monitoring, turning on of the systole beep tone
• tapering with sterile gauze
• local anaesthesia with Xylocaine
-- also for intubated patients
-- When the local anaesthesia has been conducted,
the syringe containing Xylocaine should be put to the
other end of table. Otherwise the Xylocaine-syringe
could be confused with the syringe containing saline
solution when flushing the lumens afterwards.
• filling of the syringe with 1-2 ml saline solution (not
more, because this would make aspiration more dif-
ficult and it prevents dilution: This allows you to see
whether venous or arterial blood in the syringe)
• puncture of the vein, aspiration of blood
• insertion of the Seldinger wire
• small skin incision with scalpel
• pre-stretching with the dilator (to expand the branch
channel)
• inserting of the catheter over guide wire (Seldinger
technique [named after the Swedish radiologist Sven
Ivar Seldinger, 1921-1998]); only start insertion of the
catheter into patient after appearance of the wire (cu-
tion: loss of wire)
-- internal jugular vein: right 15 cm, left 18 cm
-- subclavian vein: right 17 cm, left 22 cm
• removal of Seldinger wire
• sewing-on
• aspiration of blood and flushing of all lumens
CVC insertion: always (if possib-
le) Trendelenburg positioning for
prevention of air embolism
Puncture of internal jugular vein
• lateral positioning of the head
• puncture site
-- based on landmark ("blind technique"):
◦◦ lateral to the palpable carotid artery
▪▪ Normally, the internal jugular vein is lateral to
the carotid artery. There are, however, a number
of abnormal positions, so that this rule is not va-
lid in 30% of the cases.
▪▪ Moreover, this rule only applies, if the head lies
in a straight position. The head is often turned
to the side during CVC insertion. In this position
the vein is often directly anterior to the artery and
therefore ventral instead of lateral to the artery.
▪▪ lead structure: medial edge of the sternocleido-
mastoid muscle
-- based on sonography (at best!)
◦◦ application of a sterile cover over probe and cable
(a sterile glove as cover is hygienically not suffici-
ent!), use of sterile ultrasound gel or skin disinfec-
tant
◦◦ 7.5 MHz transducer (linear array transducer)
◦◦ compression ultrasonography (B-mode image):
The vein can be compressed, but not the artery.
◦◦ i.a. exclusion of thrombus
◦◦ In our intensive care unit we almost exclusively
perform CVC- or Shaldon-insertions into the in-
ternal jugular vein only under sonographic control:
The puncture takes places under visual control
and typically requires rarely more than one attempt
(even in obese patients). Also, it is not uncommon
to incidentally discover a thrombus in the internal
jugular vein, which would not be seen otherwise
without ultrasonography and which would then be
pushed further along by the guide wire or the di-
lator (risk of pulmonary embolism). One can cer-
tainly also drive at night without light: If you know
the way, you probably also get to the intended
destination. However, if your car has headlights,
you can also simply switch them on: So you can
see exactly where you are going! The use of ult-
rasound for the insertion of a CVC is also highly
recommended in the European Guideline for Inter-
ventional Ultrasound 2016 (EFSUMB: European
Federation of Societies for Ultrasound in Medicine
and Biology).
General Part 27

Fig. 015  CVC-insertion internal jugular vein using ult-
rasound: The probe is provided with a sterile cover. The
puncture is done under visual control.
internal jugular vein
common ca-
rotid artery
Fig. 016  Ultrasound of right cervical vessels: lateral the in-
ternal jugular vein, medial the common carotid artery (The
vein can be compressed easily, but not the artery.)
28 General Part
Fig. 017  The internal jugular vein is punctured under sono-
graphic view.
CVC-insertion into internal jugular vein
always under sonographic control
(time saving + increased patient
safety!)
There´s not only the internal jugular
vein and popcorn in the neck (cave:
risk of injury in blind punctures)!
Puncture of subclavian vein
• 3 cm below the clavicle
• exactly in MCL (midclavicular line) in the direction of
the Clavicula
• also under sonographic control, if necessary (imaging
of the vein in longitudinal view; certainly more difficult
than in the case of the internal jugular vein
• contact with periosteum, then insertion towards jugu-
lum (never deeper than jugulum due to increased risk
of pneumothorax!)
• assessment:
-- advantages:
◦◦ The ligamentous apparatus keeps open the vessel
(also open during hypovolaemic shock).
◦◦ lowest risk of infection
◦◦ no hindrance of cerebral venous drainage: There-
fore, primarily in neurosurgical intensive care units,
CVCs are more often inserted into the subclavian
vein and less often into the jugular vein, because
the venous drainage from the brain may be impe-
ded with an already inserted CVC in the jugular
vein which leads to increased brain pressure.
-- sisadvantages:
◦◦ increased pneumothorax rate (Therefore be care-
ful with patients suffering from severe respiratory
insufficiency: In this case a pneumothorax may
have serious consequences! If you nevertheless
decide to insert a CVC into the subclavian vein,
you should always choose the side which looks
 more affected in the chest x-ray or in the case
of double-sided infiltrates the side which is more
densely infiltrated.)
◦◦ no possibilty of compression in the case of faulty
arterial puncture
◦◦ sonographically-based insertion more difficult (no
compressibility) than in internal jugular vein (but
quite possible!)

Fig. 018  Anatomy of subclavian vein [14]

Puncture of femoral vein

• location of the vein medial to the artery (mnemonic
"IVAN": inner vein - artery - nerve)
• under sonographic control, whenever possible
• puncture 3 cm below the inguinal ligament
• in CAD-patients if possible on the left side (The right
groin should be spared for establishment of an access
for cardiac catheterization procedures in CAD-pati-
ents!)
• sisadvantages:
-- increased thrombosis and infection rate
-- hindrance in mobilization of the patient

Position control Fig. 019  Chest x-ray after CVC-insertion: position control
• intracardiac ECG recording (most common method; (1. picture: too deep, 2. picture: correct position of the CVC
endo-ECG, e.g. Alpha-Card) tip at the height of the main carina [= tracheal bifurcation;
see arrow)
• chest x-ray
-- The tip of the CVC should be at the height of the
tracheal bifurcation (main carina).
-- Only administer isotonic solutions through the CVC
before checking its position by x-ray examination!
-- contralateral CVC puncture of subclavian vein only
after exclusion of a pneumothorax ipsilateral (other-
wise risk of double-sided pneumothorax!)
-- The CVC should always be inserted on the side
which looks worse in the chest x-ray: If a pneumo-
thorax occurs, only the already sick lung will collapse
and not the healthy lung.
• Echocardiography (transthoracic)
• BGA (especially pO2)
• gravity infusion (When the catheter is in the artery, no
fluids can be infused by gravity alone.)
• connection to the pressure bag Fig. 020  Malposition of the CVC: The tip of the catheter,
which was inserted over the left subclavian vein, turns over
to cranial (see arrow). This must be corrected over a wire
(very helpful: x-ray-fluoroscopy).

General Part 29
Intracardiac ECG recording • rhythm disorders (The Seldinger wire often causes
• evaluation of P-wave premature ventricular contraction [ventricular extra-
systoles] in the right atrium and right ventricle, possibly
-- superior vena cava: normal P-wave (correct positi-
even a ventricular tachycardia).
on)
• myocardial perforation, pericardial tamponade
-- right atrium: peaked P-wave (incorrect position [too
deep]) • catheter-related infections, sepsis
• only possible in sinus rhythm (not in atrial fibrillation) • thrombosis (most common in femoral vein
• loss of the wire (guidewire embolism) or the CVC,
which then dislocates into the right heart or pulmonary
artery (therapy: retrieval via right heart catheter using
the GooseNeck snare [see infobox right heart catheter
retrieval of foreign bodies page 589])

study

Intravascular complications of central venous catheteriza-

Fig. 021  Intracardiac ECG recording for position control of tion by insertion site
the CVC Parienti et al, N Engl J 2015

• multicenter randomized study

• examination of 3,471 CVC-insertions in 3,027 patients
• results:
-- primary combined endpoint (catheter-related blood-
stream infection or symptomatic deep vein thrombo-
sis): least likely in CVC via subclavian vein (followed
by internal jugular vein and femoral vein)
-- secondary endpoints: i.a. pneumothorax (most com-
mon in CVC via subclavian vein)

Fig. 022  Alpha-Card: intracardiac ECG recording for positi-

on control of the CVC [8]

Complications
• hematoma (especially in limited coagulation; caution:
difficult intubation in case of a large hematoma in the
neck)
• pneumothorax (most frequently in subclavian vein),
haemothorax, pleural effusion due to infusion of fluids
("infusothorax")
• chylothorax (leakage from the thoracic duct; particular-
ly when puncturing the left subclavian vein)
• air embolism (see page 586)
• nerve injuries:
-- injury of the vagus nerve (passes medial to the in-
ternal jugular vein) → phrenic paralysis (one-sided
diaphragmatic eventration)
-- iof the ganglion stellatum (syn.: cervicothoracicum;)
either by puncture or by local anaesthesia (uninten-
ded stellatum block) → Horner's syndrome (ptosis,
miosis, enophthalmus) Fig. 023  right-sided pneumothorax
• faulty arterial puncture, bleeding (Bleeding into the
neck may cause a compression of the respiratory
tract.), via falsa insertion (e.g. aortic arch instead of
subclavian vein), dissection, A-V fistula (continuous,
i.e. systolic + diastolic murmur ["machine noise"])

30 General Part
 Fig. 026  Diaphragmatic eventration on the right side as a
complication of an unsuccessful CVC-insertion into the in-
ternal jugular vein (injury of the vagus nerve due to repea-
ted blind punctures [i.e. without ultrasound])

Fig. 024  Chylothorax (from the Greek word "chylus": milk

juice); most common left-sided; important DD to pleural
empyema; Diagnosis: triglycerides in the pleural puncture
> 110 mg/dl; Causes: iatrogenic (i.g. injury due to an CVC-
insertion), postoperative (especially after thoracic surgery),
neoplastic (No. 1; especially lymphoma [the most common
cause for a chylothorax], bronchial-, gastric-, pancrea-
tic cancer), traumatic, spontaneous; Therapy: puncture /
drainage, MCT-diet (medium-chain triglycerides [MCT get
directly into the circulation over the portal vein, so that
the chyle-production is reduced.]), Octreotide 100μg s.c. 3
times a day for 2 weeks to reduce chyle-production), ope-
ration if necessary

Fig. 027  Diaphragmatic eventration right

Fig. 025  Malposition of catheter in the mediastinum: You

can see the contrast media extravasation and a pleural ef-
fusion ("infusothorax") on the right.

General Part 31

Fig. 028  The white arrow points to the inserted CVC in the
chest x-ray (via internal jugular vein right). The CVC is lo-
cated too deep and must be withdrawn. The black arrows
point to a Shaldon-catheter, which has been inserted into
the right subclavian vein, and which is positioned com-
pletely atypically. The CT shows that the Shaldon-catheter
does not lie in the vein, but in the artery (in the truncus
brachiocephalicus right).
32 General Part
brachiocephalic
trunc
aortic arch
Fig. 029  Condition after difficult Shaldon-insertion into
right subclavian vein: In the ultrasound you can see the ca-
theter in the aortic arch (ultrasound window: jugular fossa)
You can see a catheter in the brachiocephalic trunc. This
means, that the catheter does not run via naturalis (subcla-
vian vein → subclavian artery → truncus brachiocephalicus
→ aortic arch), but via falsa directly through the aortic wall
into the aortic arch. This had to be revised by cardiothora-
cic surgery.
Infections
Definition
• colonization p.d. > 15 CFU (colony-forming units [se-
miquantitative Maki methode]) on the catheter tip
• designations (synonyma):
-- CRBSI (catheter related blood stream infection)
-- CABSI (catheter associated blood stream infection)
-- CVCBSI (central venous catheter blood stream in-
fection)
Epidemiology
• frequency:
-- 1 case per 1,000 catheter days (DEVICE-KISS)
-- 8.400 cases of CVC-associated sepsis only in Ger-
many every year
• third most common nosocomial infection (after uri-
nary tract infection and pneumonia)
• CVCs via the subclavian vein present the lowest risk
(3SITES study: Parienti et al, N Engl J 2015).
• CVCs cause 90% of all blood stream infections.
• CVC-associated sepsis: 1/100 catheter days
• Iíncrease after the first week (especially from the 10th
day on); before that, it is unlikely that the CVC causes
fever)
• mortality: 11,5%
Pathogens
• coagulase-negative staphylococci (CoNS; No.1):
primarily staphylococcus epidermidis (90% methicillin-
resistant [MRSE: methicillin-resistant staphylococcus
epidermidis])
• staphylococcus aureus (No. 2; usually MRSA)
• gram-negative bacteria (v.a. E. coli, Klebsiella, Pseu-
domonas)
• candida (No. 3)
• enterococci
Symptoms
• fever of unknown origin, occurring after longer CVC
dwell time (after approx. 10 days CVC dwell time the
CVC can be considered as a cause, before that - rather
not!)
• reddened puncture site, pus
• sepsis
Diagnosis
• smear of puncture site
• separate blood cultures (central [CVC] and peripheral)
• removal of CVC and microbiological examination
-- Cut off the CVC-tip (3-5 cm), then put into a sterile
tube (without transport medium)!
-- The CVC-tip is then rolled over an agar plate with the
help of sterile tweezers.
-- CVC-tips should not be tested in the laboratory rou-
tinely - only in the case of suspected CVC-infection.
Negative blood culture from CVC +
peripheral vein → no catheter infection
in 99% of all cases (high negative
predictive value!)
D-TTP
• differential time to positivity
• simultaneous examination of peripheral and CVC
blood cultures
• D-TTP = TTPCVC - TTPperipheral
• D-TTP > 2h → → catheter infection (90% sensitivity,
specificity 98%)
Therapy
• removal of CVC and, if necessary, placement of a new
catheter
• only fever without further symptoms → no antibio-
sis necessary ("watchful waiting")
• Antiinfectives
Antiinfectives
• CoNS:
-- means of choice : Vancomycin (alternative: Dap-
tomycin)
-- duration of therapy: 5-7 days
-- If only one blood culture is positive with CoNS, an
antibiotic treatment is not generally yet indicated (af-
ter removal of the CVC), if there is no intravascular,
intracardiac (i.g. prosthetic valve) or orthopedic for-
eign material. In most cases it is only a contaminati-
on. It is only indicated, if futher blood cultures (CVC
and peripheral respectively peipheral after removal
of the CVC) are positive.
• Staphylococcus aureus (duration of therapy: 14 days)
-- MSSA: Flucloxacillin, Cefazolin
-- MRSA: Vancomycin, Daptomycin
• Candida:
-- Fluconazol or Echinocandin
-- duration of therapy: 14 days after the last negative
blood culture
• possibly antibiotic lock (in situ-therapy, e.g. infection
of a port)
-- gram-positive (e.g. CoNS): Vancomycin 2 mg/ml
-- gram-negative: Ciprofloxacin 2 mg/ml
Prophylaxis
• aseptic insertion (MBP: maximum barrier precautions)
-- the most important prophylactic measure
-- cap, mask, sterile gown, sterile gloves, large fe-
nestrated drape, disinfection of the skin
-- This includes the clear recommendation to disinfect
hands before putting on sterile gloves, which is un-
fortunately often neglected.
-- If you use the ultrasound, not only the transducer
(probe) must be within the sterile cover, but also the
supply cable.
-- In patients with a tracheostoma a CVC in the internal
jugular vein should be avoided.
• The less lumens a CVC has, the lower the risk of in-
fection.
• guidewire exchange allowed up to a maximum of 48 h
after placement (then new CVC necessary!)
• lowest risk of infection in case of insertion via subclavi-
an vein (although highest risk of pneumothorax)
• daily inspection of the puncture site
• daily check, whether a CVC is still necessary and if not
• A routinely exchange of CVCs (e.g. placement of a
new CVC every 10 days) does not have any advan-
tage. A new catheter should only be inserted in case of
clinically suspected infection.
• Im sealing plugs are removed from the CVC (i.g. for
the injection of a drug), it is not allowed to put the same
General Part 33
 plugs on again. They have to be rejected and changed
by a new one.
• change of infusion systems:
-- If blood products are applied, the systems should bis
changed no later than 6h.
-- If lipid solutions are applied, the systems should bis
changed no later than 24h.
-- Otherwise they should be changed no more often
then after 96h.
• possibly CVC with anti-infective coating: In a French
multicenter study (Timsit et al, JAMA 2009) significant-
ly less catheter-associated infections could be obser-
ved at the CVC puncture sites of approximately 1,600
patients due to the use of chlorhexidine-impregnated
sponges (Biopatch). Meta-analysis (Hockenhull et al,
Crit Care Med 2009; Safdar et al, Crit Care Med 2014;
Maunoury et al, PLoS One 2015) also showed a reduc-
tion of the infection rate due to the use of CVCs with
anti-infective coating. In Germany they are recommen-
ded from the Commission for Hospital Hygiene and In-
fection Prevention for patients at high risk (especially
with severe immunosuppression).

Disinfection of hands already before

the start of the CVC-insertion!

Thrombosis
• no advantage of systemic anticoagulation with heparin
(exception: tumor patients [Klerk et al, Arch Int Med
2003]); accoring to the S2k-guideline on diagnostics
and therapy of venous thrombosis and pulmonary em-
bolism (2015) anticoagulation measures should be ta-
ken for 6-12 weeks
• Thrombosed CVCs should always be changed or re-
moved because of the increased risk of infection!
• If necessary, local lysis of thrombosed and urgently
needed lumens (e.g. highly catecholamine-dependent
patient) e.g. with
-- 10 mg alteplase or
-- 0.2 ml urokinase 5000 U/ml (success rate 75% [Svo-
boda et al, Crit Care 2004]) Fig. 030  Thrombosis of the right internal jugular vein (a
blind insertion of a CVC, i.e. without sonographic control,
could cause periprocedural pulmonary embolism!)

34 General Part
Excursion: Intranasal drug application

Definition
• The drug is reabsorbed in the regio olfactoria by the
mucous membrane.
• especially recommended, if intravenous access is dif-
ficult or impossible:
-- seizures (especially in children)
-- pain (especially suitable for children, e.g. for pain
treatment in case of burns / scalding [a preclinical Fig. 032  Today, intranasal administration (here by MAD) is
placement of an intravenous access is rarely neces- the first choice for preclinical drug application in children
sary in these cases!) in emergency cases (exception: risk of death such as shock
-- aggressiveness (e.g. intoxicated patient who flails or reanimation → recommended in this case: intraosseous
around and can only be held down by several per- access [no intravenous access]); special thanks to my little
daughter Lena
sons [recommendation: intranasal application of
15 mg midazolam])
Dosage
-- heroin intoxication (intranasal application of the an-
tidote naloxone) • midazolam: 1ml = 5mg (always take the highly con-
centrated vial 0.5 mg/kg; the solution is rather salty
• apply drugs with a 2 ml syringe (max. 1 ml per nostril
and acidic, so that an unpleasant burning sensation in
[otherwise it runs back down the throat would be swal-
the nose might be felt; by a gastrointestinal absorption
lowed]), always spread on both nostrils (larger absorp-
often second active summit)
tion surface and therefore faster absorption)
-- < 50kg: 2.5mg (0.5ml [Ampulle: 1ml = 5mg]; 0.2 mg/
• only use highly concentrated drug solutions (no dilu-
kg)
tions), e.g. Midazolam 5 mg/ml (not 1 mg/ml), Ketami-
ne 50 mg/ml bzw. S-Ketamine 25 mg/ml -- > 50kg: 5mg (1ml)
• especially suitable for low-molecular and lipophilic • fentanyl: 1ml = 0.05mg, 2 μg/kg (0.04 ml/kg; titration)
drugs • sufentanil: 1ml = 0.05mg, 2 μg/kg (0.04 ml/kg; titration)
• phases of absorption: • morphine: 1ml = 10mg, 0.1 mg/ml
-- early phase: nasal absorption • ketamine: 1ml = 50mg, 50mg (1ml applizieren); 1-5
-- late phase: gastrointestinal absorption (because a mg/kg (0.02-0.1 ml/kg)
certain amount is always swallowed) • S-Ketamine (Esketamin): 1ml = 25mg, 25mg (1ml ap-
• not effective in sniff or nosebleed (epistaxis) plizieren); 0.5-2.5 mg/kg (0.02-0.1 ml/kg)
• The intranasal application of a drug, however, constitu- • naloxon: 1ml = 0.4mg, 0.4-0.8mg (1-2ml)
tes an off-label-use. • flumazenil: 1ml = 0.1mg
• glucagon (e.g. in the case of hypoglycaemia, if no int-
ravascular access is possible): can also be administe-
Intranasal drug application: first choice red intranasally instead of i.v. (dosage: 2 mg dissolved
(especially preclinical) in children in 1 ml of liquid
(especially in case of seizures, pain
treatment; except for life-threatening
cases: intraosseous access)

Applicators
• MAD (mucosal atomization device; the most common
system): The applicator is inserted into the nose. The
drug is then administered intranasally (fine nozzles at
the top cause the atomization).
• Carpuject
• OptiNose
• Accuspray Nasal Automizer

Fig. 031  MAD (mucosal atomization device): for the intra-

nasal application of drugs

General Part 35
 a pressure equalization with the environment (atmos-
ARTERIAL ACCESS pheric air pressure) can take place. This is then taken
as a reference point for setting the transducer to zero
• To prevent thrombosis the measuring system is con-
nected with a continuous catheter flushing apparatus
Indications (3 ml/h with 500 ml of sodium chloride 0.9% and 500 U
• invasive (continuous; "bloody") blood pressure measu- heparin). But this is no longer usual in our ICU.
rement (IBP: invasive blood pressure)
• frequent ABG analysis necessary (e.g. non-invasive
ventilation in case of COPD exacerbation)
• Access (sheath) to (coronary) angiography

Invasive blood pressure measurement

Fig. 033  Principle of invasive blood pressure measurement

(1: pressure transducer; 2: pressure bag with saline; 3:
catheter in radial artery; 4: connections for a Swan-Ganz-
catheter; 5: pressure cable; 6: monitor; 7: triple-devided
line [14])

Principle
• The mechanical energy of the pulse wave (pressure
wave) gets to a water column in the catheter, which
ist connected with a liquid-filled hose system. In this
system the pulse wave is transmitted to a transducer, Fig. 034  Pressure transducer [14]
where the pulse wave of the water column is transdu-
ced into an electric signal. There is a waterproof mem- Indications
brane (silicone) in the transducer, which gets deformed
• management of catecholamine treatment
by the pressure wave. There are strain gauges in the
membrane, whose electrical resistance is altered due • management of antihypertensive treatment (e.g. sodi-
to the deformation. The change of the resistance is um nitroprusside)
mathematically transformed an linearized und finally • peri-operative in patients with ASA > 3 (ASA: American
demonstrated as a continuous pressure curve on the Society of Anesthesiology)
monitor. The monitor amplifies the output signal from
the transducer, filters the noise and displays the arteri- Possible errors
al waveform on a screen. • incorrect placement of the pressure transducer (should
• The arterial catheter is connected with a measuring always be at heart level!)
system, a pressure transducer, a transmission module • no zero calibration
and then with a monitor. • abnormal damping of the system
• First, a zero calibration has is required: The three-way -- types:
stopcock between the arterial catheter and the pressu-
◦◦ underdamping
re transducer must be open to the atmosphere, so that
▪▪ occurrence: Natural oscillations may occur

36 General Part
 spontaneously in liquid-filled systems. If their
frequency is in the range of the resonant fre-
quency of the measuring system, the oscillati- A
ons may be superimposed
▪▪ form: too high amplitude (too high blood pressu-
res are measured), sharp peaks
◦◦ overdamping ("moderate peak")
▪▪ occurrence: air bubbles, blood clots, contrast
medium (may clog the catheter line), thrombo- B
sis, suction of the catheter to the vessel wall,
kinked catheter, too long pressure line (distance
to pressure transducer too long [max. 1 meter!])
▪▪ form: amplitude too low (too low blood pressu-
res measured), rounded peaks
-- analysis: A so-called flush-test is conducted in or-
der to check, whether there is a normal or abnor- C
mal damping of the system. Snap flush to genera- Fig. 036  A: normal damping; B: underdamping (too high
te square wave. After flushing, the arterial curve is amplitude, sharp peaks); C: overdamping (too low amplitu-
studied: Normal damping usually causes only one de, rounded peaks)
oscillation before returning to baseline (one negative
and one positive amplitude).
◦◦ underdamping: two or more oscillations before re- Flush
turning to baseline
◦◦ overdamping: no oscillations (response speed is A
too slow).

pressure transducer at heart (korrekt)

level (correct)
Flush
Druckwandler auf Herzhöhe
B

Flush
Heart
Herz 25 cm NIEDRIGER
25cm lower than pressure transducer→
als Druckwandler pressure
→Druck 20 mmHg
20mmHg too low
zu NIEDRIG
C

Fig. 037  To check if the system is damped correctly, the

flush-test is carried out and the decay phase (after the flush
stop; oscillations return to baseline) is observed. In normal
damping (A) you have only only one oscillation during de-
Heart
Herz 25 cm HÖHER
25cm higher than
als pressure transducer
Druckwandler → pressure
→ Druck 20mmHg 20zu mmHg
HOCH too HIGH cay phase, in underdamping (B) there are several oscillati-
ons during decay phase and in underdamping (C) you find
Fig. 035  034 Different blood pressure measurement results no oscillation during decay phase.
depending on the position of the transducer: If the pressure
transducer is located above heart level, too low blood pres-
sure values will be measured. If the pressure transducer is
located below heart level, too high blood pressure values
Placement
will be measured (the typical "demo-mode" for the visit of • radial artery (standard)
the medical director) [14] • femoral artery (at the level of the inguinal ligament)
-- advantage: can often also be punctured in case of
shock (in contrast to radial artery)
-- disadvantages:
◦◦ increased thrombosis and infection rate
◦◦ reduced mobility of patient
◦◦ The right femoral artery is often used as an access
(sheath) for coronary angiography and should
therefore be spared in patients which may soon

General Part 37
 have to undergo a heart catheter examination. But
the standard access nowadays for coronary an-
giography is the radial and no more the femoral
artery.
• rarely:
-- ulnar artery
-- brachial artery
-- axillary artery
Radial artery
• dorsiflexion of the wrist and immobilization
• disinfect the puncture site, cover with fenestrated dra-
pe
• local anaesthesia with Xylocaine (maybe also in intu-
bated patients
• puncture 30-45° with Angiocath needle (tip points up-
wards not downwards [this minimises the risk of pier-
cing through the back wall of the artery])
• in case of difficulties (e.g. hardly detectable pulse) so-
nographic guidance
• when blood flows out of the needle: Advance wire (wi-
thout resistance), remove the needle, pass the plastic
cannula over the wire, remove the wire, sew on - if
necessary (in our intensive care unit, the radial artery
catheter is glued, the femoral artery catheter is sewn)
• Connection to flushing system and pressure sensor
Fig. 038  Puncture set - top: puncture needle, middle: Sel-
dinger wire, bottom: plastic cannula
Fig. 039  correctly placed cannula in the radial artery
Allen-test
• named after the American physician Edgar Van Nuys
Allen (1900-1961)
• purpose: used to evaluate the patency of the ulnar ar-
tery before puncture of the radial artery (dates from the
year 1929!)
• execution: The examiner places digital occlusive pres-
sure over the radial and ulnar arteries at the wrist for
38 General Part
one minute. The patient repeatedly makes a fist. The
hand becomes pale. Then the digital pressure over
the ulnar artery is released and colour should return to
the hand within 5-7s. Then the test is negative and the
puncture of the radial artery can be done.
• no longer strongly recommended (but advisable from a
legal and forensic viewpoint!)
• modified Allen test: pulse oximeter clip on middle finger
+ occlusive pressure on ulnar artery
Techniques
• direct (artery cannula)
• indirect (Seldinger technique)
Ultrasound is also very helpful for
arterial puncture! However, if the pulse
is easily palpable, it is usually not
necessary.
Curve
The arterial pressure curve typically shows the following
characteristics:
• high dicrotic notch
• large area under the curve
• no cardiac cycling (= amplitude fluctuation of the arte-
rial pressure curve)
mmHg
systole
SBP
dicrotic
notch
DBP
anacrotic
notch
Fig. 040  Form of arterial pressure curve: The maximum
marks the systolic, the minimum the diastolic blood pres-
sure. The mean arterial blood pressure (MAP) corresponds
to the area under the arterial pressure wave and is calcula-
ted according to the equation MAP = (SBP + 2x DBP) / 3. The
systole goes from the anacrotic notch (opening of the aor-
tic valve) to the dicrotic notch (closing of the aortic valve),
the diastole goes from the dicrotic to the anacrotic notch
(Greek: "dikrotos" double-beating; "anakrot": upstroke,
upbeat). The increase after the dicrotic notch is due to the
Windkessel function.
In case of hypovolaemia (volume depletion) the arterial
pressure curve shows the following characteristics:
• low dicrotic notch
• small area under the curve
• cardiac cycling (syn.: systolic pressure variation [SPV];
= amplitude fluctuation of the arterial pressure curve)
[possible only when sinus rhythm])
• dissection
• arterio-venous fistelula
Fig. 041  Arterial Pressure curve in case of hypovolaemia:
You can see the classic "cardiac cycling" syn.: systolic
pressure variation [SVR])!
channel (aneurysm neck) to the femoral artery
◦◦ a pseudoaneurysm
-- symptoms: groin pain, pulsatile swelling
-- diagnostic:
◦◦ auscultation: systolic murmur
◦◦ duplex-sonography
-- therapy:
◦◦ manual compression of the channel with the line-
ar transducer (for at least 30min; mostly sufficient;
then a compression dressing for 12h)
◦◦ injection of thrombin (ultrasound-guided) in the an-
eurysm sac
◦◦ operative (ligature of the connecting channel)
-- auscultation: continuous, i.e. systolic + diastolic
murmur ("machine noise")
-- therapy:
◦◦ spontaneous closure (in most cases)
◦◦ endovascular implantation of a covered stent (only
rarely necessary [e.g. in volume load due to the
left-right-shunt inpre-existing congestive heart fai-
lure])

unclear hemodynamic instability

Complications with drop in hemoglobin and back
• bleeding, hematoma (Note: The artery catheter sys- pain after puncture of the femoral
tem must always be connected to the monitor and artery: risk of retroperitoneal
must never (e.g. for transport) be plugged. If the plug hematoma (→ sonography, CT)!
falls off unnoticed, the patient could bleed to death!)
• vasospasm, ischemia
• thrombose with ischemia, embolism
• infection
• nerve lesion
• wrongly administered intra-arterial injections with ne-
crosis (please note: only use red and never blue three-
way stopcocks and plugs!)
• compartment syndrome (puncture of radial artery)
• retroperitoneal hematoma (in case of positioning in
femoral artery [never push wire against resistance!])
-- definition: bleeing into the retroperitoneal space (es-
pecially in the case of a too high puncture of the fe-
moral artery)
-- symptoms: back pain, groin pain, ipsilateral leg wea-
kness, drop in hemoglobin
-- therapy:
◦◦ conservative (mostly sufficient; i.a. administration
of erythrocyte concentrate, FFP)
◦◦ interventional (radiological; especially in hemody-
namically unstable patients): balloon occlusion,
embolisation with coils, implantation of a covered
stent
◦◦ operative (rarely necessary)
• aneurysm spurium ((especially in the case of a too low
puncture of the femoral artery)
-- definition:
◦◦ hematoma (aneurysm sac) with a connecting

General Part 39
Fig. 042  CT: retroperitoneal hematoma after puncture of
the right femoral artery

Fig. 044  X-ray fluoroscopy: retroperitoneal hematoma (You

can see the leackage of the contrast agent out of the femo-
ral artery.)

A. femoralis superf.

aneurysm-
neck

aneurysm-
sac

Fig. 045  Aneurysm spurium as a complication due to a

puncture of the femoral artery: It was punctured too deeply
(piercing throughout the backwall). You see the neck and
the sac of the aneurysm. The pw-doppler shows the typocal
flow profile of a peripheral artery (high resistance vessel)
without a diastolic flow. This is in contrast zu an AV-fistula
(here with a diastolic flow).
Fig. 043  CT: retroperitoneal hematoma after puncture of
the left femoral artery

40 General Part
Fig. 046  Aneurysm spurium as a complication due to punc-
ture of the femoral artery. You can see the channel.

Fig. 047  Dissection of the femoral artey

General Part 41

AIRWAY MANAGEMENT
national S1-Guideline "Prehospital Airwair Management"
of the German Society of Anaesthesiology and Intensive
Care Medicine 2019
Pharyngeal tubes
• oropharyngeal airway (OPA)
-- syn.: Guedel airway (named after the American an-
esthetist Arthur Ernest Guedel [1883-1956])
-- size 3-5 (ISO); proper size: measure from patient's
earlobe to patient's mouth corner
-- Insert the airway upside down so the tip of the OPA
is facing the roof of the patient’s mouth.
• nasopharyngeal airway (NPA)
-- syn.: Wendl airway (named after the German gyne-
cologist Johann Karl Wendl, who presented the tube
for the first time in 1958s)
-- size 26-34 Ch, ID 6-8 mm; proper size: measure
from the tip of the patient’s earlobe to the tip of the
patient’s nose
-- contraindication: basal skull fractures or unclear inju-
ries in connection with a traumatic brain injury

MANAGEMENT OF THE
NORMAL AIRWAY

Airway clearance Fig. 049  oropharyngeal airway [32]

• opening of obstructed airway (i.a. opening of the

mouth; inspection of mouth and pharynx, suctioning,
removal of foreign bodies digitally or with a Magill
forceps, if necessary)
• Esmarch's maneuver (jaw thrust):
-- Tilt the patient's head back and jut lower jaw forward,
which in turn moves the tongue away from the back
of the throat. The tongue often obstructs the airways
of semi- or unconscious patients.
-- It must always be ensured, that the patient is still
breathing (e.g. observation of thoracic excursions).
The Esmarch's maneuver is not useful at all in apo- Fig. 050  oropharyngeal airway: different sizes [24]
eic patients and only delays the ventilation, which
would be urgently needed!
-- Contraindications to conventional tracheal intubation
exist in patients with traumatic or severe degenera-
tive disorders of the cervical spine. In this case intu-
bation must be performed with MINS (manual in-line
stabilization of the cervical spine).
• keeping the airway clear (with pharyngeal tubes)
Fig. 051  nasopharyngeal airway [32]

Ventilation
• mask ventilation
• endotracheal ventilation (intubation)

Fig. 048  Magill forceps: a medical forceps which is angled;
the grippings jaws are roughened and broadened (used
esp. to remove foreign bodies out of mouth and pharynx,
to insert a gastric tube for intubations). Here the grippings
jaws are taped to protect the endotracheal tube.
Mask ventilation
• BMV (bag mask ventilation)
• C-grip (syn.: EC-technique: Thumb and forefinger of
one hand press the mask against the face and form a
“C” shape. The other three fingers form an "E".); doub-

42 General Part
 le C-grip (syn.: EO-technique: humb and forefinger of
both hands press the mask against the face and form
a “O” shape.) with the help of a second person, if ne-
cessary
• administration of oxygen always with reservoir / oxy-
gen demand valve (a valve that delivers oxygen only
on demand during inspiration and thus saves oxygen;
works in a similar way as the Aqua Lung for divers; is
mainly used preclinically)
• The decisive criterion for the effectiveness of mask
ventilation is the rise of the thorax.
• if necessary, with oropharyngeal airway (OPA)
• risk of gastric distension, which is a is a significant risk
for aspiration of stomach contents; therfore the the
Fig. 054  Oxygen demand valve
Sellick's maneuver (cricoid pressure) was recommen-
ded for a long time: The cricoid cartilage was pushed
against the body of the sixth cervical vertebra, in the
mistaken belief that the esophagus would be com-
pressed and closed to prevent passive regurgitation.
The Sellick's maneuver dates from the year 1961. To-
day we know that the cricoid pressure only pushes the
esophagus aside but it still remains open. The Sellick's
maneuver is no longer applied nowadays! If the pati- Fig. 055  bag-valve-mask (Ambu bag) with a connected oxy-
gen demand valve
ents vomits during the Sellick's maneuver, it has to be
solved immediately, otherwise this can lead to a rup-
ture of the esophagus.
• During a RSI (rapid sequence induction; "crush" intu-
bation) mask ventilation should be avoided due to the
increased risk of aspiration.

Fig. 056  Thumb and forefinger form the so-called C-grip.

Fig. 052  mask [33]

Fig. 057  C-grip

Fig. 053  Bag valve mask (BVM [Ambu bag]; note: With an
Ambu bag you can generate an inspiratory pessure [e.g.
over a tube] up to 80 cmH2O!)

General Part 43

Fig. 058  double C-grip: Sufficient mask ventilation can
sometimes be difficult (especially for non-anaesthesiolo-
gists). It is a lot easier with the help of a second person:
One person presses the mask onto the patient's mouth with
a double C-grip and the other one provides ventilation.
Intubation
Fig. 059  anatomical illustration [4]
Indications
Especially younger assistant physicians do often not
know when a patient should be intubated. The reasons
for intubation can be subsumed to the three entities (dys-
functions):
• respiratory dysfunction: Despite the administration of
high oxygen doses via a mask (10-1 5l O2/min) the pa-
tient no longer reaches a saturation of SO2 > 90%. A
very rare, but important exception to this rule are pati-
ents with congenital heart disease with an Eisenmen-
ger syndrome. Due to the right-to-left-shunt they have
a cyanosis and therefore only an oxygen saturation of
70-80% already for their whole life, so that you should
be careful with hasty and permature actions like intu-
bations in the emergency department. Here it is better
to consult the treating GUCH-expert / -centre (GUCH:
grown-up congenital heart disease) first.
• circulatory dysfunction (shock): During a shock the
supply of oxygen is not sufficient enough to oxygenate
all cells. It is therefore crucial to reduce the oxygen
44 General Part
consumption. This is done by means of a deep analge-
sic sedation. In this case spontaneous breathing is no
longer possible, so that the patient has to be intubated
and ventilated.
• cerebral dysfunction (disturbed consciousness; GCS <
9; GCS: Glasgow Coma Scale [see infobox]): Patients
with decreased consciousness can no longer separate
their respiratory and digestive tracts so that there is an
increased risk of aspiration. Intubation is performed to
protect the airways; mnemonic: "GCS less than eight
- airway obligate!" or "GCS seven - maneuver airway
into haven"). However, here are some important ex-
ceptions to the rule that patients with disturbed con-
sciousness should generally be intubated:
-- hypoglycaemia: A patient with hypoglycaemia should
never be intubated. Blood glucose testing is an ab-
solute standard preclinical tool. This should also not
be forgotten in the hectic of the daily clinical routine!
-- alcohol intoxication: Every now and again, there are
drunk patients with a GCS < 9 (often clearly somno-
lent) in the emergency room, which want to leave
the hospital only a short time later at their own re-
quest. In most of these cases, intubation would be
unnecessary. In a study on alcohol intoxication in the
emergency department, 23% of the patients initially
showed a higher level of disturbed consciousness,
followed by a complete recovery of all patients, no
respiratory failure occurred in any case (Grüttner et
al, Notfall Rettungsmed 2008).
-- postictal
◦◦ You often find an altered state of consciousness
after a seizure.
◦◦ Therefore check if a seizure has occurred (e.g.
did passers-by notice convulsions? tongue-biting,
enuresis) and wait 10-15 minutes before intuba-
ting, if necessary
-- CO2 narcosis (e.g. in the case of COPD exacerba-
tion): In this case, a non-invasive ventilation is the
means of first resort!
The most common reasons for intubation in the intensive
care unit are (Luedicke et al, J Crit Care 2015):
• acute respiratory distress (32%)
• protection against aspiration (30%)
• shock (17%)
• resuscitation (12%; note: the most common reason
for an preclinical intubation)
 Fig. 061  laryngoscope: different blade sizes (size 3, 4 and
5)

Endotracheal tubes
• material: The tube (incl. cuff) consists of PVC (polyvi-
nyl chloride).
• kinds:
-- cuffed
-- uncuffed (children up to the age of 8 - but, since very
recently, cuffed tubes are also possible [no increa-
sed incidence of post-extubation stridor])
• types:
-- Magill
-- Murphy (standard tube today): with hole on the side
Equipment ("Murphy eye"), allows sufficient ventilation even in
• laryngoscope case of a blocked tube tip (e.g. by a mucus plug)
• malleable stylet -- ONK (Oxford non kinking)-tube: firm, right-angled,
• endotracheal tubes pre-defined insertion length → no too deep (unila-
• tube suction teral) intubation; option for difficult intubation, where
• syringe for cuff inflation only the lower part of the glottis is visible
• material for fixation -- Woodbridge tube: flexible, with embedded spiral
• bag valve mask (Ambu bag) wire to prevent kinking or compression; for surgical
operations in the oral and pharyngolaryngeal area
Laryngoscope -- Hi-Lo tubes (high-volume low-pressure; the reduced
• handle pressure causes less tracheal injuries and less tra-
cheal stenoses)
• blade
• sizes:
-- curved (Macintosh); size 3 (normal) or 4 (oversize)
-- women: 7.0
-- straight (Foregger): for infants
-- men: 8.0

Fig. 062  Magill tube [32]

Fig. 060  laryngoscope: different handles [32]

General Part 45
 Anesthesia

Introduction
• in internal intensive care medicine mostly in emer-
gency cases (RSI: rapid sequence induction, "crush-
Intubation" [i.e. including muscle relaxants, preferably
without mask ventilation because of the increased risk
of aspiration])
• phases:
-- anesthesia induction
-- anesthesia maintenance (see chapter on analgesic
sedation [page <?>]; preclinically mostly fentanyl +
midazolam by bolus injection, inner clinically stan-
dard in our clinic sufentanil + propofol via perfusor)
• Three substances are required for anesthesia induc-
tion:
-- muscle relaxant (often necessary because the in-
tubated emergency patients usually never have an
empty stomach; obligatory for RSI; caution: can-
not intubate & cannot ventilate [CICV])
-- analgesic
-- hypnotic (sedative)

Fig. 063  Murphy tube (recognizable by the eye on the side;

see arrow) [32]

Fig. 064  Woodbridge tube: a special flexible tube with an

embedded metal spiral, which prevents kinking (e.g. for
surgical operations in the oral and pharyngolaryngeal area)

Fig. 065  components of anesthesia

46 General Part
 An anaesthesia is obligatory for an
intubation (except in cardiovascular
arrest)!
Muscle relaxants
Definition
• blocking of acetylcholine receptors (postsynaptic, nico-
tinic) at the neuromuscular junction
• indications: Muscle relaxants are mainly used for an-
esthesia induction (intubation) as well as periopera-
tively in the operating room. Muscle relaxants are rare-
ly used in the intensive care unit (except for anesthesia
induction before intubation):
-- to facilitate ventilation: You can use them when the
patient cannot be sufficiently ventilated even though
the ventilation has been adapted and the ventilation
mode has already been changed. Sufficient analge-
sia and sedation is always a prerequisite. Muscle
relaxants are never an alternative to analgesic se-
dation!
-- during invasive procedures (e.g. tracheotomy, tube
exchange)
-- early stage (< 48h) of severe ARDS (Carrico Index
[paO2/FiO2] < 150mmHg)
• relaxometry: Whenever there is a long term medication
with muscle relaxants, the effects should be monito-
red by relaxometry. Two transcutaneous electrodes
are attached of to the distal forearm above the ulnar
nerve. Then, the muscle contractions of the hand are
measured: There are various stimulation patterns. The
most commonly used stimulation pattern is TOF ("train
of four"), in which a series of 4 stimuli are given at a
frequency of 2Hz.
Fig. 066  TOF-relaxometry
Types
• depolarizing muscle relaxants (sole agent: succinyl-
choline, syn.: suxamethonium chloride):
-- agonist at the acetylcholine receptor: maintains the
end plate in a depolarized state (initial short muscle
fasciculation), thereby blocking the repeated action
potentials required to produce sustained contraction
-- not antagonizable
-- heart rate ↓
• non-depolarizing muscle relaxants (curare-like ["ar-
row poison"]: Curare is a common name for alcaloids
of various nux vomica (esp. Strychnos toxifera) and
Moonseed-species (esp. Chondrodendron tomento-
sum). It was extracted of the bark of lianas in the Ama-
zon rainforest and used by the indos of South America
["Amazona-indians"] as an arrow poison in blowguns
for hunting animals. Curare is a competitive antagonist
at the acetylcholine-rezeptor.):
-- antagonist at the acetylcholine receptor: does not
lead to a depolarization of the end plate
-- antagonizable; through:
◦◦ acetyl cholinesterase inhibitors (e.g. neostigmine:
0.04-0.08 mg/kg, always in combination with atro-
pine because of muscarinic side effects)
◦◦ sugammadex (Bridion):
▪▪ dose: 16 mg/kg
▪▪ the first selective relaxant binding agent (SRBA)
▪▪ µ-cyclodextrin (a ring-shaped sugar), which
leads to an encapsulation und therefore to an
inactivation of the muscle relexant
▪▪ antagonization within 2-3 minutes
▪▪ only works with rocuronium and, less effectively,
with vecuronium
▪▪ faster effect compared with neostigmin
-- heart rate ↑
General Part 47
Depolarizing muscle relaxants: Succinylcholi- -- hyperkalaemia
ne (Lysthenon, Pantolax) -- chronic renal insufficiency
• syn.: suxamethonium chloride -- burns
• formally double acetylcholine -- chronic bedriddenness, immobilisation, neuromu-
• 1 amp. = 5ml = 100 mg; dosage: 1-1.5 mg/kg scular disorders (including Parkinson's disease,
hemiplegia, myopathy, contractures, myasthenia
• onset of action (onset time): 30-60s, duration of action:
gravis, Lambert-Eaton myasthenic syndrome, myo-
3-5 min (This is the major advantage of succinylcholi-
tonia, motor neuron diseases, multiple sclerosis,
ne: If the intubation fails [e.g. during an elective anest-
condition after poliomyelitis): This leads to a deve-
hesia induction], you can stop the attempt quickly and
lopment of new cholinergic receptors at the peri- and
let the patient breath spontaneously.)
extra-junctional zone of the motor end plate. These
• indicationen:
are embryonic form receptors causing a 2.5-fold in-
-- standard for RSI (rapid sequence induction); of crease of potassium efflux from the skeletal muscle
the non-depolarizing muscle relaxants, which have cell, compared to adult form receptors. Succinylcho-
a significantly longer onset time, only rocuronium line-binding to these embryonic receptors may result
(advantage: less side effects; disadvantage: signifi- in a life-threatening hyperkalaemia!
cantly longer duration of action [30-40min in stead of -- amphetamines, cocaine (chronic abuse or acute in-
3-5min] and vecuronium (with limitations) are suita- toxikation):
ble for RSI
◦◦ increased risk for rhabdomyolysis and therefore
-- laryngospasm (due to the release of potassium) hyperkalaemia
• Cleavage (Hydrolysis) by the enzyme pseudocholines- ◦◦ prolonged duration of action of succinylcholine,
terase because amphetamines and cocaine are also hy-
-- caution: the activity of this enzyme is reduced by 10- drolysed by the pseudocholinesterase
20 % in 3-4% of all people due to a gene polymor- • According to a statement of the German Society of
phism! Anaesthesiology and Intensive Care Medicine, succi-
-- reduced activity also in liver insufficiency or medica- nylcholine should no longer be administered routinely
tion wirh metoclopramide for muscle relaxation in case of elective surgery. The
• side effects: last remaining indication is the RSI (rapid sequence
-- HR ↓ (therefore it is best to administer atropine in induction).
addition!), RR ↓
-- hyperkalaemia
-- muscle fasciculations, myoclonic twitches, muscle
pain (priming, if necessary: i.e. prior administration
of a low dose [1/8 of the intubation dose] of a non-
depolarizing muscle relaxant, e.g. vecuronium 1mg)
-- histamine release
Fig. 067  succinylcholine: 1 amp. = 5 ml = 100 mg
-- salivation ↑, bronchial secretion ↑
-- intra-abdominal pressure (due to contractions of the
abdominal muscles) ↑, sometimes aspiration Succinylcholine is contraindica-
-- intracranial pressure ↑ (due to an increase cerebral ted in long-term immobilized
perfusion) patients
-- intra-ocular pressure ↑
• contraindications
Non-depolarizing muscle relaxants
-- perforating eye injury, glaucoma (because intra-ocu-
lar pressure ↑)
-- increased intracranial pressure, TBI (traumatic brain
injury), brain tumour (because intracranial pressure
↑); annot.: If a hypnotic is aditionally administered
during anesthesia induction, an increase of the in-
tracranial pressure is usually prevented, so that an
increased intracranial pressure is only a relative con-
traindication for succinylcholine.
-- malignant hyperthermia
◦◦ Succinylcholine typical trigger substance!
◦◦ If a lockjaw (masseter spasm) occurs immediately
after the administration of succinylcholine, so that
the opening of the mouth and intubation becomes
impossible, the patient might suffer from malignant
hyperthermia (see page 1400)!
-- hypothermia

48 General Part
• rocuronium (Esmeron)
-- 1 amp. = 5 ml = 50mg; dosage: 0.6 mg/kg ( for
RSI 1.2 mg/kg [annot.: Typically for RSI is a dose of
100mg, i.e. 2 ampoules.])
-- onset of action:
◦◦ 0.6 mg/kg: 75-90s (rapid onset time; Rocuronium
is the non-depolarizing muscle relaxant with the
shortest onset time!), duration of action: 30-40min
◦◦ 1.2 mg/kg: 30-60s (as fast as Succinylcholin), du-
ration of action: 60min (Due to the higher dose,
the onset of action is shortened, but the duration
of action is prolonged.)
-- no histamine release
• vecuronium (Norcuron)
-- 1 amp. = 10 mg (powder); dosage: 0.1 mg/kg
-- onset of action: 2-3min (therefore only suitable to a
limited extent for RSI), duration of action: 20-30min
-- no histamine release
• mivacurium (Mivacron)
-- 1 amp. = 10 ml = 20mg; dosage: 0.2 mg/kg
-- onset of action: 3-5 min, duration of action: 10-15
min (the non-depolarizing muscle relaxant with the
shortest duration of action)
-- histamine release
• atracurium (Tracrium)
-- 1 amp. = 5ml = 50mg; dosage: 0.5 mg/kg
-- onset of action: 2-3min, duration of action: 35-45min
-- Hofmann elimination (non-enzymatic degradation
[spontaneous decay into quaternary ammonium
salts], elimination therefore regardless of renal or
liver function)
-- side effects:
◦◦ HR ↑, RR ↓
◦◦ bronchospasm (histamine release)
-- storage in refrigerator (loss of effectiveness at room
temperature)
• cisatracurium (Nimbex)
-- stereoisomer of atracurium (no histamine release,
no cardiovascular changes)
-- 1 amp. = 5ml = 10mg; dosage: 0.1 mg/kg
-- onset of action: 4-6min, duration of action: 40-50min
• pancuronium (Orgaron, Pavulon)
-- 1 amp. = 2 ml = 4 mg; dosage: 0.1 mg/kg
-- onset of action: 3-5min, duration of action: 70-
120min (muscle relaxant with the longest duration
of action)
-- side effects v.a. HR ↑, RR ↑
• alcuronium (Alloferin)
-- 1 amp. = 10 ml = 10 mg; dosage: 0.2 mg/kg
-- onset of action: 3-5min, duration of action: 45-60 min
-- withdrawn from market
study
Effect of Rocuronium vs Succinylcholine on Endotracheal
Intubation Success Rate Among Patients Undergoing Out-
of-Hospital Rapid Sequence Intubation
Guihard et al, JAMA 2019
• multicenter randomized non-inferiority study
• 1,248 patients undergoing out-of-hospital intubation
(RSI)
-- Succinylcholin 1.0 mg/kg
-- Rocuronium 1.2 mg/kg
• result: Rocuronium was inferior to succinylcholine in
the primary endpoint successful intubation on the first
attempt.
Muscle relaxant of first choice for RSI:
succinylcholine; in case of contraindi-
cations: rocuronium
Analgesics
• opioids (antagonist: Naloxone [Narcanti]; see also
chapter on analgosedation [page 175])
• ketamine (see also chapter on analgosedation [page
176])
Opioids
• fentanyl
-- effectiveness: 100 (compared to morphine)
-- standard analgesic for anesthesia induction
-- ampoule sizes:
◦◦ 1 amp. = 2 ml = 0.1mg (small ampoule)
◦◦ 1 amp. = 10 ml = 0.5mg (large ampoule)
-- dosage: 2-3 μg/kg, usually 0.1-0.2 mg IV
-- onset of action: 2-3min, duration of action: 20-30min
• sufentanil (Sufenta)
-- effectiveness: 1000 (compared to morphine)
-- ampoule sizes
◦◦ 1 amp.= 5ml = 250μg (50 µg/ml) = 0.25mg (e.g.
for perfusor: 3 amp. a 5ml + 35ml NaCl 0.9% →
0.015mg/ml)
◦◦ for spinal anesthesia (each 5 µg/ml)
▪▪ 1 amp. = 2ml = 10μg (epidural)
▪▪ 1 amp.= 10ml = 50μg (peridural)
-- 1 amp. = 5ml = 0.25mg
-- dosage: 0.2-0.4 μg/kg (10-40μg) IV
-- onset of action: 2-3min, duration of action: 20-30min
• remifentanil (Ultiva)
-- effectiveness: 500 (compared to morphine)
-- ampoules (dry powder) with 1mg, 2mg oder 5mg
(concentration when dissolved: 1mg/ml)
-- dosage: 1 μg/kg IV, then 0.5-1.0 μg/kg/min (perfusor)
-- onset of action: 1min, duration of action: 10-15min
General Part 49
 -- elimination by non-specific esterases → elimination
regardless of liver and renal function
-- only opioid, which is not eliminated through the liver
• alfentanil (Rapifen)
-- effectiveness: 30-50 (compared to morphine)
-- 1 amp. = 2ml = 1mg
-- dosage: 10-30 μg/kg (e.g. 70kg patient: 1mg)
-- onset of action: 1-2min, duration of action: only 10-
15min
-- common side effect: rigidity of thorax (tip: first only
1/2 ampoule, then hypnotic, afterwards again 1/2
ampoule)
-- We like to use alfentanil during short anaesthesia,
mainly for electrical cardioversion.
Ketamine (Ketanest)
• NMDA-receptor antagonist (N-methyl-D-aspartate;
non-competitive antagonist)
• derivative of phencyclidine
• mixture (racemate; trade name: Ketanest) of the right-
handed (R) and left-handed (S) enantiomer
-- S-ketamine has the desired effects.
-- R-ketamine has the unintended effects.
• also only available as S-ketamine (Esketamin; Keta-
nest S)
• The dose of S-ketamine corresponds to half of the
dose of the racemate R/S-ketamine.
• ampoule sizes:
-- 1 amp. = 2ml = 50mg
-- 1 amp. = 5ml = 25mg
-- 1 amp. = 10ml = 250mg
• dosage (S-ketamine):
-- analgesia
◦◦ 0.125-0.25 mg/kg IV
◦◦ 0.25-0.50 mg/kg IM
-- anaesthesia
◦◦ 0.5-1 mg/kg IV (in patients with status asthmaticus
1.5-3 mg/kg)
◦◦ 2-4 mg/kg IM (Ketamine is the substance which
is used in stunning darts in blow pipes or guns /
pistols for chemical immobilization of wild animals.
The IM-administration of ketamine is also a good
option for psychotic resp. aggressive and rioting
patients.)
• administration: inject slowly
• onset of action: 30s, duration of action: 10-20min
• effects:
-- strongly analgesic
-- only slightly hypnotic (spontaneous breathing and
protective reflexes are usually retained; "dissociative
anaesthesia"; eyes usually open)
-- sympathomimetic
-- bronchodilatory (good indication for anaesthesia in-
duction in the case of a status asthmaticus)
-- psychomimetic (i.a. nightmares)
• side effects:
-- RR ­↑ (high circulatory [i.e. hemodynamic] stability,
therefore favourable e.g. in poyltrauma with hemor-
rhagic shock), HR­↑, myocardial oxygen consump-
tion ↑­(contraindication: acute myocardial infarction
or myocardial infarction during the past 6 months,
because it leads to an increase of the infarct size;
note: In case of infarction-related cardiogenic shock
however, administration of ketamine is still possible.
In this case, ketamine is often the only way to pre-
vent a further reduction of the mean arterial pressure
and the coronary perfusion, which would be the usu-
al effects of opioids.)
-- pulmonary arterial pressure (PAP) ↑, pulmonary
vascular resistance (PVR) ↑ (i.a. Strumpher et al, J
Cardiothorac Vasc Anesth 2011), therefore contra-
indicated in the case of pulmonary hypertension or
acute right heart failure
-- psychomimetic → therefore only in combination with
a hypnotic (e.g. midazolam, propofol)
-- proconvulsive (seizure treshold ↓)
-- increased sensitivity to noise
-- hypersalivation (antagonizable by simultaneous
administration of a vagolytic drug, such as atropi-
ne or glycopyrronium bromide [Robinul]), bronchial
hypersecretion (Therefore, ketamine is well suited
for anaesthesia induction in case of status asthma-
ticus, but not for the maintenance of anaesthesia:
Propofol, which is also a bronchodilator, should be
preferred.)
-- nystagmus (common), distorted pupils (normal!)
-- intracranial pressure
◦◦ contrary to earlier opinions, no increase of intracra-
nial pressure in combination with benzodiazepines
or barbiturates (Martin et al, Ger Med Sci 2010)
◦◦ In patients with an increased intracranial pressure
(ICP) a sufficient MAP (> 90mmHg) is crucial for
the maintenance of a sufficient cerebral perfusion
pressure (CPP). This goal can easily be achieved
with ketamine due to its high circulatory stability.
-- contraindicated in anti-NMDA-rezeptor-encephalitis
(an autoimmune encephalitis; very rare)

50 General Part

Ketamine: high circulatory stability
(sympathicomimetic), therefore
favourable in hemodynamic unstable
patients (e.g. polytrauma with hemor-
rhagic shock)
Fig. 068  Because of the increased sensitivity to noise, we
put this sign (translated: "Quiet please - ketamine") in the
near of the bed in the ICU, when a patient gets ketamine for
a longer time.
Hypnotics
• propofol
-- the most frequently used hypnotic for anesthesia in-
duction (standard)
-- dosage: 2 mg/kg (usually 100-200 mg i.v.)
-- main disadvantage: circulatory depression
-- see esp. page 165
• etomidate
• barbiturates (agonist at the GABA-receptor [β-subunit]):
-- thiopental (Trapanal)
-- methohexital (Brevimytal)
◦◦ dosage: 1-2 mg/kg
◦◦ onset of action: 20-50s, duration of action: 5-10min
• benzodiazepines (agonist at the GABA-receptor
[α-subunit]; antagonist: flumazenil [Anexate]; see also
page 167)
-- midazolam (Dormicum)
◦◦ ampoule sizes:
▪▪ 1 amp. = 5ml = 5mg
▪▪ 1 amp. = 3ml = 15mg (caution: confusion!)
◦◦ dosage 0.15-0.20 mg/kg IV (for intubation usually
10-15mg IV)
◦◦ administration: all routes are possible (IV [best],
PO, SC, IM, intranasal, rectal)
-- lorazepam (Tavor; not suitable for anesthesia induc-
tion due to its long half-life)
-- diazepam (Valium; not suitable for anesthesia induc-
tion due to its long half-life)
-- flunitrazepam (Rohypnol; not suitable for anesthesia
induction due to its long half-life)
Etomidate
• an imidazole derivative
• agonist at the GABA-receptor (α-subunit; like propofol)
• solutions:
-- aqueous solution (Hypnomidate)
-- lipid emulsion (Lipuro)
• 1 amp. = 10ml = 20mg; dosage: 0.15-0.30 mg/kg IV
(usually 10-20mg IV; maximum dose: 80mg)
• onset of action: 60s, duration of action: 2-4min
• high circulatory stability (less likely to cause circulatory
depression, in contrast to propofol), thus suitable for
anesthesia induction in patients with cardiovascular
insufficiency
• t1/2 2-5h
• reduction of intracranial pressure
• side effects:
-- muscle twitches, dyskinesia
-- vein irritation (pain at injection site), thrombophlebitis
(especially when using the aqueous solution)
-- rigidity of the jaw
-- adrenocortical insufficiency:
◦◦ In the past etomidate has also been used for long-
term sedation before it was recognized that it lead
to a very high rate of adrenocortical failure (Etomi-
date inhibits the 11β-hydroxylase and the steroid
synthesis in the adrenal cortex) with a correspon-
dingly higher mortality rate.
◦◦ New studies (including Cuthbertson et al, Journal
of Intensive Care Medicine 2009; see page 741)
have shown that, especially in patients with sep-
sis, even a single administration of etomidate for
the purpose of anaesthesia induction lead to an
increased rate of adrenocortical insufficiency and
a higher mortality rate.
◦◦ Because of its adrenostatic effect etomidate is also
used for the therapy of a life threatening Cushing-
syndrome (hypercortisolism).
No more anesthesia induction with
etomidate in patients with (suspicion
of) sepsis (one in 3 intensive care
patients!): increased rate of adre-
nocortical insufficiency!
Fig. 069  Etomidate [8]
Thiopental (Trapanal)
• a barbiturate
• 1 powder ampoule = 500 mg (dissolve in 10 ml sodium
chloride 0.9% → 1ml = 50mg)
• dosage: 3-5 mg/kg
• redistribution from the CNS to the muscles (not to fat
tissue, therefore only administered by bolus injection
General Part 51
 and no dose increase in obese patients!)
• onset of action: 30s, duration of action: 5-10min
• t1/2 3-8h
• reduction of intracranial pressure (therefore suitable
in case of TBI [traumatic brain injury]; neuroprotective
effect)
• anticonvulsive (i.a. for stopping a status epilepticus)
• side effects:
-- laryngospasm, bronchospasm (histamine release;
therefore do not use in asthmatic patients!)
-- muscle twitches
-- RR ↓↓ due to vasodilatation and negative intotropic
effect (severe cardiac depression, shock is a contra-
indication! Use with caution in patients with circula-
tory instability!), HR ↓
-- tissue necrosis in case of extravasation - (strongly
alkaline pH [pH 10-11])
-- allergic reaction
-- acute intermittent porphyria (all barbiturates contra-
indicated)
-- hyperalgesia (preferably in combination with an opi-
ate)
• contraindications:
-- obstructive pulmonary disease (particularly bronchi-
al asthma)
-- shock
-- porphyria
-- myasthenia gravis
Examples for anesthesia induction
• standard:
-- fentanyl 0.1-0.2 mg
-- propofol 100-150mg or etomidate (Hypnomidate; do
not use in patients with sepsis because of increased
rate of adrenocortical insufficiency) 10-20 mg
-- succinylcholine 100mg or rocuronium 100mg
• status asthmaticus:
-- ketanest (S-ketamine) 1.5-3 mg/kg
-- midazolam 10-15mg oder propofol 100-150mg
-- succinylcholine 100mg or Rocuronium 100mg
• acute myocardial infarction, acute left-sided heart failu-
re / pulmonary oedema:
-- fentanyl 0.1-0.2mg (no Ketanest in acute myocardial
infarction)
-- propofol 100-150mg oder etomidate 10-20mg
-- succinylcholine 100mg or Rocuronium 100mg
• haemorrhagic shock (e.g. polytrauma):
-- ketanes (S-ketamine; suitable here because of its
circulatory stability) 100mg
-- etomidate 10-20mg / midazolam 10-15mg / propofol
50mg (only low-dosage of propofol here because of
its circulatory depression)
-- succinylcholine 100mg or rocuronium 100mg
52 General Part
Anesthesia induction (example):
1. fentanyl 0.2mg
2. propofol 100-150mg
3. succinylcholine 100mg or rocuroni-
um 100mg
Anaesthesia induction in children
(example):
1. fentanyl 2 μg/kg
2. propofol 2 mg/kg
3. rocuronium 1.2 mg/kg
Performance (intubation)
• examination
-- laryngoscope light
-- tube cuff
• prepare suction catheter
• anaesthesia induction
-- Deep anaesthesia is important!
-- draw up double amount into syringe for a later in-
jection
• if possible before placing a second peripheral access
with volume loading (cardiac depression; anaesthesia
→ stress / endogenous catecholamines ↓)
• positioning:
-- put upper body into elevated position 30° → reduc-
tion of aspiration
-- cervical flexion of head and atlanto-occipital extensi-
on ("sniff position")
• preoxygenation whenever possible (oxygen 10-15 l/
min over O2 mask for 3 minutes), to prevent critical
hypoxia during the apnoea time: Due to the preoxy-
genation the air (contains only 21% oxygen), which is
stored in the lung and which remains in the lung even
after expiration (FRC: functional residual capacity), is
replaced by 100% oxygen. So it takes five times longer
(5-8 minutes), until a critical hypoxia occurs.
• mask ventilation
-- with oxygen 10-15 l/min until blink reflex stops
-- not as part of the RSI, because the patients have
usually not fastened, so that the risk of aspiration is
increased (In the PReVENT study [see box], howe-
ver, bag-mask ventilation before intubation could re-
duce the risk of hypoxaemia without increasing the
risk of aspiration!)
• opening of the mouth (crossed finger technique):
-- With the thumb (of the right hand; the laryngoscope
is in the left hand) the lower jaw is pressed down at
the row of teeth, the index or middle finger supports
the hand at the row of teeth of the upper jaw.
-- The crossed finger technique should be carried out
as far to the left side in the mouth as possible, so that
there is enough space to introduce the laryngoscope
on the right side.
-- remove dentures, if necessary
• The laryngoscope is taken in the left hand. The laryn-
 goscope blade is introduced at the right side of the sufficient expertise, you should have done at least 100
mouth and advanced to the midline, displacing the intubations under supervision. To keep on the practice
tongue to the left. at least 10 intubations should be performes each year
• suction of the oropharynx, if necessary (according to the national S1-Guideline "Prehospital
• advance the tube visualizing the following anatomical Airwair Management" of the German Society of Anaes-
structures: thesiology and Intensive Care Medicine 2019).
-- vallecula at the base of the tongue • The intubation should be successful in the first attempt
-- epiglottis if possible. If already a second attempt was necessary,
the risk of complications increases threefold.
-- arytenoid cartilage
-- glottis
• lift epiglottis forward and upward i.e. in the direction of
the handle (do not use the blade as a lever - in contrast PReVENT study
to the intubation in infants, the epiglottis of adults is not
levered)
• advance tube to the base of the epiglottis and pass it
through the vocal cords until its cuff is 1-2 cm behind Bag-Mask Ventilation during Tracheal Intubation of Criti-
the glottis cally Ill Adults
• inflate cuff (10ml air via syringe; targeted cuff pressure: Casey et al, N Engl J 2019
22-32 cmH2O [16-24 mmHg]; at least 5 cmH2O above
• multicenter (7 ICU´s in the USA), randomized controlled
the set inspiratory pressure, but not more than 32 cm-
trial
H2O [maximum]; for more information on cuff pressure
• PReVENT: prevent hypoxaemia with manual ventilation
see page 881) during endotracheal intubation
• connect with Ambu bag / Jackson-Rees system • 401 critically ill patients before intubation (after anesthe-
• check tube position by auscultation: sia induction and before laryngoscopy):
-- epigastric region -- with mask ventilation (bag)
-- equal sounds on both sides of the lung -- without mask ventilation
• fixation of tube (21-22 cm from dental arch); preclini- • results: mask ventilation
cal a gauze bandage or plaster strips are used; pos- -- primary outcome (lowest oxygen saturation [SpO2]):
with 96% versus 93% significantly higher (less com-
sibly use of tube holders [e.g. Thomas Tube Holder,
mon hypoxaemia)
Laerdal])
-- secundary outcomes:
• Guedel airway (nasopharyngeal airway), if necessary
◦◦ aspirations (detected by the operator; new opacity
• insertion of a gastric tube, if necessary (This is espea- on chest radiography): no difference (not an incre-
cially important in children: Due to the mask ventilation ased rate!)
the stomach of the children may be extended so ext- ◦◦ severe hypoxemia (p.d. SpO2 < 80%): significantly
remly that the lung could no more be ventilated (ext- lower
rathoracic restriction). • Annot.: Patients with an increased risk of aspiration
• connection to ventilator; settings (so-called "rule of 10" (7.3%) were excluded.
[only serves as a rule of thumb])
-- volume-controlled (emergency ventilator) or pressu-
re-controlled (intensive care ventilator)
-- VT (tidal volume) 10 ml/kg
-- RR (respiratory rate) 10-12/min
-- RMV (respiratory minute volume) 100 ml/kg
-- FiO2 (fraction of inspired oxygen) 1.0 until the first
ABG (after 30min, at the earliest)
-- PEEP 5 mbar
• If the tube has to be changed in a patient (e.g. be-
cause the cuff has a leak), who has been ventilated for
quite a long time, you should, even if the patient was
easily to intubate initially, always use a malleable sty-
let or bougie (tube introducer), because the tube may
have caused a swelling of the mucous membrane of
the glottis, so that a re-intubation becomes difficult or
even impossible. Fig. 070  The possibility of suctioning (here for preclinical
use the ACCUVAC-rescue-system [Weinmann company] as
• training: The skil of intubation can be learned at best an example) should always be prepared before the intuba-
from the colleagues of anesthesia in the operating tion starts. After positioning of the laryngoscope it is often
room. It is useful to release the collegue for two up to necessary to suck off mucos in order to get free sight to
three weeks in the operating room, before he starts to the glottis.
work in the ICU. It is difficult to learn intubation by using
dolls, because they are quite unrealistic. To achieve a

General Part 53
 Preoxygenation whenever 3
possible (is often forgotten in the
hectic of daily routine)!

epiglottis

glottis

arytenoid
4
cartilage

Fig. 071  Anatomy

54 General Part

7 • dental injury or injury of soft tissue (e.g. larynx [i.a. vo-
Fig. 072  Intubation step-by-step: Mouth is opened (crossed
finger technique) and laryngoscope blade is introduced
at the right side (1). Tongue is pushed to the side and the
laryngoscope is advanced (2). Lift epiglottis forward and
upward (in the direction of the handle) to see the glottis
(3). Watch the tube (usually equipped with a malleable sty-
let) while passing through the glottis into the trachea (4,5).
Then the laryngoscope is removed (6) and the cuff is infla-
ted (7).
Tube exchange - caution difficult
intubation (swelling of the glottis after
ventilation for a longer time): therefo-
re only with malleable stylet or bougie
and in principle only in case of leaky
cuff!
Fig. 073  Fixation of tube [33]
Fig. 074  Different possibilities of tube fixation [33]
Complications
cal cords: edema, hematoma, rupture], trachea [espe-
cially tracheal rupture])
• hypoxia
-- termination of intubation attempt after a maximum of
30 sec and oxygenation with mask
-- No intubation attempts in hypoxemic patients!
-- In addition to the decrease of oxygen saturation, a
typical sign of hypoxia is bradycardia. But bradycar-
dia is already a very late sign, so that cardiovascular
arrest is quite imminent!
• cardiac depression (advice: draw up diluted noradre-
naline [1 amp. a 1 mg in 100ml sodium chloride 0.9%
and inject by the ml); alternative: Akrinor [1 amp. = 2ml
= 10mg theodrenaline + 200mg cafedrine]; dosage:
1-2ml i.v.; also i.m.-application possible)
• laryngospasm
• aspiration ( leading cause of death)
• incorrect intubation
-- in main bronchus (endobronchial instead of endotra-
cheal; one-sided intubation; mostly right side)
-- in esophagus (If unrecognized, this may result in a
circulatory arrest due to hypoxia within 3 minutes!)
"In doubt take it out!"
study
The occurrence of aspiration pneumonia after emergency
endotracheal intubation
Drivers et al, Am J Emerg Med 2018
• prospective observational study
• 879 intubations (adults) in the emergency department
• mostly performed by physicians in education (under su-
pervision of experienced emergency physicians)
• in 49% videolaryngoscopy
• successful:
-- 1st attempt: 85%
-- 2nd attempt: 12%
-- 3rd attempt: 3%
• in 25% SpO2 < 90% (hypoxaemia) during the intubation
• in 8% aspiration pneumonia (Intubation remains a
high-risk procedure!)
Tracheal rupture
• occurrence:
-- difficult intubation, especially when using a bougie
protruding beyond the tip or a double-lumen tube
-- cuff over-inflation (check cuff pressure!)
• localization:
-- usually in dorsal part of the trachea (pars membran-
General Part 55
 acea)
-- directly in front of the main carina
• symptoms:
-- skin emphysema (especially in the upper thorax and
neck area; produces crackling sensation!), mediasti-
nal emphysema (risk of mediastinitis [mortality 40%])
-- pneumothorax
-- ventilation problems
• diagnosis:
-- chest x-ray
-- CT
-- bronchoscopy
• treatment: surgical (possibly stent [but only if no main
bronchus is involved in the rupture])

Fig. 075  Chest x-ray: You can see the skin emphysema (ar-
rows).

Fig. 076  chest CT: You can see the mediastinal emphysema
(arrows).

Fig. 077  bronchoscopic visualization of tracheal rupture:

You can see the rupture at dorsal part of the trachea (pars
membranacea), which goes up to the proximal right main
bronchus (last picture: after surgical restoration).

56 General Part
Control
Correct tube position must be checked. There are a re-
liable and unreliable signs:
• unreliable signs
-- auscultation: Auscultate over the epigastric area
first! If the epigastric area is auscultated last, an eso-
phageal intubation cannot be ruled out any more be-
cause the stomach is already filled after 4 x 500 ml
VT and can no longer extend!
-- fogging of tube during expiration
-- fogging of tube during expiration
-- EDD
◦◦ esophagus-detection-device
◦◦ syn.: SIB (self inflating bulb)
◦◦ principle: suction of air only possible in tracheal
position, not in esophageal position
• • reliable signs
-- inspection: observation of the tube insertion through
the vocal chords (advanced under visual control)
-- bronchoscopy (fibreoptic technology)
-- sonography (not yet a standard; place linear array
transducer on the trachea: In case of incorrect in-
tubation the tube will be visible in the esophagus
[esophagus is dorsal to the left thyroid lobe]. This is
called a "double trachea". Usually the tube itself is
not detectible in the trachea.)
-- capnography
Fig. 078  EDD (esophagus-detection-device)
Never insert tube, if you cannot see
the glottis!
Fig. 079  imaging of the glottis
Capnography
Definition
• capnometry: measurement of CO2-concentration du-
ring expiration (ET [end-tidal CO2]; usually about 40
mmHg)
• capnography: graphic display (waveform) of the CO2-
concentration throughout the respiratory cycle
• measurement method:
-- infrared spectroscopy (absorption of infrared light
with a wavelength of 426 nm)
-- techniques:
◦◦ mainstream sampling (real-time measurement; no
calibration necessary; increased risk of accidental
extubation, due to the increased weight; increased
dead space)
◦◦ sidestream sampling (delayed-time measurement;
calibration necessary; increased risk of auto-trig-
gering [when using flow trigger])
• DIN ISO standard 21647: capnometry equipment is
compulsory for all ambulance vehicles registered since
2007 in Germany
• preclinically (only) used in 30% of the cases
• also recommended during reanimation (inspection of
tube position, monitoring of the quality of the cardi-
ac massage [aim: ETCO2 > 10mmHg), early sign of
ROSC
• also recommended for the ventilation with a supraglot-
tic airway devices (not only with an endotracheal tube)
• connected with pCO2 (arterial ABG):
-- The paCO2 values are usually 3-5mmHg above the
ETCO2 values due to the alveolar dead space volu-
me.
-- correlation:
◦◦ ETCO2 and paCO2 correlate almost in healthy in-
divuduals, otherwise there is no good correlation
(i.a. Warner et al, Journal of Trauma Injury 2009).
◦◦ The ventilation should be controlled by the paCO2
and not by the ETCO2.
General Part 57
 ◦◦ In a (hemodynamic unstable) pulmonary embo-
lism ETCO2 and paCO2 even show an absolutely
contrary development:
▪▪ ETCO2 ↓ (Due to the reduced perfusion less CO2
gets into the alveoli and therefore less CO2 is ex-
pirated.)
▪▪ paCO2 ↑ (Due to the pulmonary embolism the
dead space ventilation is increased: The alveoli
are still ventilated, but no more perfused [venti-
lation without perfusion]. Due to the increase of
dead space ventilation the effective ventilation is
decreased, so that paCO2 increases.)
• statements:
-- ventilation
◦◦ hyperventilation: ETCO2 ↓ Fig. 081  Easy Caps for semiquantitative CO2-detection: Af-
◦◦ hypoventilation: ETCO2­ ↑ ter intubation the Easy Cap is attached between tube and
Ambu bag. If the indicator turns yellow, end-tidal CO2 is
-- circulation (low ETCO2: hypoperfusion)
sensed which proves the correct (endotracheal) tube po-
-- metabolism (metabolic acidosis: ETCO2 ↑) sitioning [11].
-- estimation (qualitative) of the ventilation / perfusion
quotient (V/Q-ratio)
• also semiquantitatively by colour change (pH sensitive
indicator devices; e.g. Easy Cap [two sizes: for adults
and children, i.e. < 15kg])

Fig. 080  The capnography sensor (arrow) is attached bet- Fig. 082  capnography and capnometry (arrow)
ween the Y-piece and the breathing hose (mainstream tech-
nique). Left next to it is the HME-filter.

58 General Part
 Wave segments (capnogram)

Fig. 083  capnography and capnometry [32]

Fig. 085  capnogram: wave form and wave segments

Fig. 084  capnometer - different examples [32]

General Part 59
 Pathological capnograms
α

Fig. 086  From the slope of the increase (α-angle) of the Fig. 087  Obstruction - possible causes: COPD exacerbati-
phase III of the capnogram you can draw conclusions about on, status asthmaticus; kinked tube or cuff herniation (di-
the ventilation / perfusion relation (V/Q): If V/Q < 0.8. then stal end of the cuff obstructs tube opening → after unblo-
you have a shunt. Shunt means perfusion without ventilati- cking ventilation possible again [no easy diagnosis!])
on, i.e. a lot of CO2 accumulates, because on the one hand
much CO2 is delivered over the capillaries into the alveoli
due to the normal perfusion and on the other hand only few
CO2 is removed from the alveoli due to the reduced venti-
lation. The angle α therefore increases. If V/Q > 0.8. then
you have dead space. Dead space means ventilation wit-
hout perfusion, i.e. only few CO2 accumulates, because on
the one hand only few CO2 is delivered into the alveoli due
to the reduced perfusion and on the other hand the CO2 is
quickly removed from the alveoli due to the normal ventila-
tion. The angle α decreases.

Interpretation
• ETCO2 > 5 mmHg: endotracheal position Fig. 088  Accidental extubation, disconnection
• The capnometry (not the capnography) can (rarely) be
false positive after:
-- the consumption of carbonated beverages
-- long mask ventilation
• „no wave → no tube“ (The decisive factor is not the
numerical value of the capnometry, but the wave of the
capnography! The wave must be available, otherwise
the tube is not positioned correctly!)
• during reanimation usually only values between 5-15
mmHg (Due to the poor hemodynamic there is only an
Fig. 089  Patient breathes in between, i.e. he must be more
insufficient perfusion of the alveoli, so that only little
deeply sedated.
CO2 arrives in the alveoli and correspondingly only litte
CO2 can be exspirated.); ETCO2 < 10 mmHg → infaust
prognosis
• pulmonary embolism:
-- low capnometric values (e.g. ETCO2 5-10 mmHg) af-
ter the intubation of a dyspnoeic, haemodynamically
unstable patient, but normal capnogram (i.e. tube
is positioned correctly): typical signs for pulmonary
embolism!
-- A sudden fall of end-tidal CO2-concentration (e.g. in-
traoperative) is (especially in connection with a sud-
den circulatory instability) an indication of pulmonary
Fig. 090  Double-peak expiration (side differences of the
embolism! lung) - possible causes: one-sided intubation (the most
common cause), heavy kyphoscoliosis, condition after sin-
Confirmation of proper endotra- gle lung transplant
cheal tube placement by capno-
graphy (ETCO2) should be
standard!

60 General Part

Fig. 091  Rebreathing of CO2 (no decline to the zero point of
0 mmHg ETCO2; e.g. in a defect CO2-absorber of the anaes-
thetic circuit in the operation room)
DOPES
Patient cannot be ventilated:
possible cuff herniation (after
unblocking ventilation possible
again)! No easy diagnosis!
Management OF THE
DIFFICULT AIRWAY
Definition
• "difficult" airway: difficult visualization of the glottis with
the laryngoscope
• frequency: difficult intubation
-- inner-clinically (inside hospitals): 1% (i.a. emergency
room 4%, intensive care unit: 15%)
-- pre-clinically (outside hospitals): 20% (children:
34%)
• intubation-associated mortality in intensive care pati-
ents: 3%
• types
-- expected
-- unexpected (mostly in emergency and intensive
care medicine)
• If the intubation was difficult, the patient should be
handed out an anaesthesia emergency card (e.g. at
hospital discharged) with the corresponding grade of
Cormack-Lehane classification.
study
The Out-of-Hospital Esophageal and Endobronchial Intu-
bations Performed by Emergency Physicians
Timmermann et al, Anesthesia & Analgesia 2007
• 149 patients (preclinically performed intubation by pri-
mary emergency physicians on site)
• subsequently evaluated by study physicians (laryngo-
scopy, esophageal detector device, capnometry)
• incorrect one-sided intubation in 17%
-- one-sided in 10%
-- esophageal in 7%
• approx. 3000 deaths in Germany due to incorrect intu-
bation by emergency physicians (statistical projection)
General Part 61
 grade I grade II grade III grade IV
Fig. 093  Cormack-Lehane classification

Fig. 092  If a patient was difficult to intubate, the tube is

provided with a red warning tape ("difficult airway") in the
intensive care unit.

Classificationen
• difficulty levels of laryngoscopy
-- prediction by Mallampati classification (beforehand;
see infobox)
-- classification by Cormack-Lehane (afterwards; see
infobox)
• MACOCHA score: used to identify patients with an in-
creased risk of difficult intubation (according to de Jong
et al, AJRCC 2013; see infobox)

Warning signs
• short, thick neck (enlarged neck circumference)
• obesity (BMI > 30 kg/m2):
-- often thick and short neck
-- Due to the increased intra-abdominal pressure, obe-
se patients have an extrathoracic restriction. This
leads to a decrease of lung volumes, i.a. the func-
tional residual capacity (FRC) and hence to a decre-
ase of the intrapulmonary oxygen store. This is why
obese patients have a much lower apnea tolerance
than non-obese patients. Oxygen consumption and
breathing effort is also increased in obese patients.
• pregnant women (10 x higher incidence of difficult in-
tubation)
• protruding incisors, prognathism
• small mandible (retrogenia)
• limited mouth opening ( < 3cm)
• difficult head extension, e.g.
-- cervical collar: Patients with a suspected cervical
spine instability get preclinically a cervical collar
("stiff neck"): This should be openend to facilitate the
intubation. For this time an assistant provides a ma-
nual in-line stabilisation(MILS) of the cervical spine.
-- Bechterew's disease
-- condition after cervical spine injury or surgery
• ENT (ears, nose and throat): previous surgery in ENT-
area, ENT-tumor, rebleeding after ENT-operations
(tonsillectomy, adenotomy), ENT-infections (e.g. peri-
tonsillar abscess, epiglottis, Ludwig's angina [infection
of the submandibular space; see page 824])

62 General Part
• condition after radiotherapy in the throat area
• heatoma in the neck area (e.g. as a complication of a
cvc insertion [especially in limited coagulation])
• craniofacial fractures
• macroglossia (i.a. anaphylaxis, angiooedema [heredi-
tary / aquired, e.g. ACE inhibitor-induced], acromega-
lia, Down's syndrome, Beckwith-Wiedemann syndro-
me)
• goiter
• dysmorphic syndrome: Pierre-Robin, Treacher-Collins,
Franceschetti, Pfaundler-Hurler, Goldenhar, Apert,
Klippel-Feil, acromegalia, Crouzon, acromegalia
• post-extubation stridor (The reintubation is often dif-
ficult here because of laryngeal edema!)
• anatomical characteristics (e.g. lockjaw [annot.: If you
find a "lockjaw" in a patient with asystole, you should
look at the back of the patient and check if he has al-
ready livor mortis. It is not uncommon that the "lock- Fig. 095  a large retrosternal goiter with deviation an com-
haw" is only the rigor mortis.]Bechterew's disease) pression (see arrow) of the trachea
• physiognomic parameters:
-- thyromental distance < 6.5 cm (Patil´s test)
-- sternomental distance < 12.5 cm (Saffa´s test)
• upper lip bite test (ULBT): If the patient is not able to
bite with the teeth of the lower jaw above the upper
lip (vermilion border [demarcation between the lip and
the adjacent normal skin]), the intubation will probab-
ly be (in 60%) be difficult (Detsky et al, JAMA 2019).
Therefore, however, the patient has to be awake and
cooperative.

Fig. 096  Pierre-Robin syndrome: small mandible (micro­

gnathia) with receding chin (retrognathia), displacement of
tongue toward pharynx (glossoptosis) and palatine cleft

Fig. 094  ACE inhibitor-induced angioedema

General Part 63
 • return to spontaneous breathing: This is only an option
The two leading causes for a failed for elective intubations (esp. in the operation room).
intubation: insufficient depth of This is no option in the intensive care and especially
anaesthesia and incorrect head in the emergeny medicine, provided that the indication
positioning! was determined correctly.

Memo: Ventilation with oxygenation is

more important than intubation! The
patient does not die because of the
missing tube, but of missing oxygen!

Measures
• optimization measures
• supraglottic airway devices Fig. 097  introducer guide with a steerable tip (here Flextip
Bougie [Novo company])
• video laryngoscopes (improve intubation by one grade
according to the Cormack-Lehane classification )
• bronchoscopic (fibreoptic) intubation
• invasive (surgical) airway management:
-- transtracheal oxygenation
-- retrograde intubation
-- cricothyrotomy (coniotomy)

Every clinic should be equipped with an appropriate box /

car / trolley for difficult airway management and a regular
trainings in the use of the equipment should be offered.

Optimization measures
• request for personnel support (max. 3 intubation att-
empts per physician [in children max. 2 due to the es-
Fig. 098  McCoy-blade: special blade with a flexible tip to
pecially vulnerable airway]) lift the epiglottis
• intubation attempt max. 30 sec., then ventilation with
mask (oxygenation) Bonfils endoscope
• optimization of positioning:
• Karl Storz company
-- prop up the patient's head on cushion (modified
• rigid retromalleolar intubation endoscope with curved
Jackson position, ramp position; approx. 10-15 cm)
tip
-- pressure to the larynx (preferably with the help of a
• anatomically shaped metal stylet (for guiding the tube)
second person):
• especially in patients with restricted mouth opening
◦◦ BURP maneuver according to Knill: backward up-
and cervical spine mobility
ward rightward-pressure (from the patient's view)
◦◦ OELM maneuver: optimal external laryngeal ma-
nipulation
• increase depth of anesthesia, relaxation - if necessary
(already necessary at the beginning of a RSI)
• change size of the blade
• introducer guide (bougie; e.g. Eschmann introducer
[ETTI: Eschmann tracheal tube introducer]; usually
not protruding [1cm within tip of the tube]; maybe even
protruding + bend upwards ["hockey stick"]), possibly
even an introducer guide with a steerable tip
• McCoy-blade:
-- blade with adjustable hinged tip to lift the epiglottis
Fig. 099  Bonfils endoscope: rigid intubation endoscope
-- standard sizes: 3 (most commonly) and 4 with curved tip
• Bonfils endoscope
• if even mask ventilation is not possible → cannot intu-
bate & cannot ventilate (CICV; very critical situation!
Incidence in emergency departments: 1:200)

64 General Part
Supraglottic airway devices (SAD) • abbreviation: L(A)MA (laryngeal mask airway)
• The tip of the laryngeal airway device cuff lies at the
Definition base of the hypopharynx against the upper esopha-
geal sphincter. Ventilation is provided through a wide
• devices for ventilation (airway tube), which sit above opening facing the trachea. Rubber cuff acts as a seal
the glottis (supraglottic) against regurgitation and aspiration
• To achieve a sufficient expertise, at least 45 SAD
should be inserted unter supervision. To keep on the
practice, at least 3 SAD should be inserted each year
(according to rhe national S1-Guideline "Prehospital
Airwair Management" of the German Society of Anaes-
thesiology and Intensive Care Medicine 2019).

Generations
• 1st generation: without the possibility of inserting a gas-
tric tube
• 2nd deneration: with the possibility of inserting a gast-
ric tube (drainage channel) - should be preferred be-
cause:
-- you can reduce gastric pressure an therefore the risk
Fig. 100  schematic representation of a laryngeal mask air-
of apiration way [22]
-- you can perform tests to check the position (see in-
fobox)

Fig. 101  laryngeal mask airway [22]

Assessment
• advantages:
-- easy to handle
Types -- no muscle relaxant necessary
• laryngeal mask airway • disadvantages:
• laryngeal tube -- no protection against aspiration
• combitube -- no high ventilation pressure possible (which would
be necessary e.g. in pulmonary edema or status
Everyone who intubates must asthmaticus)
master at least one intubation
alternative! Placement
• extend neck
• fill cuff with some air beforehand (approx. 1/4 of the
Laryngeal mask airway filling volume)
• hold mask with right hand close to the cuff like a pencil
Definition (index finger on front side), back side glides along the
• syn.: laryngeal mask hard palate
• developed by Brain in 1981 and introduced into clinical • blind introduction of the mask (i.e. without laryngo-
practice in 1985 scope) into the into the hypopharynx

General Part 65
• Index finger exerts pressure towards the cranial di-
rection to avoid kinking of the tip and then pushes the
mask along the dorsal part of the pharynx.
• push mask down quickly with a gentle movement
• Once resistance is felt, the tip is placed in the triangu-
lar hypopharynx.
• inflate the cuff with the correct filling volume; this lifts
the mask slightly out of the pharynx. The laryngeal
mask often moves up a little during inflation (do not
hold).
• If the tongue gets blue after blocking (while the lips are
rosy), the cuff is overblocked and must be released.
• fixation like a traditional tube

Fig. 102  laryngeal mask airway - placement [22]

Sizes

size weight (kg) filling volume (ml)

1 < 6.5 4
2 6.5-20 10
2.5 20-30 14
3 30-70 20
4 70-90 30
5 > 90 40

Fig. 103  laryngeal mask airway - different sizes [22]

The laryngeal mask airway is the most

widely used intubation alternative!

Special types (laryngeal mask airway)

• ProSeal-LMA, LMA Supreme: laryngeal masks with
-- a higher oropharyngeal closing pressure (leakage
pressure) than with a conventional laryngeal mask
and thus providing a better sealing against regur-
gitation and aspiration (higher ventilation pressure
possible)
-- an additional option for suctioning of regurgitated ga-

66 General Part
 stric contents via a separate drainage channel and
thus a reduced risk of aspiration
• Fastrach-LMA
-- rigid, anatomically curved laryngeal mask (shor-
ter, rigid shaft compared to conventional laryngeal
mask) with a rigid handle
-- an intubating laryngeal mask airway (ILMA): An en-
dotracheal tube may be placed after the introduction
of the laryngeal mask airway. A special ILMA endo-
tracheal tube should be used for this purpose: This
is a spiral tube with metal reinforcement and atrau-
matic (soft), bevelled silicone tip and removable con-
nector. An 8.0-tube is the biggest tube that can be
inserted.
-- special epiglottis lifting device Fig. 104  Fastrach-LMA [22]
-- 3 sizes
epiglottis lifting device
◦◦ size 3 (children, 30-50 kg; max. filling volume cuff: cuff
20ml) removable handle
◦◦ size 4 (adults, 50-70 kg; max. filling volume cuff: connectorr
30ml)
◦◦ size 5 (adults, > 70 kg; filling volume cuff: 40ml)
• i-gel mask
-- laryngeal mask with a gel-like cuff made from a ther-
moplastic elastomer (not inflatable)
-- The elastomer extends at body temperature and
thus seals the pharynx tightly.
-- 7 different sizes

stabiliser special ILMA

endotracheal tube

General Part 67
Fig. 105  LMA Fasttrach: Like a conventional laryngeal Laryngeal tube
mask it is introduced blindly and allows ventilation. In addi-
tion, you can also place a special endotracheal tube (intu- Definition
bating laryngeal mask airway [ILMA]): First, the connector
of the tube is removed and then the tube is advanced with • introduced into clinical practice by Dörges in 1999
the handle ("stabiliser"). After removing the laryngeal mask • slightly curved tube with two cuffs
airway, the connector is attached to the tube again, the cuff -- proximal cuff
is inflated and the patient can be ventilated.
◦◦ pharyngeal
◦◦ wide opening
◦◦ stabilizes the tube and blocks the naso- and oro-
pharynx
-- distal cuff
◦◦ esophageal
◦◦ small opening
◦◦ blocks the esophagus
• The ventilation is provided via openings in the tube.
• soft, less traumatic
• higher ventilation pressures applicable than with a
(conventional) laryngeal mask airway
• introduction of a stomach tube (16 Ch) also possible
via the esophageal drainage channel
• commonly used in the emergency medical service in
Germany (especially by the emergency medical team
during resuscitation)
• not suitable for toddlers and infants because the
larynx is located too high
• laryngeal tubes of the latest generation: intubating la-
ryngeal tubes (iLT)
-- An endotracheal tube may be placed blindly or under
bronchoscopic guidance after the introduction of the
laryngeal tube.
-- iLTS-D (suction disposable)

Fig. 106  LMA ProSeal [22]

Fig. 107  i-gel laryngeal mask (here size 4)

Fig. 108  laryngeal tube [33]

68 General Part
Placement
• extend neck
• deflate cuffs
• lubricate tube
• blind introduction of the tube (i.e. without laryngo-
scope) into the pharynx, until the middle depth marking
lies on a level with the front teeth
• inject 70-100 ml of air (marking on the syringe); both
cuffs are inflated at the same time
• If the tongue gets blue after blocking (while the lips are
rosy), the cuff is overblocked and must be released.
The too strong blocking (hyperinflation) leads to an
obstruction of the venous vessels of the tongue and
therefore to a swelling of the tongue. This can cause
a difficult airway (e.g. after a successful resuscitation
during which a laryngeal tube was inserted preclini-
cally by the first responder emergency medical team),
when you want to exchange the laryngeal tube through
an endotracheal tube inner-clinically in the emergency
room. Therefore even when using a laryngeal tube the
cuff pressure should be measured, which should not
exceed 60 cmH2O. Preclinically, however, this is most-
ly impossible, because usually a manometer to mea-
sure the cuff pressure is not available on the vehicles.
• The laryngeal tube often moves up a little during infla-
tion (do not hold).

Fig. 109  laryngeal tube - placement [33]

Fig. 110  cuff inflation: simultaneous inflation of both cuffs

[33]

General Part 69
Fig. 111  blocked laryngeal tube with the blocking syringe: Placement
On the syringe the filling volume, which is necessary for
each size of the laryngeal tube, is indicated (both as a color
• deflate both cuffs with syringe
and as a number). • blind introduction of the double-lumen tube (i.e. without
laryngoscope), until the marking lies on a level with the
Seizes front teeth
• Doppellumentubus blind (d.h. ohne Laryngoskop) oral
seize weight (kg) height (cm) connector vorschieben, bis sich die Markierung auf Höhe der
color Zahnreihe befindet
0 <6 - • cuffs:
1 6-15 weiß -- proximal (pharyngeal balloon): blue pilot balloon →
inject 100 ml of air (large syringe)
2 15-30 grün
-- distal (esophageal / tracheal balloon): white pilot bal-
3 30-60 < 155 gelb loon → inject 15 ml of air (small syringe)
4 60-90 155-180 rot • test ventilation via blue connector ventilate and aus-
5 > 90 > 180 violett cultate:
-- respiratory sounds over both lungs and lack of epi-
gastric sounds: esophageal location (usually; 95%)
→ continue ventilation via blue connector (ventilati-
on via side holes)
-- no respiratory sounds over the lungs, but epigast-
ric sounds: tracheal location (seldom; 5%) → replug
(first, try to pull back the tube about 3 cm; still no
respiratory sounds above the lungs → replug) and
continue ventilation via the white connector (ventila-
tion via the distal open main hole)

Assessment
• rigid → increased risk of injury (e.g. esophageal rup-
ture)
• only for patients with a height of > 122 cm (not appro-
ved for use in children!)
• complex algorithm
• not approved for anesthesia, but for emergency medi-
cine ("emergency device")

Video laryngoscopes
Definition
• visualization of the glottis via an installed fibreoptic at
the tip of the blade
Fig. 112  laryngeal tube - different sizes [33] • syn.: indirect laryngoscopy (in contrast to direct [= con-
ventional] laryngoscopy)
Combitube • increased probability of a successful intubation (fewer
failed intubations), improved view to the glottis Sicht
Definition (meta-analysis Lewis et al, BJA 2017)
• introduced into clinical practice by Fraas in 1987 • According to rhe national S1-Guideline "Prehospital
Airwair Management" of the German Society of Anaes-
• esophageal-tracheal double-lumen tube
thesiology and Intensive Care Medicine 2019 video la-
• lumens:: ryngoscopes shoul be used primarly for the preclinical
-- distally opened lumen with cuff (white connector) intubation and not only as a rescue tool!
-- distally closed lumen with side perforations (blue • problems:
connector) -- Fogging of the optic, secrets and blood may obscure
• cuffs: the view.
-- proximal (pharyngeal balloon): blue pilot balloon -- Sometimes the tube advancement into the trachea
-- distal (esophageal / tracheal balloon): white pilot bal- may be difficult.
loon • more commonly used (esp. even preclinically [in 50%
already used in Germany])
Seizes
• use of a introducer guide is mandatory here
• Small Adult (122-183cm)
• Large Adult (> 152cm)

70 General Part
Types ◦◦ GVL 4 (> 40kg)
• Airtraq (Medisize) -- video chip with a separate monitor on handle
-- optical laryngoscope with fibreoptic tip -- A camera is mounted on the tip of the blade which
-- vizualization of the airways transfers the image to a monitor.
-- image transmission to an eyepiece through a system -- power supply: storage battery
of lenses and prisms -- price: 8900 €
-- own guiding channel -- Silverberg et al, Crit Care Med 2015: significantly
-- two sizes (adults): higher success rate of indirect laryngoscopy (with
GlideScope) compared to direct laryngoscopy in
◦◦ normal (size 3; blue) for ET (endotracheal tube)
emergency intubations by non-anesthesiologists
size 7.0-8.5
(74% versus 40%)
◦◦ small (size 2; green) for ET (endotracheal tube)
• McGrath (Aircraft medical; Surgical Company GmbH)
size 6.0-7.5
-- video chip with monitor on handle
-- A regular endotracheal tube is integrated into the
guiding channel, then laryngoscopy is performed -- power supply: battery (run time about 60 min)
as usual. You can also use the rotation technique: -- price: 5200 €
The Airtraq-laryngoscope is rotated by 180° before • A.P. Advance (LMA Germany)
insertion. After passing the tongue it is turned into its
normal position (as with the Guedel airway).
-- reduction of intubation time by 15 s compared to con-
ventional laryngoscopy (Lu et al, Anaesthesia 2011)
-- Types:
◦◦ Airtraq SP: only for single use
◦◦ Airtraq Avant: reusable (additionally a camera and
monitor)
-- power supply: battery (run time about 90min)
-- price: 54 € (disposable
• C-Mac (Karl Storz)
-- video chip with a separate monitor on the handle
-- reusable stainless steel blade with integrated LED
light source and camera
-- The video laryngoscopy can be performded with two
different blades:
◦◦ lowly (a conventional laryngoscope blade [Macin-
tosh blade]): standard (as well indirect as direct
larnygoskopy possible)
◦◦ highly curved (135° [hyperangulated]; D-Blade):
▪▪ special blade for the difficult intubation (very ra-
rely indicated)
▪▪ introduction of the blade in the middle of the
tongue (not on the side)
▪▪ only indirect larnygoscopy possible
▪▪ indeed proper view to the glottis, but difficult ad-
vancement of the tube into the trachea to to the
extreme angulation (You should advance a tube
stylet first and then advance the tube ober the
stylet.)
-- power supply: storage battery (run time about 120
min)
-- price: 4046 €
• V-Mac (MacIntosh)
• Airway-Scope (Pentax)
• GlideScope (Ranger; Verathon Medical)
-- plastic handle and blade (reusable)
-- blade sizes: depending on weight of patient
◦◦ GVL 0 (< 1.5kg)
◦◦ GVL 1 (1.5-3.6kg)
◦◦ GVL 2 (1.8-10kg)
◦◦ GVL 3 (10-40kg)

General Part 71
 Fig. 115  Airtraq avant: I can be used several times and has
a monitor.

Fig. 113  Airtraq SP: different sizes (blue for tube size 7.0-
8.5, green for tube size 6.0-7.5)

Fig. 116  C-Mac [16]

Fig. 114  Airtraq SP [24]

Fig. 117  Airway-Scope [33]

72 General Part
 Fig. 119  fibreoptic intubation: the tube is slid up the shaft
of the bronchoscope.

Fig. 120  fibreoptic intubation [26]

Fig. 118  A.P. Advance [22]

If it is already quite clear that the
intubation will be difficult (e.g. extreme
Bronchoscopic (fibreoptic) intubation adiposity) → perform fibreoptic awake
• gold standard in the clinic for difficult airway intubation straight away (not very
• Before the intubation the tube is pushed over the bron- complicated, relatively safe and easy!)
choscope (use silicone spray).
• Then an ordinary bronchoscopy with orotracheal ac-
cess is performed (Do not forget mouth guard!). Invasive airway management
• insert tube and inflate cuff • transtracheal oxygenation
• in case of expected difficult intubation in awake pa- • retrograde intubation
tients with appropriate local anaesthesia (fibreoptic • cricothyrotomy (coniotomy)
awake intubation): When the patient is still awake,
slide the tube up the shaft of the bronchoscope. Per-
form ordinary bronchoscopy with orotracheal access:
After passing the glottis, induct general anesthesia and
push tube forward.
• Insert bronchoscope deeply towards distal direction
before pushing the tube forward, otherwise the bron-
choscope may kink! cricothyroid
thyroid cartilage
membrane
• A critical point in bronchoscopic intubation is the ad-
vancement of the tube along the inserted broncho- thyroid
scope (especially through the glottis): This is often not
easy. It is helpful to push the tube forward with a rotary
motion (180°). cricoid cartilage

Fig. 121  cricothyroid membrane (= median cricothyroid li-

gament [ligamentum conicum]: the membrane between cri-
coid and thyroid cartilage)

General Part 73
Transtracheal oxygenation tube adapter
• local anaesthesia with Xylocaine
• puncture of the cricothyroid membrane (ligamentum
conicum) with 14G cannula (orange), special cannula
or Seldinger needle (Shaldon catheterization kit)
• caudal insertion direction (45°) with fixation of the tra-
chea
• Aspiration of air with 10 ml-syringe (filled with 5ml of 2ml-syringe
sodium chloride 0.9%) indicates the endotracheal po-
sition of the cannula tip.
• oxygenation
-- direct connection of an oxygen tube (15 l/min) or
-- attach (via 3-way stopcock) a 2 ml-syringe and re-
move its piston; connection with Ambu bag with O2
via tube adapter (connector for a tube sized 8.0 or
7.5 mm ID) → high-frequency ventilation ("jet-ven-
tilation")
• if necessary, leave the cannula in situ (Tissue pressure
may otherwise obstruct the plastic cannula!)
• A manually controlled oxygen insufflation can be also
be performed as an alternative to jet-ventilation. There
are different systems:
-- Ventrain system (a manually operable flow-regula-
ted ejector ventilator; Dolphys Medical company)
-- Oxygen Flow Modulator (Cook Medical company)
-- Manujet Ventilation Catheter (Cook Medical compa-
ny)

Fig. 123  When the piston of a 2 ml-syringe is removed, the

Ambu bag can be connected via a tube adapter (ET size 8.0
or 7.5 mm ID) and a jet-ventilation (with high-flow oxygen)
can be performed.

Fig. 122  jet-ventilation catheter for transtracheal oxygena-

tion: left for adults, center for children, right for infants [33]

74 General Part
Fig. 124  Transtracheal oxygenation can also be perform-
ded via a Shaldon catheter, which is normally used for renal
replacement therapy: You puncture the cricothyroid mem-
brane with the Seldinger needle of the Shaldon catheteriza-
tion kit (insertion direction: 45° caudally). After aspiration
of air you advance a Seldinger wire downward, dilate mit
the bougie of the kit and introduce the Shaldon catheter
into the trachea. One of the two lumens is connected with a
2ml-syringe, which piston is removed. Here you can attach
an ambu-bag via a tube adapter and perform a jet ventilati-
on with high-flow oxygen. The other lumen of the Shaldon
catheter must be sealed, so that the air does not escape.
Retrograde intubation
• CVC-set for femoral vein
• puncture of the trachea between 2.-3. cartilage ring or
cricothyroid membrane with 10 ml-syringe (filled with 5
ml of sodium chloride 0.9%)
• cranial insertion direction (45°) with fixation of the tra-
chea
• advancement of the Seldinger guidewire (important:
sufficient length [> 50 cm; e.g. 120 cm) towards cranial
direction, if necessary use Magill forceps
• fixate wire with a clamp at injection site
• thread Murphy tube (size 6.0 or 6.5 sufficient) through
lateral eye
• keep the wire taut, push tube down with rotating mo-
vements
• release clamp shortly before resistance is felt, pull out
the wire and push down the tube
Fig. 125  Puncture of the cricothyroid membrane with 45°
cranial insertion direction
Cricothyrotomy
Definition
• incision through the cricothyroid membrane
• syn.: coniotomy
• ≠ tracheotomy (another location [between 2.-3. thyro-
id cartilage] and another indication [a purely elective
measure]); annot.: When the airway has been secured
with a coniotomy (e.g. preclinically by the emergency
medical team), you should soon change the coniotomy
into a tracheotomy (open, surgical).
• occasional mistake: The thyroid notch is sometimes
mistaken for the cricothyroid membrane.
• indication: cannot intubate & cannot ventilate (CICV)
The alternative to the performance of a
cricothyrotomy is the death of the
patient!
The coniotomy is not necessarily
followed by a craniotomy (as sceptics
say)!
Types
• according to the tools
-- cricothyrotomy without kit
-- cricothyrotomy with kit :
◦◦ Airfree (Medisize)
◦◦ Melker Krikothyreotomie-Set (Cook)
◦◦ Patil Krikothyreotomie-Set (Cook)
◦◦ Quicktrach (VBM)
◦◦ Surgicric (VBM)
◦◦ Portex Crico-Kit (Smiths-Medical)
• according to the technique
-- surgical cricothyrotomy
-- percutaneous cricothyrotomy
Procedure
• surgical cricothyrotomy
-- palpate the cricothyroid membrane (median crico-
thyroid ligament) between thyroid and cricoid car-
tilage (annot.: Ultrasound-guided identification of
the cricothyroid membrane [Kristensen et al, Br J
Anaesth 2015], especially in hospital very helpful)
-- 3cm longitudinal incision of the skin
-- blunt dissection with scissors to the cricothyroid
membrane
-- suctioning of blood and secret by an assistent
-- puncture incision of the cricothyroid membrane
(max. lenght: 10mm), additionally make two lateral
incisions with scissors
-- spread the incision with scissors (or with a Thudicum
speculum) and insert tube (size 6.0)
• percutaneous cricothyrotomy
-- palpate the cricothyroid membrane
-- 5mm vertical skin incision
-- puncture of the cricothyroid membrane with a con-
ventional Seldinger needle (insertion direction: 45°
caudally)
-- - the aspiration of air with 10 ml-syringe (filled with
5 ml of sodium chloride 0.9%) indicates the endotra-
cheal position of the needle tip.
-- advance a Seldinger guidewire over the needle
down into the trachea, then remove the needle
-- skin incision with scalpel at the insertion point of the
wire
-- dilatation (e.g. with the dilator of a Shaldon catheter
kit)
-- advancment of a tube (size 6) of the over the wire,
General Part 75
 removal of the wire
-- annot.: Melker emergency cricothyrotomy kit is often
used for percutaneous cricothyrotomy. The puncture
is made with a Teflon-coated cannula. The tracheal
cannula with an integrated dilator is inserted over the
wire. Then the dilator is removed
Equipment for percutaneous cricothy-
rotomy: Shaldon catheterization kit
(contains puncture needle, Seldinger
guidewire, and dilator), scalpel, size 6
tube
Airfree-cricothyrotomy kit
Definition
• one-step cricothyrotomy
• average time to completion of the a cricothyrotomy: 22
sec (according to manufacturer)
• construction
-- straight needle with ventilation attachment
-- trocar with integrated scalpel
-- side flanges (limiting insertion depth)
-- Bead at the end of the cannula keeps it from slipping
out.
• approved from the age of 6
• price: 98 €

Fig. 126  required equipment for the percutaneous crico-

thyrotomy: puncture needle, Seldinger guidewire, dilator
(all included in Shaldon catheterization kit), scalpel and
size 6 tube

Fig. 128  Airfree-cricothyrotomy kit [16]

crycothyroid Placement
membrane thyroid
(front) • palpation of the cricothyroid membrane (median crico-
thyroid ligament) between thyroid and cricoid cartilage
cartilage
• position the tip of the trocar and fixate the larynx with
the other hand, vertical 5mm skin incision
• push cannula down vertically until a loss of resistance
crycothyroid ("click") is felt
thyroid membrane cricoid • push cannula down until flanges rest on the skin
cartilage (back) cartilage • fixate cannula with neck strap
• connect Ambu bag
Fig. 127  Ultrasound-guided identification of the crycothy-
roid membrane (front an back) with a linear scanner in a
longitudinal view of the neck

Complications
• early (acute):
-- bleeding
-- injury / laceration of larynx (vocal cords, thyroid /
cricoid cartilage), thyroid, esophagus, blood vessels
(neck)
-- paratracheal placement (consequence: subcutane-
ous and mediastinal emphysema)
• late (long-term; therefore only a bridging measure to
surgical tracheotomy):
-- subglottic stenosis
-- stricture of trachea
-- infection

76 General Part
 Fig. 131  Quicktrach cricothyrotomy kit [33]

Fig. 129  Airfree-cricothyrotomy kit: placement [16]

Fig. 130  Cook Medical cricothyrotomy kit [10]

General Part 77
Fig. 132  Quicktrach cricothyrotomy kit: placement [33]

78 General Part
 Ventilation Mortality of a ventilated internal
intensive care patient: 75%

Aims
• bridge breathing disturbances (Ventilation is not a cu-
rative treatment!)
• secure sufficient gas exchange:
-- Oxygenierung (p.d. paO2 > 60mmHg [not paO2 >
100mmHg! Abundant oxygenation is not necessa-
ry!], SpO2 > 90%)
-- decarboxylation (secure alveolar ventilation )
• lower risk of injury and protection of the lung from ven-
tilator-associated lung injury (VALI, syn.: VILI [ventila-
tor-induced lung injury])
• avoid dyssynchrony between patient and ventilator
(may induce major damage to the lung!)
• early spontaneous breathing and weaning

Introduction
• Ventilation is a basic intervention in intensive care and Physiology
during anaesthesia.
• relatively new, viewed historically Blood gases
• development and introduction of
-- negative pressure ventilation 1929 during the po-
liomyelitis epidemics in the Scandinavian countries
("iron lung", "tank respirators")
-- positive pressure ventilation in the 1950s by the Da- O2
nish anesthetist Björn Ibsen (1915-2007); 1952 long
term ventilation of a 12 years old girl with a severe
poliomyelitis; considered as the founder of intensive lung
care medicine)
• About 30% of patients in intensive care units are venti-
lated (Esteban et al: Mechanical Ventilation Internatio- erythro-
nal Study Group; JAMA 2002). cyte
• mortality: CO2
-- mortality at one year (of a patient ventilated for more
than 14 days): 62% (Damuth et al, Lancet Resp Med
2015)
-- mortality at two years (of a ventilated internal inten-
sive care patient): 75% (u.a. Lieberman, J Crit organs
Care 2009, Roch et al, J Crit Care 2011; Anm.: Das
hängt natürlich ganz stark auch davon ab, wen man Fig. 133  The two most important blood gases are oxygen
noch auf die Intensivstation legt und dann auch noch (O2) and carbon dioxide (CO2). Oxygen is taken up through
intubiert.) the lungs and then transported to the organs in the blood,
mostly bound to hemoglobin. The carbon dioxide produ-
• Hours of ventilation are shown in the DRG-system (a ced there is also predominantly bound to hemoglobin and
widespread hospital remuneration system in Europe) transported to the lungs where it is exhaled.
and are extremely cost relevant ("ventilation hours are
money"). Unfortunately, the DRG reimbursement is
graded according to ventilation hours so that there is
a risk that the patient is ventilated for an unnecessari-
ly long time, only to upgrade him into the next higher
group
• S3-Guideline 2017 "Mechanical Ventilation and Extra-
corporeal Membrane Oxygenation in Acute Respirato-
ry Insufficiency" (German Society for Anaesthesiology
and Intensive Medicine [DGAI])

General Part 79
Oxygen
Definition
• syn.: Oxygenium (molecular formula: O2)
• discovered in 1771 by the German-Swedish chemist
Carl Wilhelm Scheele (1742-1786); first described as
"fire air")
• extremely poorly water-soluble (hydrophobic; carbon
dioxide is 20 times more water-soluble)
Uptake
• partial pressure: the pressure that one component of
a mixture of gases would exert if it were alone in a
container (unit: mmHg respectively kPa (kilopascal;
conversion: 1 mmHg = 0.133 kPa).
• composition of the gas mixture air (inspired air):
-- nitrogen: 78%
-- oxygen: 21%
-- rest (0.96% argon, 0.04% carbon dioxide): 1%
• The total pressure of air (syn .: air /atmosphere /baro-
meter pressure) is 760 mmHg at sea level. Therefore
the partial pressure of oxygen pO2 in the gas mixture
inspired air is piO2 = 760 mmHg x 0.21 = 160 mmHg.
The air pressure and thus the partial pressure of oxy-
gen in the arterial blood paO2 decreases with increa-
sing altitude: At a height of 2000m the paO2 already
drops by a quarter (paO2 only approx. 60 mmHg), at
a height of 4000m already by half (paO2 only approx.
40 mmHg). For ventilation, a FiO2 (fraction of inspired
oxygen) above 21% is usually used, so that the partial
pressure of oxygen is higher (example: FiO2 = 0.50 [i.e.
50%] → piO2 = 760 mmHg x 0.50 = 380 mmHg).
• In inspiration, moistening of the airways leads to satu-
ration (dilution) with water vapor. The partial pressure
of water vapor (proportion 6.7%) is 21 mmHg at room
temperature and 47 mmHg at a body temperature of
37°C. The partial pressure of oxygen in the alveolar
gas pAO2 is therefore arithmetically: pAO2 = (760 mmHg
- 47 mmHg) x 0.21 = 713 mmHg x 0.21 = 150 mmHg.
Factually however, the partial pressure of oxygen in
the alveolar gas pAO2 is lower with 106 mmHg: Diffusi-
on of O2 into the capillaries ("migration") occurs in the
alveolar space, so that the proportion of oxygen in the
alveolar gas is no longer 21%, but only 15%. Therefore
the partial pressure of oxygen in the alveolar gas is:
pAO2 = 713 mmHg x 0.15 = 106 mmHg. Furthermore,
carbon dioxide diffuses from the capillaries into the al-
veoli: The proportion of carbon dioxide in the alveolar
80 General Part
gas is 5.6%, so that a partial pressure of carbon dioxi-
de in the alveolar gas of pACO2 = 713 mmHg x 0.056
= 40 mmHg can be calculated (see also alveolar gas
equation [page 96]).
• The oxygen then diffuses from the alveoli through the
alveolo-capillary membrane into the capillaries. The
driving force is the partial pressure difference (partial
pressure gradient) between the partial pressure of oxy-
gen in the alveolar gas pAO2 and the partial pressure
of oxygen in the venous blood pvO2. The oxygen then
diffuses from the arterial blood into the cells, and spe-
cifically here into the mitochondria. The driving force
for the diffusion is again the partial pressure difference,
in this case between the partial pressure of oxygen in
the arterial blood (90 mmHg) and the partial pressure
of oxygen in the mitochondria (only 1-2 mmHg). The
movement of the oxygen therefore always takes place
along a partial pressure gradient, whilethe partial pres-
sure continuously decreasea on its way ("cascade").
• oxygen content:
-- inspired air: 21%
-- expired air: 16% (i.a. the rationale for mouth-to-
mouth ventilation as part of a lay resuscitation)
• composition of the expired air:
-- nitrogen: 78% (the same proportion as in the inspi-
red air, since nitrogen is neither absorbed nor con-
sumed in the body)
-- oxygen: 16%
-- carbon dioxide: 4% (100 x more than in inspired air)
-- argon: 0.93%
fractions partial pressures
O2 CO2 O2 CO2
inspired air 21% 0.04% 160 mmHg 0.2 mmHg
alveolar gas 15% 5.6% 105 mmHg 40 mmHg
blood arterial 90 mmHg 40 mmHg
blood venous 40 mmHg 46 mmHg
expired air 16% 4% 115 mmHg 30 mmHg
Transport
• Oxygen is a gas that is extremely poorly soluble in wa-
ter and therefore also in blood. For this reason, oxy-
gen transport in the blood is predominantly chemically
bound (98.5%) to hemoglobin. Only a very small part
of the oxygen (1.5%) is physically (dissolved) transpor-
ted in the blood. The physically dissolved amount de-
pends on the partial pressure (Henry's law; for the gas
laws see page 1497): The higher the partial pressure,
the more oxygen is dissolved in the blood. For examp-
le, under hyperbaric conditions (3bar) the proportion
can be increased from 1.5% (normobar [1bar]) to 8%,
which is used in pressure chamber therapy (hyperbaric
oxygenation [HBO]).
• hemoglobin:
-- transporter protein for oxygen
-- structure:
◦◦ globin: 2 α-chains, 2 β-chains
◦◦ 4 heme molecules: each one with a bivalent iron
(Fe2+) in the center, which reversibly binds oxygen;
 1 molecule of hemoglobin can therefore bind a
maximum of 4 molecules of oxygen (O2). Fe2+ hem
-- designations:
α-chain of
◦◦ oxygenated hemoglobin (oxy-hemoglobin): hemo- globin •
globin that has bound oxygen (not to be confused
with oxidized hemoglobin [syn.: met-hemoglobin,
hemiglobin, ferrihemoglobin]: Certain substances
[methemoglobin formers] lead to an oxidation of
the bivalent iron Fe2+ to trivalent iron Fe3+: This can
only bind water and no more oxygen.)
◦◦ deoxygenated hemoglobin (deoxy-hemoglobin):
hemoglobin that has no oxygen bound
• cyanosis:
-- definition: blue discoloration of the skin β-chain of O2
-- visible from an absolute content of deoxygenated globin
hemoglobin > 5 g/dl (Therefore, cyanosis occurs Fig. 134  schematic representation of the hemoglobin mo-
much later in patients with anemia than in patients lecule
with polyglobulia!)
-- types:
◦◦ central (reduced oxygen saturation; especially
lips, tongue, oral mucosa; extremities: warm)
▪▪ pulmonary
▪▪ cardiac (right-to-left shunt)
◦◦ peripheral (increased oxygen consumption, incre-
ased oxygen extraction rate; especially digits [fin-
gers, toes]; extremities: cold)
• saturation of oxygen (SO2):
-- proportion of oxygenated hemoglobin in total he- Fig. 135  illustration of cyanosis: It occurs when the con-
moglobin (In addition to the oxygenated and deoxy- centration of non-oxygenated (deoxygenated) hemoglobin
genated hemoglobin, there are also physiologically (empty wagons in the picture) is > 5 g dl. In both cases the
saturation is only 50%. In the picture above (hemoglobin 10
small amounts of met-hemoglobin [0.5%] and CO-
g/dl) cyanosis occurs, the concentration of deoxygenated
hemoglobin [1-2%].) hemoglobin is 5 g/dl. In the picture below there is anemia
-- SO2 = Oxy-Hb / (Oxy-Hb + Desoxy-Hb + Met-Hb + (only 2 instead of 4 wagons) with an hemoglobin of 5 g/dl:
CO-Hb) The concentration of deoxygenated hemoglobin is only 2.5
• oxygen binding capacity: g/dl, so that no cyanosis occurs.
-- maximum amount of oxygen that can be bound by
1g hemoglobin
-- 1.34 ml O2 / g Hämoglobin (1.34: Hüfner number; in
vivo value in vitro value: 1.39])
• content of oxygen (cO2):
-- amount of oxygen bound to hemoglobin per 100ml
blood
-- depending on hemoglobin and oxygen saturation
-- cO2 = Hb x SO2 x 1.34 (1.34: Hüfner number)
-- norm:
◦◦ arterial: 18-20 ml O2/100ml
◦◦ venous: 14-15 ml O2/100ml
• oxygen supply (see page 188)
-- oxygen delivery (DO2: delivery of oxygen); norm:
1000 ml/min):
Fig. 136  Oxygen diffuses along a partial pressure gradient
◦◦ procuct of content of oxygen and cardiac output from the arterial blood (partial pressure paO2 90 mmHg) into
◦◦ DO2 = cO2 x CO = Hb x SaO2 x 1.34 x CO the cell (exactly into the mitochondria [arrow], where there
▪▪ cO2: content of oxygen is only a partial pressure of 1-2 mmHg). Mitochondria are
the "power plants" of the cell: This is where the energy is
▪▪ Hb: hemoglobin generated (oxidative metabolism, respiratory chain). Ade-
▪▪ SaO2: arterial oxygen saturation nosine triphosphate (ATP; from ADP [adenosine diphos-
▪▪ CO: cardiac output phate] and phosphate]) is formed, the most important ener-
-- oxygen consumption (VO2: volume per time of oxy- gy source ("energy currency").
gen; norm: 200-250 ml/min)

General Part 81
Oxygen-hemoglobin dissociation curve

oxygen saturation SO2 (%)

• syn.: oxygen dissociation curve (simplified) 90 venous arterial
• The higher the partial pressure of oxygen in the blood,
the greater the saturation of the hemoglobin with oxy-
gen.
• However, the relationship is not linear, but S-shaped.
This is because the configuration of the hemoglobin
changes after the binding of the first oxygen molecule,
so that further oxygen molecules can now bind much
more easily.
• parts:
-- arterial (flat) part (pO2 > 60 mmHg [> 8 kPa]): Here
changes in the pO2 have only little impact on the sa-
turation. For example, if the pO2 drops from 90 to 60 60 100
mmHg (drop by 33%), the saturation only drops from oxygen partial pressure
95 to 90% (drop by only 5%). pO2 (mmHg)
-- venous (steep) part (pO2 < 60 mmHg [< 8 kPa]): Fig. 137  oxygen-hemoglobin dissociation curve: It shows
Here changes in the pO2 have a significant impact the relationship between the partial pressure of oxygen in
on the saturation. Even a small drop in pO2 leads to the blood pO2 and the saturation SO2. The relationship is
a pronounced drop in saturation. not linear, but S-shaped. In the flat part of the curve (red), a
drop in pO2 only leads to a slight decrease, but in the steep
• shifts: part of the curve (blue) to a considerable drop in saturation.
-- right shift: The affinity of oxygen for hemoglobin de- Just think of an icy ski slope: At the top in the flat part you
creases, i.e. oxygen is now more easily released to are still in the safe area, but down in the steep part you
the tissue. It occurs in: can quickly slide, so it can be very dangerous: Because the
◦◦ acidosis (ph value ↓): The effect of pH on oxygen- decisive factor for the oxygen supply (oxygen delivery) of
the cell (besides the hemoglobin and cardiac output) is the
hemoglobin dissociation is referred to as the Bohr saturation SO2 (and not the partial pressure of oxygen pO2).
effect (see esp. also page 781); oxygen satura-
tion SO2 depending on the pH value (at pO2 100
mmHg): pO2 (mmHg) saturation SO2
▪▪ pH 7.2 → SO2 95% 150 99
▪▪ pH 7.4 → SO2 97% 100 97
▪▪ pH 7.6 → SO2 99%
90 95
◦◦ hyperkapnia (pCO2 ↑)
◦◦ hyperthermia (fever [Oxygen consumption is in- 60 90
creased here.]; warm blood releases oxygen 50 84
much better than cold blood!) 40 75
◦◦ increase in 2,3-DPG (diphosphoglycerate; e.g. in
30 58
anemia: In order to avoid tissue hypoxia even with
reduced hemoglobin and to supply the cells with 20 36
sufficient oxygen, 2,3-DPG is up-regulated so that 10 13
the oxygen is more easily released to the tissue.)
-- left shift: The affinity of oxygen for hemoglobin incre- numerical relationship between oxygen partial pressure
ases, i.e. the oxygen release to the tissue is redu- pO2 and oxygen saturation SO2 (at T = 37°C, pH 7.4,
ced. It occurs in: pCO2 40mmHg)
◦◦ alkalosis (pH value↑)
◦◦ hypokapnia (pCO2 ↓) left right
◦◦ hypothermia shift shift
oxygen saturation SO2

◦◦ decrease in 2,3-DPG (Among other things, this is pH ↑ pH ↓

also a major disadvantage of red cell concentra- pCO2 ↓ pCO2 ↑
tes: Almost no 2,3-DPG is contained in them any- T↓ T↑
2,3-DPG ↓ 2,3-DPG ↑
more, so that they still can transport oxygen, but
unfortunately they can release only little oxygen
to the tissue.)

oxygen partial pressure pO2

82 General Part
Fig. 138  shifts of the oxygen-hemoglobin dissociation cur- therefore 6 mmHg.
ve: The right shift ensures that oxygen is released more • CO2 content:
easily into the tissue in order to avoid tissue hypoxia.
-- inspired air: 0.04%
Carbon dioxide -- expired air: 4%

VCO2
paCO2 ~
VD
RMV x (1 - )
VT
Fig. 139  influencing factors of the partial pressure of car-
bon dioxide in arterial blood paCO2: VCO2: CO2 production
in the tissue; by increasing the respiratory minute venti-
lation (RMV) paCO2 can be decreased. An increasing dead
space ventilation VD (e.g. in pulmonary embolism) leads to
an increased paCO2.

Respiration
• molecular formula: CO2 • internal respiration (oxidation in the mitochondrial res-
• end product of the oxidative (aerobic) metabolism in piratory chain)
the mitochondria (For every molecule of O2 consumed, • external respiration (gas exchange)
0.8 molecules of CO2 result [respiratory quotient RQ
-- O2-absorption (oxygenation)
= 0.8])
-- CO2-release (decarboxylation)
• readily water soluble (hydrophilic; 20 times better than
oxygen; just think of sparkling water: Carbon dioxide is
dissolved in it!) External respiration (sub-processes)
• transport: • ventilation
-- physically (dissolved; 12% [in a much higher amount • perfusion
than oxygen]) • diffusion
-- chemically (bound; 88%): • distribution
◦◦ bicarbonate
▪▪ erythrocytes (50%): In the erythrocytes, carbon ventilation
dioxide and water are quickly converted into
carbonic acid by carbonic anhydrase, which im-
mediately dissociates into bicarbonate and H+
ions (protons). Not only oxygen, but also carbon
dioxide in the blood is mainly transported in the
erythrocytes. calillary oxygen-poor
deoxygenated
▪▪ plasma (27%) blood
blood
◦◦ carbamate (11%)
alveolus
• CO2 dissociation curve:
-- definition: relationship between the carbon dioxide border
partial pressure pCO2 and the CO2 binding
-- course: In contrast to the O2 dissociation curve, the
CO2 dissociation curve is not S-shaped, but linear. perfusion
• Haldane effect: Oxygen-poor (deoxygenated) blood
can take up more CO2 (increased CO2 affinity) than
oxygen-rich (oxygenated) blood (decreased CO2 affi- oxygen-rich
nity). blood
• The driving force for diffusion is again the partial pres-
sure gradient: The pCO2 in the mitochrondria is 46
mmHg, in arterial blood 40 mmHg, the partial pressure Fig. 140  Sub-processes of external respiration: Ventilation
difference is therefore 6 mmHg. In the further course, and perfusion are pictured here.
carbon dioxide diffuses from the capillaries through the
alveolo-capillary membrane into the alveoli, where it is Ventilation
finally exhaled. The partial pressure in venous blood
• definition:
pvCO2 is 46 mmHg, the partial pressure in alveolar gas
pACO2 is 40mmHg, the partial pressure difference is -- mechanical movement of air in and out of the lungs

General Part 83
 -- delivery (oxygen) and release (carbon dioxide) of
breathing gases Ventilation is essential for the release
• Ventilation is determined by the respiratory minute vo- of CO2 (decarboxylation)!
lume (RMV).
• The respiratory minute volume is calculated from the
tidal volume (TV) and the respiratory rate (RR):
RMV = tidal volume TV x respiratory rate RR The higher the pressure difference Δp
• The respiratory minute volume is the amount of gas, between inspiratory pressure (IPAP)
which gets in- respectively outside the patient in one and PEEP, the higher the tidal volume
respiratory cycle. The inspiratory and expiratory respi-
ratory minute volume are equal normally.
• standard values:
An increase of the respiratory minute
-- respiratory rate RR: 12/min
volume and hence also the ventilati-
-- tidal volume TV: 0.5 l (exactly: 6 ml/kg ideal body on should be achieved by increasing
weight) the respiratory rate and not the tidal
-- respiratory minute volume RMV: 5-6l (70 ml/kg) volume, since this may cause
• disturbances: damage to the lung!
-- obstruction/ restriction
-- hyper-/ hypoventilation (central / peripheral)
• types:
-- alveolar ventilation (effective gas exchange)
-- dead space ventilation
• The decisive factor for ventilation is the pCO2 (not the
pO2): In the event of a ventilation disturbance, the pCO2
usually increases (hypercapnic respiratory failure).
• Ventilation is determined by the respiratory minute vo-
lume, i.e. the respiratory rate and the tidal volume. Ac-
cordingly, ventilation can be increased by:
-- increasing the respiratory rate (mostly best!)
-- increasing the tidal volume: This is achieved by in-
creasing the pressure amplitude Δp ("driving pressu-
re"), i.e. the difference between inspiratory positive Fig. 141  3-zones-model of the ventilation: Ventilation is not
airway pressure (IPAP) and positive end-expiratory homogeneous overall the complete lung. It decreases from
pressure (PEEP): Δp = IPAP - PEEP. The pressure apical to basal. Due to the own weight of the lung the pleu-
difference and thus the tidal volume can be increa- ral pressure increases depending on gravity from apical
sed by: to basal. With an increasing pleural pressure (= pressure
around the alveoli) the alveolus gets more and more com-
◦◦ increasing the inspiratory pressure (IPAP)
pressed and smaller, so that the ventilation decreases. This
◦◦ decreasing the PEEP applies to the upright position. To supine position the same
• The tidal volume depends on the pressure difference changes are applied from ventral to dorsal instead of from
as well as on the compliance and the resistance of the apical to basal.
lung.
• In case of ARDS, ventilation should only be provided Mechanics of breathing
with low tidal volume (6 ml/kg) to avoid damage to the • parameters:
lung: It is therefore necessary to work (in case of a -- pressures
pressure-controlled ventilation) with a small pressure -- compliance, resistance
amplitude, i.e. a low inspiratory pressure and a high
• phases:
PEEP! But in order to achieve a sufficient respiratory
minute volume (RMV = RR x TV) the respiratory rate -- inspiration
must be increased (16-30/min). -- expiration
• The inspiratory pressure should be limited to a maxi-
mum of 30 cmH2O. The higher the inspiratory pressu- Pressures
re, the greater the mortality (meta-analysis Brower et • transpulmonary pressure (Ptp):
al, AJRCCM 2002). -- difference between intrapulmonary (alveolar pres-
sure; pressure in alveolus ["internal pressure"]) and
intrapleural (pleural pressure; pressure around the
The physiological tidal volume is 6 ml/ alveolus ["ambient pressure") pressure
kg ideal body weight!
-- The level of the transpulmonary pressure determi-
nes the filling volume and hence the expansion of
the alveoli.
-- The transpulmonary pressure is the key determinant

84 General Part
 of gas exchange.
-- The transpulmonary pressure should always be
positive (i.e. > 0) to prevent atelectasis. The trans­
pulmonary pressure is only positive if the alveolar
pressure is higher than the pleural pressure.
-- A positive transpulmonary pressure is required to
keep the alveoli open. A negative transpulmonary
pressure leads to alveolar collapse which may cause
atelectasis.
-- A too high (> 20 mbar) transpulmonary pressure
leads to an overdistension (strain) of the alveoli,
which causes barotrauma (i.g. pneumothorax) or
volutrauma.
-- standard value: 10-20 mbar
• intrapulmonary pressure (alveolar pressure [Palv], air-
way pressure): ranges between -2 mbar and +2 mbar
(corresponds to ventilation pressure during ventilation)
• intrapleural pressure (pleural pressure [Ppl]; intrathora-
cic pressure
-- negative (sub-atmospheric)
-- ranges between -4 and -8 mbar during spontaneous
breathing
-- Due to the own weight of the lung the pleural pressu-
re increases depending to gravity
◦◦ when patient sits / stays (upright position): from
apical to basal
◦◦ when patient lies on the back (supine position):
from ventral to dorsal
-- for more information on pleural pressure (incl. sche-
matic drawing and measurement) see also page
701
Ptp = Palv - Ppl
Ptp: transpulmonary pressure, Palv: alveolar pressure,
Ppl: pleural pressue
pressure (mbar)
intrapulmonary pressure
0 day the cuff of the single-use tubes are made of
-4
-8
intrapleural pressure
expiration inspiration
Fig. 142  top: intrapulmonary pressure (alveolar pressure,
airway pressure [when ventilated]); bottom: intrapleural
pressure (pleural pressure)
Examples
• healthy person under spontaneuous breathing: There
is a alveolar pressure of 0 mbar and a pleural pressure
of e.g. - 8 mbar vor. This results in a transpulmonary
pressure (0 mbar minus - 8 mbar) of + 8 mbar.
• Trumpet player: The alveolar pressure here is enor-
mously high (e.g. 150 mbar). But this does not result
in a barotrauma (pneumothorax on both sides), be-
cause there is a very high pleural pressure (e.g. 140
mbar) due to the back pressure of the musculature at
the same time and therefore a normal transpulmonary
pressure of +10 mbar.
• ARDS: The patient is ventilated with a PEEP of 15
mbar (alveolar pressure). There is a high pleural pres-
sure (20 mbar) here for example. This results finally in
a negative transpulmonary pressure (- 5 mbar), which
causes atelectasis. The PEEP must be increased.
Resistance R
• airway resistance
• measure for the flow resistance that has to be over-
come by the air flow during inspiration and expiration
• The tube represents the greatest resistance!
• the mouth-to-alveoli pressure difference divided by the
rate of air flow
• unit: mbar/l/s
• standard value in healthy adults under spontaneous
breathing: 2-4 mbar/l/s
• may increase tenfold in patients with obstructive lung
diseases
• Hagen-Poiseuille equation: R ~ 1/r4 (the smaller the
diameter [e.g. the bronchi], the higher the resistance.
When the diameter is reduced by half, the resistance is
not only doubled, but increased by 16 times [r4]!)
• causes of increased airway resistance (obstructive
lung disorders):
-- secret retention
-- bronchospasm (bronchial asthma and COPD)
-- swelling of the mucous membrane (bronchitis, bron-
chial asthma, pulmonary edema [cardiac asthma])
-- emphysema (dynamic airway compression)
-- kinked tube
-- cuff hernia
◦◦ Due to a too strong blocking of the tube the distal
end of the cuff obstructs the tube opening, so that
no more ventilation is possible. It is only possible
again after unblocking (no easy diagnosis!).
◦◦ In former times the cuffs consisted of rubber (la-
tex) and the tube were used for several times. To-
plastic, so that cuff hernias are very rare.
-- - foreign objects (e.g. dental crown), tumor
Compartments
• quicker compartments: fill up quickly with air during in-
spiration (small time constant; low resistance)
• slower compartments: fill up slowly with air during in­
spiration (big time constant; high resistance)
Compliance C
• measure for the elasticity of the lung (elastic properties
of the respiratory system)
• quotient of the displaced breathing gas volume and the
change in the airway pressure
• compliance = tidal volume / (plateau pressure - PEEP)
• unit: ml/mbar
General Part 85
• standard value for intubated adults with healthy lungs:
> 50 ml/mbar
• to compliance curve (syn.: volume-perssure curve,
VP-curve) see page 117
• should be measured in case of ARDS (usually reduced
compliance ["stiff lung"!])
• reduction of the surface tension of the alveoli due to
surfactant (produced by alveolar macrophages = type
II pneumocytes)
• causes of reduced compliance (restrictive respiratory
disorders): see infobox

Fig. 144  117 CT scan of the thorax: A large heart can lead
to a volume reduction of the lung and hence to a (extra-
pulmonary) restriction. The compliance (elasticity) of the
lung is reduced.

Fig. 143  Compliance is measured automatically with the

EVITA XL. The measured value C can be easily read off un-
der "Data - Table 1". Here the compliance with 36.9 ml/mbar
reduced (standard value: > 50 ml/mbar).

Fig. 145  CT scan of the thorax: extrathoracic restriction in

severe obesity (You can also see here how small the lung in
obese patients actually is. That is the reason why the respi-
ratory minute volume is based on the ideal and not on the
real body weight. The fat has not to be ventilated!)

Pressure-volume curve
• syn.: static PV-curve (loop)
• It describes the static compliance of the lung and the
thorax.
• Strictly speaking, this is a hysteresis curve, but only a
part is shown for simplification.
• sections:
-- flat bottom section: too low end-expiratory lung vo-
lume → end-expiratory closure of the small airways
(airway closure) with collapse of the downstream al-
veolar regions (alveolar collapse, atelectasis)
-- flat upper section of curve: maximum elasticity of the
alveoli is exceeded, an additional pressure increase
will not lead to a significant additional volume incre-
ase → hypertension (barotrauma)
-- center of the curve: highest compliance
• inflection points:
-- lower inflection point (LIP; alveolar closing pressu-
re):
◦◦ point at which a small pressure increase is follo-
wed by a larger volume increase
◦◦ < LIP: atelectasis [atelectotrauma; "stress"]), ten-

86 General Part
 sion: acting of force [due to pushing or pulling] to
the lung tissue; surrogate parameter for the tensi-
on: transpulmonary pressure)
-- upper inflection point (UIP):
◦◦ point at which the elastic properties of the lung tis-
sue are overcharged and the lung is overinflated
(beginning of overdistension)
◦◦ > UIP: overdistension (volutrauma; "strain": elon-
gation of the lung structure compared with its res-
ting position; surrogate parameter for the strain:
ratio between tidal volume and endexpiratory lung
volume [VT/EELV])
• To deflate the lung points it is necessary to relax the
patient and disconnect him from the ventilator (quite
complicated)
• super-syringe method (see page 701; no clinical rou-
tine)
• low-flow PV loop (Evita XL, Dräger; see page 629)
→ determination of the pressure-volume curve and the
two inflection points
• The ventilation pressures (inspiratory pressure and Fig. 147  The diaphragma is the main muscle of breathing
PEEP) should be adjusted so that the end-inspiratory and constantly active. It is a muscle-tendon plate, that sepa-
and end-tidal volume are in the steep part of the curve. rates the thoracic cavity from the abdomen. It is typically in
a dome-shaped position, which is crucial for the function. A
• settings: flattened diaphragm (e.g. COPD exacerbation with hyperin-
-- The optimal PEEP should be 2 mbar over the LIP. flation) is ineffective. The contraction of the muscle leads to
-- IPAP (inspiratory pressure) should not exceed the inspiration. Is is a skeletal muscle. The muscular part has 3
UIP. attachments: at the lumbar spine (lumbar part), at the ribs
(costal part) and at the sternum (sternal part). They merge
volume into a tendinous center (centrum tendinosum). During brea-
thing at rest the slowly contracting muscle fibers (type I)
are acitive, during breathing at exercise the fast contracting
muscle fibers (type II). The latter get their energy by gly-
upper inlection point colysis and therefore get exhausted quickly. The cotractile
proteins are actin and myosin. The diaphragm is innervated
by the phrenic nerve.
tidal
volume

lower inlection point

PEEP IPAP pressure

Fig. 146  pressure-volume curve (PV-curve; simplified; it is
actually a hysteresis curve)
Inspiration
• spontaneous breathing:
-- The contraction of the respiratory musculature (dia-
phragm, intercostal muscles) leads to an increase in
volume of the intrathoracic pressure and hence to
a negative pressure (2-3 cmH2O; atmospheric pres-
sure > intrapulmonary pressure). This result in an
intake of air into the lungs.
-- The main muscle of breathing is the diaphragm (Dia-
Expiration
phragma [Greek: "partition", also "seat of the soul"]). • passive process (both during spontaneous breathing
-- The work of breathing (WOB) in a healthy adult is as well as ventilation), only an active process in the
0.7-1.0 J/l. case of forced expiration (contraction of muscles of
expiration)
-- The intrapulmonary pressure ranges between -2
mbar and +2 mbar, the intrapleural pressure ranges • elastic retraction forces of lung and thorax
between - 4 and -8 mbar • outflow of air from the alveoli
• ventilation: Air flows into the alveoli due to positive
pressure applied to the air ducts.

General Part 87
 inspiration expiration
Fig. 148  spontaneous breathing: The inspiration is an ac-
tive process (contraction of the diaphragm [man berathing
muscle]) and the intercostal musculature. The expiration,
however, is a completely passive process.
Perfusion
• blood circulation in the alveoli
• transport of CO2 with the blood to the alveoli and trans-
port of O2 out of the alveoli with the blood to the organs
• Perfusion is not homogeneous overall the complete
lung. It increases depending to gravity from apical to
basal (in case of upright position) respectively from
ventral to dorsal (in case of supine position) zu. It is
illustrated in the 3-zones-model (according to West).
• An extreme example of a perfusion disorder is the
cardiac arrest: no more lung perfusion, i.e. no more
transport of carbon dioxide to the alveoli and no oxy-
gen transported out of the alveoli. In case of a cardi-
ac arrest there is also a disturbance of gas exchange
(increase of pCO2 and decrease of pO2 in the blood).
• A good parameter for perfusion, which is also easy
to measure in ventilated patients (capnometry), is the
end-tidal CO2-concentration ETCO2: The worse the
perfusion, the less CO2 is removed and the lower the
end-tidal CO2-concentration in the expired air.
• disorders (typical examples): pulmonary embolism,
pulmonary arterial hypertension, cardiac insufficiency,
shock
Fig. 149  Perfusion: Via the pulmonal artery oxygen-poor
and carbon dioxide-rich blood gets to the lung capillary.
There the gas exchange with the alveolus takes place. Then
the oxygen-rich and carbon dioxide-poor blood is transpor-
ted away via the pulmonal vein.
88 General Part
Fig. 150  3-zones-model of perfusion (lung perfusion; ac-
cording to West): Perfusion is not homogeneous overall
the complete lung. Due to gravity it increases from apical
to basal. In the zone I (apical zone) the pulmonary arteri-
al pressure (Pa) and the pulmonary venous pressure (Pv) a
very low. Due to the alveolar pressure (PA) the lung capil-
lary gets compressed, so that there is only a very low per-
fusion. In the zone II (middel zone) the pulmonary arterial
pressure(Pa) and the pulmonary venous pressure (Pv) now
are significantly higher, so that her signifikant more perfu-
sion occurs. In the zone III (basal zone; the largest zone)
due to gravity as well the pulmonary arterial pressure (Pa)
as the pulmonary venous pressure (Pv) are higher than the
alveolar pressure (PA), so that the lung capillary is no more
compressed and stays open. The perfusion therefore is
highest in this zone. This applies to the upright position. To
supine position the same changes are applied from ventral
to dorsal instead of from apical to basal.
Ventilation
oxygen-poor
blood
oxygen-poor
blood
Embolie
oxygen-rich
blood
Fig. 151  disturbance of the perfusion in case of pulmonary
embolism
Diffusion
• syn.: alveolar gas exchange
• transport of gases through the alveolar-capillary mem-
brane (movement of gases between alveolar air space
and the surrounding capillary blood vessels)
• amount of gas that is exchanged between alveolar air
and blood through the alveolar-capillary membrane
 (essential role in gas exchange)
• The driving force is the partial pressure gradient bet-
ween the partial pressure of oxygen in the alveolar gas
pAO2 and the the partial pressure of oxygen in the ve-
nous (exactly: mixed venous) blood pvO2.
• The time it takes for an erythrocyte to deliver its CO2
and to take up its O2 (so-called contact time) is extre-
mely short (only 0.15 sec).
• Bohr effect (drilling effect; for the graphical illustration
see 781): The affinity of hemoglobin for oxygen de-
creases with an increasing pCO2 and a decreasing pH,
i.e. the oxygen release to the tissue increases. There-
fore a metabolic acidosis should only be bufferd at a
pH < 7,2, because a moderate acidosis improves the
oxygen release to the tissue.
• Diffusion is described by Fick's law of diffusion.
Fick's law of diffusion
Diffusion According to Fick's law of diffusion (named af-
ter the German physiologist Adolf Fick [1829-1901]) the
diffusion is determined by four factors:
tial pressure difference (difference in concentration)
of the respective gas between two containers (here:
alveolus and capillary) separated by a semiperme-
able membrane (here: alveolar-capillary membra-
ne). The bigger the partial pressure difference, the
faster the diffusion.
-- The partial pressure of oxygen in the alveolar gas
is pAO2 = 105 mmHg, the partial pressure of oxygen
in the venous blood pvO2 40 mmHg, i.e. the partial
pressure gradient (driving force for diffusion) is 65
mmHg.
• diffusion length (0.5 mm; the alveolar-capillary mem­
brane itself is very thin [0.3 μm):
-- The diffusion is indirectly proportional to the diffusion
length.
-- An extension of the diffusion length (i.e. thickened
alveolar-capillary membrane in case of pulmonary
edema, ARDS, pneumonia) would lead to a diffusion
impairment.

diffusion x diffusion x diffusion

surface coefficient gradient
diffusion ~
diffusion
length

• diffusion surface (surface area for gas exchange):

-- 300 million alveoli: 160 m2 (approximately corre-
sponds to the size of a tennis court; the skin only
has a gas exchange surface of about 1.5 m2 which
is approx. 1% of the human gas exchange [i.e. even
if the entire skin would be covered with gold like in
the James Bond movie "Goldfinger", one would not
choke])
-- Diffusion is directly proportional to the diffusion sur-
face. If the diffusion surface is reduced (e.g. lung Fig. 152  illustration of the bronchioli and und alveoli
resection, atelectasis, pneumonia, pulmonary contu-
sion from trauma), diffusion decreases.
• diffusion coefficient (syn.: Krogh's diffusion coefficient):
Oxygen and carbon dioxide have different blood-gas
partition coefficients.
alveolus
-- Carbon dioxide is 20 times more soluble than O2 CO2
oxygen (just think of carbonated beverages such as
alveolar
Coke: It contains far more carbon dioxide than oxy-
wall
gen, because carbon dioxide simply dissolves much
better in water).
-- Zherefore, the pO2 is the parameter for diffusion im- Luft
capillary erythro-
pairments! Diffusion disorders (e.g. pulmonary ede- cyte
ma, pneumonia) therefore typically lead to hypoxe- O2-uptake
mia (so-called hypoxic respiratory failure) and not (or (oxygenation)
much later) to hypercapnia. CO2-delivery
(decarboxylation)
-- The treatment of first choice in case of a diffusion
impairment is therefore the administration of oxygen. Fig. 153  illustration of the alveolar gas exchange
• diffusion gradient (is determined by the partial pressu-
re difference):
-- partial pressure: the pressure that one component
of a mixture of gases would exert if it were alone in
a container
-- The diffusion rate is directly proportional to the par-

General Part 89

CO2 is 20-times more soluble than O2!
Therefore, a decreased pO2 (hypoxe-
mia) is the key parameter of a diffusion
impairment!
Fig. 154  illustration of the alveolar-capillary membrane
ventilation
-- lung perfusion (Q; = cardiac output): 5 l/min
• standard value (ventilation-perfusion ratio): V/Q = 0.8
• The ventilation-perfusion ratio determines the gas ex-
change in any lung area.
• gravity dependent changes:
-- Perfusion increases from apical to basal (see 3-zo-
nes-model of perfusion according to West [page
88].
-- Ventilation decreases from apical to basal (see page
84). That is because the pleural pressure incre-
ases due to gravity and the weight of the lung from
apical to basal, so that the alveoli get more and more
compressed.
• 3 zones (annot.: This applies to the upright position.
To supine position the same changes are applied from
ventral to dorsal instead of from apical to basal.):
-- zone I (apical zone): ventilation perfusion ratio V/Q
↑ (> 0.8), because
◦◦ ventilation (V) ↑
◦◦ perfusion (Q) ↓
-- zone II (middle zone): ventilation perfusion ratio V/Q
normal (0.8), because
◦◦ ventilation (V) normal
◦◦ perfusion (Q) normal
-- zone III (basal zone): ventilation perfusion ratio V/Q
↓ (< 0.8), because
◦◦ ventilation (V) ↓
◦◦ perfusion (Q) ↑

perfusion thickened
alveolar-
capillary
membrane

oyxgen-poor blood
Fig. 156  3-zones-model of ventilation and perfusion in one
figure projected on top of each other: Ventilation decrea-
ses from apical to basal, perfusion increases from apical to
basal. Both is caused by gravity. In zone I (apical zone) the
Fig. 155  impairment of diffusion in case of pulmonary ede- ventilation is increased, the perfusion is decreases. There-
ma (thickened alveolar-capillary membrane) fore the ventilation perfusion ratio V/Q here is increased (>
0.8). In zone II (middle zone) both ventilation and perfusion
and therefore the ventilation perfusion ratio V/Q are normal
Typical example for a diffusion (0.8). In zone III (basal zone) the ventilation is decreased
impairment: pulmonary edema! and perfusion increased. Accordingly the ventilation per-
fusion ratio V/Q here is decreased (< 0.8). This applies to
the upright position. To supine position the same changes
are applied from ventral to dorsal instead of from apical to
Distribution basal.

Definition Euler-Liljestrand mechanism

• ratio between the ventilation (V) and the perfusion (Q) • named after the Swedish physiologist Ulf von Euler
in the lung (1905-1983) and the Swedish pharmacologist Göran
-- alveolar ventilation (VA) in adults: 4-5 l/ min Liljestrand (1886-1968)

90 General Part
• syn.: hypoxic pulmonary vasoconstriction (HPV)
• Regional alveolar hypoventilation causes reflexive va-
soconstriction in the affected area.
• significance: Blood from poorly ventilated lung areas
is redistributed to better-ventilated areas. The Euler-
Liljestrand mechanism is a physiological mechanism
to reduce shunt (main pathomechanism of lung failu-
re): Alveoli which are not ventilated any longer should
not been perfused any longer.
• Hypocapnia (direct vasodilatation also in hypoxic are-
as) and hypercapnia (direct vasoconstriction in well-
ventilated lung areas) inhibit the Euler-Liljestrand me-
chanism.
• The Euler-Liljestrand mechanism may reduce shunt a
little, but not completely: Lack of perfusion in a non-
ventilated area of the lung (e.g. right upper lobe pneu-
monia) would cause a massive increase of the right
ventricular afterload (similar to pulmonary embolism)
and lead to an acute right heart failure.
Extreme cases
• V/Q < 0.8: shunt (Lung areas are perfused but not ven-
tilated.)
• V/Q > 0.8: dead space (Lung areas are ventilated, but
not perfused.)
shunt: perfusion without ventilation
dead space: ventilation without
perfusion
typical sign of an increasing
- dead space: pCO2 ↑ (hyper-
capnia)
- shunt: pO2 ↓ (hypoxemia)
Dead space
• A dead space is a part of the respiratory system that
does not participate in gas exchange. These areas are
ventilated, but not perfused.
• functional dead space:
-- physiological: anatomical dead space (150 ml; rule
of thumb: body weight x 2)
◦◦ spontaneous breathing: nose, mouth, trachea,
bronchi
◦◦ ventilation: tube, filter, tube extension ("goo-
seneck")
-- pathological: alveolar dead space (ventilated, but
not perfused alveoli due to a disease [characteristic
of pulmonary embolism])
• reduction of the anatomical dead space to approx. 80
ml through intubation (approx. 50 ml through tracheo-
tomy)
• The increase of dead space is also the reason why
the maximum ventilation rate is limited to 30/min: In-
creasing the ventilation rate increases dead space
ventilation and decreases alveolar ventilation. This is
described by the following example: A RMV (respirato-
ry minute volume) of 6 l/min can be achieved by a RR
(respiratory rate) of 10/min and a VT (tidal volume) of
600 ml as well as by a RR of 30/min and a VT of 200
ml. The dead space of 150 ml per mandatory breath
does not decrease with an increasing respiration rate
- it remains unchanged. The last possibility therefore
only leads to an alveolar ventilation of 50 ml x 30/min
= 1.5 l/min, which represents a hypoventilation. Incre-
asing dead space impairs ventilation and this leads to
hypercapnia.
• occurrence (pathological dead space):
-- pulmonary embolism
-- hyperinflation (e.g. air trapping in case of COPD
exacerbation): Hyperinflation causes a compression
of the adjacent capillaries: Dead space increases
and the reduced alveolar ventilation leads to an in-
crease of the pCO2 (hypercapnia).
-- too high PEEP (also compresses the adjacent
capillaries)
• An increasing dead space ventilation reduces the al-
veolar (effective) ventilation. Ventilation is essential for
the release of CO2. Hence, an increase of dead space
ventilation increases the pCO2 (hypercapnia)!
proportion of the (physiological)
dead space in the tidal volume: 150
ml (per breath)
A too high pCO2 can also be
caused by a too high PEEP!
Shunt
• perfused but not ventilated alveoli
• intrapulmonary right-to-left-shunt (up to 8% physiolo-
gical)
• Desaturated blood from these lung areas mixes with
oxygenated blood from other lung areas (venous ad-
mixture).
• main pathomechanism of lung failure
• leading cause of hypoxemia
• no sufficient increase in pO2 despite administration of
oxygen (no matter how high the FiO2: There will be no
more significant increase in pO2!); from a shunt per-
centage of > 35% of the cardiac output (shunt fraction),
an increase in FiO2 no longer has any influence on the
oxygenation of arterial blood
• examples:
-- pneumonia (infiltrated alveoli)
-- atelectasis
-- mucus plug
-- ARDS
-- hepatopulmonary syndrome
• The impact of a shunt is described by the following
example: If the right upper lobe of a patient with bron-
chial carcinoma is removed, he will usually not suffer
from dyspnea or hypoxemia afterwards and can lead
General Part 91
 a normal life. No shunt occurs because the pulmona-
ventilation
ry vessels are ligated in the course of the lobectomy.
However, if a patient suffers from lobe pneumonia in
the right upper lobe (complete functional failure of the
right upper lobe), this leads to severe dyspnea and hy-
poxemia due to shunt.
• The aim of ventilation in case of shunt is to reopen the
oxygen-poor
non-ventilated alveoli for the gas exchange ("alveolar
blood
recruitment") by applying sufficient inspiratory pressu-
re and to keep them from collapsing again by applying
adequate expiratory pressure (PEEP). infiltrate
• The right-to-left-shunt (RLS) can theoretically be cal-
culcated (according to Fick´s method [page <?>]).
However, this is relatively complex (i.a. pulmonary
artery catheter [PAC] necessary) and complicated, so shunt
this is practically almost never done. The interested
reader may be referred to the infobox.
oxygen-poor
blood

Fig. 157  shunt: Du to an infiltrate (e.g. pneumonia) the alve-

olus is perfused, but not ventilated.

ventilation pressure

low high

infiltrated reopened
alveolus alveolus

Fig. 158  If shunt is the cause of impaired oxygenation, in-

creasing the FiO2 will not be very useful: One should rather
try to reopen the alveolus by increasing the inspiratory
pressure and to keep it open by applying sufficient expira-
tory pressure (PEEP).

Shunt: Major problem in daily

clinical practice! The most
important pathomechanism of
lung failure!

92 General Part
Fig. 159  lobe pneumonia in the right upper lobe: Functio-
nally the complete right upper lobe is missing. But in con-
Respiratory failure (insufficiency)
trast to a patient, whom the right upper lobe was removed
by lobectomy due to an bronchial carcinoma and whom the
right upper lobe therefore is also completely missing, this
patient is in an extremely bad clinical condition and suf-
fers from severe dyspnea. The reason for this is the shunt!
In the course of the lobectomy of the right upper lobe the
pulmonary vessels were ligated by the thoracic surgeon,
so that there is no shunt and the patient is in a very good
conditition (no dyspnea) later when he is discharged from
hospital.

Respiratory regulation
• via neurons in the medulla oblongata
• controlled variables
-- pO2 (standard: > 100 mmHg [rule of thumb: A healthy
person should achive an paO2 that ist approximately
five time higher than the FiO2 in %.]) Respiratory insufficiency (failure) can be categorized ac-
-- pCO2 (standard: 36-44 mmHg) cording to several aspects (see infobox). The respirato-
ry system consists of two components: the respiratory
-- pCO2 (hypercapnia; the main respiratory drive; stan-
pump (especially diaphragm) for respiration (ventilation)
dard: 36-44 mmHg); annot.: Patients with obstructi-
and the lung parenchyma for gas exchange. Depending
ve lung diseases usually are adapted to increased
on which of the components fails, a distinction is made
levels of pCO2, so that hypercapnia is not a respi-
between the following entities of the acute respiratory in-
ratory drive here anymore, but only hypoxemia. If
sufficiency (ARI):
hypoxemia here is resolved by the application of
• hypercapnic
oxygen, it may be that there is no more respiratory
drive at all. That is why a restricted use of oxygen in • hypoxemic
patients with obstructive lung diseases was postula-
ted formerly. But a hypoxemic patient should always
get oxygen! If there is in deed then no respiratory
drive the patient must be ventilated.
-- pH (standard: 7.36-7.44)

CNS
(motor neurons in the medulla oblongata)

PNS
(phrenic nerve)
Hypercapnic respiratory failure

neuromuscular junction
inspiratory muscles (diaphragm)
Fig. 160  respiratory regulation
Definition
• respiratory pump failure (especially the inspiratory mu-
scles [especially the diaphragm])
• disorder of ventilation (respiration)
• key parameter: pCO2­ ↑
• Ventilation can be disturbed at different points of the
respiratory pump:
-- nervous system
◦◦ CNS (respiratory center): inhibition of the respira-
tory drive in the CNS; examples:
▪▪ heroin intoxication
▪▪ administration of opioids for anesthesia
▪▪ encephalitis
▪▪ pain-related hypoventilation

General Part 93
 ▪▪ idiopathic hypoventilation (Ondine's curse)
▪▪ obesity hypoventilation syndrome (former
name: Pickwickian syndrome ; p.d. BMI > 30 kg/
m2, daytime hypercapnia [pCO2 > 45 mmHg] wi-
thout explanatory pulmonary or neuromuscular
disease)
◦◦ PNS; i.a.
▪▪ Guillain-Barré-Strohl syndrome
▪▪ amyotrophic lateral sclerosis
▪▪ myasthenia gravis
▪▪ spinal muscular atrophy
▪▪ CIP (critical illness-polyneuropathy)
▪▪ diaphragmatic paralysis as a result of injury of
the phrenic nerve (e.g. as a complication of a
CVC in the internal jugular vein)
▪▪ paraplegia (above C4)
-- musculature
◦◦ primary muscle of respiration (diaphragm):
▪▪ COPD: Due to hyperinflation the diaphragm is
distally relocated and flattened so that it can no
longer contract properly. The flattening of the
diaphragm leads to insufficient mechanical pow-
er development and hence to a deterioration of
efficiency (insufficient diaphragm action).
▪▪ diaphragm atrophy after long-term ventilation
(already begins after 48 hours of ventilation!
VIDD [ventilator induced diaphragmatic dys-
function, almost always reversible])
▪▪ progressive muscular dystrophy
▪▪ post-polio syndrome (in 25 % after acute polio-
myelitis; usually after 25-35 years)
▪▪ CIM (critical illness-myopathy)
◦◦ secondary muscles of respiration: auxiliary respi-
ratory muscles
-- thorax (e.g. kyphoscoliosis, Bechterew's disease,
pleural fibrosis, post-tuberculosis syndrome [long-
term effects after pulmonary tuberculosis; especially
thoracic deformities; i.a. paraffin plombage after ex-
trapleural pneumonolysis of caverns], pleural effusi-
on)
-- abdomen: Increased intra-abdominal pressure (e.g.
ileus, ascites, pancreatitis) prevents the diaphragm
from descending (insufficient diaphragm action).
• representatives (common)
-- COPD exacerbation (classic)
-- neuromuscular diseases
◦◦ progressive muscular dystrophy
◦◦ Guillain-Barré-Strohl syndrome (GBS)
◦◦ amyotrophic lateral sclerosis (ALS)
-- kyphoscoliosis
• Ventilation was developed in 1929 in the Scandinavi-
an countries during the polio epidemics: Polio was the
classical representative of a respiratory muscle failu-
re (especially of the diaphragm) with a disturbance of
ventilation, the lung itself is fine during a polio infection.
• There is an imbalance between the capacity and load
of the respiratory muscle.
• treatment: ventilation (non-invasive / invasive)
• In case of a hypercapnic respiratory failure, ventilati-
94 General Part
on is aimed at relieving the respiratory pump and the
improvement of ventilation. If a patient has to be intu-
bated due to exhaustion of the respiratory pump, he
should be ventilated for at least 48 hours (even if his
condition improves after a couple of hours) so that his
respiratory musculature can recover (refilling of glyco-
gen storage).
The main respiratory muscle is the
diaphragm!
capacity
load
Fig. 161  Imbalance between load and capacity of the res-
piratory musculature (especially of the diaphragm) is the
cause of hypercapnic respiratory failure.
Diagnosis
• clinical (signs of exhaustion of the respiratory pump):
-- dyspnea
-- rapid (tachypnea: respiratory rate > 35/min) and
shallow breathing (rapid shallow breathing)
-- use of auxiliary respiratory muscles
◦◦ shoulder girdle musculature, sternocleidomastoid
muscle, intercostal muscles
◦◦ The patient supports himself on his arms and uses
his shoulder girdle musculature to breathe ("sup-
port to support!").
-- inward movement of the thoracic outlet
-- Hoover sign (modified intercostal movements in
case of COPD or pulmonary emphysema)
-- paradoxical breathing: retraction of the abdominal
wall during inspiration (see figure)
-- reverse breathing ("frog" breathing": change bet-
ween normal respiration (active diaphragm) and pa-
radoxical breathing (passive [exhausted] diaphragm)
-- respiratory alternans (= thoracic movement then ab-
dominal movement, so that there is a short recovery
phase for each muscle group)
-- disturbance of consciousness, decrease in vigilance
(due to CO2-anesthesia)
• laborchemical:
-- pCO2 ↑, pH ↓ (respiratory acidosis)
-- An increased base excess (BE) with normal
pCO2 and normal pH (with normal renal function) is a
sign for chronic insufficiency of the respiratory pump
 (compensatory renal counter-regulation).
• functional:
-- increased RSB-index (RSB: rapid shallow breathing)
◦◦ RSB = respiratory rate / tidal volume
◦◦ The increase of the RSB-index is actually a phy-
siological adaptation, since the increase of the re-
spiratory rate and the decrease of the tidal volume
lead to a reduction of the mean inspiratory pres-
sure and thus the energy consumption. However,
this increases the dead space ventilation.
-- P0.1
◦◦ airway occlusion pressure (negative pressure 0.1
sesonds after the beginning of inspiration against
a closed airway)
◦◦ measure for central respiratory work (work of
breathing [WOB]) and thus effort of patient during
spontaneous breathing
◦◦ normal value: 1-6 mbar
▪▪ P0.1 > 6 mbar: sign of exhaustion of the respirato-
ry pump, high probability of weaning failure
▪▪ P0.1 < 1 mbar: decreased respiratory drive (cen-
tral respiratory depression)
-- NIF (negative inspiratory force)
◦◦ syn.:
▪▪ MIP (maximal inspiratory pressure)
▪▪ PI-max
◦◦ maximum underpressure (negative perssure; va-
cuum) that the patient can generate during inspi-
ration (Müller's maneuver)
◦◦ NIF > - 30mbar (normal value: < - 30 mbar) →
insufficiency of respiratory pump
◦◦ P0.1 / PImax > 10% (normal value: < 2%) → insuffici-
ency of respiratory pump
-- TTI (tension time index)
◦◦ TTI = (pI / pImax) x (ti / ttot)
▪▪ PI: pleural pressure (measurement by esopha-
geal probe; no clinical routine)
▪▪ ti: inspiratory time
▪▪ ttot: time of the total respiratory cycle
◦◦ TTI > 0.15 (normal value: < 0.15) → insufficiency
of respiratory pump
• sonographic:
-- ultrasound examination of the diaphragm with echo
probe (convex scanner) and then switch to M-mode
into the diaphragm: A diaphragmatic excursion of
less than 10 mm is indicative of diaphragm weak-
ness (see pictures on page <?>).
-- ET-index (see page 151)
expiration inspiration
diaphragm
Fig. 162  normal (orthodoxical) breathing: The diaphragm
moves downwards during inspiration (active contraction of
the diaphragm).
auxiliary respiratory
muscles
expiration inspiration
Fig. 163  paradoxical breathing: The diaphragm moves up-
wards during inspiration (is only passively pulled upwards
by the auxillary respiratory muscels).
Hypoxemic respiratory failure
• loss of functional lung tissue (lung parenchyma); dis-
turbed gas exchange
• disorder of oxygenation (diffusion impairment or shunt
• key parameter: pO2 ↓ (note: A disturbance of the gas
exchange can be detected more reliably by looking at
the alveolar-arterial oxygen gradient AaDO2 [see info-
box]!)
• representatives:
-- pulmonary edema
◦◦ The leading cause of hypoxic respiratory failure is
a (cardiac) pulmonary edema!
◦◦ Diffusivity through edematous tissue is 20 times
better for CO2 than for O2, which mostly leads to
hypoxic respiratory failure.
-- ARDS (permeability pulmonary edema)
-- pneumonia
-- atelectasis
-- decompensated pulmonary fibrosis
• The increased oxygen consumption and the increased
breathing effort during a primary hypoxic respiratory
failure may cause a fatigue of the respiratory pump
and thus lead to secondary hypercapnic respiratory
failure.
• treatment: administration of oxygen (While ventilation
is primarily important in hypercapnic respiratory failure,
the administration of oxygen, on the other hand, is es-
sential in case of hypoxemic respiratory failure!)
• In case of a hypoxemic respiratory failure, ventialtion is
aimed at the improvement of the gas exchange.
General Part 95
• Hypoxemic respiratory failure (e.g. pulmonary ede-
ma) usually leads to hyperventilation and thus to hy-
pocapnia! Increasing the respiratory rate is an attempt
to compensate the hypoxemia (on-demad hyperventi-
lation). Hypocapnia induces a respiratory alkalosis. A
decrease of the respiratory rate and a normalization
of the pCO2 already indicates (in case of a persisting
hypoxemia) a beginning exhaustion! blood gas analy-
sis example:
-- pulmonary edema, initial stage: pO2 = 54 mmHg,
pCO2 = 29 mmHg, respiratory rate 24/min
-- after a further 20 min exhaustion of respiratory
pump: pO2 = 49 mmHg, pCO2 = 44 mmHg, respirato-
ry rate 8/min (increasing hypoxemia despite oxygen
administration)

Caution - pulmonary edema

(usually lowered pCO2 due to
reactive hyperventilation): A
normalization of the pCO2 already
indicates a respiratory fatigue!

A low paO2 (BGA) cannot automati-

cally be equated with a disturbed gas
exchange. Neither does a normal
paO2 rule out a disturbed gas
exchange!

Oxygen therapy
• low-flow oxygen therapy: < 15 l/min
-- 1-5 l/min: via cannula (nose)
◦◦ maximum achievable inspiratory oxygen concent-
ration (FiO2): 0.4
◦◦ should be avoided at a flow > 5 l/min, since this
leads to a drying of the nasal mucosa
-- 5-15 l/min: via mask (nose and mouth)
◦◦ syn.: Venturi mask, Hudson mask
◦◦ should be avoided at a flow < 5 l/min, since this
leads to a CO2 rebreathing
◦◦ maximum achievable inspiratory oxygen concen-
tration (FiO2): 0.6 (with reservoir: 0.8 [Beyound a
flow > 10 l/min a reservoir should additionally al-
ways be used to increase the FiO2!]).
• high-flow oxygen therapy: > 15 l/min (NHF [nasal high
flow], HFNOT [high-flow nasal oxygen therapy]; see
page 139)

96 General Part
 ▪▪ I:E = 1:1 (standard setting today )
▪▪ Especially in a sick lung the elasticity (compli-
ance) is massively reduced. The prolongation
of the inspiration is necessary in oder to avoid
barotrauma (e.g. pneumothorax). So ventilation
gets more protective. Due to the prolongation of
the inspiration the velocity of the air inflow is lo-
wered: There are less turbulences, so that the
resistance and hence the peak pressure decre-
ase.
◦◦ hypercapnic respiratory failure: obstruction (COPD
exacerbation, status asthmaticus):
Fig. 164  different devices for the administration of oxygen ▪▪ prolongation of the expiration (to improve decar-
(left to right): nasal cannulas, mask without reservoir, mask boxylation [to avoid hyperinflation])
with reservoir) ▪▪ I:E = 1:3 (The disturbance is in the expiration:
This takes time and must be prolonged here!)
◦◦ annot.: inverse ratio ventilation (IRV): 2:1 / 3:1
(leave today!)
-- The I:E ratio must always be considered within the
context of the respiratory rate; example: TI = 2s, TE
= 4s
◦◦ total duration of the cycle = 6s
◦◦ I:E = 1:2
◦◦ respiratory rate = 10/min
-- For a correct setting of the I:E ratio it is impor-
tant to check the flow curves on the monitor of the
ventilator!

inspiration expiration
Fig. 165  Beyound an oxygen flow > 10 l/min you should use
a mask with reservoir: Thereby the FiO2 can significantly
be increased (from approx. 0.6 [without reservoir] up to ap-
prox. 0.8 [with reservoir]).

Cycle TI TE time
• definition: A cycle is the time T from the beginning of
the inspiration to the end of the expiration. Fig. 166  I:E ratio
• T = TI + TE
-- TI: inspiratory time
Inspiration: O2-uptake (Prolongation
◦◦ flow phase (syn.: inflation time [The lung is infla- therefore improves the oxygenation.)
ted here.] Expiration: CO2-release (Prolongation
◦◦ plateau phase (pause; inflation hold) therefore improves the decarboxylati-
-- TE: expiratory time on.)
◦◦ flow phase
◦◦ plateau phase (pause)
• phases: I:E ration: normally 1:2
-- flow phase: During the flow phase, breathing gas hypoyemic ARI (e.g. ARDS) →
flows into the lung with a certain strength and in a prolongation of inspiration (1:1)
particular time interval. hypercapnic ARI (e.g. AECOPD) →
-- plateau phase: During the plateau phase, the brea- prolongation of Expiration (1:3)
thing gas can distribute in the lung as uniformly as
possible.
• respiratory time ratio = I:E
-- normal (spontaneous breathing): 1:2
-- - settings: depending on the cause of the respiratory
failure
◦◦ hypoxemic respiratory failure (especially ARDS):
▪▪ prolongation of the inspiration (to improve oxy-
genation)

General Part 97

-- left heart:
◦◦ left ventricular preload ↓: The positive pressure
Fig. 167  When setting the I:E ratio it is important to always
take the flow curves on the monitor of the ventilator into
account: In the first example the inspiratory time has been
set too short: There is no complete inspiration. In the se-
cond example the expiratory time has been set too short:
The is no complete expiration. Hyperinflation occurs ("air
trapping").
Ventilation cycle
• phase I: inspiratory phase (inspiratory valve open, ex-
piratory valve closed)
• phase II: plateau phase
• phase III: expiratory phase (inspiratory valve closed,
expiratory valve open)
• phase IV: expiratory hold
◦◦ left ventricular afterload ↓:
Side effects
• cardiac:
-- right heart:
◦◦ right ventricular preload ↓: Positive pressure venti-
lation increases the intrathoracic pressure with the
result that less blood can flow into the thorax and
therefore the venous backflow to the right heart is
decreased (right ventricular preload ↓). The pres-
sure gradient between extra- and intrathoracic ve-
ins is reduced.
◦◦ right ventricular afterload ↑: Positive pressure ven-
tilation increases the intrathoracic pressure. This
leads to an overdistension of the alveoli, which in
98 General Part
turn leads to a compression of the pulmonary ca-
pillaries with the result that the right ventricular af-
terload increases. This is, however, only the case
with high PEEP-levels. Low PEEP-levels do not
lead to any increase of the right ventricular after-
load. If a patient with a right heart failure is venti-
lated (especially with a higher PEEP) his condition
may worsen due to the increase of the right ventri-
cular afterload.
ventilation and the increase of the intrathoracic
pressure lead to a compression of the pulmona-
ry capillaries with the result that less blood flows
to the left atrium and therefore the left ventricular
preload decreases. Due to the positive thoracic
pressure, furthermore less venous blood flows into
the thorax. Like nitroglycerin, ventilation decrea-
ses the left ventricular preload ("nitro-effect" of the
ventilation). The decreased left ventricular pre-
load leads to a reduced filling of the left ventricle,
so that the stroke volume and hence the cardiac
output decrease as a result of the Frank-Starling-
mechanism. This applies to patients with a normal
volume status (section 2 of the Frank-Starling-cur-
ve [see page 195]) and is very pronounced in pa-
tients with a decreased volume status (section 1 of
the Frank-Starling-curve). That is why in patients
with polytrauma, who are mostly hypovolemic due
to a bleeding, only low ventilation pressures (es-
pecially a low PEEP) should be adjusted. Howe-
ver, in patients with volume overload (e.g. cardiac
decompensation with pulmonary edema; section 3
of the Frank-Starling curve) ventilation causes an
increase of the stroke volume and the cardiac out-
put due to the decrease of left ventricular preload
and hence the left shift of the Frank-Starling-cur-
ve! Furthermore, high ventilation pressures may
lead to a dilatation of the right ventricle due to an
increased right ventricular afterload. This causes
a shift of the septum towards the left ventricle, so
that the left ventricle can no longer fill properly in
the sense of a diastolic dysfunction with a reduced
left ventricular compliance (Bonnheim effect; syn.:
LV-RV crosstalk, ventricular interdependence). As
a result, the blood pressure drops and therefore
the heart rate increases.
▪▪ Laplace´s law (named after the French physicist
Pierre-Simon Laplace [1749-1827]): T = P x r /
2d: Due to positive pressure ventilation the in-
trathoracic pressure increases, so that pressure
around the left ventricle (pressure outside) in-
creases and therefore the transmural pressure
P (difference between the pressure inside and
the pressure outside of the left ventricle) and
therefore the wall tension T decreases. Thereby
the afterload (exactly defined as the wall tension
of the left ventricle during the systolic ejection
period) decreases.
▪▪ The increased gradient between the intrathora-
cic (high pressure) and the extrathoracic (low
 pressure) pressure has the effect that blood can -- mucosal edema, ulcerations, granulomas, vocal
be pumped easier from the heart to the systemic chord immobility
circulation. -- occurs in 73 % of all cases after ventilation (Tadie et
• pulmonary: al, Intensive Care Med 2010)
-- VALI (ventilator associated lung injury)
-- pulmonary vascular resistance ↑ (PA pressure ↑
[pulmonary hypertension])
-- oxygen toxicity
-- VAP (ventilator-associated pneumonia)
◦◦ main cause for sepsis and hence most frequent
cause of death in intensive care units!
◦◦ main complication of (invasive) ventilation positive
pressure
◦◦ occurrence: ventilation
▪▪ 7% of all patients ventilated for > 48h lowering of the
increased left
▪▪ 75% of all patients ventilated for > 10 days ventricular filling
• abdominal: increase of the intra-abdominal pressure
(IAP); consequences: decreased decreased
pressure difference
-- intestinal (hypoperfusion in the splanchnic area → preload extrathoracic - intrathoracic
afterload
motility ↓, bacterial translocation, ischemia)
-- renal (renal perfusion ↓ → renal failure) Fig. 168  impact of ventilation on pre- and afterload: The
-- hepatic (hepatic perfusion ↓ → hepatic failure) positive pressure ventilation leads to a decrease of the (left
ventricular) pre- and afterload.
-- pulmonary (diaphragmatic elevation; extrathoracic
restriction; increased ventilation pressures required)
pressure outside
-- cardiac (intrathoracic pressure ↑­ → preload ↓, after-
(intrathoracic
load ↑)
pressure)
-- cerebral (intracranial pressure ↑­)
• cerebral: Due to the positive pressure ventilation, the
venous backflow to the right heart decreases. This re-
duces the cerebral venous drainage and the intracra- transmural
nial pressure increases. pressure P
• renal: pressure radius r
-- The decrease of the CO (cardiac output) leads to a inside
decrease of the renal perfusion (prerenal acute kid-
ney failure).
-- Due to the positive pressure ventilation, the venous
backflow to the right heart decreases, so that the ve-
nous pressure in the kidney increases (venous con-
gestion) adn the GFR decreases.
-- Due to the positive pressure ventilation and the re-
duced the venous backflow to the right heart and the wall thickness d
compression of the pulmonary capillaries the filling Fig. 169  Laplace´s law (T = P x r / 2d): The left ventricle (red)
of the left atrium is decreases. This leads to an in- is simplified considered as a ball (sphere). Positive pres-
creased ADH-release. This causes a decrease of sure ventilation increases the intrathoracic pressure and
the diuresis and leads to water and sodium retention therefore the pressure around the left ventricle (pressure
outside). Therefore the transmural pressure P (difference
(hyponatremia) and edema!
between the pressure inside and the pressure outside of
-- SIADH: Ventilation with a high PEEP may cause a the left ventricle) decreases. Consecutively the wall tension
SIADH (consequence: hyponatremia). T decreases. The wall tension during the systolic ejection
-- activation of the RAAS (renin-angiotensin-aldostero- period is defined as the afterload. It is a measure of the
ne system) workload of the left ventricle. Due to the high intrathoracic
pressure (pressure around the left ventricle) the left ven-
-- increase of the intra-abdominal pressure → decrea-
tricle is supported at contraction and ejection ("help"), so
se of the renal perfusion pressure that its work is facilitated and the workload reduced
• hepatic: The decreased venous backflow to the right
heart causes liver congestion (i.a. liver function rea-
dings ↑). The decreased cardiac output due to ventila- ventilation & heart:
tion as well as the increased intra-abdominal pressure left ventricular:
lead to a reduced liver perfusion. preload ↓ + afterload ↓
• tracheal: tracheal stenosis (a side effect especially in right ventricular:
long-term ventilation) preload ↓ + afterload ↑
• laryngeal: laryngeal damage

General Part 99

"nitro-effect" of the ventilation:
decrease of the left ventricular
preload → left shift of the Frank-
Starling-curve!
Impact of the ventilation on the
cardiac output (CO):
normo-/hypovolemic: CO ↓
hypervolemic: CO ↑
Fig. 170  CT scan of the neck: tracheal stenosis (a possible
complication after long-term ventilation; various examples)
VALI (ventilator associated lung injury)
syn.: VILI (ventilator induced lung injury), "respirator
lung"
• barotrauma (e.g. pneumothorax [RAP: respirator-as-
sociated pneumothorax]; increased risk particularly in
case of viral infections or pneumocystis jiroveci)
100 General Part
• volutrauma (overdistension of the alveoli)
• atelectotrauma (overdistension of the alveoli [shear
stress] → i.a. damage to type II pneumocytes [alveolar
macrophages] → surfactant ↓)
• biotrauma
-- overdistension of the alveoli → release of pro-in-
flammatory cytokines ↑ (mechanotransduction) →
systemic inflammation
-- the main cause of death in case of ARDS: septic
multi-organ failure (not the therapy-refractory hypo-
xemia!)
• VIDD (ventilator-induced diaphragmatic dysfunction)
Ventilation parameters
• pressure controlled ventilation: ventilation pressu-
res (inspiratory pressure, PEEP), pressure rise time
(ramp)
• volume controlled ventilation: respiratory minute volu-
me, inspiratory flow, plateau
• respiratory rate
• I:E ratio
• trigger (in spontaneous breathing modes)
Usually there are several options to optimize ventilation:
Basically, you should always "twiddle a knob" first and
then check the result by performing a BGA after 30 min.
As a general rule, you should adjust the ventilator to the
patient and not adjust the patient to the ventilator.
Respiratory rate
• In many textbooks on artificial ventilation, a respiratory
rate of 10-12/min is indicated as the standard setting.
Also, most of the ventilators today still have a standard
setting of 10-12/min, which is complete nonsense.
• The respiratory rate should rather be set higher: 16-
30/min (especially in case of ARDS 20-30/min: Here a
lung-protective ventilation has to be performed which
includes low tidal volumes [6 ml/kg]. This, in turn, re-
quires a higher respiratory rate to attain a sufficient re-
spiratory minute volume.)
• The upper limit is a ventilation rate of 30/min. Eve-
rything beyond this rate would lead to a dynamic hy-
perinflation and to an increased dead space ventilation
The standard respiratory rate
today is 16-20/min (no longer
10-12/min)!
Trigger
• definition: possibility to recognize the patient's own in-
spiratory efforts with the help of the ventilator (monito-
ring of the diaphragm activity) and to give synchronous
mandatory breaths
• A trigger is only set in assisted (augmented) ventilation
modes (spontaneous breathing modes [e.g.. CPAP-
ASB]), not in controlled (mandatory) ventilation.
• principle:
 -- If the trigger is set too high, the work of breathing
(WOB; breathing effort) increases and this leads to
exhaustion.
-- If the trigger is set too low, causes other than the
patient's own inspiratory efforts (e.g. manipulation of
ventilator settings, water in tube system) may also
trigger mandatory breaths ("auto-trigger", "external
trigger").
• types:
-- according to technology
◦◦ pressure-triggering:
▪▪ After exceeding a certain negative pressure built
up in the patient's thorax during inspiration, the
ventilator gives a mandatory breath.
▪▪ usually 2 mbar below the PEEP
▪▪ obsolete today
◦◦ flow-triggering:
▪▪ After exceeding a certain flow rate (gas flow)
threshold built up in the patient's thorax during
inspiration, the ventilator gives a mandatory
breath.
▪▪ usually 2-4 l/min (in case of spontaneous brea-
thing: 0.5- 1 l/min)
▪▪ standard today
-- according to ventilation phase
◦◦ inspiratory trigger
◦◦ expiratory trigger (syn.: "cycling off", inspiratory
termination): The expiratory trigger (a flow trigger)
determines the time to switch from inspiration to
expiration. The default setting is usually 25%, me-
aning the ventilation machine only stops inspirati-
on when the inspiratory flow has fallen 25% below
the maximum flow (peak flow). In case of an obs-
truction this takes very long and extends the total
inspiratory time which is not very desirable (the
aim is a long expiratory time). Therefore the ex-
piratory trigger here should usually be set at 60%.
A drop below 60% of the maximum flow already
causes the ventilator to switch from inspiration to
expiration. On the other hand, the expiratory trig-
ger should be set lower in patients suffering from
muscle weakness or obese patients, i.e. < 25%.
Fig. 171  setting the trigger (inspiratory trigger; standard
today: flow trigger)
inspiration
flow (l/min)
0
time (s)
inspiratory trigger
expiration
Fig. 172  inspiratory trigger: If the negative pressure gene-
rated by the patient himself exceeds a certain threshold
value (flow; highlighted in yellow), the ventilator gives a
breath.
inspiration
flow (l/min)
peak flow
expiratory trigger (25%)
0
time (s)
expiration
Fig. 173  expiratory trigger: If the inspiratory flow drops
below 25% of the maximum inspiratory flow (peak flow), the
ventilator switches from inspiration to expiration.
Plateau
• post-inspiratory phase during which both the inspirato-
ry and the expiratory valve stay closed
• syn.: no-flow-phase
• redistribution of breathing gas from compartments with
a short time constant to compartments with a long time
constant (oscillating air) → improved oxygenation
• only used in volume-controlled ventilation
• In the first part of the inspiration (flow phase) the gas
volume is blown into the lung gets inflated (inflation
time). The maximal pressure, which is achieved in the
inspiration, is called peak pressure. In the second part
of the inspiration (no-flow phase) there is a pause with
no gas flow (inspiratory pause, inflation hold, plateau):
In this time the breathing gas distributes in the lung
as uniformly as possible. The pressure decreases. The
pressure at the end of the inspiration is called plateau
pressure. Hence the inspiration time is composed of
the inflation time an the inspiratory pause.
• In a volume-controlled ventilation there are 2 inspira-
tory pressures:
-- peak pressure (higher; mainly depends on the re-
sistance
General Part 101
 -- plateau pressure (lower; mainly depends on the
compliance)
peak pressure
pressure (mbar)
plateau
plateau pressure
inspiration expiration
inflation inspiratory
time pause
Fig. 174  illustration of the plateau with the respective pres-
sures
Pressure rise time
• syn.: rampe, slope
• parameter for pressure-controlled ventilation to preset
the time for pressure increase (time in seconds until
the ventilator reaches the set inspiratory pressure )
• threshold:
-- If the time is set too short (ramp too steep), the
high flow may cause the patient to exhale ("press")
against the ventilator, which may temporarily increa-
se the intrapulmonary pressure.
-- If the time is set too long (ramp too flat), it may lead
(especially when only a short inspiratory time is set,
e.g. in case of an obstruction [here, the I:E ratio is
usually set to 1:3]) to incomplete inspiration. Further-
more, work of breathing increases during spontane-
ous breathing procedures due to the low flow.
• Experience has shown that the pressure rise time
should rather be set short (i.e. rather steep ramp; 0.1-
0.2 s; particularly during spontaneous breathing).
• The higher the respiratory drive of the patient (e.g.
tachypnea, high RMV), the steeper the ramp and the
shorter the pressure rise time should be set.
• Especially in case of obstructive lung diseases, a short
pressure rise time (i.e. a steep ramp) should be set in
order to quickly overcome the pressure in the bronchial
system. This applies especially to the weaning of these
patients: The shorter the pressure rise time, the lower
is the work of breathing. In case of restrictive pulmo-
nary diseases (especially pulmonary fibrosis, obesity),
however, a rather a long pressure rise time (i.e. flat
ramp) should be set.
102 General Part
Fig. 175  eetting of the ramp (pressure rise time)
pressure rise time:
- obstruction: short (steep ramp)
- restriction: long (flat ramp)
Types of ventilation
• according to the type of pressure:
-- positive pressure ventilation (PPV; standard)
-- negative pressure ventilation (NPV; vacuum ventila-
tion, rarity):
◦◦ "iron lung" (metal tank ventilator [used during the
polio epidemic])
◦◦ cuirass device (rigid breast plate; BCV: biphasic
cuirass ventilation)
• according to the extent of respiratory assistance:
-- controlled (syn.: mandatory) ventilation (CMV: cont-
rolled / continuous mechanical / mandatory ventila-
tion): The work of breathing is complitely taken over
by the ventilator. There is no spontaneous breathing.
The ventilator determines the respiratory rate!
◦◦ pressure-controlled ventilation (PCV; standard in
Europe)
◦◦ volume-controlled ventilation (VCV; standard in
America)
-- assisted (syn.: augmented) ventilation (IPPB: inter-
mittent positive pressure breathing): The work of
breathing is only partially taken over by the venti-
lator. There is spontaneous berathing, which is only
supported. A trigger is set. The patient determines
the respiratory rate!
• according to invasiveness:
-- invasive ventilation (IV; via tube or tracheal cannula)
-- non-invasive ventilation (NIV; see chapter on non-
invasive ventilation [page <?>])
• according to the control mechanism (guiding the
change from inspiration to expiration)
-- pressure-guided
-- volume-guided
-- flow-guided
-- time-guided (standard)
Ventilation methods
There is a bewildering variety of ventilation methods,
which shall be mentioned here for the sake of comple-
teness. However, we only use two ventilation methods
in our clinic: BIPAP (pressure-controlled [PCV]) for con-
trolled ventilation and CPAP-ASB [pressure-supported
ventilation (PSV)] for weaning. We pretty much never
use the other ventilation methods..
Ventilation methods in a nutshell:
standard mode: BIPAP, for weaning:
CPAP-ASB
Controlled ventilation
• indications:
-- reduction of the oxygen consumption (especially
in shock: There is an imbalance between oxygen
supply and oxygen demand. A deep analgosedation
can reduce the oxygen consumption. This, however,
has the disadvantage that the patient must be ven-
tilated.)
-- recovery of the respiratory musculature in case of
obvious exhaustion
-- protection against possible aspiration in somnolent /
comatose patients ("protective" intubation)
-- strict pCO2 setting (especially for treatment of int-
racranial hypertension)
• modes:
-- pressure-controlled (PCV: pressure-controlled venti-
lation; PC-CMV: pressure-controlled continuous me-
chanical ventilation)
-- volume-controlled (VCV: volume-controlled ventilati-
on; VC-CMV: volume-controlled continuous mecha-
nical ventilation)
Pressure-controlled ventilation (PCV)
• standard mode of ventilation in Europe
• There is no evidence that pressure-controlled ventila-
tion is better than volume-controlled ventilation (i.a.
Esteban et al, Chest 2000; Branson et al, Resp Care
2007; Chacko et al, Cochrane Database Syst Rev
2015).
• The ventilator emits the breathing gas during the set
inspiratory time with a constant, preset pressure (de-
celerating flow).
• pressure constant ventilation (constant pressure le-
vel): The pressure is maintained during the whole in-
spiration.
• The resulting volume (tidal volume [TV]) is determined
by:
-- pressure difference ("driving pressure") between the
inspiratory pressure (IPAP [inspiratory positive air-
way pressure]) and expiratory pressure (PEEP [po-
sitive end-expiratory pressure])
-- resistance and compliance of the respiratory system
(lung, thorax)
-- inspiratory time
• The ventilation pressure determines the tidal volume.
• lower risk of barotrauma (e.g. pneumothorax) than with
volume-controlled ventilation, since pressures peaks
are avoided
• In the beginning of the respiratory cycle the set pres-
sure is tried to achieve with high flow. In the course the
flow is decreased by the internal control (decelerating
flow), so that pressure peaks are avoided. In a pressu-
re-controlled ventilation there is no distinction between
peak pressure and plateau pressure, nor is there any
plateau here.
• ventilation parameters:
-- primary (independent): pressure (ventilation pressu-
re)
-- secondary (dependent): volume (tidal volume [TV])
• settings:
-- inspiratory pressure (IPAP [inspiratory positive air-
way pressure])
-- PEEP ((positive end-expiratory pressure))
-- respiratory rate
-- I:E ratio
-- RMV monitoring
• pressure alarm for monitoring patient-induced pressu-
re increases (e.g. "pressing", coughing)
• A drop of the tidal volume can be caused by:
-- airway obstruction, kinking of tube
-- increased airway resistance
-- reduced elasticity (compliance) of the lungs or thorax
-- coughing / "pressing" of the patient
General Part 103

pressure
flow
volume
inspiration expiration
Fig. 176  pressure-controlled ventilation (PCV)
Volume-controlled ventilation (VCV)
• standard mode of ventilation in America (USA)
• The ventilator delivers a preset tidal volume (TV) within
the set inspiratory time (constant flow).
• syn.: IPPV (intermittend positive pressure ventilation)
• volume constant ventilation (constant volume level):
• The resulting pressure (ventilation pressure) is deter-
mined by:
-- tidal volume
-- resistance and compliance of the respiratory system
(lung, thorax)
-- inspiratory time
• The tidal volume determines the ventilation pressure.
• ventilation parameters:
-- primary (independent): volume (tidal volume [TV])
-- secondary (dependent): pressure (ventilation pres-
sure)
• settings:
-- tidal volume (TV)
-- respiratory rate
-- I:E ratio
-- inspiratory flow
◦◦ flow rate (common approx. 30 l/min)
▪▪ speed of the ventilator emitting the breathing
gas during inspiration (syn.: peak flow; unit: l/
min)
▪▪ The higher the inspiratory flow, the higher is the
ventilation pressure (peak pressure). High flow
rates induce turbulences, which heighten the
airway resistance.
◦◦ flow profiles (patterns)
▪▪ constant ("rectangle" flow; standard today)
▪▪ decelerating (especially for conscious patients):
Initially the flow is higher and then decreases.
This corresponds better to the pressure increa-
se in the lung.
▪▪ sinusoidal (obsolete today)
-- pressure limit (If the set pressure limits are excee-
ded, the not delivered volume is released [very simi-
lar to the principle of the steam cooker].)
• In the first part of the inspiration (flow phase; inflation
phase) the preset volume is applicated into the lung,
that leads to relativ high peak perssure. In the second
part of the inspiration (no-flow phase; plateau phase)
the breathing gas distributes in the lung uniformly. The
pressure decreases. The pressure at the end of the
inspiration is called plateau pressure.
• changes of the ventilation pressure
-- An increase of the ventilation pressure can be
caused by:
◦◦ airway obstruction, kinking of tube
◦◦ increased airway resistance
◦◦ reduced elasticity (compliance) of the lungs or tho-
rax
◦◦ coughing / "pressing" of the patient
-- A decrease of the ventilation pressure is mostly
caused by a leakage.
• assessment:
-- advantage: Compared to pressure-controlled ven-
tilation, volume-controlled ventilation leads to less
desynchronisations and derecruitments. Therefore,
some clinics perform a volume-controlled ventilation
in the early phase of a severe ARDS.
-- disadvantages:
◦◦ often high ventilation pressures, so that the volu-
me controlled ventilation was almost completely
abandoned in Europe
◦◦ higher risk of barotrauma (e.g. pneumothorax)
than in pressure-controlled ventilation
◦◦ no automatic leakage compensation
• Emergency ventilators (e.g. Medumat, Oxylog) provi-
de a volume-controlled ventilation. However, the latest
generations also allow pressure-controlled ventilation.
Anaesthesia ventilators (circuits) in the operation room
provide both pressure- and volumed-controlled ventila-
tion. Especially in case of abdominal surgery procedu-
res often volumed-controlled ventilation is used.
• special mode: noisy ventilation
-- ventilation with different tidal volumes (generated
randomly)
-- both for volume-controlled (noisy-VCV: randomly dif-
ferent tidal volumes) and pressure-controlled (noisy-
PSV: randomly different inspiratory pressures) ven-
tilation
-- extremely lung-protective (Gama de Abreu, Crit
Care Med 2008; Spieth et al, AJRCCM 2009 [impro-
vement of oxygenation in animal models])
-- no clinical use yet

104 General Part

 pressure

flow (l/min)
sinusoidal

time (s)

flow

Fig. 178  the three different flow profiles (patterns of the

volume inspiratory flow) in volume-controlled ventilation: The con-
stant flow (“rectangle” flow) is standard today. The decele-
rating flow is mainly used in conscious patients, the sinu-
soidal flow is no longer used today.

inspiration espiration
Fig. 177  volume-controlled ventilation (VCV)

inspiration
flow (l/min)

constant

time (s)

Fig. 179  IPPV (intermittend positive pressure ventilation):

a typical volume-controlled ventilation (annot.: The correct
term is continuous positive pressure ventilation [CPPV],
because there is continuously a positive perssure in the
airway and not only in the inspiration. Strictly speaking
in IPPV there is no positive perssure in the expiration (no
expiration PEEP).
flow (l/min)

Flow:
- pressure-controlled ventilation:
decelerating decelerating
- volume-controlled ventilation:
constant

time (s)
Ventilation pressures
• inspiratory pressures:
-- peak pressure
-- plateau perssure
• expiratory pressure: The pressure at the end of the ex-
piration os called PEEP.
• mean airway pressure (MAP): the average pressure
generated during the respiratory cycle
• units:

General Part 105

 -- 1 mbar = 1 cmH20
-- 1 mmHg = 1.36 cmH20
peak pressure

pressure (mbar)
Inspiratory pressures
The distinction between peak pressure and plateau plateau pressure
pressure is only made in volume- and not in pressure-
controlled ventilation. In case of a pressure-controlled
ventilation there is always the same pressure during the
inspiration (a pressure constant ventilation with only one
pressure level). Practically there is no peak pressure. In PEEP
case of a pressure-controlled ventilation one speaks only
of the inspiratoy pressure (inspiratory airway pressure
[IPAP]). inspiration expiration
• peak pressure
flow-phase no flow-
-- the maximum pressure in the inspiration (pressure at phase
the end of inflation time), the maximum airway pres-
Fig. 180  the different ventilation pressures in a volume-
sure during the entire respiratory cycle controlled ventilation: There are two inspiratory pressures
-- higher than the plateau pressure (peak pressure and plateau perssure) and one expiratory
-- dependant on the resistance (e.g. relevant in obs- pressure (PEEP). The maximum pressure during the inspi-
tructive lung diseases [bronchial asthma, COPD], ration is the peak pressure, the pressure at the end of the
inspiration the plateau pressure. The pressure at the end of
relatively small tube diameter, high inspiratory flow
the expiration is called PEEP.
[turbulences]); A disorder of resistance (e.g. bron-
chospasm, ob­ struction by mucos) increases the
peak pressure. In oropharyngeal surgery for ex- peak pressure: dependent on resi-
ample because of the limited space often tubes with stance
small diameter (seize 5-6) are used, which lead to plateau pressure (decisive for the
increased peak pressures. If a tracheostoma (seize alveolar pressure): dependent on
10) is performed during the procedure, the airway com­pliance
resistance und hence the peak pressure significantly
decrease.
-- dependant on the inspiratory flow (The higher the in-
spiratory flow, the higher is the peak pressure.)
pressure (mbar)

• plateau pressure
-- pressure at the end of the inspiration (therefore syn.:
endinspiratory pressure)
-- lower than the peak perssure
-- depending on the compliance (A disorder of the com-
pliance [e.g. decrease of the elasticity of the lung in
ARDS] increases the plateau pressure.)
-- independant of the inspiratory flow
-- The decisive pressure for the pressure in the alve-
oli (alveolar pressure; i.a. responsible for ventilator-
associated lung injuries) is the plateau pressure and
not the peak pressure. The peak pressure is indeed
higher, but there is still a gas flow (flow phase). That
is no longer the case at the plateau perssure (no flow inspiration expiration time
phase). As long as a flow is available, the pressure in Fig. 181  impact of different inspiratory flow rates (speed of
the alveolus (alveolar pressure) is still smaller than the ventilator emitting the breathing gas during inspiration)
the pressure in the airways (airway pressure). during a volume-controlled ventilation: high (blue), middle
(black) and low (red). The higher the inspiratory flow rate,
the higher is the peak pressure. This is because a high flow
rate causes turbulences which increase the airway resis-
tance and therefore the peak pressure. The plateau pressu-
re remains unchanged. The higher the inspiratory flow rate,
so longer also gets the plateau phase.

106 General Part


pressure-controlled
pressure (mbar)
ventilation
inspiration
volume-controlled
pressure (mbar)
ventilation
inspiration
Fig. 182  different pressure profiles (pattern): In case of a
pressure-controlled ventilation there is a rectangle profile
(pressure constant), in case of a volume-controlled ventila-
tion (when no plateau phase is set) a triangle profile.
PEEP
• positive end-expiratory pressure
• positive pressure level at the end of expiration (pres-
sure at the end of the expiration)
• usually 5-20 cmH2O ( PEEP should always be set
> 5 cmH2O! Due to the tube a closure of the glottis is
no longer possible, so that the endexpiratory pressure
would decrease to zero. This should be avoided since
is induces atelectasis.)
• terms:
-- if PEEP = 0 cmH2O: ZEEP (zero end-expiratory
pressure; should be avoided) → IPPV (intermittend
positive pressure ventilation: This dates from former
times, when a PEEP was not yet routinely used.
There was a positive perssure in the airways only
during inspiration. This is obsolete today.)
-- if PEEP > 0 cmH2O → CPPV (continuous positive
pressure ventilation; standard today)
• types:
-- extrinsic-PEEP (PEEP applied by the ventilator)
-- intrinsic-PEEP (PEEP caused by a non-complete
exhalation)
• effective PEEP = extrinsic-PEEP + intrinsic-PEEP
• effects (analogous to CPAP):
-- reduction of the work of breathing (for Eexplanati-
on see compliance-curve in chapter CPAP on page
<?>)
-- improvement of oxygenation
-- reduction of end-expiratory alveolar collapse (pre-
vention of cyclic alveolar collapse ["alveolar cyc-
ling"])
-- improvement of breathing gas distribution
-- increase of FRC (functional residual capacity: volu-
me that remains in the lung after a normal expiration)
-- reduction of atelectasis (larger pulmonary gas ex-
change surface) → decrease of intra-pulmonary
right-to-left shunt
-- reduction of extravascular lung water (EVLW ↓;
PEEP pushes the water from the alveoli back into
the blood vessels)
• principle (of the PEEP setting):
-- PEEP too low → development of atelectasis (dere-
cruitment) with the result that a shunt develops (al-
veoli are still perfused but no longer ventilated). The
oxygenation is disturbed (pO2 ↓).
-- PEEP too high:
◦◦ hyperinfaltion
◦◦ overtension (hyperinfaltion) of the alveoli with com-
pression of the adjacent capillaries and therefore
increased dead space ventilation (dead space:
alveolus still ventilated, but no longer perfused).
The increasing dead space ventilation leads to a
decrease of the alveolar (i.e. effective) ventilation
so that the pCO2 rises.
◦◦ increase of the right-ventricular afterload due to
capillar compression (PAP ↑, PVR ↑)
◦◦ decrease of the venous blood backflow to the
heart (right- and leftventricular preload ↓), decrea-
se of the cardiac output (unless hypervolemic)
◦◦ increase of intracranial pressure
◦◦ increase of intra-abdominal pressure (i.a. renal fai-
lure, hepatic failure
• for more information on setting the PEEP ("best
PEEP") see chapter on ARDS (page 700)
PEEP too low → atelectases →
shunt → pO2 ↓ (hypoxemia)
PEEP too high → overtension →
dead space → pCO2 ↑ (hypercap-
nia)
PEEP: improves the left ventricular but
worsens the right ventricular function!
Intrinsic-PEEP
• syn.:
-- auto-PEEP
-- airtrapping
• physiologically 0.5-2 mbar (because of the resistance
of the glottis and the upper airways)
• occurrence:
-- obstructive pulmonary disease (main cause for an
intrinsic-PEEP)
-- inverse ratio ventilation (IRV): In the past, ARDS was
treated by inverse I:E ratio ventilation (e.g. I:E 2:1).
General Part 107
 An intrinsic PEEP was created by intentionally shor-
tening the expiratory time in order to avoid alveolar
collapse. However, the intrinsic-PEEP is only difficult
to control, so this kind of treatment was abandoned.
In order to improve oxygenation, one should be bet-
ter work with the extrinsic-PEEP, which can be set on
the ventilator and is therefore better to control.
-- respiratory rate set too high
• redistribution of breathing gas from compartments with
shorter time constant to compartments with a longer
time constant (oscillating air) → improvement of oxy-
genation
• iI it is too high, it leads to a dynamic hyperinflation (air
trapping, typical of obstructive pulmonary diseases)
with increased mean airway pressure. The resting
end-expiratory position is higher and the inspiratory
load increases. The energy consumption is increased
• measurement of the intrinsic-PEEP
-- by closing the expiration side of the tube for 10-30
seconds s at the end of the expiration (e.g. Evita:
expiration hold) → set 80% or 2/3 of the measured
intrinsic-PEEP as PEEP for ventilation of a patient
with obstructive pulmonary disease (particularly in
case of COPD)
-- For this purpose, the patient should preferably be
relaxed!
• One should also always look at the the flow curve on
the ventilator (for pressure-controlled ventilation): The
end-expiratory flow should be zero to avoid hyperin-
flation.
• In case of assisted spontaneous breathing (CPAP-
ASB), first the intrinsic-PEEP has to be decreased
before the pressure drops in the alveoli and the ven-
tilator starts to trigger. These "missed efforts" (= non-
triggered inspiratory efforts; recognizable in the flow
curve [for pictures see page 699]) lead to a massive
increase of work of breathing.
• reduction of the intrinsic-PEEP by extending the expi-
ratory time
-- I:E 1:2/1:3
-- decrease of the respiratory rate to 10-12/min (no
"down-ventilation" of an increased pCO2 by increa-
sing the respiratory rate!)
-- if necessary, decompression maneuver: A very long
expiratory time is set for a few cycles (under suffici-
ent sedation). If the tidal volume increases, it was
successful.
• also see chapter "obstructive pulmonary diseases"
(page 702)
Special modes: dual-controlled ventila-
tion modes (hybrid modes)
Special modes of ventilation nowadays allow both
pressure- and volume-controlled ventilation (i.e. dual-
controlled; "hybrid" ventilation modes). The pressure is
adjusted and set as low as possible (limited pressure) to
reach the preset tidal volume. These ventilation modes
have different names, depending on the company and
the control mode (time or flow):
• time-controlled:
108 General Part
-- adaptive pressure ventilation (APV; Hamilton com-
pany bzw. Galileo [Bennet])
-- pressure regulated volume controll (PRVC; Siemens
company [Servo 300])
-- Autoflow (Dräger company [Evita])
• flow-controlled: volume support (VS; triggered by pati-
ent; Siemens company [Servo 300])
APV
• adaptive pressure ventilation
• a pressure-limited time-controlled ventilation (like
PRVC)
• Hamilton company or Galileo (Bennett)
• It is a pressure-controlled ventilation with a preset tidal
volume.
• The pressure is automatically adjusted and set as low
as possible (limited pressure) to reach the preset tidal
volume.
• The device measures the compliance, resistance and
the intrinsic-PEEP (auto-PEEP) during a series of
mandatory breaths.
• The I:E ratio is constantly adjusted to avoid hyperinfla-
tion (intrinsic-PEEP).
• In the SERVE-HF study (Cowie et al, N Engl J 2015)
APV showed an increased mortality in home-ventilated
patients with central sleep apnea syndrome and heart
failure.
PRVC
• pressure-regulated volume control
• a pressure-limited time-controlled ventilation (like APV)
• Siemens company (Servo 300, Servo i)
• application of a tidal volume with a as low as possible
pressure (pressure-limited)
• distinguishing features:
-- In contrast to a purely volume-controlled ventilation,
the flow here is not constant, but decelerating.
-- In contrast to a purely pressure-controlled ventilati-
on, the pressure (inspiratory pressure) here is not
constant, but variable. The pressure varies depen-
ding on the targeted volume and the respiratory me-
chanics (compliance, resistance).
Autoflow
• a special volume-controlled ventilation
• additional setting for Dräger (Evita) for volume-cont-
rolled ventilation modes (e.g. IPPV / AutoFlow)
• a pressure-controlled volume-constant ventilation
• automatic control of the inspiratory flow (adaptation to
the respective resistance and compliance) in volume-
controlled ventilation
• The ventilator automatically calculates the compliance
and resistance and then determines the gas flow that
is necessary to reach the set tidal volume.
• This is to make sure that the set tidal volume is reached
with the lowest possible pressure.
• At any time of the cycle, the patient can breathe spon-
taneously.
• IPPV / AutoFlow is an option for the ventilation of pati-
 ents with ARDS: here, a tidal volume of 6 ml/kg (max.)
would be necessary. With BIPAP, which is a pressure-
controlled ventilation mode, only the pressures can be
set but not the tidal volume (only a variable size). With
IPPV / AutoFlow, which is an volume-controlled ventila-
tion mode, the desired tidal volume can be set and the
application of high pressures is avoided at the same
time. In the ARDS Network Study (see page 706), all
patients received volume- and not pressure-controlled
ventilation! IPPV / AutoFlow can also be used in the
early phase of a severe ARDS, if a completely manda-
tory ventilation without spontaneous breathing is inten-
ded. However, there is no clear advantage over BIPAP.
Fig. 183  IPPV - Autoflow
PLV
• pressure limited ventilation (Dräger company)
• The closer the measured pressure gets to the set ma-
ximum pressure, the more the inspiratory flow decre-
ases.
Augmented (syn.: assisted) ventilation
• assist-control ventilation (ACV); syn.: AMV (assisted
mechanical ventilation), SCMV (synchronized CMV)
• SIMV (synchronized intermittend mandatory ventilati-
on)
• inspiratory pressure support
• BIPAP (biphasic positive airway pressure)
• APRV (airway pressure release ventilation)
• MMV (mandatory minute ventilation)
• modern weaning procedures:
-- PAV (proportional assist ventilation)
-- ASV (adaptive support ventilation)
-- NAVA (neurally adjusted ventilatory assist)
ACV
• assist-control ventilation
• patient-controlled switch from expiration to inspiration
when the trigger threshold is reached
• The assisted mandatory breath corresponds to the
controlled mandatory breath.
• setting: trigger threshold
-- pressure trigger (e.g. 1 mbar below the PEEP; ob-
solete today)
-- flow trigger (e.g. 0.5-1.0 l/min)
SIMV
• synchronized intermittend mandatory ventilation
• combination of spontaneous breathing and mechani-
cal breaths that can be triggered by the patient
• the set mandatory breaths provide a minimum venti-
lation of the patient (SIMV-frequency [6-8/min], SIMV-
tidal volume or SIMV-ventilation pressure).
• within a specific time window prior to the delivery of the
mandatory breath, the patient can trigger the breath
himself.
• In case of a complete absence of spontaneous brea-
thing, the SIMV-ventilation corresponds to a normal
controlled ventilation.
• SIMV is possible both as pressure-controlled (PC-
SIMV) as volume-controlled (VC-SIMV).
• assessment
-- advantage: backup-ventilation via set SIMV-frequen-
cy
-- disadvantage: no "breath-to-breath support" of the
respiratory pump
• the classic weaning procedure in the past, today lar-
gely obsolete
• The main problem is the poor synchronization: The
respiratory center cannot react quickly enough to the
rapid change between supported and spontaneous re-
spiration. The consequence is that the respiratory mu-
sculature is still active during the supported breaths,
which leads to overload and fatigue of the respiratory
muscles (enormous breathing effort). SIMV is signifi-
cantly worse than CPAB-ASB (Brochard et al, Am J
Resp Care Med 2014).
• no longer recommended in the German S2-guideline
2014 "Prolonged Weaning"
General Part 109
 • settings:
-- ASB (inspiratory pressure support; is usually speci-
fied as ΔPASB, i.e. as a pressure above the PEEP;
example: PEEP 8 mbar, ΔPASB 12 mbar → The pres-
sure that the patient receives during inspiration [PASB]
is 20 mbar.)
-- PEEP
-- pressure rise time (ramp)
-- trigger sensitivity (usually flow trigger with 0.5-1.0 l/
min)
-- apnea ventilation (most important monitoring func-
tion here): switch on
-- inspiratory time limit in case of leakages

pressure
volume 1 time

volume
volume 2

time

Fig. 184  SIMV

SIMV: the classic weaning procedure

in the past, but no longer recommen-
ded today!

Inspiratory pressure support

• spontaneous breathing mode with inspiratory pressure
support (supported spontaneous inspiration)
• Prerequisite is an unimpaired respiratory drive of the
patient!
• syn.:
-- IPS: inspiratory pressure support
-- IFA: inspiratory flow assist
-- PSV: pressure support ventilation (Siemens)
-- ASB: assisted spontaneous breathing (Dräger)
• The patient breathes himself, he only receives pressu-
re support (ASB) during inspiration. This is no ventilati-
on method in the stricter sense, since the patient alrea-
dy breathes spontaneously, but merely a spontaneous
breathing method.
• The patient and not the ventilator determines the res-
piratory rate.
• flow type: decelerating
• designations
-- CPAP-ASB (assisted spontaneous breathing; Drä-
ger) Fig. 185  CPAP-ASB: the weaning method of choice today
-- PSV (pressure support ventilation; Siemens)
• standard weaning method today

110 General Part

CPAP • If an additional pressure support is set, this is known as
• continuous positive airway pressure CPAP-ASB (ASB: assisted spontaneous breathing)..
• spontaneous breathing mode (no ventilation mode
in the narrower sense) with maintenance of positive

pressure
(cm H2O)
airway pressure during the entire cycle ("continuous
PEEP"): There is not only intermittently, but conti-
nuously a positive pressure present. The pressur in
the airways an the lung is sustained above the atmos- 15
pheric pressure..
10
• There is no support of spontaneous breathing here in
inspiration. 5
• CPAP is often incorrectly equated with NIV. CPAP can
0
be invasive but also non-invasive.
• The ventilator ensures a constant positive pressure -5
through the tube or mask: inspiration expiration inspiration expiration
- 10
-- In inspiration, where there is a pressure drop in the
tube, the ventilator increases the gas flow to com- Fig. 186  CPAP (continuous positive airway pressure): A
pensate for the pressure loss. positive perssure is not only present intermittendly (black
-- In expiration, where there is a pressure increase in curve; spontaneous breathing), but continuously (blue cur-
the tube, the ventilator reduces the gas flow to com- ve). The berathing pressure curve is elevated.
pensate for the pressure rise. .
• effects (analogous to the PEEP):
pressure
-- reduction of the work of breathing (The positive pres-
sure pre-streches the lung. Thereby the lung is in the
flat part of the compliance curve, i.e. in the part with
high compliance: Here a significantly lower pressure volume 1 time
(pressure gradient) is necessary to achieve a certain
volume

tidal volume as in the steep part in the beginning of volume 2

the curve, where the compliance is low.
-- decrease of end-expiratory alveolar collapse (pre-
vention of cyclic alveolar collapse ["alveolar cyc-
ling"]) and therefore prophylaxis / treatment of ate- time
lectasis
Fig. 187  CPAP (continuous positive airway pressure)
-- reduction of atelectasis (larger pulmonary gas ex-
change surface) → decrease of intra-pulmonary
right-to-left shunt → improvement of oxygenation
(cm H2O)
pressure

-- improvement of breathing gas distribution

-- increase of FRC (functional residual capacity: volu-
me that remains in the lung after a normal expiration)
-- improvement of coronary perfusion; reasons:
◦◦ Due to the positive pressure less blood flows into 15
the right atrium, so that the perssure in the right
atrium (RA-pressure) decreases and therefore the 10
coronary perfusion pressure CCP (CPP = RRdias -
RA-Druck) increases. 5
◦◦ Due to the positive pressure the intrathoracic pres-
VT
sure increases, so that the wall tension of the left 0
0,5 1,0 1,5 (liter)
ventricle decreases: The coronary arteries are
less compressed.
• settings:
-- CPAP prophylactically (prophylaxis of atelectasis): 5
cmH2O
-- CPAP therapeutically (therapy of atelectasis): 10
cmH2O
• No mandatory breaths delivered. Prerequisite is an in-
tact respiratory drive of the patient!
• Since this is no ventilation mode, ventilation is not pos-
sible with CPAP.
• most important monitoring function: apnea monitoring
(apnea ventilation)

General Part 111

Fig. 188  Here the volume-pressure curve (VP-curve; syn.:
compliance curve; analogous to the pressure-volume cur-
ve [PV-curve: see page <?>], only that abscissa and or-
dinate are exchanged here) is shown. The relationship is
not linear, but sigmoidal (S-shaped): The initial part (red) is
steep (low compliance): Here a significantly higher pressu-
re (pressure gradient Δp) is necessary to achieve a certain
tidal volume (VT) as in the middle part: Here the curve is
flat (blue; high compliance). If you start at a pressure of
0 cmH2O, then 10 cmH2O are necessary to achieve a tidal
volume (VT) of 0.5l. But if you start already at a pressure of
10 cmH2O, only additional 5 cmH2O (alltogether 15 cmH2O)
are necessary to achieve a tidal volume (VT) of 0.5l. This is
the purpose of CPAP: The lung is prestreched, so that the
lung is in the flat part of the compliance curve, where the
work of breathing is significantly lower. The effect of PEEP
is analogous.
Fig. 189  The lung can be compared with a balloon: At the
beginning the inflation is very exhausting (steep part of the
compliance curve). You need a high pressure, only to get
a little bit volume (air) inside. But as soon as some air is
inside and the balloon is slightly prestreched, the infalti-
on is much more easier and you only need a low pressure
(flat part of the compliance curve). Due to CPAP the balloon
(analogous the lung) is a little bit inflated, so that the work
of breathing is reduced (thanks to my son Lukas).
the both main effects of CPAP (analo-
gous PEEP): decrease of work of
breathing and decrease of atelectasis
and therefore shunts!
112 General Part
CPAP is no ventilation method, but a
spontaneous breathing mode!
pressure
spontaneous
breathing CPAP CPAP-ASB
IPAP
ASB
PEEP
(EPAP)
Fig. 190  presentation of the different pressure levels in
spontaneous breathing, CPAP and CPAP-ASB
BIPAP
• biphasic positive airway pressure (protected trade-
mark of the Dräger company; ≠ BiPAP: bilevel positive
airway pressure [home ventilation device of the Respi-
ronics company, Inc.])
• use:
-- nationally widespread especially in Germany and
Austria (90%; standard vetilation mode here)
-- internationally: not widely used (only 10%)
• syn.: BILEVEL, Bi-Vent, DuoPAP
• fathers of the BIPAP: anesthesiologist Prof. Dr. Herbert
Benzer (1946-2009) and Graduate engineer Marcel
Baum from Austria (Journal "The Anesthetist" 1989:
"BIPAP - a new form of augmented ventilation"); was
initially developed as a ventilation method for weaning
• a pressure-controlled ventilation method (i.e. the two
pressures are set, the resulting tidal volume is variable
[degree of freedom])
• time-controlled cyclic change between two diffe-
rent pressure levels (CPAP-levels [BIPAP = "double
CPAP"])
-- upper pressure level: pmax = p1 = IPAP
-- lower pressure level: pmin = p2 = EPAP = PEEP
• The pressure difference between IPAP and EPAP de-
termines the applied volume (tidal volume).
• The change from the low to the high pressure level
leads to inspiration, the change from the high to the
low pressure level leads to expiration.
• The special feature of BIPAP is the fact, that spon-
taneous breathing is possible
-- on both pressure levels, i.e. on the upper as well as
on the lower pressure level and
-- in both phases of the respiratory cycle, i.e. in the
inspiration as well as in the expiration ("free brea-
thing" in each phase of the respiratory cycle). This
is even possible if a (e.g. also triggered) mandatory
breath is delivered. At any point in the respiratory
cycle, the patient can breathe spontaneously, both
 on the upper and on the lower pressure level. This inspiration
is not the case in a complete controlled (mandatory) tidal volume
ventilation: Spontaneous breathing is not possible
simultaneously with a mandatory breath, because

volume
the expiratory valve is closed during the application
of a mandatory breath in the inspiration and cannot
be opened. In a complete controlled (mandatory) expiration time
ventilation the expiratory valve is opened pneumati-
Fig. 192  BIPAP - volume curve
cally: The mandatory breath is interrupted due to the
increased airway pressure by opening the pneuma-
tic expiratory valve. With BIPAP, the expiratory valve inspiration
opens electronically: Here both the inspiratory and
expiratory valve are virtually always open! gas flow
• The pressure change from the lower to the upper to the patient
pressure level and vice versa is synchronized with the
spontaneous breathing of the patient.

flow
• BIPAP can be disadvantageous in patients with an ob- time
structive ventilatory disease (e.g. COPD), because it gas flow
may lead unnoticed to a significant hyperinflation. This to the ventilator
may be, if the patient triggers a breath in the middle
of the expiration, so that the inspiration starts already, expiration
although the expiration has not been completed yet.
Fig. 193  BIPAP - flow curve
The shortened expiration can lead to a hyperinflation.
However, BIPAP can certainly also be applied here, a
possible hyperinflation must then be treated accordin- pressure
gly (e.g. reduction of the respiratory rate, change of the
I:E ratio to 1:3).
• BIPAP represents an universal ventilation method P1
(smooth transition from complete pressure-controlled IPAP
ventilation to augmented ventilation to spontaneous
breathing):
-- controlled ventilation
-- augmented ventilation
-- spontaneous breathing (p1 = p2 → CPAP-ASB)
• BIPAP-ASB: Pressure-supported spontaneous brea- P2
EPAP
thing can be set on the lower pressure level (BIPAP-
expiration inspiration
ASB). However, there is an increased risk of asyn-
chrony (especially in higher respiratory rates), so that Fig. 194  BIPAP: Spontaneous breathing (blue) is on the
BIPAP-ASB is not recommended generally. It only ma- one hand possible on both pressure levels: on the upper le-
kes sense, if the upper and lower pressure level are vel (p1; IPAP) as well as on the lower level (p2; EPAP, PEEP).
Spontaneous breathing is on the other hand possible in
equal. But then this is p.d. CPAP-ASB.
both phases of the respiratory cycle, i.e. in inspiration as
• settings: well as in expiration. This is enabled by the crucial tech-
-- pmax (IPAP; upper pressure level; aim: < 35 mbar) niqual feature, that the valves are controlled electronically
-- PEEP (EPAP; lower pressure level; aim of the pres- and not pneumatically!
sure gradient Δp = IPAP - PEEP < 15 mbar)
-- respiratory rate (RR 15-30/min)
-- I:E ratio
• special type: APRV (airway pressure release ventila-
tion: BIPAP with inverse-ratio-ventilation; APRV = BI-
PAP + IRV); see page 116

inspiration
P1 = Pmax = Pinsp
pressure

P2 = Pmin = Pexp = PEEP

expiration time
Fig. 191  BIPAP - pressure curve

General Part 113


Fig. 195  BIPAP
BIPAP: standard mode today in
controlled ventilation (at least in
Germany and Austria)
MMV
• mandatory minute ventilation (Dräger)
• syn.: AMV (augmented minute volume)
• a spontaneous breathing mode with a fixed minimum
respiratory minute volume
• delivery of controlled mandatory breaths if the set AMV
could not be reached
Modern weaning procedures
The standard weaning procedure today is CPAP-ASB.
However, there are currently many modern weaning pro-
cedures (diaphragm-controlled): Unlike with CPAP-ASB,
the ventilator here does not always apply the same sup-
port pressure during each inspiration, but the pressure
support is adjusted proportionally to the inspiratory effort
of the patient ("power assisted steering"). The inspiratory
effort (respiratory drive) of the patient is not always the
same, but varies depending on the respiratory cycle. The
following weaning procedures can only be performed
with the ventilators of the respective companies. There
are different variants (depending on the company and
the type of measurement):
• measurement of resistance and compliance:
-- PAV (proportional assist ventilation; Covidien com-
pany)
-- PPS (proportional pressure support; Dräger compa-
ny)
-- ASV (adaptive support ventilation; Hamilton compa-
ny)
• measurement of the electrical activity of the diaphragm
signal: NAVA (neurally adjusted ventilatory assist;
company Maquet)
PAV
• proportional assist ventilation (Covidien company
[ventilator Bennett])
• syn.: proportional pressure support (PPS; Dräger com-
114 General Part
pany [ventilator Evita XL])
• indication: weaning (modern weaning procedures)
• a spontaneous breathing mode
• Pressure support is applied here proportionally to each
inspiratory effort of the patient.
• The ventilator continuously measures the resistance
and compliance and determines inspiratory effort of
the patient with a complex microprocessor technology.
• principle:
-- low inspiratory effort → low pressure support
-- high inspiratory effort → high pressure support
• The inspiratory effort (Pmus [pressure of muscles]) is
shown on the display (e.g. Bennet 840, Covidien) as
WOB (work of breathing).
• Pressure support is applied directly proportional to the
measured resistance and indirectly proportional to the
measured compliance.
• The degree of compensation, i.e. of the breathing ef-
fort, can be set in percent on the device.
• Two support parameters are set on the ventilator (e.g.
Evita XL):
-- flow-assist
-- volume-assist
• control circuit with positive feedback (closed-loop ven-
tilation): The greater the inspiratory effort of the patient,
the greater is the support through the ventilator.
• relatively modern weaning procedure (like the power
assisted steering of a car)
• relatively complex (i.a. resistance and compliance are
often difficult to identify in spontaneously breathing pa-
tients)
• reduction of the work of breathing in weaning espaci-
ally in patients with COPD (Vitacca et a, Crit Care Med
2000)
• problem of overcompensation (instability; "runaway
phenomenon"):
-- If the set volume assistance exceeds the elastic resi-
lience of the lungs, the ventilator continues to supply
inspiratory pressure when the patient has already
gone into the expiratory phase (so-called "runaway
phenomenon"; overcompensation).
-- This may occur e.g. in case of leakages.
-- may lead to hyperventilation
-- The "runaway phenomenon" can be recognized
when:
◦◦ the "high volume" alert sounds again and again
◦◦ the flow curve quickly rises to very high values and
then quickly declines
◦◦ the patient uses his expiratory muscles
-- To avoid the problem of overcompensation, the
support parameters flow-assist and volume-assist
should be adjusted so that they exceed 80% of the
measured resistance or elastance.
-- If a "runaway" occurs, the support (flow-assist and
volume-assist) must be reduced.
-- The "runaway"- problem is avoided in the newer ver-
sions of the PAV (PAV with adjustable gain factors)
by a continuous measurement of the resistance and
compliance.
ASV -- weaning (main indication today; modern weaning
• adaptive support ventilation ("intelligent ventilation") procedure)
• indication: weaning (modern weaning procedure) • not validated (no studies, that would have shown a be-
nefit in mortality)
• Hamilton company
• combination of pressure-controlled SIMV and PSV
(pressure support ventilation)
• The ventilator itself determines the degree of pressure
support and the rate of the mandatory breathes.
• settings:
-- PEEP
-- FiO2
-- (ideal) body weight
• measurement of the inspiratory effort of the patient by
determination of the compliance
• calculation of respiratory rate and tidal volume with
a mathematical algorithm (Otis equation) to keep the
work of breathing as little as possible
• continuous adaptation of the ventilation pattern and
the lung protective parameters to the mechanics of
breathing (closed-loop-mode)
• A "runaway" phenomenon is also possible here (simi-
lar to PAV).
• INTELLiVENT-ASV (Hamilton company): After ente-
ring height, gender and the target values for ETCO2
and SpO2, the ventilator itself completely controls the
ventilation. It automatically sets the inspiratory pressu-
re, PEEP, ventilation rate and the I:E ratio. Furthermo-
re, the ventilator autonomously switches from manda-
tory to augmented and finally to spontaneous-assisted
ventilation (including automated weaning procedure
["QuickWean"]).

NAVA
• neurally adjusted ventilatory assist
• Marquet company (ventilator Servi i; only possible
here)
• developed by Sinderby in 1999 for childhood ARDS
• recording of the diaphragm signal (diaphragm elec-
tromyogram [EMG]) by electrodes in a stomach probe
positioned in the lower esophagus
• special stomach probe with integrated electrodes
("esophageal catheter"; with this stomach probe, tube
feeding is possible)
• synchronous pressure support proportional to the dia-
phragm signal (a highly synchronous ventilation mode!
The patient controls the ventilation himself!)
• However, daily clinical practice shows that a significant
proportion of the inspiration (30%) is not synchronous-
ly supported because the signal cannot be evaluated.
• neural triggering and not (as usual) pneumatic trigge-
ring
• a closed-loop-procedure
• approved worldwide since 2007
• possible even in non-invasive ventilation
• indications:
-- ARDS (children, adults)
-- COPD
-- severe obesity
Fig. 196  ventilator Servo i (Maquet) with NAVA
Recruitment maneuver
Definition
• maneuvers to reopen blocked (atelectatic) lung areas
that do no longer contribute to the gas exchange
• The most common recruitment maneuver is (or better
was) the Lachmann-maneuver.
• effective, especially in the early phase of extrapulmo-
nary ARDS
• ART study (see page 716): even harmful (i.a. even
increased mortality!)
• no longer recommended (i.a. meta-analysis of Fan
et al, the J Respir Crit Care Med 2008)
• Short recruitment maneuver (< 10 seconds) can defini-
tely be performed and are often very helpful. However,
it is a fact that atelectases, which do not reopen after
3 seconds, will also not reopen after 60 seconds, so
that the typical protracted recruitment maneuvers (e.g.
Lachmann maneuver) should no longer be performed,
especially because of their adverse effect on hemo-
dynamics because of an significantly increased risk of
barotrauma (specially pneumothorax).

General Part 115

Types
• sigh
• airway-pressure-release-Ventilation (APRV)
• low-flow PV-Loop (automatic recruitment maneuver of
Evita XL)
• Lachmann recruitment maneuver ("open the lung and
keep it open"; see chapter "ARDS" [page 708])
Sigh
• ventilation mode in which several breaths are given in-
termittently with a high tidal volume / high PEEP with a
set frequency per hour
• recruitment of atelectatic areas through lung inflation
APRV
• airway pressure release ventilation
• a spontaneous breathing mode
• spontaneous breathing at a high pressure level (20-30
cmH2O) with short-term (1-2 seconds) reduction to a
lower pressure level ("pressure release")
• The high pressure phase (P1) is considerably longer
than the low pressure phase (P2).
• APRV was initially developed for spontaneously brea-
thing patients requiring a high PEEP and a high mean
airway pressure.
• APRV corresponds to BIPAP with IRV (inverse ratio
ventilation). The I:E ratio is usually set to 5:1.
• Due due the very short expiration time IRV generates
an intrinsic-PEEP that leads to improved oxygenation.
• indication: recruitment maneuvers in ARDS
• an option to implement early spontaneous breathing in
ARDS (BiRDS-trial 2019 [see page 717]: no benefit
in mortality)
• APRV is merely of minor importance: It leads i.a. to
pronounced panting. Due to the very short duration of
expiration the decarboxylation is reduced. That leads
to a to severe hypercapnia (pCO2 ↑) and respiratory
acidosis. Furthermore the intrinsic-PEEP increases.
All in all this ventilation mode is often impracticable.
We almost never perform APRV. It may be an option
in patients where the carbon dioxide is extracorporally
eliminated (vv-ECMO).
Fig. 197  APRV (airway pressure release ventilation)
116 General Part
meta-analysis
Airway pressure release ventilation during acute hypox-
emic respiratory failure
Carsetti et al, Annals of Intensive Care 2019
• 330 patients (5 RCT) hypoxemic respiratory failure
-- APRV
-- conventional ventilation
• results: APRV
-- significantly more ventilator-free days
-- significant reduction of mortality (hospital)
-- significantly higher MAP
-- no difference in oxygenation (Horovitz quotient)
-- no difference in frequency of pneumothorax
Additional settings
• ATC (automatic tube compensation)
• Autoflow (see page 108)
ATC
• automatic tube compensation (a protected trademark
of the Dräger company; Hamilton Medical: TRC [tube
resistance compensation])
• The main airway resistance is caused by the tube.
• additional function for nearly all ventilation modes (but
practically mostly used for spontaneous breathing mo-
des such as CPAP-ASB)
• The tube causes an increased resistance which leads
to an increased breathing effort. This can be compen-
sated with ATC.
• The gas flow in the tube is not laminar but turbulent. The
tube resistance increases disproportionately to the gas
flow (square [Hagen-Poiseuille's-law]). If the inspirato-
ry flow is too high (e.g. stress, pain), a preset pressure
support (CPAP-ASB) is not enough to compensate for
the increased tube resistance (under-compensation).
That can lead to respiratory fatigue. If the inspiratory
flow is too low, a preset pressure support (CPAP-ASB)
would lead to overcompensation. The objective of ATC
is to avoid both under- and overcompensation.
• The ventilator calculates the pressure drop (pressure
difference) via the endotracheal tube. It depends on
the internal diameter of the tube and the breathing gas
flow. The pressure before the tube is then increased by
the exact amount of this pressure difference.
• The internal diameter of the tube is decisive for the
resistance (depending on the fourth power) and must
also be entered. The length (only depending on the
first power) of the tube is negligible.
• additional pressure support whose flow decreases with
increasing duration of inspiration (flow-proportional
pressure support: no constant application of a fixed
pressure, but of an individual, demand-based pressu-
re)
• The tube compensation is applied for both inspiration
(positive pressure) as well as expiration:
-- During inspiration, a positive pressure is built up at
the proximal end of the tube to overcome the tube
resistance
-- During expiration, a negative pressure is built up at
the proximal end of the tube to overcome the tube
resistance. But this is only possible to a limited ex-
tent: The pressure during expiration (PEEP) can be
lowered to atmospheric pressure at most, so that
expiratory tube compensation is only partially pos-
sible. A complete expiratory tube compensation is
currently not possible with any ventilator. In case of
obstructive diseases, the expiratory part of the tube
compensation should be deactivated, because the
expiratory PEEP decrease would reverse the desi-
red effect of the pursed-lip breathing. On EVITA XL
the expiratory ATC can be switched off as follows
(not so easy): System Setup, Therapy, Modi & Ein-
stellung, enter access code, ATC, Exp. compensa-
tion off
• ATC allows to predict the success of a planned extuba-
tion. ATC simulates the condition without tube ("elect-
ronic extubation").
• indication: weaning of already spontaneously brea-
thing patients, ventilated via a tube or a tracheal can-
nula (especially useful in case of obstructive pulmona-
ry diseases in order to facilitate work of breathing [But
here only the inspiratory tube compensation should be
switched on, the expiratory tube compensation should
be turned off.])
• The degree of compensation is adjustable (advice: If
you switch on the ATC, then you should always set it to
100% [and not just to 70%].)
• no benefit demonstrated in the studies (i.a. Haber­thür
et al, Acta Anaesthesiol Scand 2003; Cohen et al, Crit
Care 2009)

Fig. 198  ATC (automatic tube compensation)

General Part 117

 most important monitoring
function for all spontaneous
breathing modes: apnea moni-
toring!

Fig. 199  The expiratory ATC can be switched off on EVITA

XL (necessary esp. in obtructive disease) as follows: In the
"System Setup" you choose "Therapy" and enter access
code. Then you choose "ATC" and finally "Exsp. Compen-
sation off".

Monitoring
• monitoring of the patient
-- respiratory rate (spontaneous breathing): measure- Fig. 200  During spontaneous breathing modes (here:
CPAP-ASB) apnea ventilation must always be switched on!
ment by means of impedance pneumography
-- pulse oximetry (SpO2 [oxygen saturation]; see page
187)
-- capnometry, capnography
-- BGA
◦◦ remove at the earliest 30 min after the change of
the ventilation parameter
◦◦ i.a. Horovitz quotient (paO2/FiO2; syn.: P/F-Ratio)
• monitoring of the tube: measurement of the cuff pres-
sure (see page 881)
• monitoring on the ventilator (ventilator monitoring)

Ventilator monitoring
• ventilation pressure
• respiratory rate, tidal volume, respiratory minute volu-
me
• apnea: Apnea monitoring must be switched on in Fig. 201  If a patient becomes apneic suddenly during a
any spontaneous breathing mode (e.g. CPAP-ASB spontaneous breathing mode, apnea ventilation is turned
in weaning). This is the only way to keep the patient on automatically (if apnea monitoring is activated) as a
ventilated in the unforeseen event of a failure of the backup.
respiration of the patient. Apnea ventilation is a volu-
me-controlled ventilation mode (default setting: usually
AZV 8ml/kg, respiratory rate 10/min).
• curves on the display:
-- pressure curve
pressure curve
-- flow curve
-- volume curve
• FiO2 (fraction of inspired oxygen) flow curve
• mechanics of breathing (resistance, compliance)
• gas and power supply
• breathing gas temperature (for active humidification)

volume curve

118 General Part

 • Especially after acute ischemic events (e.g. myocardi-
al infarction, stroke, resuscitation), liberal oxygenation
should strictly be avoided in the initial phase, since this
could cause a release of free oxygen radicals, which
pressure curve would increase the ischemic area.

flow curve
oxygenation: SpO2 > 90% resp. paO2 >
60 mmHg quite sufficient!
volume curve

Oxygen-ICU study
Fig. 202  You should also watch the curves on the display
of the ventilator. They often give important information (e.g.
airtrapping in the flow curve in case of COPD)!

Effect of Conservative vs Conventional Oxygen Therapy

FiO2 on Mortality Among Patients in an Intensive Care Unit
• fraction of inspired oxygen Girardis et al, JAMA 2016
• admixture of oxygen
• single-center randomized controlled study
• adjustable from 0-100%
• 480 critically ill patients with an expected ICU length of
• rule of thumb: paO2 = FiO2 x 5 (The BGA of a patient stay > 3d; oxygen administration:
with healthy lungs should show an arterial pO2 corre- -- liberal (SpO2 97-100%, paO2 up to 150 mmHg)
sponding to five times the currently set FiO2. A lower -- restrictive (SpO2 94-98%, paO2 < 100mmHg)
paO2 might point to a disturbance of the gas exchange! • results: restrictive oxygen administration
• conversion in spontaneous breathing: FiO2 = 0.21 + -- primary endpoint (ICU mortality): significantly re-
0.03 x litres of O2; e.g. 6 l O2/min: FiO2 = 0.21 + 0.18 duced
= 0.39 -- secondary endpoints (i.a. shock, hepatic failure, bac-
• The setting of the FiO2 is mainly guided by the saturati- teremia): significantly reduced
on SpO2 (aim > 90%) and less by the paO2!
• S3-Guideline 2017 "Mechanical Ventilation and Extra-
corporeal Membrane Oxygenation in Acute Respirato-
ry Insufficiency" (German Society for Anaesthesiology
and Intensive Medicine [DGAI]): IOTA study
-- target SpO2: 90-94%
-- target paO2: 60-80mmHg
• Three-digit paO2 values (i.e. > 100 mmHg) are not ne-
Mortality and morbidity in acutely ill adults treated with lib-
cessary (no "luxury oxygenation") eral versus conservative oxygen therapy
• The ANZICS study (Panwar et al, Am J Respir Crit Med Chu et al, Lancet 2018
2015) did not show any significant differences between
liberal (SpO2 ≥ 96%) and conservative (SpO2 88-92%) • meta-analysis (25 RCT)
oxygenation regarding new organ dysfunction or mor- • IOTA: Improving Oxygen Therapy in Acute Illness
tality. The subgroup of patients in the conservative arm • 16037 critically ill patients requiring mechanical ventilati-
with a baseline paO2/FiO2 < 300 mmHg (ARDS) ten- on; oxygen administration:
ded to lower mortality. -- liberal (SpO2 94-99% [average 96%])
• oxygen toxicity: Too much oxygen can also be harm- -- restrictive
ful. On the one hand, free oxygen radicals could be • result: liberal oxygen administration → significantly
released, which damage the lung parenchyma. On the increased mortality
other hand, resorption atelectases might occur and
cause shunt. If you ventilate with a FiO2 of 1.0 (100%
oxygen), there is only oxygen in the alveolus and no
more nitrogen. If the oxygen diffuses into the capilla-
ries, the alveolus collapses (resorption atelectasis).
To avoid resorption atelectases, the FiO2 should, e.g.
during a bronchoscopy via a tube, only be set to 0.9
and not to 1.0.
• In the HYPERS2S study (see box) hyperoxia compa-
red to normoxia in ventilated patients with septic shock
lead to considerably more severe side effects (esp.
CIP/CIM and atelectases).

General Part 119

 Ventilators (Respirators)

HYPERS2S study

Hyperoxia and hypertonic saline in patients with septic

shock 
Asfar et al, Lancet Resp Med 2019

• multicenter randomized double-arm study

• 442 mechanically ventilated patients with septic shock
• 2 arms:
-- FiO2
◦◦ hyperoxia (FiO2 1.0)
◦◦ normoxia (FiO2 according to SaO2 with target 88-
95%)
-- saline solution
◦◦ hypertonic (3%)
◦◦ isotonic (0.9%)
• Ergebnis
-- arm oxygenation:
◦◦ no difference in mortality at day 28 (primary end-
poit)
◦◦ premature termination of the study due to signi-
ficantly more severe side effects in the hyperoxia-
group (especially CIP/CIM and atelectases)
-- arm saline solution: no difference
ICU-ROX study
Conservative Oxygen Therapy during Mechanical Ventila-
tion in the ICU  electronically (microprocessors).
The ICU-ROX Investigators, N Engl J 2019
• multicenter (Australia, New Zealand) randomized cont-
rolled study
• ICU-ROX: Intensive Care Unit Randomized Trial Com-
paring Two Approaches to Oxygen Therapy
• 1000 critically ill patients requiring mechanical ventilati-
on; oxygen administration:
-- liberal
-- restrictive
• result
-- primary endpoint (number of ventilation-free days at
day 28): no difference (was reduced in the restrictive
group only in the subgroup analysis of patients with
hypoxic-ischemic encephalopathy due to an asphy-
xia)
-- sedondary endpoints (i.a. mortality, cognition, health-
related quality of life): no difference
Components
• control part
-- ventilation modes, ventilation parameters
-- alarms / monitoring
-- measurement devices (pressure, flow, respiratory
rate, tidal volume, trigger)
• pneumatic part
Pneumatic part
• connections
-- compressed air, oxygen
-- power, potential equalization
• mains connection
• inspiration part
-- A piston (air pump, bellows) builds up pressure when
the expiratory valve is closed. The drive is provided
either pneumatically (compressed air, oxygen) or
-- inspiration hose
-- Jackson-Rees' system (for manual ventilation)
-- tube extension ("catheter mount")
-- air/oxygen-blender (mixes oxygen and compressed
air in accordance with the set FiO2)
-- - gas module (control of the inspiratory flow)
-- pressure transducer
-- Y-piece
-- breathing gas humidifier
• expiration part
-- expiration hose (exception: Home-ventilation de-
vices, emergency ventilators and turbine technology
devices for non-invasive ventilation only have one
hose [only inspiration hose, no expiration hose].)
-- condensed water separator ("water trap")

120 General Part

 expiration
hose

Y-piece
tube
inspiration
Fig. 203  Jackson-Rees' system (for manual ventilation)
hose
[33]

Fig. 206  The Y-piece is the connection between the tuve

and both ventilation hoses (inspiration and expiration
hose). The Y-piece incl. both ventilation hoses are changed
every 7 days.

Respiratory gas conditioning

Definition
• preparation of the inspired air to enter the lower respi-
ratory tract
• warming (to body temperature to avoid hypothermia)
Fig. 204  tube extension ("catheter mount") [33] and humidification of the respiratory gases (inspired
air)
• humidity (syn.: moisture; physiological water content)
of the respiratorygases:
-- absolute humidity: 44mg water / liter of air
-- relative humidity: 100% (at a temperature of 37°C
[Therefore, in addition to moistening, heating is also
absolutely necessary: The lower the temperature,
the less water the air can absorb.])
• rational:
-- This function is usually performed by the upper res-
piratory tract (nose, nasopharynx). However, this is
switched off in the case of invasively ventilated pa-
tients through the tube or the tracheal cannula, so
that the respiratory gas conditioning must therefore
Fig. 205  PEEP-valve [33] be carried out artificially. The gases supplied by the
ventilator are dry and cold.
-- Respiratory gas conditioning is crucial to maintain
Y-piece
mucociliary clearance as a natural protection against
infection, to avoid airway obstruction due to viscous
mucus with damage to the bronchi and lungs, to pre-
vent atelectales and hypothermia.

In invasively ventilated patients

(tube, tracheal cannula), the
respiratory gas must always be
humidified and warmed!

Types
• active humidification (HH: heated humidifier)
-- Distilled water is evaporated by heating elements.
-- types:
◦◦ passover humidifier (e.g. MR 850; Fisher & Pay-
kel)
◦◦ counter-flow humidifier (e.g. Humicare 200;

General Part 121

 Gründler Medical)
◦◦ wick humidifier (e.g. ConchaTherm Neptune; Te-
leflex)
-- The ventilation hoses are heated to prevent that con-
dense water (cave germ colonization) accumulates
in them. Furthermore, water traps are integrated into
the system at the lowest point, which must be emp-
tied regularly aseptically.
-- disadvantages:
◦◦ increased risk of contamination, possibly increa-
Fig. 207  HME-filter (heat moisture exchange): It is attached
sed risk of ventilator-associated pneumonia (note: between the tube and the breathing hose. It absorbs the
In contrast to previous studies, newer meta-ana- moisture during expiration, which is then taken up again
lyses [Siempos et al, Crit Care Med 2007; Kelly during inspiration (passive humidification). It should be
et al, Cochrane Database 2010; Menegueti et al, changed after 24 hours [24,32].
BMC Anesthesiology 2014] however showed no
increased VAP rate under active humidification
compared to passive humidification.)
◦◦ uuto triggering by the condense water HME filter sensor
(capnography)
◦◦ more complex and more expensive
-- indications (Active humidification is useful in the
following cases. Otherwise, passive humidification,
which is cheaper and less complex, can also be per-
formed.):
◦◦ damaged lungs (e.g. ARDS, polytrauma): Active
humidification is much more effective in terms of HME booster
humidification and warming and therefore better
protects the already damaged lungs. power cable for
◦◦ obstruction (exacerbated COPD, bronchial asth- socket
ma; less dead space and airway resistance than
with passive humidification)
◦◦ difficult weaning (lower airway resistance and
therefore lower work of breathing than with passi-
ve humidification) water supply line
◦◦ longer duration of ventilation (> 48-72h)
◦◦ non-invasive ventilation
◦◦ leaks, fistulas
-- change every 7 days
• passive humidification: HME filter
-- HME: heat and moisture exchanger
-- "artificial nose"
-- a filter that is attached between the tube and the
breathing hose
-- It captures the moisture and heat during expiration,
which is then taken up again during inspiration.
-- provided with hygroscopic (water-binding) substan-
ces (Hygrovent) to increase the water binding capa-
city
-- disadvantages:
◦◦ increased dead space (depending on the product
up to 150ml [with the newer HME filters only 49ml])
◦◦ increased airway resistance
◦◦ less effective (only limited humidification capacity):
maximum achievable absolute humidity 36.8 mg/l
and relative humidity 80% (at 37°C); to improve
the effectiveness combination with an active humi- ceramic plate
dification (HME-booster [Medisize]: Here, a cera- (heating plate)
mic plate in the T-piece is heated by electricity, so
that the water evaporates and enters the breathing
hose through a Goretex membrane.)
-- change every 24h (daily)

122 General Part

 Emergency respirators (exaples)
• Medumat (Weinmann)
• Oxylog, Oxylog 2000, 3000 (Dräger)
• Hamilton T1 (Heinen + Löwenstein)
• Var plus (Vartran)

ceramic plate
(heating plate)
Fig. 208  We use the HME booster in addition to the HME
filter as standard for ventilation duration longer than 24
hours. This is inserted between the HME filter and the brea-
thing hose. It contains a ceramic plate (heating plate) that is
heated by electricity (socket) to 70°C (relatively hot, there-
fore always put a towel underneath to protect the patient).
Distilled water is passed onto the heating plate (60ml per
24h) and heated there so that water vapor is generated,
Fig. 210  Medumat (Weinmann) - a common emergency res-
which then enters the breathing hose through the Goretex
pirator in (emergency) ambulance
membrane of the HME booster, which is only permeable to
water vapor.The HME filter is changed every 24 hours, the
HME booster every 48 hours.

Types
• home-ventilation device (e.g. BiPAP [bilevel positive
airway pressure], Legendair)
• emergency respirators (history: The first emergency
respirator in Germany was developed 1907 by the Drä-
ger company in Lübeck and was named "Pulmotor". It
had to be driven by a hand crank and was especially
used for resuscitation due to gas poisoning [e.g. in mi- Fig. 211  Oxylog (Dräger)
ners].)
• intensive care respirators
• anesthesia respirators

Fig. 212  Oxylog 2000 (Dräger)

Fig. 209  home-ventilation device (e.g. Legendair)

General Part 123

 Fig. 215  Evita XL (Dräger)

Fig. 213  Hamilton T1 (Heinen + Löwenstein)

Fig. 214  Var plus (Vartran company): a mini ventilation de-

vice that only requires oxygen connection (costs: 95€; only
for single-use)

Intensive care ventilators (examples)

Fig. 216  Evita V300 (Dräger)
• Evita 2, Evita 4, Evita XL, Evita V300, Evita Infinity
V500 (Dräger)
• Servo i, Servo s, Servo Ventilator 300A, 900C, 900D
(Siemens)
• Puritan Bennett NPB 760, 840 (Tyco Healthcare)
• Raphael Color, Galileo Gold (Hamilton Medical)
• Centiva (Datex-Ohmeda)

124 General Part

Fig. 217  Evita Infinity V500 (Dräger)

Fig. 220  Engström Carestation (GE Healthcare; also possi-

ble pleural pressure and FRC measurement using nitrogen
washin / washout [CVOF module])

Fig. 218  Servo i (Siemens) [23]

Fig. 221  Carescape R860 (GE Healthcare)

Fig. 219  Hamilton C3 (Heinen + Löwenstein)

General Part 125

 Anesthesia ventilators (examples)
• Julian (Dräger)
• Cicero EM (Dräger)
• Fabius CE (Dräger)
• Kion (Siemens)

Fig. 222  Bennett 840 (Tyco Healthcare) [11]

Fig. 223  Bennett 760 (Tyco Healthcare) [11]

Fig. 225  anesthesia circuit component (example Cato, Drä-
ger)

Fig. 224  Puritan Bennett 980 (Covidian)

126 General Part


Non-invasive
ventilation
Definition
• mechanical ventilation without tube/ tracheostoma
• already performed 80 years ago in case of cardiac pul-
monary edema
• clinical renaissance only since sleep apnea syndrome
• guidelines:
-- German: S3-guideline for non-invasive ventilation as
a treatment for acute respiratory insufficiency of the
German Society for Pneumonology and Respiratory
Medicine (2015)
-- European: clinical practice guidelines (2017) on
noninvasive ventilation for acute respiratory failure
of ERS (European Respiratory Society) and ATS
(American Thoracic Society)
Effects
• increase of alveolar ventilation (relief of breathing
pump)
• increase of oxygen supply
• positive pressure ventilation → intrathoracic pressure
↑→
-- preload ↓ (reduced venous backflow to heart )
-- afterload ↓ (transmural pressure on heart muscle [=
difference between the pressure in the left ventricle
and the intrathoracic pressure) ↓ → wall tension ↓)
• improvement of left ventricular contractility
-- through a shift of the septum to the right
-- Through a reduction of left ventricular preload in pa-
tients with volume overload, the ejection fraction and
therefore the stroke volume can be increased accor-
ding to the Frank-Starling-mechanism.
-- Moreover, the reduction of the left ventricular after-
load leads to an increase of the ejection fraction .
• increase of the cardiac output (in case of volume over-
load; about 20%)
• increased sensitivity of the respiratory center through a
reduction of the pCO2
• reopening of collapsed alveoli (through the inspiratory
pressure) and keeping them open (through the expira-
tory pressure [PEEP])
• reduction of intrapulmonary shunt (already perfused
alveoli are ventilated again)
• reduction of hyperinflation through PEEP (prevents
collapse of the alveoli at the end of expiration so that
the entire air can be exhaled)
• generation of an extrinsic PEEP, which antagonizes the
intrinsic PEEP caused by hyperinflation in exacerbated
COPD, and thereby reducing the respiratory load
Assessment
Advantages
• maintainance of cough clearance → risk of infection ↓
• reduced risk of ventilator-associated pneumonia (main
complication of invasive ventilation!) )
• no tracheal injury
• no tube-imduced additional work of breathing
• eating / drinking and communication possible
• (almost) no sedation necessary → side effects (gast-
rointestinal atony, cardiac depression, withdrawal syn-
drome) ↓
• possible breaks
• cheaper
Disadvantages
• no secured airway
• difficult pulmonary toilet
• pressure ulcers in the face (only in case of long-term
ventilation)
• aerophagia, sometimes vomiting (but usually mainte-
nance of protective reflexes)
• depending on the compliance of the patient
• usually more complex than invasive ventilation
Intubation and ventilation are usually
less complex than non-invasive
ventilation!
Indications
• obstructive pulmonary diseases:
-- exacerbated COPD (main indication for NIV)
-- Status asthmaticus: A status asthmaticus can often
not (or only with difficulty) be ventilated with NIV. This
is mainly due to the fact that these patients often suf-
fer from severe hypersecretion (mucoid impaction).
Invasive ventilation is also extremely difficult in pati-
ents with status asthmaticus because of the severe
hyperinflation! However, a study (Gupta et al, Respir
Care 2010) showed that NIV, in comparison to the
General Part 127
 standard therapy for severe asthma, shortens the
ICU- and hospital stay and reduces the use of bron-
chodilators. A low PEEP (3-5 mbar) should be set
at the beginning (then adjustment according to the
measured intrinsic PEEP [set 80 % of intrinsic PEEP
on ventilator]). Inspiratory pressure of 25 mbar must
not be exceeded (caution: barotrauma like pneumo-
thorax).
• pulmonary edema (cardiac)
• pneumonia
-- but high failure rate ( 70% [Domenighetti et al,
Intensive Care Med 2002]) → no general recom-
mendation (note: good indication here, however, for
high-flow nasal oxygen therapy [HFNOT instead of
NIV]!)
-- good indications:
◦◦ pneumonia in COPD patients
◦◦ congestion pneumonia in a (leading) cardiac pul-
monary edema
◦◦ pneumonia in immunosuppressed patients (VAP
↓ [u.a. Hilbert et al, N Engl J 2001]; note: A more
recent study [Lemiale et al, JAMA 2015], however,
showed that NIV had no advantages compared to
oxygen therapy in immunosuppressed patients.)
◦◦ pneumocystis jiroveci pneumonia in AIDS patients
• obesity hypoventilation syndrome (OHS; usually high-
er ventilation pressure necessary here [IPAP > 30 cm-
H2O, PEEP > 8 cmH2O])
• in palliative care situations
-- DNR (do not resuscitate), AND (allow natural death),
DNI (do not intubate)
-- The most common reason for admission of a cancer
patient to the ICU is acute respiratory insufficiency.
In this case, NIV leads to a significant reduction of
mortality (Hilbert et al, N Engl J 2001; Molina et al,
Crit Care 2012) and should be performed at an early
stage in order to avoid intubation. A more recent stu-
dy (Lemiale et al, JAMA 2015), however, could not
show that NIV reduces mortality in cancer patients
with acute respiratory insufficiency (usually caused
by pneumonia) compared to oxygen therapy as a
sole treatment.
-- for soothing of a torturous dyspnea (but no prolon-
ged suffering through NIV); note: There are, howe-
ver, other options for soothing of a torturous dyspnea
such as a morphine via perfusor. NIV is usually not
possible in a hospital out of an intensive care unit, so
that a palliative patient has to be relocated especially
for this to intensive care unit.
• peri-interventional; examples:
-- bronchoscopy with bronchoalveolar lavage (BAL) in
patients with severe pneumonia (through NIV-mask;
swivel adapter): The more severe a pneumonia is,
the more important it is to perform a bronchoscopy
to collect bacteria. In practice, quite the opposite is
the case: The more severe a pneumonia is, the less
often a bronchoscopy is performed because the ad-
ministration of the necessary sedatives (e.g. mida-
zolam) might cause respiratory insufficiency and the
patient would then have to be intubated.
-- percutaneous endoscopic gastrostomy (PEG; e.g. in
128 General Part
patients with neuromuscular diseases)
• preoxygenation before intubation (preoperative in an-
esthesia before elective operations, not in case of a
emergency intubation [because the patients have usu-
ally not fastened, so that the risk of aspiration is incre-
ased due to the gastric hyperinflation])
• weaning: early extubation and change to NIV ("facili-
tated weaning"; NIV as a weaning strategy; i.a. also to
avoid tracheotomy) in case of:
-- COPD
-- obesity
• preclinically, if necessary (emergency ambulance,
MICU [medical intensive care unit])
-- e.g. with flow-CPAP-system
-- studies:
◦◦ Jerrentrup et al, Notfall Rettungsmed 2009: 108
patients with cardiac pulmonary edema, flow-
CPAP 5-8 mbar → significant increase of SO2,
only 7% needed to be intubated
◦◦ meta-analysis (Goodacre, Acad Emerg Med
2014): significant reduction of mortality and intu-
bation rate due to preclinical performance of NIV
in acute respiratory insufficiency
-- 80% of patients who were preclinically treated with
NIV also need NIV in hospital. Therefore, when the
patient has been registered via the emergency call
center, he should not be transferred to the emergen-
cy department of the hospital, if NIV is not possible
there, but directly to the ICU to provide a seamless
continuation of the NIV! However, NIV should be
standard in today's emergency departments! In 72%
of all emergency departments in Germany NIV is
available (Huber et al, Notfall + Rettungsmed 2019).
-- 38% of all emergency headquarters in Germany pro-
vide NIV on their vehicles (federal survey; Sellmann
et al, Anästh 2014).
• cystic fibrosis: no general recommendation but good
for example for
-- secretion mobilisation (in combination with physio-
therapy)
-- in case of acute respiratory deterioration (NIV should
be tried here to avoid intubation.)
-- to support weaning or to avoid reintubation
-- as a bridge to lung transplantation
Typical indications for NIV: exacerba-
ted COPD and cardiac pulmonary
edema!
Fig. 226  COPD: horizontal ribs, flat diaphragm, hyperinfla-
tion, myopathy

Fig. 229  NIV preclinically in the MICU (here: Medumat

Transport, Weinmann)

Fig. 227  cardiac pulmonary edema study

Noninvasive mechanical ventilation in acute respiratory fai-

lure: trends in use and outcomes
Schnell et al, Intensive Care Med 2014

• longitudinal analysis in France (14 intensive care units)

during the observation period from 1997-2011
• 3163 patients with acute respiratory insufficiency requi-
ring ventilation (NIV in 39%)
• results: NIV
-- increase of use (from 29% to 42%)
-- increase of success rate (from 69% to 84%)
Fig. 228  NIV in the shock room (here with Oxylog 3000, -- decrease of infection rate
Dräger) -- decrease of mortality (but not in case of hypoxemic
respiratory failure)

General Part 129

NIV in hypercapnic respiratory failure
Effects
• significant decrease of infection rate (by half)
• significant decrease of intubation rate
• significantly shortened ICU- and hospital stay
• significant reduction of mortality (by 50% [Cochrane-
analysis 2005])
Studies
• Wysocki, Chest 1995; Krammer, ARCCM 1995; Nava,
Ann Int Med 1995; Brochard, N Eng J Med 1995 (85
patients with acute exacerbated COPD with respirato-
ry insufficiency were randomized into a standard the-
rapy group and a NIV-group. NIV lead to a significant
reduction of the intubation rate and mortality.); Celikel,
Chest 1998; Plant, Lancet 2000
• meta-analysis Ram et al, Cochrane Database Syst
Rev 2004: NIV is a highly effective therapy for exacer-
bated COPD.
-- avoidance of intubation: NNT 5
-- avoidance of death: NNT 8
meta-analysis
Non-invasive ventilation for the management of acute hy-
percapnic respiratory failure due to exacerbation of chronic
obstructive pulmonary disease: a Cochrane review update
Osadnik et al, European Resp J 2017
• meta-analysis (23 RCT)
• 1470 patients with an acute exacerbation of COPD (AE-
COPD) and pH < 7.35 (paCO2 > 45mmHg)
-- without NIV
-- with NIV
• results:
-- reduction of intubation by 64% (NNT 8)
-- reduction of mortality va 46% (NNT 15)
NIV in hypoxemic respiratory failure
Effects
• positive pressure ventilation → intrathoracic pressure
↑ → preload /afterload↓ → faster decrease of cardiac
cavity size (dilated due to volume overload)
• improvement of coronary perfusion; reasons:
-- Due to the positive pressure less blood flows into the
right atrium, so that the perssure in the right atrium
(RA-pressure) decreases and therefore the coronary
perfusion pressure CCP (CPP = RRdias - RA-Druck)
increases.
-- Due to the positive pressure the intrathoracic pres-
sure increases, so that the wall tension of the left
ventricle decreases: The coronary arteries are less
compressed.
130 General Part
• ideal mode for the treatment of pulmonary edema:
CPAP (sufficient in itself; often CPAP-ASB is used)
• usually only short-term ventilation (<< 24h) required
• significant reduction of intubation rate and mortality
with NIV
Studies
• The study of Antonelli (N Engl J 1998) showed that
non-invasive ventilation is just as effective as invasive
ventilation in case of hypoxic respiratory failure (pul-
monary edema, pneumonia).
• The study of Ferrer (Resp Crit Care Med 2003) showed
significantly lower intubation rate, a lower incidence of
septic shock and also a reduction of mortality.
• A meta-analysis (Vital et al, Cochrane Database Syst
Rev 2008) showed that NIV caused a significant re-
duction of the intubation and mortality rate in 1071 pa-
tients with cardiac pulmonary edema.
• The 3CPO study (Gray et al, N Engl J 2008 [see box])
was actually intended to figure out which ventilation
mode is better for patients with cardiac pulmonary
edema. Surprisingly, this study showed no advantage
of NIV concerning mortality or necessity for intubation,
regardless of the applied ventilation mode. Neverthe-
less, NIV is still clearly recommended for the treatment
of pulmonary edema!
3CPO study
Noninvasive Ventilation in Acute Cardiogenic Pulmonary
Edema
Gray et al, N Engl J 2008
• 1069 patients with cardiac pulmonary edema
• 3 groups
-- only oxygen therapy
-- CPAP
-- NIPPV
• results
-- no reduction of mortality
-- no reduction of intubation rate
-- faster improvement of dyspnea, heart rate, pH, pCO2
• critical remark: Due to lack of tolerance there was often
a crossover to a different form of therapy. Only 80% of
the participants completed the study in accordance with
the study protocol.

meta-analysis
Noninvasive Ventilation and Survival in Acute Care Set-
tings: A Comprehensive Systematic Review and Meta-
Analysis of Randomized Controlled Trials
Cabrini et al, CCM 2015
• meta-analysis (78 RCT)
• 7365 patients; NIV versus conservative therapy for pre-
vention / treatment of acute respiratory insufficiency or
for early extubation
• result: NIV → significant reduction of mortality (NNT 19)
Contraindications
• no spontaneous breathing, agonal respiration (respi-
ratory reate < 6/min)
• no protective reflexes (cough / swallowing reflex)
• somnolence, coma
-- only relative, since hypercapnia can also be the
cause of somnolence Diaz et al, Chest 2005: 95 pa-
tients with GCS < 8 → after 4h NIV 85% GCS 15)
-- Only the non-hypercapnia induced coma is a contra-
indication for NIV!
• lack of compliance, uncooperative patient , delirium
• craniofacial trauma
• gastrointestinal bleeding (e.g. bleeding esophageal
varices), ileus
• hemodynamic instability, shock (any cause)
• malignant arrhytmia
• excessive secretion (> 2 bronchoscopies/day neces-
sary)
• acute myocardial infarction: An increase in the number
of myocardial infarctions has been observed during NIV
(study Mehta et al, Crit Care Med 1997; meta-analysis
Peter et al, Lancet 2006). This has been interpreted
as a result of the reduced coronary perfusion during
NIV. It is unclear whether the myocardial infarction the
cause for the pulmonary edema or the consequence
of NIV. This could not be confirmed in further studies
(Nadar et al, Int J Cardiol 2005; Bellone et al, Crit Care
Med 2004). Three meta-analyses (Masip et al, JAMA
2005; Vital et al, Cochrane Database Syst Rev 2008
Weng et al, Ann Intern Med 2010) did also not show
an increased infarction rate in patients with cardiac
pulmonary edema, so that pulmonary edema due to
a myocardial infarction is explicitly no contraindication
for NIV. However, it must not delay the necessary mea-
sures (e.g. coronary angiography with PTCA). NIV is
only contraindicated for myocardial infarction with car-
diogenic shock: The Patient must be intubated here.
Modes
• NIV with negative pressure (NPV: negative pressure
ventilation):
-- "iron lung" (metal tank [polio epidemic])
-- Cuirass system ("breast plate"; ; BCV: biphasic cui-
rass ventilation)
• NIV with positive pressure (PPV: positive pressure
ventilation; standard)
Fig. 230  iron lung: It was used since 1929 during of the po-
lio epidemic in the Scandinavian countries in the past. Is is
a typical NIV with negative pressure.
Devices
• intensive care respirators
• turbine technology devices
• mechanical devices (only CPAP possible), i.a.
-- nasal-high-flow therapy
-- EzPAP-system (8cm plastic tube for tracheal cannu-
la or nose-and-mouth mask; generates PEEP with
compressed air)
Intensive care respirators
• examples: Evita 4, Evita XL, Servo
• disadvantages
-- bad trigger function
-- only low inspiratory flow (shortness of breath ["air
hunger"])
-- frequent alarms (leakage)
-- heavy double-barreled breathing circuits (Intensive
care respirators have two ventilation hoses: one for
the inspiration and one for the expiration.) → mask
slipping out of position when head is moved (trac-
tion)
• only suitable to a limited extent for NIV in ICU
• However, by using a special NIV-software, some dis­
advantages can be compensated nowadays.
Turbine technology devices
• examples: BIPAP-Vision, Respironics V60, Respiro-
nics Trilogy 202, Zephyrus, Carina
• well suited for NIV in intensive care
• advantages
General Part 131
 -- good trigger function
-- high inspiratory flow
-- very good leakage compensation (automatic increa-
se of the gas flow)
-- lightweight breathing circuits (only one hose [inspi-
ration])

Fig. 233  Turbinengerät (hier Beispiel Zephyrus der Firma

Medisize) [24]

Fig. 231  turbine technology device (here for example: Phi-

lips Respironics V60 [succeeding model of the BiPAP-Visi-
on] of the Heine + Löwenstein company) Fig. 234  turbine technology device (here for example Cari-
na of Dräger company)

Fig. 235  CPAP device (here for example: Charisma of the

Fig. 232  turbine technology device (here for example: Re- Heinen + Löwenstein company)
spironics Trilogy 202 of the Heine + Löwenstein company)

132 General Part

 in Germany judged in July 2019, that HFNOT is not
considered as mechnical ventilation according to the
coding rules and thus not billable as ventilation. This
judgement referred spcially to the HFNOT in prematu-
re babies in neonatology.

Effects
• increase of the inspiratory oxygen supply (FiO2 up to
100%)
• reduction of nasopharyngeal airway resistance and
therefore also reduction of breathing effort (only to a
limited extent)
• increase of the functional residual capacity (FRC)
• reduction of the pCO2 due to washout effect (The high
flow causes the CO2 is "washed out" from the dead
space in the upper airways [especially pharynx]; only
to a limited extent)

Examples (systems)
• Optiflow (Fisher & Paykel Healthcare)
• AcuCare HFNC (ResMed)
• Soft Flow 50 (TNI)
• O2-RESQ (Pulmodyne)

Fig. 236  CPAP device (here for example: Alpha 101c of the
Salvia Lifetec company)

Nasal-high-flow (NHF)
Definition
• syn.:
-- high-flow nasal oxygen therapy (HFNOT)
-- high-flow nasal cannula (HFNC)
• classification of oxygen therapy:
-- low-flow oxygen therapy: < 15 l/min
◦◦ 1-5 l/min: via cannula
◦◦ 5-15 l/min: via mask (Hudson-Maske)
-- high-flow oxygen therapy: > 15 l/min
• administration of oxygen (humidified and warmed) with
a high flow (p.d. > 15 l/min; usually 30-60 l/min) via
a special nasal tube (wide lumen, soft) → generation
of a positive end-expiratory pressure (especially in the
upper airways; a CPAP-procedure)
• indication: respiratory insufficiency (hypoxemic respi-
ratory failure [e.g. severe pneumonia]); even a good
(but rare) indication: carbon monoxide poisoning
• maximum flow in der pediatrics: 2 l/kg/min
• even possible via a tracheostomy tube (via a special
connector [usually included in the set])
• the innovation in intensive care medicine in the last
years Fig. 237  Optiflow system [43]
• to predict the probability of success or failure of HF-
NOT in acute hypoxemic lung failure: ROX index (see
infobox)
• remuneration: In Germany, it still does not exist. Due
to HFNOT, furthermore the number of hours of venti-
lation, that would be relevant for the payment in the
DRG-system, decreases. The Federal Social Court

General Part 133

 Fig. 240  AcuCare system

Fig. 238  special wide lumen, soft nasal tube (here for ex-
ample: Optiflow system)

Fig. 239  Optiflow system

Fig. 241  HFNOT is also possible via a tracheostomy tube

by using a special connector.

Problems
• dehydration of mucosa (therefore always combine with
active humidification)
• oxygen toxicity due to high FiO2 (possibly increased
fibroblast proliferation and fibrosis)
• (nearly) no mechanical support of respiratory muscu-
lature (therefore only useful in case of hypoxemic but
not hypercapnic lung failure [here only optional in case
of NIV failure])

134 General Part

Studies
• FLORALI study (see box)
• BiPOP study (Stephan et al, JAMA 2015: HFNOT and
NIV equally efficient in patients with respiratory failure
after cardiothoracic surgery)
• Hernandez et al, JAMA 2016 (see page 151): HFNOT
equal to NIV in prophylaxis of a postextubation respira-
tory failure (especially in bei high-risk patients)
O2-RESQ system
• CPAP-system with mask
• The system is connected with oxygen with a flow of 12-
15 l/min. A flow of 80-140 l/min and a FiO2 of 30-35% is
generated via a flow generator.
• PEEP adjustable: 5, 7.5 und 10 cmH2O

FLORALI study

High-Flow Oxygen through Nasal Cannula in Acute Hypo-

xemic Respiratory Failure
Frat et al, N Engl J 2015

• multicenter randomized controlled study

• 310 patients with acute hypoxic respiratory failure (Horo-
vitz quotient < 300mmHg)
-- standard oxygen therapy
-- high-flow oxygen therapy
-- NIV
• results: high-flow oxygen therapy
-- primary endpoint: intubation rate → no difference (in
subgroup with Horovitz quotient < 200 mmHg, howe-
ver, significant reduction)
-- secondary endpoints, i.a.
◦◦ mortality: significantly reduced
◦◦ ventilator-free days: significantly increases
high-flow nasal oxygen therapy
(HFNOT): very efficient in case of
hypoxemic respiratory failure!
Fig. 242  O2-RESQ system
Masks (Interfaces)
Construction
• transparent masks made of rigid PVC
• soft silicone cushion
• head straps
Types
• mouth-nose mask (no.1)
• nasal mask
-- disadvantage: Mouth-breathers cannot be ventilated
sufficiently (rather for sleep laboratory, not suitable
for NIV in intensive care unit).
-- advantage: in case of vomiting lower risk of aspirati-
on than mouth-nose or total face mask
• total face masks (full face masks; No.2)
• helmet (CPAP hood; e.g. CaStar [StarMed company])
-- more dead space, lower trigger sensitivity, less ef-
ficient than mouth-nose mask [i.a. Navalesi et al, Int
Care Med 2007])
-- more suitable for the treatment of hypoxemic and
less for hypercapnic respiratory failure (i.a. CO2 re-
breathing)
-- preferred for NIV during the corona pandemic due to
the lower risk of contagion for the medical staff
-- Usually only CPAP is possible with a helmet and
no augmented ventilation like CPAP-ASB, since the
helmet has a relatively high compressible volume.
-- A monocenter study (Patel et al, JAMA 2016) show-
ed that the helmet was more effective than the nose-
mouth mask in patients with ARDS (especially lower
intubation rate and lower mortality).

General Part 135

Fig. 243  mouth-nose mask: standard mask for NIV [33]

Fig. 244  mouth-nose mask - fixation with head straps [24]

Fig. 246  total face mask

Fig. 247  helmet (CPAP hood)

Fig. 245  mouth-nose mask

136 General Part


Fig. 248  helmet (CPAP hood) [24]
Ventilation techniques
• spontaneous
• augmented
• controlled
Ventilation modes
• standard:
-- CPAP: continuous positive airway pressure
-- PSV/ASB: pressure support ventilation, assisted
spontaneous breathing
• PAV: proportional assist ventilation
• CMV: controlled mechanical ventilation
• ACV: assisted controlled ventilation
Procedure
• positioning:
-- always in semi-sitting position (improved breathing
mechanics)
-- also slightly elevate arms of the patient
• The patient should first get used to the mask: First, you
only lay the mask onto the patient's face. You should a
little bit before fixating it with the head straps.
• For a long-term NIV (especially in case of exacerbated
COPD) one should choose active humidification and
not passive (HME). Reason: It reduces the breathing
effort (HME-filters have a larger dead space), increa-
ses CO2-elimination and leads to an efficient humidi-
fication even in the event of leakages, which are not
uncommon. This is also recommended in the AARC
Clinical Practice Guidelines 2012.
• inhalation therapy (in AECOPD): most efficient under
spontaneous breathing (If possible, NIV should be
stopped for inhalation! However, active humidification
leads to a dilution and therefore to a reduction of the
dose of the inhaled substance by 50%.)
• If there is no improvement under non-invasive ventila-
tion or if the patient's condition gets worse, he should
be intubated early. During NIV, it is generally advisable
not to exceed a maximum FiO2 of 0.6. If you then deci-
de to intubate, you still have sufficient reserves (switch
to a FiO2 of 1.0 shortly before).
Settings
• hypercapnic respiratory failure
• hypoxemic respiratory failure
Hypercapnic respiratory failure
(exacerbated COPD)
• ventilation mode: The respiratory musculature in the
patients with exacerbated COPD is often completely
fatigued so that it often can't even cope with the trig-
gering during assisted spontaneous breathing. That's
the reason why controlled ventilation (e.g. BIPAP) is
performed in several hospitals. However, it is neces-
sary to ensure that it does not lead to patient-ventilator
asynchrony, since the work of breathing and the dyna-
mic hyperinflation would further deteriorate. Therefo-
re, assisted spontaneous breathing (e.g. CPAP-ASB)
with a low and therefore relatively sensitive flow trigger
(0.25-0.50 l/min) is usually the best option (PEEP 5-8
mbar, ASB 10-15 mbar). In case of bronchial asthma,
one should start with lower pressures (PEEP 3-5 mbar,
ASB 5-10 mbar). Since this is a spontaneous breathing
mode, apnea monitoring must be switched on to en-
sure that the patient is ventilated if he stops breathing
(apnea ventilation). Forthermore a short pressure rise
time (steep ramp; 0.1sec) should be set: The shorter
the pressure rise time, the lower the work of breathing
is.
• A controlled ventilation (e.g. BIPAP) instead of spon-
taneous breathing will only be performed if the patient
is somnolent (e.g. because of CO2-anesthesia or a ne-
cessary sedation [e.g. with propofol], without which the
patient would not have tolerated NIV). Due to the som-
nolence, the patient can no longer trigger a mandatory
breath. settings
-- pressures:
◦◦ IPAP 15-20 mbar (increase up to 30 mbar)
◦◦ EPAP (PEEP) 5-8 mbar
-- short inspiratory time (Tinsp; objective: long expiratory
time); I:E ratio = 1:3
Hypoxic respiratory failure
(cardiac pulmonary edema)
• CPAP (8-10 mbar): Here the continuously positive air-
way pressure, which presses the water out of the al-
veoli back into the blood vessels, is decisive, not the
ventilatory support (pressure support) as in case of
exacerbated COPD, where the breathing musculature
(respiratory pum) is exhausted. That is the reason why
here only CPAP and not CPAP-ASB is usually neces-
sary.
• in case of additional hypercapnia (due to exhaustion of
the breathing musculature: Here a pressure support is
necessary): CPAP-ASB
• in case of additional somnolence (Here the patient can
General Part 137
 no longer trigger a mandatory breath.): BIPAP
-- IPAP: start with 15 mbar, then gradually increase to
20 mbar
-- EPAP (PEEP): at least 5 mbar
• NIV usually only required for a short time
• NIV may i.a. be terminated if SO2 > 90% for over 30
min under CPAP 5 cmH2O or IPAP 10 mbar and EPAP
5 mbar.
-- respiratory rate too low
-- inspiratory flow too low (shortness of breath ["air
hunger"])
• RR-decrease
• late failure of NIV (average: after 8 days; especially in
case of hypercapnic respiratory failure)

Ventilation modes:
exacerbated COPD: CPAP-ASB
cardiac pulmonary edema: CPAP
(CPAP-ASB, if necessary)

Fig. 249  Pressure sores in the face (like here for example
on the nasal bridge) usually occur only in case of long-term
Sedation non-invasive ventilation.
• opiates:
-- morphine: repetitive administration of 5 mg i.v. (cau-
tion: histamine release; first-choice treatment, how-
ever!)
-- piritramide (Dipidolor) repetitive administration (e.g.
3.75 mg i.v. 1-1-1-1)
• propofol (low dose)
• α2-agonists (no respiratory depression)
-- clonidine
-- dexmedetomidine
• no benzodiazepines
-- reason: respiratory depressant and muscle relaxant
-- exception: Lormetazepam (Sedalam; page 167)
neither has a respiratory depressant nor a muscle
relaxant effect. Therefore it is a good option for se-
dation during non-invasive ventilation especially for
patients with the leading symptom anxiety.

Fig. 250  The x-ray shows a severe gastric distension (here:

First choice for sedation in NIV: after NIV). An incorrect, esophageal intubation looks simi-
morphine! lar on the x-ray

Monitoring
Complications • clinical
-- chest rise
• mask problems
-- synchronous breathing pattern
-- tolerance issues
-- increase of vigilance
-- leakage
-- decrease of respiratory rate
-- pressure sores / skin defects in the face (especially
nasal bridge; usually only in case of long-term ap- • technical
plication) -- blood pressure, heart rate
• dehydration of the mucosa -- pulse oximetry
• gastric distension (If the belly bloats during non-inva- -- ECG (i.a. arrhythmia)
sive ventilation, a gastric tube should be inserted [be -- ABG (arterial-blood gas)
aware of extrathoracic restriction].)
• conjunctivitis (caused by drafts due to air leak)
• obstruction of upper airways → Wendl tube (naso-
Success criteria
pharyngeal airway [NPA]) • chest rise
• asynchrony( ventilator / patient; in case of controlled • decrease of dyspnea
ventilation); causes: • decrease of respiratory rate
-- IPAP too low • decrease of heart rate

138 General Part

• increase of vigilance
• decrease of pCO2, increase of pH
Errors
• leakage of the mask (air leaks)
-- check position of mask
-- if necessary, choose other mask size or type of
mask (e.g. exchange nose-mouth mask for total-
face mask)
• missing exhalation valve behind the mask: Turbine
technology devices have only an inspiratory but no
expiratory hose. The exhaled air can only escape, if
there is an have an additional exhalation valve. Other-
wise this would lead to an increasingly high airway re-
sistance with increased hyperinflation and increased
pCO2! This is not necessary when using intensive care
respirators for NIV, hence there is a also expiratory
hose.
• disconnection of mask and ventilator
Limitations of NIV (indications for
intubation)
• increasing respiratory rate, decreasing tidal volume
(rapid shallow breathing index, Yang index [= RR/TV]
> 105 [VT unit: l and not ml])
• increasing somnolence / impaired consciousness
• life-threatening hypoxemia ( Horovitz quotient < 100
mmHg: In this case the patient should always be intu-
bated! Because if the mask dislocates here, the patient
quickly suffers from a hypoxic induced cardiovascular
arrest!)
• no improvement / deterioration of the ABG level after
2h at the latest (better: 30 min)
• pH < 7,2
What is important is not the pCO2, but
the pH
pH < 7.35 → NIV
pH < 7.1 → IV (invasive ventilation)
no improvement with NIV in the
first 2 h (better: 30 min) →
intubation
Predictors (NIV failure)
• low pH (at pH 7.2: failure rate 50%!)
• reduced vigilance (Glasgow Coma Scale < 11 p.)
• no improvement of pH, pCO2, RR and consciousness
after 1 h
• high APACHE II-Score
• massive bronchial secretion (e.g. bronchial asthma)
• pneumonia as a cause
NIV is no substitute for IV (invasive
ventilation), but a complement!
Controversial indications
• ARDS
• post-extubation failure
• trauma-related acute lung injury (annot.: no indication)
NIV in ARDS
• often (esp. permanently) high ventilation pressures
needed
• NIV at most only indicated in very mild cases
• A maximum FiO2 of 0.6 should not be exceed. This
should be the trigger for the intubation and invasive
ventilation. So you still have sufficient reserves (switch
to a FiO2 of 1.0 shortly before intubation).
• only very cautious and reserved
• If you perform a non-invasive ventilation in ARDS, you
should take care that as well as in invasive ventilation
a lung protective ventilation is provided, i.e. tidal volu-
me 6 ml/kg and pressure gradient Δp between inspira-
tory pressure and PEEP < 15 mbar.
• There is no controlled study in which non-invasive
ventilation is compared to invasive ventilation in ARDS
patients.
• usually no indication (only in combination with an ext-
racorporeal procedure
• A ventilation helmet (CPAP-hood) may be better than a
nose-mouth mask in this case (Patel et al, JAMA 2016
[only single-center study]) .
• note: But very efficient here is high-flow nasal oxygen
therapy (HFNOT; see page 133), although strictly
speaking an ARDS according to the Berlin definition
is only possible in ventilation and not in spontaneous
breathing like HFNOT.
NIV in post-extubation failure
• post-extubation failure (PEF)
-- definition: need for need for ventilation again (usu-
ally reintubation) within 48h after extubation due to
acute respiratory insufficience
-- incidence: 20% of all long-term ventilated patients
• rate of reintubation in NIV: 70% (cannot be reduced
through NIV!)
• NIV in case of post-extubation failure only with caution
and performance only by suitably experienced staff; a
short attempt is allowed, but intubation should not be
delayed to long (<< 10 hours).
• NIV mainly for the prophylaxis (not therapy) of post-ex-
tubation failure (especially in case of risk factors [heart
failure, COPD, obesity, hypersecretion])
• studies:
-- The rate of reintubation could not be reduced with
NIV in long-term ventilated patients who again deve-
loped acute lung failure within 48 h after extubation
(Keenan et al, JAMA 2002).
General Part 139
 -- The results were alarming in the study of Esteban (N
Engl J 2004): Compared to the standard drug the-
rapy, NIV could not reduce the reintubation rate in
patients after long-term ventilation, who again deve- VHYPER study
loped acute lung failure within 48 h after extubation.
Surprisingly, the study also showed an increased
rate of mortality (i.a. because the mean time to rein-
tubation with an average of ten hours was very long; Intermittent noninvasive ventilation after extubation in pa-
main cause of death: sepsis). tients with chronic respiratory disorders
• S3-Leitlinie 2015: NIV is worth a try in hypercapnic Vargas et al, Int Care Med 2017
post-extubation failure (especially patients with COPD)
• multicenter randomized controlled study
but should be avoided in hypoxemic post-extubation
failure: The patients should be reintubated here wit- • 144 patients with chronic pulmonary disease (esp.
COPD); immediatly after extubation:
hout delay and if necessary, a tracheotomy should be
-- with NIV (for 48h)
performed soon.
-- without NIV (only administration of oxygen)
• results: NIV
-- rate of post-extubation failure: significantly redu-
meta-analysis ced
-- mortality: no difference

Noninvasive ventilation as a weaning strategy for mechani-

cal ventilation in adults with respiratory failure: Cochrane study
systematic review
Burns et al, CMAJ 2014

• metaanalysis: 994 invasively ventilated patients (espe-

cially COPD); NIV in weaning
-- early extubation and non-invasive ventilation
-- continued invasive ventilation
• results
-- significantly lower risk of VAP
-- significantly shorter ICU/hospital stay
-- significantly less tracheotomies
-- significantly reduced rate of reintubation
-- significantly reduced mortality
study
Noninvasive Ventilation and Weaning in Patients With
Chronic Hypercapnic Respiratory Failure: A Randomized
Multicenter Trial
Girault al, Am J Resp Crit Care 2011
Early extubation followed by immediate noninvasive venti-
lation versus standard extubation in hypoxemic patients: a
randomized clinical trial
Vaschetto et al, Int Care Med 2019
• multicenter randomized controlled study
• 130 (highly selected) patients with hypoxemic respirato-
ry failure, who were at least 48h invasivelly ventilated:
-- early extubation and NIV (for 48h)
-- standard-extubation (without NIV)
• results: early extubation and NIV
-- primary endpoints:
◦◦ duration of invasive ventilation: significantly redu-
ced
◦◦ duration of ICU stay: no difference
-- secundary endpoints:
◦◦ rate of VAP: significantly reduced
◦◦ duration of hospital stay: significantly reduced
◦◦ mortality: no difference

• multicenter (13 intensive care units) randomized study

• 208 invasively ventilated patients with pre-existing chro-
nic hypercapnic respiratory insufficiency and failed the
first spontaneous breathing trial
-- continued invasive ventilation
-- extubation + administration of oxygen
-- extubation + NIV
• Result: Weaning failure occured least frequently in the
group "extubation + NIV".

140 General Part

 Weaning Approx. 50% of the total ventilation
time is used for weaning!

Long-term ventilation
A lot of different definitions of long-term ventilation are
circulating:
• ventilation > 48h
• multiple unsuccessful weaning trials
• mechanical ventilation for more than 6 h/day necessa-
ry for about 2-3 weeks

In 2007, a TASK-FORCE (the Budapest Consensus

Conference) determined that ventilation for more than 7
days is referred to as long-term ventilation.

Definition
• discontinuing of dependency on assisted ventilation
• reduction of the invasiveness of ventilation with the ob-
jective of spontaneous breathing
• gradual transfer of the work of breathing from the res-
pirator to the patient
-- decrease of
◦◦ FiO2
◦◦ IPAP, PEEP
-- normalisation of I:E ratio (e.g. from before 1:1 now
to 1:2)
• Mortality increases by 2% with each day of ventilation
• average duration: 47% of the time of mandatory venti-
lation (Esteban et al, Chest 1994) is used for weaning.
• guidelines (German):
-- S2k-guideline 2014 "Prolonged Weaning" (German
Respiratory Society [DGP]); revised 2019
-- S3-Guideline 2017 "Mechanical Ventilation and Ext-
racorporeal Membrane Oxygenation in Acute Respi-
ratory Insufficiency" (German Society for Anaesthe- weaning criteria fulfilled
siology and Intensive Medicine [DGAI; chapter No. („ready to wean“)
7: weaning from invasive ventilation)
7th day
• Especially in the prolonged weaning the ventilation has (after the 1st SBT)
to be continued although the initial (original) indication,
that lead to ventilation (e.g. severe pneumonia), has
been repaired long ago. 1st SBT 2nd SBT 3rd SBT more than 3 SBT
• successful weaning: extubation and then no ventilatory
support necessary for 48 h
• weaning failure:
-- failed spontaneous breathing trial
-- need for reintubation / recannulation or for ventilato-
easy difficult prolonged
ry support within 48 h after the extubation
weaning weaning weaning
-- death within 48 h after extubation
Fig. 251  overview of weaning categories

General Part 141

According to the S2k-guideline 2014 weaning is catego-
rized into the following groups:
• 1: easy
• 2: difficult
• 3: prolonged
-- 3a: successful without NIV
◦◦ I: with extubation / decannulation
◦◦ II: without decannulation
-- 3b: successful with NIV; according to the revised
S2k-guideline 2019 further categorized:
◦◦ I: without additional care needs (independent [e.g.
intermittent self-ventilation at home at night)
◦◦ II: with additional care needs (e.g. nursing home,
shared apartments for people undergoing ventila-
tion)
-- 3c: unsuccessful (permanent ventilation via trache-
al cannula or death); according to the revised S2k-
guideline 2019 further categorized:
◦◦ I: permanent ventilation via tracheal cannula (out-
of-hospital ventilation)
◦◦ II: death
study
Incidence and outcome of weaning from mechanical venti-
lation according to new categories
Funk et al, Eur Respir J 2010
• prospective multicenter cohort study
• weaning of 257 invasivelly ventilated patients
-- easy: 59% (mortality 13%)
-- difficult: 26% (mortality 9% [no significant difference in
mortaliy between easy and difficult weaning])
-- prolonged: 14% (mortality: 32%)
study
Predictors of prolonged weaning und survival during venti-
lator weaning in a respiratory ICU
Sellares et al, Intensive Care Med 2011
• prospective multicenter cohort study
• weaning of 181 invasivelly ventilated patients
-- easy: 43%
-- difficult: 39% (no significant difference in mortaliy bet-
ween easy and difficult weaning)
-- prolongiert: 18% (significantly increases mortality)
142 General Part
WIND study
Epidemiology of Weaning Outcome According to a New
Definition
Beduneau et al, AJRCCM 2016
• prospective multicenter cohort study
• WIND: Weaning accordIng to New Definition
• weaning of 2729 invasivelly ventilated patients
-- easy: 57% (mortality 6%)
-- difficult: 10% (mortality 17%)
-- prolongiert: 9% (mortality 29%)
Causes (difficult weaning)
• fatigue / weakness of the respiratory musculature (es-
pecially diaphragm; leading cause); causes :
-- COPD
-- obesity
-- anemia
-- neuromuscular disease, e.g.
◦◦ critical illness-polyneuropathy (CIP), critical illness
myopathy (CIM): In case of ventilation > 7 days,
CIP is present in 60% and in case of severe sepsis
in 70%!
◦◦ diabetic neuropathy
-- steroid myopathy
-- VIDD (ventilator-induced diaphragmatic dysfunction;
inactivity induced atrophy of the diaphragm already
after 48h ventilation [Levine et al, N Engl J 2008])
• comorbidities (Charlson Comorbidity Index)
• delirium
• central respiratory depression
-- to strong analgosedation (leading cause)
-- cerebral pathologies (i.a. ischemia, hemorrhage)
-- metabolic alkalosis (reduces the respiratory drive; if
necessary, compensate with Acetazolamide 500 mg)
• pleural effusion: Pleural effusion is often overlooked
and is a common cause for difficult weaning. A chest x-
ray is completely unsuitable for detecting a pleural ef-
fusion. Sonography is the means of choice and should
be performed in case of difficult weaning! Therapeuti-
cally, a pleurocentesis is performed.
• heart failure:
-- In many cases, a previously unknown heart failure is
omly unmasked during weaning. During controlled
ventilation (positive pressure), the pre- and afterload
are low due to the high intrathoracic pressure, which
is favorable for a weak heart. In weaning, however,
spontaneous breathing increases (negative pres-
sure), with the result that the intrathoracic pressu-
re drops so that the pre- and afterload increases,
leading to cardiac decompensation ( so-called
weaning-induced cardiac insufficiency or weaning-
induced pulmonary oedema [WIPO]). Therapeutic
 options are preload-reducing medication (e.g., diu-
retics, nitroglycerin) and inotropic support (e.g. with
dobutamine). Indications of weaning-induced cardi-
ac insufficiency: ABCDE
◦◦ increase of the CVP
◦◦ decrease of the central or mixed venous saturation
◦◦ increase of the proBNP
◦◦ increase of the E/E' ratio (an echocardiographic
parameter for estimating the LVEDP; see page
222)
◦◦ increase of total protein (as a result of the hemo-
concentration due to oedemata) > 9% at the end
of a failed spontaneous breathing trial in compa-
rison to the initial value (highly specific; increase
of < 3%: weaning-induced pulmonary oedema can
most probably be ruled out [Anguel et al, Intensive
Care Med 2008])
-- diagnostics:
◦◦ echocardiography: not only the systolic, but also
the diastolic function should be considered. The
best parameter for the detection of a diastolic dys-
function is the E/E' ratio (for measurement see
page 222). An increased E/E' ratio is strongly as-
sociated with a weaning failure (Moschietto et al,
Crit Care 2012).
◦◦ pleural sonography
◦◦ proBNP
• CAD (coronary artery disease): A pre-existing, hae-
modynamically not yet relevant CAD can evolve into
a cardiac ischemia in weaning due to the increased FAIL TO WEAN
myocardial oxygen consumption during spontaneous
breathing (so-called weaning-induced acute coronary
syndrome). For data acquisition, a 12-channel ECG
should be recorded and a cardiac enzyme test should
be conducted. Sometimes patients can only be wea-
ned after a completed cardiac catheterization with re-
vascularization.
• malnutrition: especially
-- hypophosphatemia
◦◦ Phosphate is essential for the formation of ATP
and thus an important energy supplier
◦◦ often in intensive care units (30% of intensive care
patients, even 80% of all patients with sepsis!), es-
pecially in renal replacement therapy
◦◦ remember and substitute!
-- vitamin D deficiency
• nosocomial pneumonia (especially VAP), aspiration
• trigger set too high on the ventilator (in spontaneous
betrathing forms such as CPAP-ASB) → breathing ef- The main reason for difficult
fort ↑ weaning is the weakness of
respiratory musculature!
If you stand at the patient's bedside wondering why
weaning simply does not work, it is very helpful to go
through the ABCDE of weaning (see infobox), which
points out the leading causes for difficult weaning. Then Difficult weaning: always perform
make a diagnosis and start the appropriate therapy. pleural ultrasound on both sides (to
see if there are pleural effusions) and
echocardiography!

General Part 143

Epidemiology
• Occurrence
-- difficult weaning: 25 %
-- prolonged weaning or long-term ventilation: 15%
(but will consume 50% of the resources of an intensi-
ve care unit): After 1 year, 30% of these patients die
(75% due to therapy limitations or discontinuation of
therapy).
• often unnecessarily long ventilation: in case of acci-
dental extubation
-- - in patients under controlled ventilation → only 81%
need to be reintubated
-- in patients undergoing weaning → only 16% need to
be reintubated (Tindol et al, Chest 1994; Betbese et
al, Crit Care Med 1998)
-- Epstein et al (Am J Respir Crit Care, 2000) were
able to show that only 56% of the patients had to be
reintubated after accidental extubation (in weaning
even only 30%).
Only about half of all patients has to
be reintubated after self-extubation!
"Weaning starts with intubation!"
Conditions (Prerequisites)
144 General Part
Methods
• reduction of the respiratory rate in BIPAP (increase of
the pCO2 and thus stimulation of the respiratory center)
• SIMV
-- synchronized intermittend mandatory ventilation
-- preset ventilation rate: Ventilator will provide a me-
chanical breath if the patient fails to breathe himself
within the set interval.
-- reduction of SIMV frequency and of the pressure
support during weaning
-- used to be the classic weaning procedure (today lar-
gely obsolete)
-- The main problem is the poor synchronization: The
respiratory center cannot react quickly enough to the
rapid change between supported and spontaneous
respiration. The consequence is that the respirato-
ry musculature is still active during the supported
breaths, which leads to overload and fatigue of the
respiratory muscles (enormous breathing effort).
SIMV is significantly worse than CPAB-ASB (Bro-
chard et al, Am J Resp Care Med 2014).
-- no longer recommended in the S2-guideline 2014
"Prolonged Weaning"
• spontaneous breathing forms with inspiratory pres-
sure support (weaning method of choice today; CPAP-
ASB, PSV)
• modern weaning procedures (diaphragm-controlled)
-- Not always the same pressure support during inspi-
ration like in CPAP-ASB is applied her, but individu-
alized pressure support proportional to the patient's
breathing effort ("power assisted steering").
-- types:
◦◦ by measuring resistance and compliance:
▪▪ PAV (proportional assist ventilation; Covidien
company: see page 114)
▪▪ ASV (adaptive support ventilation; Hamilton
company; see page 115)
◦◦ by measuring the electrical activity of the dia-
phragm: NAVA (neurally adjusted ventilatory as-
sist; Maquet company; see page 115)
• NIV
-- PEF-prophylaxis (PEF: post-extubation failure)
◦◦ hypercapnic respiratory failure (esp. COPD, obe-
sity): recommended (i.a. Burns et al, BJM 2009)
◦◦ hypoxemic respiratory failure: not recommended
-- PEF-therapy:
◦◦ increased mortality (Esteban et al, N Engl J 2004)
◦◦ In case of a hypercapnic post-extubation failure
(esp. COPD) an attempt with NIV is an option, but
not in case of a hypoxemic post-extubation failure:
Here the patient should be intubated without any
delay.
• spontaneous breathing trials
• tracheotomy
Patients with COPD: early extubation
and non-invasive ventilation!
CPAP-ASB, PSV
• spontaneous breathing forms with inspiratory pressure
support
• syn.:
-- inspiratory pressure support (IPS)
-- inspiratory flow assistance (IFA)
• pressure support of the spontaneous inspiration
• designations
-- CPAP-ASB (assisted spontaneous breathing; Drä-
ger)
-- PSV (pressure support ventilation; Siemens)
• weaning procedure of choice!
• settings:
-- ASB (inspiratory pressure support; is usually speci-
fied as ΔPASB, i.e. as a pressure above the PEEP;
example: PEEP 8 mbar, ΔPASB 12 mbar → The pres-
sure that the patient receives during inspiration [PASB]
is 20 mbar).
-- pressure rise time (ramp)
-- trigger
◦◦ inspiratory trigger
◦◦ expiratory trigger (cycling-off: Inspiration should
be terminated at 40% of the peak flow. In daily
practice, however, this setting is rarely changed.)
• most important monitoring function: apnea ventilation
• for schemes see also page 110
pressures
time
Fig. 252  CPAP-ASB in weaning: Spontaneous breathing
phases are extended (above) and pressure support is re-
duced (below).
Spontaneous breathing trial (SBT)
• performance
-- tube:
◦◦ spontaneous breathing form, e.g. CPAP-ASB
◦◦ A T-piece trial should only be performed via a tra-
cheal cannula and never via a tube. This would be
too strenuous for the patient since it is comparab-
le to breathing through a drinking straw! Although
the resistance R only increases with the 1st power
of the length I (but with the 4th power of the radi-
us r; R ~ l / r4), it still increases. Using a (inflated
[blocked]) tube, a spontaneous breathing trial can
only be performed with the ventilator: A pressure
support (ΔPASB, i.e. PASB + PEEP) of 7 mbar and a
PEEP of 5 mbar are set. Therefore only the self-
generated work of breathing of the tube and the
ventilator is compensated ("functional extubati-
on"). A spontaneous breathing trial via a tube wi-
thout the ventilator is only an option if the tube is
deflated (unblocked). But here the risk of disloca-
tion is too high.
-- tracheal cannula: T-piece (with an ventilation attach-
ment ["Swedish nose"])
◦◦ spontaneous breathing via T-piece with oxygen
and humidification of breathing air
◦◦ in spontaneous breathing trials via tracheal can-
nula the cuff should be deflated: The trachea has
a diameter of 22-26 mm, the internal diameter of
the tracheal cannula is only 8-9 mm, so that work
of breathing is much higher when the cuff is infla-
ted. The deflation of the cuff during the sponta-
neous breathing trial is also highly recommended
in the current S2k-guideline "Prolonged Weaning",
since this reduces the breathing effort, provided
that that there is no increased risk of aspiration.
The fear that this increases the risk of aspiration
and therefore the risk of pneumonia is unsubstan-
tiated. In fact, the reverse is true: Patients whose
cuff is deflated are less likely to come down with
pneumonia than patients with an inflated cuff (i.a.
Hernandez et al, Intensive Care Med 2013; see
box). The reason for this is that the deflation of the
cuff reduces the breathing effort, accelerates the
weaning and reduces the duration of ventilation,
so there are less cases of ventilator-associated
pneumonia.
◦◦ According to the recommendations of the S2k-
guideline "Prolonged Weaning" 2014, the tube cuff
should also be deflated during the spontaneous
breathing trial.
• for assessment and improvement (reconditioning of
the respiratory muscles; esp. in prolonged weaning) of
the ability to breathe spontaneously
• several times (or even hourly!) daily for up to 1h (bet-
ter: 5-10 min)
• According to the S2k-guideline "Prolonged Weaning"
2014, the cuffs of the tracheal cannula or the tube
should be deflated during the spontaneous breathing
phases, unless there is an obvious risk of aspiration.
• A manifest fatigue of the respiratory pump should be
avoided by all means, since it would take several hours
or even days until the patient recovers and the initi-
al status is restored. Furthermore, fatigue may cause
permanent structural damage to the respiratory musc-
les. Sufficiently long recovery phases for the respirato-
ry muscles are important so that the glycogen stores
can be replenished. Weaning should rather be a chal-
lenge for the physician less for the patient!
• failure (cancellation) criteria, i.e. criteria for an unsuc-
cessful (negative) spontaneous breathing trial: see in-
fobox
General Part 145
 Spontaneous breathing trials via a
During spontaneous breathing trials
tube: only with ventilator (ASB 7
using a tracheal cannula: deflate cuff!
mbar, PEEP 5 mbar) ("functional
Even lower risk of pneumonia with
extubation")
deflated cuff!

study

Effect of pressure support vs unassisted breathing through

a tracheostomy collar on weaning duration in patients re-
quiring prolonged mechanical ventilation: a randomized
Fig. 253  ventilation attachment ("Swedish nose") and T- trial
piece [24, 33] Jubran et al, JAMA 2013

• monocenter prospective randomized controlled study

• 312 long-term ventilated (> 21 days) tracheostomized
patients in weaning
-- continuous: pressure support (Patients were conti-
nuously connected with the ventilator, pressure sup-
port was gradually reduced.)
-- discontinuous: spontaneous breathing trials (SBT; the
patients were repeatedly disconnected from the venti-
lator and allowed to breathe through a "Swedish nose"
for up to 12 h; without pressure support)
• results: discontinuous (spontaneous breathing trials)
-- significantly shorter and more often successful
weaning
-- no difference in mortality

Weaning tracheal cannula: disconti-

nuous better than continuous! S2k-
guideline 2019: both possible (equal)

Weaning protocols
Here weaning should be performedstandardized accor-
study ding to an algorithm. Their benefits are not uncontrover-
sial: Many studies (i.a. Ely et al, N Engl J 1996; Kollef et
al, Crit Care Med 1997) showed a benefit of weaning pro-
tocols, many other studies (i.a. AJRCCM Krishnan et al,
The effects of increasing effective airway diameter on 2004; Randolph et al, JAMA 2002; Namen et al, AJRC-
weaning from mechanical ventilation in tracheostomized CM 2001), however, could not prove positive effects.
patients: a randomized trials Successful weaning certainly strongly depends on expe-
Hernandez et al, Intensive Care Med 2013 rience (esp. of the nursing staff). A meta-analysis (Black-
wood et al, Cochrane Database Syst Rev 2014) showed
• 195 tracheostomized patients: spontaneous breathing
trials via tracheal cannula
in 2434 ventilated patients that the use of weaning proto-
-- cuff deflated
cols lead to a significantly shorter duration of controlled
ventilation (by 26%), of weaning (by 70%) and of the ICU
-- cuff not deflated
stay (by 11%). There was no benefit with regard to morta-
• results: cuff deflated
lity. Only the combination of a weaning and sedation pro-
-- significantly shorter weaning duration (3 days)
tocol leads to a decerase of mortality (Girard et al, Clin
-- significantly less (!) respiratory infections (due to shor- Chest Med 2008). The use of a wening protocol is re-
ter ventilation period)
commended in the guidelines (S2k-guideline „Prolonged
-- significantly better swallowing function
Weaning“ 2014 + 2019 [German Respiratory Society],
S3-guideline „Mechanical Ventilation and Extracorporeal

146 General Part

Membrane Oxygenation in Acute Respiratory Insufficien-
cy" (German Society for Anaesthesiology and Intensive
Medicine). Weaning protocols will be relevant for the ac-
counting (financial reimbursement) of ventilation.
Weaning protocol (example)
• prerequisites:
-- Horovitz quotient > 250 mmHg
-- PEEP < 7 mbar
-- Af/VT < 105
-- no more (or only low-dose) catecholamines
-- adequate neurological status
• spontaneous breathing trial (CPAP-ASB with ASB 7
mbar or T-piece)
-- tolerated (over 30 min; SO2 > 90%, hemodynami-
cally stable, RR 8-30/min) → extubation
-- not tolerated → continue ventilation with gradual re-
duction of the ventilation parameters, daily sponta-
neous breathing trials
study
Mechanical ventilation weaning protocol improves medical
adherence and results
Borges et al, J Crit Care 2017
• monocenter prospective cohort study (for 7 years)
• 2469 ventilated patients
• implementation of a weaning protocol:
-- no positive fluid balance 24h before extubation
-- daily interruption of sedation
-- paO2 > 60mmHg at a FiO2 < 0.4, PEEP < 8 mbar
-- no more (or only low-dose) catecholamines
-- no increases ICP (intracranial pressure)
-- check of the weaning predictors (RSB, p0.1, NIF)
-- extubation, if RSBI < 30, SpO2 > 90%, HR < 130/min
-- immediately NIV (esp. in heart failure or COPD)
• significant increase of successful (from 73% to 85%)
within 7 years
Automated weaning procedures
• Quick-Wean (part of ASV [adaptive support ventilation;
Hamilton company; see page 115])
• SmartCare (Dräger company)
SmartCare
• automated weaning program of Evita XL (Dräger)
• in CPAP-ASB-mode
• according to weaning protocol of Prof. Laurent
Brochard(St. Michael's Hospital, Toronto [Canada])
• 3 measured values:
-- ETCO2
-- spontaneous respiratory rate
-- TV (tidal volume)
• controlled variable: CPAP-ASB (pressure for the inspi-
ratory support)
• assessment: controversial
-- faster weaning (i.a. Lellouche et al, Am J Resp Care-
Med 2006 [by an average of 30%])
-- no faster weaning (Rose et al, Int Care Med 2008;
WEAN study [Burns et al, Am J Respir Crit Care
2013]); in the study of Taniguchi et al, Crit Care 2015
even slower weaning!)
meta-analysis
Automated versus non-automated weaning for reducing
the duration of mechanical ventilation for critically ill adults
and children: a cochrane systematic review and meta-
analysis
Rose et al, Crit Care Med 2015
• meta-analysis (16 studies)
• 1676 patients in weaning
-- automated weaning procedure (i.a. SmartCare,
Quick-Wean)
-- non-automated weaning procedure
• result (automated weaning procedure): significantly
shorter time of ventilation (by 30%)
Accompanying measures
• tube
-- sufficient diameter (tube exchange, if necessary
[physiological breathing resistance only with tube
diameter 9 or larger]; a tube exchange only for the
purpose of successful weaning should only be done
very carefully and only with a malleable stylet, since
especially long-term-ventilated patients often suffer
from pronounced swellings of the mucosa, which
complicates reintubation; in principle a tube ex-
change should only be performed when the cuff of
the tube is leaky!)
-- engage automatic tube compensation (see page
116; especially always engage in case of COPD in
order to make work of breathing easier; always set
to 100%!); note: In case of an obstruction, the tube
compensation should be confined to inspiration.
Expiratory tube compensation should be switched
off because this would prevent the desired effect of
"pursed lips breathing" due to the lowered PEEP du-
ring expiration (how to switch off the expiratoty ATC
on the EVITA XL: see page 117).
-- if necessary, cut the tube or use a shorter catheter
mount (reduction of dead space); note: The shorte-
ning of a tube, which is common practice in some
hospitals, is of no benefit because the resistance R
only depends on the 1st power of the length I, but on
the 4th power of the radius r: R ~ l / r4
• prevention of anemia
-- Anemia reduces the O2-transport capacity and ince-
rases the work of breathing.
-- transfusion of red cell concentrates, if necessary:
General Part 147
 But also in weaning, red cell concentrates you should
only be transfused restrictively, i.e. only from a Hb
< 7 g/dl (SI unit: 4.3 mmol/l). A liberal transfusion
strategy neither reduces the duration of ventilation
nor the duration of weaning (i.a. Hebert et al, Chest
2001)! However, no consensus could be found about
the transfusion strategy in weaning at the guideline
conference within the framework of the preparation
of the S2k-guideline "Prolonged Weaning" 2014. In
the revised S2k-guideline 2019 an agreement now
was reached: An individual strategy is redommen-
ded.
• analgosedation
-- discontinuous (interruption of sedation every
morning [Kress et al, N Engl J 2004: significant re-
duction of the duration of mechanical ventilation])
-- use of an α2-agonist (e.g. clonidine) in weaning
• negative fluid balance (if possible)
-- especially in case of heart failure
-- especially before extubation (A positive fluid balance
before extubation increases the rate of reintubation
[Frutos-Vivar et al, Chest 2006]!)
• diet
-- reduction of carbohydrates (only a share of approxi-
mately 35-40% [normally 50-60%]; S2k-Guidelines
2014: recommended!)
◦◦ Among all macronutrients carbohydrates have the
highest respiratory quotient (RQ). That means that
through their metabolism the most CO2 is produ-
ced. Due to a reduction of carbohydrates less CO2
is produced and the work of breathin decreases.
◦◦ rate of CIP ↓
◦◦ shorter ventilation time (al-Saady et al, Intensive
Care Med 1989)
-- increase of fats (share of approximately 50% [nor-
mally only 30-35%]); note: This can be achieved with
energy-enteral feeding formulas (1.5 kcal/ml): high-
fat and low-carb. Energy-enteral feeding formulas
should therefore generously be used during weaning
(especially in COPD patients).
-- normocaloric (20-25 kcal/kg body weight per day)
-- trace elements
• acid alkaline and electrolyte balance: i.a. compensa-
tion for
-- metabolic alkalosis
◦◦ An alkalosis impedes the respiratory drive and
leads to hyperkapnia.
◦◦ if necessary, administartion of acetazolamide (Dia-
mox; 500-1000mg i.v. 2 x daily)
▪▪ a carbonic anhydrase inhibitor
▪▪ main indication: acute glaucoma
▪▪ DIABOLO study (Faisy et al, JAMA 2016; see
box): no benefit
-- hypophosphatemia (often in intensive care units!
Phosphate is an important energy supplier [ATP],
also especially for the respiratory muscles!)
• improvement of body position (e.g. Anti-Trendelen-
burg-position in obese patients)
• theophylline: formerly used in weaning to increase the
contractility of the diaphragm and to stimulate the re-
148 General Part
spiratory center (analeptic), but it is obsolete today in
this indication
• use of nicotine patches in case of known chronic nico-
tine consumption
• if necessary, delirium treatment
• maintenance of day-night rhythm (circadian)
• physiotherapy
-- muscle building
-- mobilization (early)
-- possibly neuromuscular electrical stimulation (i.a.
upper / lower leg muscles; still no general recom-
mendation)
-- daily (if possible, 7 days per week; note: The provi-
sion of physiotherapy 7 days per week is necessary
for the accounting of complex intensive care treat-
ment [OPS-Code 8-980]!)
• secretion mobilisation: i.a.
-- inhalation therapy with saline solution
-- positioning therapy
-- huffing (forced expiration with open glottis used to
clear secretions from the airway)
-- PEP-systems (PEP: positive expiratory pressure)
-- cough assist devices (e.g. mechanical insufflator-
exsufflator)
-- vibration devices (e.g. Vibrax)
-- if necessary, bronchoscopy for secretion removal
(generously)
-- if necessary, mini-tracheotomy for secretion suction
(tracheotomy with only a very small diameter [usu-
ally 4 mm]); especially in patients with
◦◦ weakness of coughing (expectoration)
◦◦ with neuromuscular diseases requiring NIV after
decannulation
-- possibly recombinant human DNAse (rhDNA; Dor-
nase alpha; use, however, only recommended in pa-
tients with cystic fibrosis)
• possibly Levosimendan (a calcium sensitizer)
-- An experimental study involving healthy young peo-
ple (Doordain et al, AJRCCM 2012) showed that Le-
vosimendan improves diaphragm function.
-- not only a strengthening (= inotropic) effect on the
heart (therefore frequently used in case of cardioge-
nic shock), but also on the diaphragm
-- Levosimendan can optionally be used in prolonged
weaning as an individual treatment attempt (off-lab-
le-use and no general recommendation).
• possibly transvenous temporary stimulation of the dia-
phram (invasive stimulation of the phrenic nerve; no
clinical routine yet; actually ongoing study: RESCUE-2)
 DIABOLO study
Effect of Acetazolamide vs Placebo on Duration of Invasive
Mechanical Ventilation Among Patients With Chronic Ob-
structive Pulmonary Disease
Faisy et al, JAMA 2016
• multicenter randomized controlled study
• 382 invasivelly ventilated patients with COPD und me-
tabolic alkalosis
-- with acetazolamide (500-1000mg i.v. 2 x daily)
-- without acetazolamide
• results: acetazolamide
-- primary endpoint (duration of invasive ventilation): no
difference
-- secondary endpoints (i.a. duration of weaning, ICU
stay, mortality): no difference
Preferably use energy-enteral feeding
formulas in weaning (low-carb,
high-fat), espacially in patients with
COPD!
Fig. 254  Vibrax: a vibration massage device (We use it in
patients who have difficulties with mucus mobilisation and
expectoration.)
Fig. 255  respiratory trainer [24]
Mobilization
• early (within 72 h after admission to the ICU), if possi-
ble already during ventilation (i.a. German network for
early mobilization of ventilated intensive care patients)
• The desired stage of mobilization (see infobox) should
daily be defined and discussed with the ICU staff.
• types:
-- passive (esp. different positionings, limb movement,
transfer in mobilisation chair)
-- active (e.g. pedal exerciser, attempt to stand)
• Several studies (u.a. Morris et al, Crit Care Med 2008;
Schweickert et al, Lancet 2009 [see box]; Burtin et al,
Crit Care Med 2009; Patel et al, Chest 2014; TEAM
study [Hodgson et al, Crit Care Med 2015]; Harrold et
al, Crit Care 2015; SOMS study [Schaller et al, Lancet
2016]) could show positive effects due to early mobili-
zation (within 72 h).
Mobilization should already be started
within 72 h after admission to the ICU
(early mobilisation)! "Move to improve!"
General Part 149

Fig. 256  mobilization of a ventilated patient in weaning in a
mobilization chair
Fig. 257  early mobilization: The patient was taken to the
roof terrace during the spontaneous breathing phase. This
very important not only from a physical but also from a
psychological view. However, in daily practice this is Unfor-
tunately performed too rarely.
150 General Part
Fig. 258  training with the pedal exerciser
study
Early physical and occupational therapy in mechanically
ventilated, critically ill patients: a randomized controlled
trial
Schweickert et al, Lancet 2009
• 104 (selected) ventilated patients in the first three days
of ventilation during sedation break
-- early training + mobilization
-- standard physiotherapy
• results
-- better functional status
-- shorter duration of delirium
-- more ventilator-free days
Weaning failure
• Definition: Patients must be reintubated within 48h af-
ter extubation due to an acute respiratory failure
• syn.: post-extubation failure (PEF)
• incidence:
-- 20% of all difficult to wean patients
-- 20% of all long-term ventilated patients
• relevance: reintubation → significant increase of mor-
tality (33%; i.a. Thille et al, AJRCC 2013)
• reasons:
-- failure of respiratory pump (No.1)
-- comorbidities (esp. COPD, heart failure)
-- laryngeal edema (PELE: post extubation laryngeal
edema)
• criteria (according to Boles et al, TASK-Force 2007):
-- RR > 25/min for 2h
-- HR > 140/min, persistent increase/decrease > 20%
-- SO2 < 90%
-- pCO2 > 45mmHg or 20% higher than before extuba-
tion, pH < 7.33
-- clinical symptoms of exhaustion
• risk factors: esp.
-- heart failure
-- COPD
 -- obesity
-- long-term ventilation (p.d. > 7d)
-- delirium
-- renal insufficiency
-- neuromuscular diseases (especially CIP)
• prophylaxis (especially in high-risk patients):
-- NIV (regarding studies on NIV for post-extubation
failure prophylaxis see page 139)
-- HFNOT (high-flow nasal oxygen therapy)
◦◦ equivalent to NIV (Hernandez et al, JAMA 2016
[siehe infobox])
◦◦ but in combination with NIV better (lower reintuba-
tion rate) than HFNOT allone (Thille et al, JAMA
2019)
• predictors: It would be desirable if one could already
predict weaning failure before extubation. There are
several predictors
study
Effect of Postextubation High-Flow Nasal Cannula vs Non-
invasive Ventilation on Reintubation and Postextubation
Respiratory Failure in High-Risk Patients
Hernandez et al, JAMA 2016
• multicenter randomized non-inferiority trial
• 604 ventilated patients with at least one risk factor (heart
failure, COPD, obesity (BMI > 30 kg/m2), age > 60 years,
APACHE-Score > 12P., long-term ventilation [ventilation
> 7 d]); as post-extubation failure prophylaxis for 24 h
after extubation:
-- NIV
-- HFNOT
• results: HFNOT was not inferior to NIV (no difference
in reintubation rate, even lower risk of post-extubation
failure).
Predictors
• RSB-index (RSB: rapid-shallow-breathing):
-- quotient of respiratory rate and tidal volume (RR/VT
[unit VT: l and not ml]); respiratory frequency to tidal
volume ratio
-- syn.:
◦◦ Yang-index
◦◦ Tobin-index
-- best predictor; if RSB-index > 105: 95% proba-
bility of weaning failure! (Yang et al, N Engl J 1991)!
-- should be measured at the end of the spontaneous
breathin trial
• failed spontaneous breathin trial
• P0.1 > 6 mbar → weaning failure
-- airway occlusion pressure (negative pressure 0.1 s
after the beginning of inspiration against a closed
system)
-- P0.1 < 1 mbar: decreased respiratory drive (central
respiratory depression)
-- measure for central respiratory work and hence for
the spontaneous breathing effort of the patient
• NIF (negative inspiratory force)
-- syn.:
◦◦ MIP (maximal inspiratory pressure)
◦◦ PI-max
-- maximum negative pressure that the patient can ge-
nerate during inspiration (Müller's maneuver)
-- should be < - 30 mbar; if > - 30 mbar → weaning
failure
-- P0.1 / PImax > 10% (standard value < 2%) → weaning
failure
• IWI (integrative weaning index):
-- IWI = C x SaO2 / RSBI
◦◦ C: statistical compliance (can be measured by the
ventilator)
◦◦ SaO2: arterial oxygen saturation
◦◦ RSBI: rapid shallow breathing index (RR/TV)
-- IWI < 25 ml/cmH2O → weaning failure
• reduced peak flow:
-- PEF (peak exspiratory flow): expiratory peak flow
◦◦ measurement with an inline peak flow meter on
the tube during spontaneous berathing
◦◦ < 35 l/min → weaning failure (< 60 l/min → extu-
bation indeed possible, but a following intensive
secret management obligatory then)
-- PCF (peak cough flow):
◦◦ < 160 l/min → weaning failure
◦◦ The peak cough flow cannot be measured in pa-
tients with tube or tracheal cannula because the
function of the glottis to generate an intrathoracic
pressure gradient is missing here. Alternatively
the cough strength can me measured semiquan-
titatively (semiquantitative cough strength score
[SCSS; SCSS < 3 → weaning failure; Duan et al,
Am J Crit Care 2015]):
▪▪ 0: no cough on command
▪▪ 1: no cough, but audible movement of air
through the tube
▪▪ 2: weak (barely audible) cough
▪▪ 3: moderate (clearly audible) cough
▪▪ 4: strong cough
▪▪ 5: several sequential strong coughs
• ultrasound:
-- reduced diaphragmatic excursion (< 10 mm): Dia-
phragm weakness can quite easily be detected with
ultrasound. You perform a ultrasound examination of
the diaphragm with echo probe and then switch to
M-mode: A diaphragmatic excursion of less than 10
mm is indicative of diaphragm weakness. A study of
Kim et al (Crit Care Med 2011) showed that an ex-
cursion < 10 mm both the duration of weaning (401
versus 90 h) and the duration of ventilation (576 ver-
sus 203h) are significantly increased.
-- ET-index
◦◦ product of excursion of diaphragm (in cm) and ins-
piratory time (in seconds)
◦◦ At first the index is derived during controlled ven-
tilation and then during spontaneous breathing. A
General Part 151
 decrease of the index less than 3.8% is indicative
of a successful extubation (specifity 75%, sensiti-
vity 79% [Palkar et al, Chest 2018]).

best predictor of weaning failure: RSB

(rapid shallow breathing)-index!!

Fig. 262  on the left side measurement of the occlusion

pressure P0.1 (4.5 mbar; standard 1-6 mbar), on the right
side measurement of the negative inspiratory force (NIF,
PImax: - 37 mbar, standard < -30 mbar)

3 parameters indicate whether a

patient is ready for extubation: RSB,
P0.1 und NIF (PImax)!

Fig. 259  A rapid shallow-breathing (RSB) index of 51 can

be calculated from a respiratory rate of 22/min and a tidal
volume of 425 ml.

Fig. 263  normal diaphragmatic excursion (> 10 mm; here:

35 mm)

Fig. 260  Evita XL: Under the menu item "Special Procedu-
re - Diagnostics", the occlusion pressure P0.1 and the NIF
(negative inspiratory force) can be measured.

Fig. 264  decreased diaphragmatic excursion (< 10 mm;

here: 8 mm)

To see whether a patient is ready for

extubation, simply check the diaphrag-
Fig. 261  Measurement of the occlusion pressure P0.1 (2.3
matic excursion using ultrasound on
mbar; standard 1-6 mbar)
spontaneous breathing mode (CPAP-
ASB)!

152 General Part

Extubation
Indication
• stable circulation
• awake, cooperative (e.g. patient squeezes the hand
upon request)
• spontaneous breathing (CPAP-ASB)
• Horovitz quotient (oxygenation index, P/F ratio) > 300
mmHg
• PEEP < 7 mbar
• RSBI (RR/TV) < 105
Functional extubation, in which only the respiratory work
generated by the tube and the ventilator itself is compen-
sated, is defined by the following criteria:
• ΔPASB 7 mbar +
• PEEP 5 mbar +
• FiO2 < 0.3
• well-tolerated over 30 min (p.d. RR/VT < 105, Horovitz
quotient > 300 mmHg)
Procedure
• suction via stomach probe (orotracheal suctioning, if
necessary)
• Upper body elevation
• cuff leak test (see page 154)
• deflation, then removal of the tube
• Extubation (and not only the intubation) is a high-risk
intervention too, particularly if the patient was previ-
ously difficult to intubate. Especially in previously long-
term ventilated intensive care patients, extubation is
often underestimated.
• It should only be performed by a physician who is ex-
perienced in intubation. He should stay in the patient's
room for at least 10 minutes after extubation
• Furthermore the extubation should not be performed in
the nighttime if possible, where only the physician on
duty (POD) is present, but in the daytime, where even
experienced staff (e.g. consultant) is present. Corres-
pondingly a study (Gershengorn et al, JAMA Int Med
2016) could demonstrate, that extubation in the night-
time is associated with a higher mortality compared
with extubation in the daytime.
• always be prepared to reintubate
Weaning centers
• centres specialized in weaning as well as in perfor-
mance and monitoring of out-of-hospital ventilation
(home ventilation) under the pneumology guidance
• DIGAB: German Interdisciplinary Society of Out-of-
Hospital Ventilation
• multiprofessional (including physiotherapy, speech
therapy, ergotherapy)
• especially for patients in prolonged weaning (espe-
cially subgroup 3b and 3c)
• transition management
• 112 weaning centers in Germany (as of 2019, 452 of
them already certified)
• WeanNet: competence network of pneumology
weaning centers
• WeanNet-register data 2018 (congress presentation
DGIIN DGIIN 2018):
-- 14% (previously 20-30%) of all patients in weaning
centers die
-- 41% of all patients in weaning centers are dischar-
ged with home ventilation (20% NIV; 21% invasive)
-- 43% completely ventilator-free
• assessment
-- advantage: significantly lower mortality (Kahn et al,
N Engl J 2006)
-- disadvantages:
◦◦ no sufficient bed capacity: There are not enough
beds by far to be able to transfer every difficult-to-
wean-patient to a weaning center
◦◦ DRG (diagnosis related groups): Ventilation hours
(weaning constitutes 50% of the total ventilation
time!) are money so that some intensive care units
won't transfer their patients to a weaning center for
financial reasons.
Terminal Weaning
It means the withdrawal of mechanical ventilation from a
patient who is not expected to survive without respiratory
support (in the end-of-life setting; e.g. patient with termi-
nal lung cancer, who has been intubated and admitted
to the ICU by an emergency physician who did not know
about the patient's disease). In these cases, the FiO2 is
often reduced to 21% and the PEEP set to 0 mbar (zero-
PEEP). It is also possible to stop ventilation by switching
off the ventilator (is allowed; does not constitute active
euthanasia; i.a. Möller et al, Dtsch Med Wochenschr
2008) or to extubate terminal patients (palliative ore final
extubation). The decision should also be clearly docu-
mented in writing (e.g. no resuscitation), this is explicitly
allowed. Acronyms or abbreviations (e.g. AND [allow na-
tural death], DNR [do not resuscitate]) are not necessa-
ry. In the final stage, "death rattle" is not unusual: This
is mostly due to increased pharyngotracheal secretion,
which is often very gruelling for family members, so that
appropriate measures should be taken (mainly suctio-
ning, administration of glycopyrronium bromide [Robinul;
1 amp. = 1ml = 0.2mg I.V.]).
Post-extubation stridor (PES)
Definition
• occurrence of stridor (inspiratory) after extubation due
to swelling and edema in the laryngeal area (laryngeal
edema)
• syn.: PELE (post extubation laryngeal edema)
• induced by direct trauma caused by the tube
Epidemiology
• incidence: 10% of all newly extubated intensive care
patients
• time: usually within 30 min after extubation (in 50% of
General Part 153
 the cases within 5 min [That´s the reason why the phy-
sician should stay in the patient´s room for at least 10
minutes after extubation.]) VTinspiratory

Screening
• Therefor the cuff leak test can be performed before
the planned extubation: You deflate the cuff (prior suc-
tioning of nasopharyngeal space), then the expiratory
and inspiratory tidal volume is measured on the venti- VTexpiratory
lator. The inspiratory tidal volume corresponds to the
VT displayed on the ventilator, the expiratory tidal vo-
lume is measured separately (e.g. with Evita XL under
"data").
• if the difference between the inspiratory and expiratory
tidal volume (= cuff leak volume) is greater than 110
ml, the risk of laryngeal edema is very low (e.g. Miller
et al, Chest, 1996).
• validity of the cuff leak test for a relevant swelling in the
VTinspiratory
area of the upper airways (meta-analysis Ochoa et al,
Intensive Care Med 2009):
-- specifity: 86%
-- sensitivity: 63%
• The cuff leak test has a high negative (99%), but un-
fortunately only a low positive (11%) predictive value. VTexpiratory
A positive cuff leak test therefore is not automatically
always a reason against the extubation: The test can
even be (false) positive, if the swelling is only in the
area, where tube and gastric probe compressed the
tissue, and the vocal cords themselves are completely
not affected. Here an extubation ist possible. Therefore
in case of a positive cuff leak test always a fiberoptic
control should be performed to avoid an unnecessary Fig. 265  cuff leak test: The difference (= cuff leak volume)
long ventilation. between inspiratory and expiratory tidal volume is measu-
red (In the first picture, the tube cuff is still inflated [no sig-
• The cuff leak test may be false negative in patients nificant cuff leak volume], in the second picture, it is defla-
with obesity hypoventilation syndrome or sleep-related ted [here: cuff leak volume 654 ml]): If the cuff leak volume
breathing disorders, as the body position and the sleep is more than 110 ml after cuff deflation, a relevant laryngeal
stage are relevant factors for the occurrence of dyna- edema can be ruled out.
mic upper airway obstruction.
• Before starting the test an endotracheal and oral suc- Risk factors
tioning should be performed.
• ventilation > 48h
• According to the S2k-guideline "Prolonged Weaning"
• large tube diameter
2014 a cuff leak test should be performed before ex-
tubation to assess the likelihood of a post-extubation • female gender (especially small women)
stridor. • infants, children
• Laryngeal edema may be present if the tidal volume
does not significantly decrease after deflation of the Therapy
cuff. • steroids (e.g. prednisolone 100-250 mg IV)
• In case of a positive cuff leak test (cuff leak volume • nebulisation with adrenaline (e.g. 1 amp. Suprarenin 1
< 110 ml), the administration of a steroid is indicated. mg + 5 ml sodium chloride 0.9%)
• simplified cuff leak test (e.g. in the operation room): • If necessary, reintubation (attention: often difficult be-
The cuff is deflated an the tube disconnected from the cause of laryngeal edema!)
ventilator. With the thrumb the tube is closed at the • If you are not sure, whether a laryngeal edema is pre-
upper end. If the patients keeps on breathing audible, sent or not and the patient was furthermore previously
there is no laryngeal edema. very difficult to intubate (e.g. Cormack IV), a broncho-
scopic extubation can be performed: You perform a
bronchoskopy via the tube and insert a guiding wire
good and simple screening test prior to into the trachea for safety. Then the tube cuff is delfa-
extubation, whether a laryngeal edema ted and the tube is drawn out (extubation). If there is a
is present: cuff leak test pronounced laryngeal edema then with swellowing of
the airways, the reintubation can be performed easily
over the inserted guiding wire and the bronchoscope.

154 General Part

Prophylaxis
• To prevent post-extubation stridor (laryngeal edema), it
is usual in many clinics to administer steroids intrave-
nously before extubation.
• It is debatable whether this is helpful. It is crucial to
administer the steroids early (6 h at least!) before ex-
tubation. This could also be shown in a meta-analysis
(McCaffrey et al, ICM 2009 [see box]). Most of the time
steroids are administered much too late before the ex-
tubation. The application of steroids (at least 6 h prior
to extubation) for the prophylaxis of post-extubation
stridors should be effected in any patient ventilated for
> 48h: prednisolone 250 mg intravenously or methyl-
prednisolone (Urbason) 20 mg (alternatively predniso-
lone 25 mg) intravenously 12 h, 8 h, 4 h and immedia-
tely before extubation.
• This recommendation, however, is not always feasible
in practice: Frequently, steroid administration is started
12 h before the planned extubation. If then, for any re-
ason, extubation cannot be performed, the patient has
been given steroids (often repeatedly) completely in
vain. Therefore, the administration of steroids should
not be a standard procedure and should only be done
when the patient was difficult to intubate or the cuff
leak test is positive (cuff leak volume < 110 ml).
study
12-h pretreatment with methylprednisolone versus placebo
for prevention of postextubation laryngeal oedema: a rand-
omized double-blind trial
Francois et al, Lancet 2007
• multicenter randomized controlled double-blid study
• 761 patients, ventilation > 36h
-- methylprednisolone (Urbason) 20mg i.v. 12 h, 8 h, 4 h
immediately before extubation
-- placebo
• result: methylprednisolone → significant reduction of
the incidence of laryngeal edema and reintubation rate
meta-analysis
Corticosteroids to prevent extubation failure: a sytemic re-
view and meta-analysis
McCaffrey et al, Journal of Intensive Care Medicine 2009
• meta-analysis (14 studies, 2600 patients)
• steroid administration during ventilation > 72 h → signifi-
cant reduction of reintubation rate
• especially in case of administration > 12 h prior to
extubation
Tracheotomy
History
• one of the oldest operations ever
• Originally tracheostomy was used as an access to the
trachea to secure the airway in obstructing supraglottic
tumors.
• even mentioned already in writings from Old Egypt
(4000 BC)
• Armand Trousseau (a French internist; 1801-1867): He
established the tracheotomy as a routine surgery in the
context of diphtheria ("strangling angel of children") .
• Sheldon CH (not to be confused with Scottish nephro-
logist Stanley Shaldon) established the percutaneous
tracheotomy in 1955 ("A new method for tracheosto-
my; J Neurosurg 1955).
Epidemiology
• incidence ↑
• one the most common operation in the intensive care
unit
• 25% of all invasive ventilations in the intensive care
unit are performed via a tracheal cannula instead of an
endotracheal tube.
• Most of the patients (worldwide), who are ventilated
longer than 10 days, have a tracheostoma (i.a. Mehta
et al, Am J Respir Crit Care Med 2015; Vargas et al,
Crit Care 2015).
Types
• percutaneous tracheotomy (first choice because of fe-
wer bleeding complications and infections and a better
cosmetic result [Silvester et al, Crit Care Med 2006])
• surgical tracheotomy (epithelialized)
Percutaneous tracheotomy
• percutaneous dilatation tracheotomy (PDT)
-- antegrade
◦◦ using several dilators of increasing diameter (ac-
cording to Ciaglia; multiple dilatation tracheotomy
[MDT])
◦◦ using a conus (single-step dilator; according to
Byhahn; single-step dilatation tracheotomy [SSDT;
standard today])
◦◦ using a twist (according to Frova ["Percu Twist"];
rotational dilatation tracheotomy [RDT])
◦◦ using an angioplasty-balloon (according to Zgoda
["Ciaglia Blue Dolphin"]; balloon dilatation tracheo-
tomy [BDT])
-- retrograde (according to Fantoni; translaryngeal tra-
cheotomy [TLT])
• percutaneous dissection tracheotomy (according to
Griggs; spreading technique; GWDF [guidewire dila-
ting forceps]; obsolete)
General Part 155
Indications
• Long-term ventilation (i.a. expected ventilation > 21
days)
• weaning (especially after an unsuccessful extubation
attempt; the most frequent indication)
• airway obstruction (injury, tumor)
• neuromuscular disorders
• high paraplegia
• persistent coma
before (especially in COPD patients)
always check if an extubation with
immediate NIV is possible to avoid
tracheotomy
Contraindications (percutaneous tracheo-
tomy)
• emergency → coniotomy
• Age < 16 years. (possibly retrograde according to Fan-
toni)
• no bronchoscopy possibility (alternatively ultrasound
control is possible
• very difficult / non-intubatable patients (Cormack III/IV;
accidental decannulation in the first days) → surgical
tracheotomy
• difficult anatomical conditions (e.g. extremely short
neck, pre-operation in the neck/larynx area)
• severe coagulation disorders; note:
-- A dual platelet inhibition with ASA and clopidogrel /
prasugrel / ticagrelor (e.g. history of PTCA + stent in
case of cardiogenic shock) is not a contraindication.
-- A therapeutic anticoagulation should be discontinu-
ed, low-dose anticoagulation (e.g. to prevent throm-
bosis) is permitted.
-- Platelets should be > 30000/μl .
• severe gas exchange disorders (note: A high PEEP is
not a contraindication for tracheotomy!)
• lack of legally valid consent (problematic especially in
the case of early tracheotomy: A tracheotomy is not an
emergency measure but an elective intervention and
therefore not covered by the emergency indication.)
Tracheotomy is not an emergency
measure (purely elective!); in an
emergency: coniotomy
The difficult airway is a contraindica-
tion for percutaneous tracheotomy
(here surgical tracheotomy)! !
156 General Part
Advantages
• avoidance of laryngotracheal damage caused by long-
term ventilation
• reduction of the airway resistance
-- only from a tube diameter of 9.3 physiological
-- Tracheal cannula has a larger inner diameter (ID)
than the tube (ID tracheal cannula = ID endotracheal
tube + 1).
• dead space ventilation ↓ (decrease of the dead space
from approx. 80ml [tube] to 50ml [tracheal cannula])
• need for analgosedation ↓
• faster weaning
• reduction of ventilator-associated pneumonia
• improved oral care
• improved mobilisation
• possibility of oral food intake and communication
(speech cannula); in contrast to the endotracheal tube
the function o the glottis here is preserved)
PDT according to Ciaglia
• named after the American surgeon Pasquale Ciaglia
(1912-2000)
• muscle relaxation (so that the patient does not cough
exactly during the moment of puncture, so that the
needle injures the posterior wall of the trachea; e.g.
atracurium 50mg)
• set FiO2 on the ventilator to 1.0
• Resuscitation equipment should be within reach.
• Before this, the patient should be suctioned laryngo-
scopically under visual control, so that after unblocking
of the tube cuff no secretion into the bronchi can run
distally
• puncture of the interspace between 2nd and 3rd tracheal
ring (strictly median)
• Seldinger technique: inserion of a Seldinger wire via
the puncture cannula distally into the trachea, then re-
moval of the cannula
• over the wire successive introduction of dilators of in-
creasing diameter (note: Nowadays, however, single-
dilator systems [e.g. Ciaglia Blue Rhino] are the stan-
dard.)
• under bronchoscopic control (alternative: sonographic
control [linear transducer; i.a. Alansari et al, Crit Care
2015; Gobatto et al, J Crit Care 2015] possible; in the
TRACHUS study [Gobatto et al, Intensive Care Med
2016] it was shown that with exclusively sonographic
control there were not more complications than under
exclusively bronchoscopic control.)
• insertion of the tracheal cannula
 hyoid bone
2
thyreoid
cartilage

coniotomy
• annular
cartilage

tracheotomy
trachea

Fig. 266  Schematic representation of the anatomy: Tra-

cheotomy is performed between the 2nd and 3rd tracheal
3
ring. Coniotomy, on the other hand, is performed further
cranially: between the thyroid and cricoid cartilage (crico-
thyreoid membrane).

Fig. 267  tracheal cannula with accessories [32]

1
5

General Part 157

6

11
7

12

8
13

10 14
Fig. 268  The individual steps of percutaneous dilatation
tracheotomy: First, a trial puncture (1) is performed strictly
median between the 2nd and 3rd cartilage (between the jugu-
lum and the larynx) with a thin needle under bronchoscopic
control (bronchoscopy via the indwelling tube). Then the
puncture with the Seldinger needle is performed (2). The
wire is now advanced over the Seldinger needle (3, 4). All
this is always done under strict bronchoscopic control (5).
This is followed by pre-stretching with the small dilator (6,
7), then insertion of the conically shaped large dilator (up
to the black mark) and stretching (8. 9, 10). Finally, the tra-
cheal cannula can be inserted over the indwelling wire (11,
12, 13) and is then attached to the side with the retaining
bands (14).

158 General Part

Further developments
• Ciaglia Blue Rhino
-- conical shaped dilator study
-- dilatation in one step (single-step)
-- on the market since 1999
• Ciaglia Blue Dolphin
-- combination of dilatation (angioplasty balloon) and Comparison between single-step and balloon dilatational
cannula placement in one step tracheostomy in intensive care unit: a single-centre, rando-
-- an antegrade percutaneous dilatation tracheotomy mized controlled study
(according Zgoda) Cianchi et al, British Journal of Anaesthesiology 2010
-- on the market since 2008 • monocenter randomized-controlled study
• 70 percutaneous dilatation tracheotomies:
-- Ciaglia Blue Rhino
-- Ciaglia Blue Dolphin
• results: Ciaglia Blue Dolphin
-- significantly longer duration of placement
-- significantly more tracheal injuries and bleeding (mi-
nor bleeding; no difference in major bleeding)

Tracheal cannula
Sizes (Rule of thumb: "tube + 1")
• women: 8.0
• men: 9.0

Fig. 269  Ciaglia Blue Rhino [10]

Fig. 272  tracheal cannula

Fig. 270  Ciaglia Blue Dolphin [10]

Fig. 271  Ciaglia Blue Dolphin

General Part 159


Fig. 273  tracheal cannulae: different shapes [32]
Fig. 274  ventilation via tracheal cannula
Exchange
• exchange (e.g. due to a defective cuff) in the first 5
days only with a stylet (Otherwise the different tissue
layers would immediately lay on top of each other, so
that the hole closes immediately, the tracheal cannula
cannot be placed anymore and the patient has to be
intubated in an emergency!)
• planned change at the earliest from the 10th day; an
elective change (e.g. after 20 days) is usually comple-
tely unproblematic and can almost always be carried
out without a stylet
• On our ward it is obligatory that a tracheal spreader
and a tracheal cannula of the same size and one of
smaller size in case of an accidental decannulation or
a leaking cuff are always ready to hand directly next
to the bed.
• Tip: In order to reduce the risk of accidental decan-
nulation, the (percutaneously dilated) tracheal cannula
should simply be sewn on and the stitches removed
after 10 days!
• For hygienic reasons, the tracheal cannula should be
changed electively at the latest after 28 days (also ac-
cording to the manufacturer's specifications). Usually
in clinical practice a tracheal cannula is exchanged
every 2-3 weeks. The price for a tracheal cannula usu-
ally ranges between 30-40€. The exchange after 28
days is even necessary from a purely legal point of
view: According to the Medical Devices Act a foreign
material which is inserted in the body becomes an
160 General Part
implantate beyond 29 days, to what other directives
apply. Furthermore the material is not constructed for
a longer use, so that beyond 29 days the manufacturer
does not assumes a guarantee for it any longer.
Fig. 275  guide from Cook company (Cook´s stylet) for
exchanging the tracheal cannula (obligatory in the first 7
days!) [33]
Fig. 276  S-Guide guide from Kanniocath company (additio-
nal option for oxygen insufflation and ventilation)
Fig. 277  tracheal spreader
Speaking
• Speech attachment (speaking valve): During the
course of the procedure, a speech attachment (spea-
king valve) can be attached so that the patient can
communicate adequately with his environment again
This is a special speaking valve, which is attached
between the tracheal cannula and the breathing tube
(alternatively also without ventilation) instead of the
Swedish nose. This valve opens during inspiration
and closes during expiration. Thus the exhaled air is
directed past the unblocked tracheal cannula into the
larynx, where phonation finally takes place. For this
the tracheal cannula must be unblocked so that the
exhaled air can flow upwards through the glottis.
• speech cannula: Alternatively, the conventional trache-
al cannula can be replaced by a speech cannula. This
is unblocked. It is either also fitted with a speaking at-
tachment or contains an inner part (silver slide valve,
sieve, "soul" [directs the exhaled air to the larynx], e.g.
Passy-Muir valve). Inhalation is via the cannula, exha-
lation via the sieve.
• special type of speech cannula: Blom cannula (Pulmo-
dyne company: This tracheal cannula has a fenestrati-
on, so that here even during ventilation and despite a
blocked cannula speaking is possible due to a special
arrangement of a flap and bubble valve.)

Fig. 278  speech attachment
When attaching the speech
attachment, the tracheal cannula
must always be unblocked!
Swallowing tests
• When attempting to swallow, the tracheal cannula
should be unblocked, as the blocked cuff can lead to
compression of the oesophagus and thus per se to a
difficulty in swallowing.
• The blocking of the cannula does not provide sufficient
aspiration protection anyway.
Decannulation
• Once the patient has managed to breathe spontane-
ously for three days, the decannulation can take place.
• The remaining hole is simply taped off (e.g. colloid
bandage). As a rule, we only use a placeholder ("but-
ton") if there is still a pronounced mucostasis or if the
risk of post-extubation failure is very high.
• The remaining hole closes itself within a short time. If
this has still not occurred within 14 days after removal
of the cannula, a bronchoscopic examination of the la-
rynx and trachea should be necessary to rule out sub-
glottic stenosis as the cause of the delayed tracheos-
toma closure.
Fig. 279  After decannulation is complete, the still open sto-
ma is simply taped off. We use a self-adhesive wound dres-
sing made of polyurethane foam (e.g. Allevyn Thin).
Fig. 280  placeholders (various examples)
study
High-Flow Oxygen with Capping or Suctioning for Tracheo-
stomy Decannulation
Martínez et al, N Engl J 2020
• multicenter, randomized controlled study
• 330 critical care patients with tracheal cannula who were
no longer ventilated for > 24 hours; all patients received
HFNOT; decannulation if (2 different algorithms):
-- patient was able to breathe spontaneously for 24
hours through the unblocked and closed (with a plug)
tracheal cannula ("capping" attempt) or
-- patient had to be suctioned less than 2 times per 8h in
24h (suctioning frequency)
• results: significantly faster decannulation (by 7 days;
already after 6 instead of 13 days), if one was guided by
the criteria of the suctioning frequency
Complications
• bleeding (most frequent)
-- e.g. from thyroid vessels or brachiocephalic vein
-- possibly preoperative duplex sonography to iden-
tify aberrant vessels (e.g. "blinking frog"-sign: in the
cross section pretracheal above the thyroid isthmus
[mouth of the frog] two transversely cut thyroid ves-
sels, which impress like the eyes of the frog)
-- therapy
◦◦ minor bleeding: usually stops by itself after inserti-
on of the tracheal cannula due to the compression
effect
◦◦ severe bleeding: surgical treatment (e.g. ligation)
• injury to the trachea
-- cartilage braces (fracture)
-- back wall
• via falsa (Mediastinum)
• pneumothorax (1%; a routine chest X-ray after tra-
cheotomy, however, is not indicated), possibly pneu-
momediastinum
• stoma infection
• Decannulation
• tracheo-arterial fistula
-- very rare, but catastrophic
-- massive endotracheal haemorrhage
General Part 161
 -- still occurring up to 6 weeks after the tracheotomy
• tracheal stenosis
-- in long-term course in 15% (Rumbak et al, Crit Care
2004)
-- diagnostisc:
◦◦ clinical: After decannulation the stoma is closed
with the finger (wearing a glove). A thereby indu-
ced inspiratory stridor is indicative of a tracheal
stenosis.
◦◦ bronchoscopic ( The performance of a bron-
choscopy after decannulation even without clinical
suspicion is generously recommended [S2k-gui-
deline "Prolonged Weaning" 2019]!)
• death (mortality of tracheotomy 1:600 [0.17%; Simon
et al, Crit Care 2014])
Surgical tracheotomy
• syn.:
-- conventional tracheotomy
-- open tracheotomy
• creation of a mucocutaneous anastomosis between
the tracheal mucosa and the skin (Björk flap)
• Jackson surgery
• indications:
-- difficult anatomical conditions (e.g. extremely short
neck, pre-operation in the neck/larynx area)
-- only very difficult / non-intubatable patients: If a per-
cutaneous tracheotomy is followed by accidental
decannulation in the first few days, the hole closes
very quickly, so that the tracheal cannula cannot be
inserted. Then the patient has to be intubated, which
can be extremely problematic if he has already been
difficult or almost impossible to intubate before (e.g.
only by an experienced anaesthesiologist). Therefo-
re, if you have decided to perform a tracheotomy on
a patient with a difficult airway (Cormack III/IV), you
should always perform a surgical tracheotomy here:
In this case the hole remains open after accidental
decannulation and the tracheal cannula can be in-
serted again without any problems
-- after successful coniotomy: If the airway of a patient
could only be secured by emergency coniotomy, it
should be converted into a tracheotomy (open, sur-
gical) at an early stage.
-- need for long-term ventilation (e.g. home ventilation)
162 General Part
• If the tracheostoma is no longer needed, a surgical clo-
sure under local anaesthesia possible.
Fig. 281  epithelialized (surgical) tracheostomy
Annotation for the relocation of a patient who is invasively
ventilated via tracheal cannula from ICU into the nursing
home: This often causes problems, since the staff of the
emergency service is not instructed in the patient's res-
pective home ventilator and therefore refuses to trans-
port them, based on the Medical Devices Act. Often, an
emergency physican is then additionally ordered, who on
the one hand is completely overqualified for a transport
from hospital to the nursing home (and is actually used
for other things) and on the other hand is not instruc-
ted in the patient's respective home ventilator either and
therefore switches during the transport to the emergency
ventilator of the emergency vehicle with which only con-
trolled ventilation is possible. It is therefore best to con-
tact an employee of the company of the ventilator or a
caregiver of the nursing home beforehand, who will then
accompany the transport back to the nursing home.
Timing
• meta-analysis Griffith et al, Brit Med J 2005: early vser-
sus late tracheotomy → no influence on mortality
• Rumback (Crit Care Med 2004) was able to show a
significantly shorter ventilation time, significantly less
ventilator associated pneumonia and a significant re-
duction of the 30-day mortality in internal intensive
care patients due to early tracheotomy. However, it
should be noted that an objective assessment of the
expected ventilation duration is difficult in practice and
that in the control group (planned tracheotomy d14-16)
13% were already extubated before the tracheotomy
was even performed (i.e. some patients were unne-
cessarily tracheostomized!).
• So far there is no firm evidence for the right timing.
Usually tracheotomy is performed between day 5-10.
However, the optimal time for tracheostomy is still
unclear. In two studies (ELT, TracMan; see box) and
two meta-analyses (see box) no advantage for early
tracheotomy was found, so that the saying "Life puni-
shes those who delay" does not (no longer) apply to
 tracheotomy.
• S3-Guideline 2017 "Mechanical Ventilation and Extra-
corporeal Membrane Oxygenation in Acute Respirato-
ry Insufficiency" (German Society for Anaesthesiology meta-analysis
and Intensive Medicine): early tracheotomy in invasi-
vely ventilated patients explicitly not recommended
(strong recommendation)
• However, due to the above mentioned advantages, it Early versus late tracheostomy for critically ill patients
is important to think of a tracheostomy at all especially Gomes et al, Cochrane Database 2012
in case of prolonged weaning.
• meta-analysis (673 Patienten)
• For a tracheotomy a declaration of consent is indispen-
• tracheotomy
sable. A tracheotomy is not an emergency measure,
-- early (< 10 days)
but a purely elective procedure. For this, a caregiver
-- late (> 10 days)
must first be appointed for the patient via the local
court, which usually takes at least 1-2 days, which can • result: early tracheotomy → no difference in mortality
be problematic in the case of an early tracheotomy.

meta-analysis
ELT study

Timing of tracheostomy in critically ill patients: a meta-

Early versus Late Tracheotomy for Prevention of Pneumo- analysis
nia in Mechanically Ventilated Adult ICU Patients Huang et al, PLoS One 2014
Terragni et al, JAMA 2010
• meta-analysis (9 studies, 2072 patients)
• multicenter randomized controlled study • tracheotomy
• 419 ventilated patients (without pneumonia) -- early (< 10 days)
• tracheotomy (percutaneous) -- late (> 10 days)
-- early (6-8 days)
• result: early tracheotomy → no difference in mortali-
-- late (13-15 days) ty, length of ICU stay, VAP rate or ventilation time
• results:
-- primary endpoint (VAP): no difference
-- secondary endpoints
◦◦ ICU length of stay: no difference „Tracheostoma does definitely not
◦◦ mortality: no difference belong to the intensive care patient like
• critical points: a CVC"!
-- Only 65% in the early and only 57% in the late group
were tracheotomized at all.
-- Patients with COPD, pneumonia or hemato-oncologi-
cal diseases were excluded. The early tracheotomy is out (again)!

TracMan study In principle, every patient should get at

least one extubation attempt!

Effect of early vs late tracheostomy placement on survival

in patients receiving mechanical ventilation
Young et al, JAMA 2013

• multicenter randomized controlled study

• 909 patients (largest study on this topic!)
-- early tracheotomy (day 1-4)
-- late tracheotomy (> 10 days)
• results:
-- mortality (primary endpoint) → no difference
-- Only 44.9% were tracheostomized at all in the late tra-
cheostomy group.

General Part 163


ANALGOSEDATION
Introduction
• analgesia often neglected
-- 74% of patients after long-term ventilation stated in
a follow-up survey that they had pain (Whipple et al,
Pharmatherapy 1995).
-- often misconception that sedated patients do not
feel pain (they just cannot tell it!)
• post-traumatic stress disorder (PTSD)
-- syn.: PICS (post intensive care syndrome)
-- frequency: in 30% of all long-term ventilated patients
-- also possible in family members (PICS-F [F: family])
Guidelines
• German: S3-guideline 2015 Analgesia, Sedation and
Delirium Management in Intensive Care; syn.: DAS-
Guideline (D: Delirium, A: Analgesia, S: Sedation) of
the DIVI (German Interdisciplinary Association for In-
tensive and Emergency Medicine) and DGAI (German
Society for Anaesthesiology and Intensive Care Medi-
cine); in total 17 professional societies
• American: Clinical Practice Guidelines for the Manage-
ment of Pain, Agitation, and Delirium in Adult Patients
in the Intensive Care Unit (Barr et al, Crit Care Med
2013); syn.: PAD Guidelines (P: Pain, A: Agitation, D:
Delirium)
analgesia: mostly understated
sedation: mostly overstated
164 General Part
Objectives
• analgesia of pain caused by
-- primary or secondary diseases
-- therapeutic (e.g. thoracic drainage), diagnostic (e.g.
bronchoscopy) or nursing (e.g. changing bandages)
measures
• anxiolysis (stress reduction)
• sedation (e.g. for screening from traumatic measures);
however, analgesia comes first, followed by sedation;
sedation is neither a therapy of pain nor of delirium!
• vegetative shielding with the aim of haemodynamic
stability
• awake and cooperative
-- The patient should tolerate the intensive care mea-
sures (including tube, ventilation [no "fight the venti-
lator"]) and actively support them within the scope of
his possibilities.
-- significant reduction of the ventilation and ICU length
of stay as well as mortality (Kress et al, N Engl 2000)
-- deep sedation only in exceptional cases
-- However, the depth of sedation always depends on
the ratio nurse to patient (according to the formula:
consumption of sedatives ~ 1 / number of nurses).
The goal is the awake and cooperative
patient, not the sleeping patient
(significant mortality reduction)!
In most cases the sedation is much
too deep!
Analgesia before sedation!
Sedation is neither a therapy of pain
nor of delirium!
Deep sedation is disadvantageous: It leads to increased
problems in weaning, prolonged ventilation duration with
an increased rate of ventilator-associated pneumonia
(VAP), more frequent delirium, more frequent venous
thromboembolism due to immobilization and finally to
increased mortality (e.g. SPICE study [Shehabi et al,
Am J Crit Care Med 2012])! Deep sedation also does
not protect against psychiatric secondary diseases (e.g.
Treggiani et al, Crit Care Med 2009).
Deep sedation, as it is unfortunately performed far too
often in practice, should only be used in exceptional si-
tuations and requires a clear indication and justification:
• shock (reduction of oxygen consumption; e.g. septic,
cardiogenic)
• kinetic therapy (e.g. prone positioning)
• hypothermia (e.g. after resuscitation)
• inadequate ventilation under mechanical ventilation
 ("difficult to ventilate"; often the patient presses against
the ventilator, so that deeper sedation is then necessa-
ry in order to ventilate the patient at all)
• reduction of oxygen consumption with imminent hypo-
xia
• increases intracranial pressure (ICP) with imminent
herniation
• interventions (e.g. tracheotomy, thoracic drainage)
• surgical reasons (e.g. free flaps, split skin transplants)
-- deepening of sedation at night (e.g. propofol at night
to maintain the day-night rhythm; however, this does
not correspond to physiological sleep; one does not
achieve REM sleep with it!)
-- possibly melatonin (see page <?>; no general re-
commendation)

Day-night rhythm

Fig. 282  In order to maintain the day-night rhythm, daylight

should be allowed to enter the intensive care room during
the day (including opening of venetian blinds, switching off
room lighting if possible).

Pharmaceuticals
• Sedatives
• Analgesics

Definition Sedatives
• goal: maintainance of the circadian rhythm (i.a. war- • intravenous (standard):
ranty of sleep!) -- propofol (the most commonly used sedative)
• Sleep promotes recovery, wound healing, cellular im- -- benzodiazepines
munity and reduces the risk of delirium. -- α2-agonists:
• sleep disorder in intensive care units ◦◦ clonidine
-- 80% of long-term ventilated patients reported sleep ◦◦ dexmedetomidine
disorder in follow-up surveys, so that, by analogy • inhalative:
with organ failure, one can also speak of "sleep fai-
-- sevoflurane
lure" of critically ill patients.
-- isoflurane
-- Especially the sleep stages III and IV (deep sleep
stages) and REM sleep are missing hwat would be -- desflurane
essential for recovery.
Propofol (Diprivan)
Measures Effects
• non-pharmacological (higher priority)
• sedative
-- reduction of noise (rest at night in intensive care!
• hypnotic
Among other things, the alarms in the patient's room
should be switched to mute, so that they can only be • bronchodilative
heard in the base.) • anticonvulsive
-- reduction of light at night (as little lighting as possible • non-analgesic
[i.a. switching the display of the ventilator to night
mode]), sunlight during the day (i.a. open the vene-
Pharmacology
tian blinds!) • agonist at the GABA receptor (α-subunit; like etomi-
-- restriction at night to the necessary measures (no date
elective measures at night) • a phenol derivative (an alkyl-phenol [2,6 diisopropyl-
• pharmacological (lower priority) phenol]): This is very lipophilic and poorly water-solub-
le. Therefore it must be dissolved in oil: For this soybe-

General Part 165

 an oil is used standardly today. This is emulsified with
lecithin (from the egg). The emulsion of soybean oil
and lecithin induces the white (milky) colour. Propofol
itself is yellow and clear.
• constant short context-sensitive half-time (= half-time
[half-life] of a drug depending on its application dura-
tion)
• no active metabolites, almost no accumulation (very
high metabolic clearance)
• rapid wake-up time
• very well controllable
• Catecholamines lead to a reduction of the propofol
dose on site, so that an increase in the propofol dose
is often necessary (Vice versa it is often necessary to
increase the dose of catecholamines when you increa-
se the propofol dose.)
Dosage
• Propofol 1%: 10 mg/ml, max. 20 ml/h
• Propofol 2%: 20 mg/ml, max. 10 ml/h
• rate according to RASS (e.g. target: RASS daytime 0,
night -1)
Approval
• only approved from the age of 17
• for a maximum of 7 days (according to manufacturer's
specifications)
context sensitive T1/2
typically after 48-72h → switch sedative [e.g. to mida-
zolam])
• green discoloration of the urine
• allergy (especially in case of known allergy to soybean
oil [in which Propofol is dissolved], eggs [include leci-
thin which is in the emulsion] and nuts [cross allergy to
soy; especially peanut and hazelnut]); annot.: Accor-
ding to the official product information a known allergy
to soy, eggs or nuts is a contraindication for propo-
fol. However, this is controverely discussed. The fre-
quency is very low (1:60000). Several guidelines (i.a.
English, French, Austria) do not aggree. Accoring to
a statement "Soy in drugs: no danger for allergic per-
sons" of the working group allergology of the Austrian
Society for Dermatology and Venereology for example
this warning notice is not justified at all. The content of
proteins after refining is nearly zero and is not enough
to induce an allergy.)
• propofol infusion syndrome
Propofol infusion syndrome (PRIS)
Definition
• very rare, life-threatening clinical picture
• mortality: 85%
• almost only observed at excessively high dosage (20-
50 mg/kg/h [70kg: Propofol 1% 10mg/ml, infusion rate
> 140 ml/h]); therefore dose limit < 4 mg/kg/h; recom-
mended dosage, however, in status epilepticus: 10

mg/kg/h [German Neurological Society]; note: Often

bolus doses of Propofol are not even documented in
the curve in intensive care units!
thiopental
• especially in children

Pathophysiology
• disturbance of the mitochondrial respiratory chain (de-
midazolam
coupling)
ketamine
• insufficient fatty acid oxidation with reduced energy
supply and consecutive cell death (exactly: Propofol
propofol leads to an increase in malonyl carnitine: This inhibits
etomidat
the carnitine-palmityl transferase and thus the supply
of acetyl-CoA for the citric acid cycle, so that ATP can
infusion duration
no longer be produced.)
Fig. 283  context-sensitive T1/2 (= half-time [half-life] of a
drug according to its application duration) of various se- Symptoms
datives • cardiac:
-- cardiac arrhythmia (especially therapy-refractory
Side effects
bradycardia to asystole), ECG changes:
• injection pain (burning sensation due to irritation of the
◦◦ bradycardia, escape rhythm
vein; e.g. in anaesthesia induction)
◦◦ right bundle branch block (RBBB)
• decrease in blood pressure, circulatory instability (Pro-
◦◦ QT interval prolongation, maybe torsades de poin-
pofol has a vasodilator effect [SVR ↓] and a negative
tes
inotropic effect [EF ↓]. Propofol inhibits the release of
catecholamines.) ◦◦ T-negativations
• triglycerides ↑ ◦◦ shoulder/tent shaped raised J-point with descen-
ding ST depressions in V1-V3 (as in Brugada syn-
-- regular laboratory tests
drome [Note: Propofol is therefore also contraindi-
-- Fat for parenteral nutrition can possibly be reduced.
cated in a patient with known Brugada syndrome!])
-- The fat load is significantly lower with 2% propofol
-- myocardial failure (heart failure; increased catechol-
than with 1% propofol!
amine requirement)
• lipase­ ↑ (pancreatitis)
• severe metabolic acidosis (lactic acidosis, increased
• development of tachyphylaxis (altogether rare effect; anion gap; therefore regular monitoring of pH and lac-

166 General Part

 tate!)
• rhabdomyolysis (massive increase in CK, myoglobin),
possibly acute kidney failure
• steatohepatitis (i.a. hepatomegaly, transaminases ↑)
• lipemic plasma
under propofol regular checks of:
lipase, transaminases, lactate,
triglycerides
unclear severe metabolic acidosis →
think of propofol infusion syndrome
(PRIS)!
Therapy
• stop propofol (also stop all other fats!)
• high-dose glucose administration
• temporary pacemaker if necessary (in case of therapy-
refractory bradycardia)
• volume and catecholamine therapy
• renal replacement therapy if necessary
Benzodiazepines
• short acting: midazolam (Dormicum; T½ 1-2h)
• medium-long acting:
-- lormetazepam (Sedalam; T1/2 12h)
-- lorazepam (Tavor; T½ 14h)
• long acting: flunitrazepam (Rohypnol; T½ 18h)
Midazolam (Dormicum)
• short-acting benzodiazepine (T½ 1-2h)
• the second most commonly used sedative (after pro-
pofol) in Germany (Martin et al, Crit Care 2005)
• effects:
-- sedative-hypnotic
-- anxiolytic
-- anticonvulsive
-- muscle relaxant
-- respiratory depressant
• ceiling effect (The effect cannot be increased with in-
creasing dosage.)
• dosage:
-- perfusor:
◦◦ 0.1-0.3 mg/kg/h
◦◦ 6 amp. a 3ml a 15mg + 32ml NaCl 0.9% → 1.8 mg/
ml, infusion rate 1-12 ml/h or
◦◦ 16 amp. a 3ml a 15mg (pure) → 5 mg/ml, infusion
rate 0.5-4 ml/h
-- bolus-wise 2.5mg i.v., z.B. 1-1-1(-1)
• disadvantages:
-- strong accumulation
◦◦ especially in renal and liver insufficiency
◦◦ pharmacologically active metabolite: OH-midazo-
lam
◦◦ long overhang, long follow-up sleep times
-- - high variability of clearance (therefore much more
difficult to control than propofol)
-- relaxation of the respiratory muscles (problems
especially in weaning)
-- respiratory depression
-- more frequent delirium than under propofol (Benzo-
diazepines are delirious drugs!)
-- more frequent acute kidney failure than under propo-
fol (Leite et al, Clin J Am Soc Nephtol 2015)
Fig. 284  The two most common sedatives in intensive
care: propofol and midazolam [8]
Lormetazepam (Sedalam)
• medium-long acting benzodiazepine (T1/2 12h)
• 1 amp. = 10ml = 2mg
• Dosierung:
-- 0.5mg as a bolus, if necessary then continuously
0.002-0.004 mg/kg/h (daily therapy costs approx.
30€)
-- perfusor: 0.04 mg/ml, infusion rate 2 ml/h
-- max. 5 mg/day (but only relatively; there are nu-
merous case studies where up to 30mg were given
daily without relevant side effects)
• advantages:
-- in contrast to midazolam no pharmacologically rele-
vant metabolite (degradation via glucuronidation in
the liver), therefore no accumulation
General Part 167
 -- no respiratory depression cholamines are ineffective in clonidine-related bra-
-- no sleep state (patient remains arousable) dycardia → temporary pacemaker necessary!)
• very good anxiolytic effect -- hypotension
• no deep sedation possible -- gastro-intestinal motility ↓↓ (massive!)
• indications: -- seizure threshold ↓ (proconvulsive!)
-- maybe for basic sedation • dosage:
-- delirium with anxiety as the main symptom -- 1 amp. = 1ml = 0.15mg
• no randomized controlled trials of lormetazepam yet -- 0.3-1.2 µg/kg/h
-- perfusor: 10 amp. + 40ml NaCl 0.9% → 0.03 mg/ml
-- infusion rate: 0.5-3 ml/h
-- initially (if possible) 2 ml/h for 1h to build up a level
• indications:
-- basic sedation (especially in hypertensive patients)
-- weaning (early use)
Fig. 285  lormetazepam (Sedalam): 1 amp. = 10ml = 2mg -- postoperative shivering
-- withdrawal syndrome
Lorazepam (Tavor) • not officially approved for sedation (unlike dexmede-
• medium-long acting benzodiazepine (T½ 14h) tomidine)
• indication: only low-dose additional bolus (e.g. for an- • Adjuvant therapy with clonidine can reduce the dose
xiety) of analgesics and other sedatives (conserving effect) .
• 1 amp. = 2 mg; bolus 1-2 mg
• analogous to midazolam also here increased risk of Dexmedetomidine (Dexdor, Precedex)
delirium and overdose (Pandharipande et al, Anest-
hesiol 2006) Definition
• α2-agonist (like clonidine, but much more selective [8-
Flunitrazepam (Rohypnol) fold])
• long acting benzodiazepine (T½ 18h) • different ampoule sizes: 2ml, 4ml and 10ml (always
• Ionly in problem patients (e.g. quadruple sedation) of 100 μg/ml)
analgosedation as benzodiazepine instead of midazo- • filling the perfusor syringe :
lam (often helpful! Annot.: We don´s use it anymore in -- 2ml + 48ml NaCl 0.9% → 4 μg/ml
our clinic.) -- 4ml + 46ml NaCl 0.9% → 8 μg/ml (saves volume)
• dosage: • dosage: initially 0.7 μg/kg/h (for 30min to build up a
-- 1 amp. = 1 ml = 2 mg level), then 0.2-1.4 μg/kg/h
-- application: • short half-life (T1/2 = 2.3h; shorter than clonidine),
◦◦ perfusor: 20 amp. + 30 ml NaCl 0.9% oder G5% therefore relatively easy to control
→ 0.4 mg/ml • side effects and contraindications similar to clonidine
◦◦ Infusion: 2-4 amp. in 250 ml G5% over 24h (including bradycardia [more pronounced than under
◦◦ i.v.-bolus: 1mg 1-1-1(-1) clonidine!] and higher degree AV block)
-- maintenance dose: 1-2 mg/d • causes sedation very similar to natural sleep ("arousal
sedation": sleepy, but can be immediately aroused by
verbal stimulation)
α2-agonists • also suitable for the therapy of withdrawal (e.g. alcohol
• clonidine withdrawal)
• dexmedetomidine • no dose reduction for renal insufficiency, (95% hepatic
metabolism), but for liver insufficiency
Clonidine (Catapresan, Paracefan) • approved in Germany since 2011 (for adult intensive
• α2-agonist → Inhibition of norepinephrine release in care patients requiring a depth of sedation that allows
the locus coeruleus (central sympatholytic; sympathe- awakening by verbal stimulation)
tic tone ↓) • advantages:
• T1/2 9-12h -- good controllability (due to the short half-life)
• originally developed as a local vasoconstrictor to redu- -- no respirator depression
ce swelling of the nasal mucosa -- less delirium
• effects: • not approved for patients < 18 years (children, adole-
-- sympathicolytic scents)
-- sedative • pregnancy: contraindicated (lack of experience)
-- analgesic • costs: relative expensive (however, since 2018 generic
• side effects: and therefore cheaper)
-- bradycardia (contraindication: HR < 50/min; cate-

168 General Part


Fig. 286  Dexmedetomidine (Dexdor): There are different
ampoule sizes: here 1 amp. = 2ml = 200μg.
Studies
• MENDS study (Pandharipande et al, JAMA 2007): si-
gnificant reduction of coma and delirium compared to
lorazepam (in patients with sepsis even significant re-
duction of mortality)
• SEDCOM-studiy (Riker et al, JAMA 2009): Compared
to midazolam, dexmedetomidine is equally effective in
terms of sedation with a significantly shorter duration
of ventilation and significantly lower incidence of de-
lirium.
• MIDEX study (Jakob et al, JAMA 2012; see box)
• PRODEX study(Jakob et al, JAMA 2012; see box)
• DahLIA study (Reade et al, JAMA 2016; see box)
studies
MIDEX & PRODEX
Dexmedetomidine vs Midazolam or Propofol for Seda-
tion During Prolonged Mechanical Ventilation: Two Rand-
omized Controlled Trials
Jakob et al, JAMA 2012
• multicenter randomized controlled trial (annot.: sponso-
red by Orion Pharma)
• 1000 ventilated (> 24h) patients (44 intensive care units)
-- MIDEX: dexmedetomidine versus midazolam
-- PRODEX: dexmedetomidine versus propofol
• results: dexmedetomidine
-- no inferiority in maintaining low to moderate sedation
-- significantly shorter duration of ventilation than under
midazolam (no difference with propofol)
-- no difference in mortality
-- no reduction of intensive care or hospital stay
-- significantly more cardiovascular side effects than
under midazolam (especially hypotension and brady-
cardia)
Inhalative sedation
Definition
• For a long time, volatile anaesthetics (anaesthetic
• S3 guideline: optional as an alternative to intravenous
DahLIA study
Effect of Dexmedetomidine Added to Standard Care on
Ventilator-Free Time in Patients With Agitated Delirium
Reade et al, JAMA 2016
• multicenter randomized controlled study
• DahLIA: Dexmedetomidine to Lessen ICU Agitation
• 74 still ventilated patients, who were considered not to
be able to be extubated due to an agitated delirium:
-- dexmedetomidine (additional to standard therapy)
-- placebo (standard therapy)
• resultrs:
-- primary endpoint: significant more ventilator-free days
(after 7 days)
-- secundary endpoints: i.a.
◦◦ signifikant faster extubation
◦◦ significant faster decrease of delirium
SPICE III study
Early Sedation with Dexmedetomidine in Critically Ill Pa-
tients
Shehabi et al, N Engl J 2019
• open multicenter randomized controlled study
• SPICE: Sedation Practice in Intensive Care Evaluation
• 3918 ICU patients, ventilated less than 11h but expected
for at least more than 24h; sedation:
-- dexmedetomidine
-- standard sedation (propofol, midazolam)
• resultas:
-- primary endpoint (mortality after 90 days): no diffe-
rence
-- secundary endpoints (i.a. mortality after 180 days,
quality of life after 180 days, frequency of delirium,
ventilator-free days): no difference; increased rate of
bradycardia and hypotension under dexmedetomidine
gases) were only used in the operating theatre, be-
cause only there appropriate devices for the suction of
anaesthetic gases existed. In the meantime, new sys-
tems are on the market, which make the application
now also possible in intensive care units (without the
use of soda lime).
sedation in intensive care units (e.g. in case of prob-
lems with i.v. sedation)
General Part 169
• use of inhalative sedation instead of and not in additi-
on to intravenous sedation (in addition only analgesia,
e.g. opioid perfusor; no additional intravenous sedati-
on then)
• In addition to inhalation sedation, an opioid (e.g. suf-
entanil perfusor) must be administered as analgesic in
the same way as intravenous sedation. If one switches
from intravenous to inhalative sedation, the dosage of
the opiate can usually be halved.
Assessment
• advantages:
-- good controllability (very short context-sensitive half-
life! therefore rapid recovery time [e.g. a neurological
evaluation is possible relatively soon])
-- no accumulation, no active metabolites
-- metabolism independent of liver and kidney function
(The gas is simply exhaled!)
-- no development of tolerance
-- organ protective
• disadvantages:
-- relatively large dead space volume (AnaConDa: ap-
prox. 100ml; therefore only approved for ventilation
with a tidal volume > 350ml), so that it should be
reduced in case of problems with decarboxylation
(constantly high pCO2 values); note: There is me-
anwhile a smaller systems (AnaConDa S), that has
only a dead space of 50ml hat.
-- only possible with invasive ventilation (endotracheal
tube or tracheal cannula), not with non-invasive ven-
tilation (NIV)
-- autoimmune hepatitis (as a side effect; "halothane"
hepatitis)
Substances
Definition
• volatile anaesthetics (anaesthetic gases)
• fluorinated ether compounds
• state of aggregation: In room air they are present in
liquid form (important: storage therefore also at room
temperature!). For application they are converted into
a gaseous state by evaporation (evaporator).
• description of the potency by the minimum alveolar
concentration (MAC)
• Officially, the substances are only approved for anaes-
thesia during surgery, not for sedation in intensive care
units (off-label use).
• dosage: The dosage is controlled by the infusion rate
of the syringe pump.
-- depending on:
◦◦ body weight
◦◦ body temperature
◦◦ respiratory minute volume: The higher the respi-
ratory minute volume, the higher is the necessary
infusion rate.
◦◦ desired sedation depth (RASS score)
◦◦ target concentration (gas monitor)
◦◦ alveolar surface, diffusion distance (e.g. increased
170 General Part
in the case of a diffusion disorder such as pulmo-
nary oedema)
-- Dosage schemes (e.g. Sedana setting dial [unofficial
only]) can be used for this purpose.
• elimination:
-- mainly pulmonary (almost not hepatic or renal)
-- no metabolites, no accumulation
• other effects (besides the sedative effect):
-- bronchodilatory (good therefore e.g. in status asth-
maticus)
-- anticonvulsive (good therefore e.g. in status epilep-
ticus)
-- organ-protective: after undergone organic ischemia
(pre- / postconditioning; especially neuro- and car-
dioprotective; good therefore in ventilated patients
after stroke, myocardial infarction or after resuscita-
tion)
-- Mydriasis: Under volatile anaesthetics, the pupils
often dilate with a reduced light reaction, which is
completely normal and does not indicate increased
intracranial pressure..
-- note: not analgesic!
Representatives
• isoflurane (cheapest)
• sevoflurane (leads to an increase of fluoride by 50
μmol/l per day, therefore obligatory daily fluoride mea-
surement in serum if administered > 48h)
• desflurane
-- for longer-term sedation (probably) best, as it is
washed out fastest (after 6h of administration, 90%
washout occurs after 86min for isoflurane, 65min for
sevoflurane and 14min for desflurane [Bailey et al,
Anesth Analg 1997])
-- relatively low boiling point, therefore difficult to apply
by infusion
-- only possible with the MIRUS system (not with the
AnaConDa system)
Fig. 287  isoflurane

Fig. 288  sevoflurane [6]
Contraindications
• malignant hyperthermia (see page 1400):
-- Volatile anesthetics are a classic trigger substance
for triggering malignant hyperthermia! Malignant
hyperthermia should be considered especially if in-
halative sedation leads to an increasing respiratory
acidosis with a pronounced increase in pCO2 and
high fever!
-- An undergone malignant hyperthermia or a proven
genetic disposition is an absolute contraindication
for inhalative sedation.
-- If inhalation sedation is performed as standard in
an intensive care unit, dantrolene must always be
available there (and not only in the operating theatre;
furthermore in a sufficient amount).
• undergone autoimmune hepatitis caused by inhalati-
on anesthetics ("halothane" hepatitis; because of the
possibility of a successful immunization against trifluo-
roacetic acid epitopes)
• increased intracranial pressure (ICP)
• pregnancy
caution volatile anesthetics:
trigger substance for malignant
hyperthermia!
Anaesthetic gas monitor
• measurement of the end-tidal concentration (Fet%) of
the volatile anaesthetic
• either in mainstream or sidestream sampling
• target values:
-- isoflurane: 0.4-0.6 Vol%
-- sevoflurane: 0.7-1.0 Vol%
-- desflurane: 2.0-3.0 Vol%
• examples:
-- Vamos (Dräger)
-- G5 (Philipps)
-- Anastasia (Acutronic Medical)
• The anaesthetic gas monitor is meanwhile also availa-
ble in battery mode, so that during transport no switch
from inhalative to intravenous sedation is necessary.
Fig. 289  anaesthetic gas monitor (here example Vamos,
Dräger): measurement of the end-tidal concentration of the
volatile anaesthetic system
Systems
• AnaConDa system
• MIRUS system
AnaConDa system
• AnaConDa: anaesthetic conserving device (Sedana
Medical company)
• on the market since 2004
• plastic housing incl. evaporator with substance supply
line (via a syringe pump), carbon filter and check valve
• It is placed between the tube and the Y-piece instead
of the HME filter. An additional HME filter is not neces-
sary. Active humidification is not possible.
• use of commercially available intensive respirators (i.a.
no circuit section, soda lime or separate anaesthetic
vaporiser required)
• We use it in our clinic for problem patients (e.g. 4-fold
sedation) of analgosedation instead of intravenous se-
dation.
• substances (volatile anaesthetics [anaesthetic gases])
-- isoflurane (bolus of 1.5ml, then start with 3 ml/h)
-- sevoflurane (bolus of 1.5ml, then start with 5 ml/h)
• control of the dosage via infusion rate of the syringe
pump
• The exhaled anaesthetic gas is bound to a carbon
filter (reflector; consisting of activated carbon fibres)
and 90% is inhaled again (principle of anaesthetic re-
flection). The carbon filter is integrated in the plastic
housing. According to the manufacturer, the housing
should be changed every 24 hours (alternatively, every
48 hours is also possible). The remaining 10% are not
bound and released into the room air.
• reflection quotient (Rq):
-- quotient of the anaesthetic gas concentration before
and after the plastic housing
-- Rq for the AnaConDa system: 0.1 (i.e. the anaesthe-
tic gas concentration in the side of the tube system
facing away from the patient is 10% of the anaesthe-
tic gas concentration in the side facing to the patient)
• price for one set: 65€
• indoor air pollution: The limit value required by law in
Germany for isoflurane in indoor air is 10 ppm. Even
General Part 171
 without extraction, numerous measurements showed
a maximum of 1.2 ppm using the AnaConDa system.
Some clinics therefore do not even use an extraction
of the anaesthetic gases (anaesthetic gas scavenging)
if there is sufficient extraction (room air exchange rate
> 8/h) in the room. For the protection of the employees
(medical staff), we carry out an extraction of the anaes-
thetic gases via the ventilator's exhaust port. However,
this possibility is not ubiquitously available in the inten-
sive care units. It is also possible to use residual gas
filters (syn.: anaesthetic gas filter; e.g. NovaSorb from
NovaMed; Contrafluran from ZeoSys).
• For endotracheal aspiration only closed suction sys-
tems should be used. Disconnections should be avoi-
ded if possible and should be on the side of the system
remote from the patient. In case of disconnection, the
syringe pump must be stopped. The inhalative sedati- Fig. 291  AnaConDa-System: It is placed between the tube
on must also be paused during bronchoscopy, sedati- and the Y-piece instead of the HME filter (this is then not
on can be performed here, e.g. with i.v. propofol boli. necessary).

Fig. 292  The liquid anaesthetic is drawn up with a syringe

and then directed via a conventional perfusor to the plastic
Fig. 290  AnaConDa system: front and back of the plastic housing where it is vaporised.
housing

Fig. 293  In our clinic the anaesthetic gases are extracted

via the ventilator's exhaust port (see arrow).

172 General Part

Fig. 294  Meanwhile there is a smaller variant on the market
(AnaConDa S [s: small]). It has a significantly lower dead
room space (50ml instead of 100ml).
study
Long-term sedation in intensive care unit: a randomized
comparison between inhaled sevoflurane and intravenous
propofol or midazolam
Mesnil et al, Intensive Care Med 2011
• randomized controlled trial
• 74 ventilated intensive care patients (analgesia with re-
mifentanil); sedation with:
-- sevoflurane (inhalative)
-- propofol (intravenous)
-- midazolam (intravenous)
• result: sedation with sevoflurane (inhalative)
-- significantly shorter wake-up time
-- significantly shorter extubation delay
MIRUS system
• system for inhalation sedation (Pall company, Dreieich
[Germany])
• the market since 2013
• here also application of desfluran is possible
• construction:
-- MIRUS exchanger: plastic housing, which is placed
between tube and Y-piece
-- MIRUS controller: control unit (vaporizer, 250ml re-
servoir for the anaesthetics, gas monitor)
• The anaesthetic is only injected during the inspiratory
high flow phase (DOGA: diffusion optimized gas ap-
plication).
• By recording the ventilation parameters, the dose is
automatically controlled by the MIRUS system (in con-
trast to the AnaConDa system).
• built-in rechargeable battery (10min operating time)
Fig. 295  MIRUS system
Sedation
• continuous
• discontinuous
Discontinuous Sedation
In the study by Kress (Daily Interruption of Sedative In-
fusions in Critically Ill Patients Undergoing Mechanical
Ventilation; N Engl J 2000) a daily interruption of seda-
tion (especially in the morning; wake-up attempt; DSI
[daily sedation interruption], SAT [spontaneous awake-
ning trial]) showed a significant reduction in the duration
of ventilation and ICU length of stay. In the ABC study
(Girard et al, Lancet 2008), patients (ventilation > 12
days) who underwent a spontaneous wake-up attempt
in the morning also showed a shorter ventilation durati-
on, a shorter ICU length of stay and a significantly lower
mortality (NNT only 7 [an extremely efficient therapy!]).
For this reason, sedation (not analgesia [cave withdra-
wal!]) should be completely switched off ("drug holidays")
in all ventilated patients in the morning (preferably after
washing) until the patient has woken up (SAT [spontane-
ous awakening trial]; "daily morning wake up call"; "wake
up & breathe!"). However, if you manage to sedate the
patients in your intensive care unit according to the cur-
rent S3 guideline according to RASS (0 during the day,
-1 at night), you can even do without wake-up attempt,
since the patients are awake anyway with a RASS of 0 or
-1! Awake patients can no longer wake up! One should
get used to awake patients on his intensive care unit!
If you sedate strictly according to the sedation protocol,
an additional wake-up attempt will not have an additional
benefit. Here you can save youtrself a wake-up attempt!
This could also be shown in a study (Mehta et al, JAMA
2012; see box). Accordingly, the S3 guideline 2015 no
longer recommends a wake-up attempt (only in case of
RASS < -2).
General Part 173
 Wake up & breathe!
Switch off sedation in the morning until
the patient is awake!
study
A protocol of no sedation for critically ill patients receiving
mechanical ventilation: A randomized trial
Strom et al, Lancet 2010
• monocenter randomized controlled study (Odense/ Den-
mark)
• 140 ventilated patients (morphine bolus to analgesia)
-- with sedation (propofol, midazolam; including daily in-
terruption of sedation)
-- without sedation
• results: patients without sedation
-- mortality: no difference
-- significantly shorter ventilation time
-- significantly shorter ICU length of stay
-- significantly more frequent delirium
• Annotations:
-- Here the ratio of nurse to patient was extremely good
with 1:1. In addition, an additional nurse was available
at any time if required.
-- 18% of the patients had sedation after all
Analgesics
• opioides
• ketamine
• maybe peridural anesthesia in special cases (e.g. acu-
174 General Part
study
Daily Sedation Interruption in Mechanically Ventilated Criti-
cally Ill Patients Cared for With a Sedation Protocol: A Ran-
domized Controlled Trial
Mehta et al, JAMA 2012
• multicenter randomized controlled study
• 430 critically ill ventilated patients
• sedation with protocol:
-- without additional sedation interruption (wake-up att-
empt)
-- with additional sedation interruption (wake-up att-
empt)
• results:
-- no difference in ventilation duration
-- no difference in intensive care / hospitalization dura-
tion
-- no difference in frequency of delirium
study
Effectiveness and safety of the awakening and breathing
coordination, delirium monitoring / management and early
exercise / mobility bundle
Balas et al, Crit Care Med 2014
• prospective cohort study over 18 months
• ABCDE protocol ("bundle")
-- ABC: awakening (SAT [spontaneous awakening tri-
al]), breathing coordination (SBT [spontaneous brea-
thing trial])
-- D: delirium (monitoring [CAM-ICU] and management)
-- E: early exercise
• 296 critically ill ventilated patients
-- with application of the ABCDE-protocol
-- without application of the ABCDE-protocol
• results: with application of the ABCDE-protocol
-- significantly shorter duration of ventilation (more ven-
tilator-free days)
-- significantly less delirium
-- no difference in mortality
-- no increased rate of accidental self-extubation
te pancreatitis [see page 874])
-- with local anaesthetics (bupivacaine, ripivacaine)
-- with opioids (sufentanil, morphine)
Opioids
• definition: agonists at the opoid receptor Opioids > 72h: never stop abruptly,
but taper off! Otherwise it leads to
• terminology:
withdrawal!
-- opioids: synthetic (created chemically; examples:
fentanyl, sufentanil, remifentanil, piritramid, pethidi-
ne, puprenorphin, heroin) Representatives
-- opiats: natural (in opium: milky juice of the opium
• fentanyl
poppy [Papaver somniferum]; exapmles: morphine,
codeine) • sufentanil (Sufenta)
• opioid receptors: Nearly all opioids are pure agonists • remifentanil (Ultiva)
at the μ-receptor (speek "mü"). Only buprenorphine is • piritramide (Dipidolor)
additionally an agonist at the κ-receptor (speek "kap-
pa"). Antagonists (at all opioid rezeptors) are naloxone
Fentanyl
(Narcanti; see page 1419) and naltrexone (Relistor; • potency: 100 (compared to morphine)
see page 887). • dosage: perfusor 0.05 mg/ml, infusion rate: 1-7 ml/h
• side effects: see page 50 • no fixed combination with midazolam (former "Fenta-
• maximum dose: There is no clinically relevant maxi- Mida" perfusor)
mum dose for opiates.

Withdrawal
• definition: If opioids are given for more than 72 hours,
the perfusor must never suddenly be switched off,
otherwise withdrawal may develop.
• symptoms:
-- fever
-- perspiration
-- tachykardia, hypertension
-- tachypnea Fig. 296  fentanyl [8]
-- mydriasis
-- tremor, muscle cramps Sufentanil (Sufenta)
-- colicky abdominal pain, nausea, vomiting, diarrhoa • the most frequently used analgesic in Germany (Martin
• differential diagnosis: An opioid withdrawal is often et al, Crit Care 2007)
misinterpreted as sepsis, gastroenteritis or delirium. • potency: 1000 (compared to morphine)
• prophylaxis: If opioids are given for more than 72 • Dosierung:
hours, they must always be reduced gradually (tape- -- dosage:
red off) to avoid a withdrawal, i.e. reduction of 25%/ ◦◦ perfusor: 3 amp. a 5ml 0.25mg + 35ml NaCl 0.9%
day initially, then 10%/day. If you do not have time to → 0.015 mg/ml
reduce the perfusor successively (e.g. urgent transfer ◦◦ infusion rate: 1-10 ml/h
of a patient to normal ward due to lack of beds urged
• im Vergleich zu Fentanyl
from the surgical departments or a psychotic patient
to psychiatry), you can also switch to oral opioids (see -- better sedating (partly even as a mono substance for
the corresponding opioid conversion tables on the In- analgosedation usuable)
ternet, i.a. potencies compared to morphine [fentanyl: -- less withdrawal
100; sufentanil: 1000, oxycodone: 1.52, hydromorpho- -- shorter context sensitive T½
ne: 5; note: applies to morphine i.v, for morphine p.o. • no inhibition of the respiratory drive at a dosage of 1
again x 2, since oral bioavailability of morphine is only μg/kg/h (extubation possible)
50%]), e.g
-- Oxycodone + Naloxone (Targin): e.g. 2 x 20/10mg, Remifentanil (Ultiva)
then 3 x 10/5mg, then 2 x 10/5mg, then 1 x 10/5mg • degradation by unspecific esterases → elimination in-
(disadvantage: cannot be administered by gastric dependent of liver and kidney function (therefore espe-
tube) cially beneficial for multimorbid patients with liver and
-- Hydromorphone (Palladon): e.g. 8mg-0-8mg, then kidney dysfunction)
8mg-0-4mg, then 4mg-0-4mg, then 4mg0-0 (advan- • only opioid that is not degraded by the liver
tage: can also be administered by gastric tube) • pure μ-rezeptor-agonist
• potency: 500 (compared to morphine)
• very well controllable
• extremely short context-sensitive T1/2 (always remains
at approx. 3min independet of the infusion duration)
• dosage:

General Part 175

 -- perfusor: 0.1 mg/ml, infusion rate: 2-10 ml/h
-- no bolus administration (only continuously)
• side effects: especially pronounced here
-- bradykardie, decrease of blood pressure (Therefore
remifentanyl should be discontinued in case a seve-
re circulatory instability or high dose catecholamine
therapy [noradrenaline > 1.2 mg/h].)
-- thoracic rigidity
• good combination: propofol + remifentanil
• costs: expensive (however, patent expired in 2013)
study
A prospective, randomized, double-blind, multicenter study
comparing remifentanil with fentanyl in mechanically ven-
tilated patients
Spies et al, Intensive Care Med 2010
• multiventer prospective randomized controlled studiy
• 60 patients, ventilation > 24h
-- fentanyl
-- remifentanil
• results: Remifentanil (study stopped prematurely after
interim analysis)
-- primary endpoint (RASS 0/-1, VAS pain scale < 4):
no difference
-- secondary endpoints (duration of ventilation, ICU/
hospital length of stay, pneumonia rate, delirium rate):
no difference
context sensitive T1/2
-- max. 4 x 30 mg (8 amp.) per day
• also optionally via PCA pump (PCA: patient controlled
analgesia)
Ketamine (Ketanest)
• a NMDA antagonist (N-Methyl-D-Aspartate)
• for effects and side effects see page 50
• dosage:
-- perfusor: 30 mg/ml = 1500 mg/50ml
-- infusion rate: 2-10 ml/h
• indications:
-- bronchospasm (e.g. status asthmaticus)
-- ventilated patients with hypotensive circulation (from
non-cardiac cause [Ketanest is contraindicated in
acute myocardial infarction because it leads due to
its sympathicomimetic effect to an increase of the
infarct size.])
-- persistent gastrointestinal atony: ketamine is
neutral with regard to gastrointestinal motility (pos-
sibly change from opioid to ketamine)
-- psychotic or aggressive and rioting patients (Here
the i.m.-administration is a good option.)

fentanyl

sufentanil

Monitoring

remifentanil Introduction
• definition of patient-specific goals
infusion duration • evaluation every 8h (once per shift!) using scoring sys-
Fig. 297  context-sensitive T1/2 (= half-time [half-life] of a tems and documentation
drug according to its application duration) of various an- • scoring systems
algesics -- types
Piritramide (Dipidolor) ◦◦ sedation scores
◦◦ analgesia scores
• potency: 0.7 (compared to morphine)
◦◦ delirium scores
• indication: as analgesic when ventilated < 72h
-- use
• dosage:
◦◦ 2002: only 8% of all intensive care units
-- 1 amp. = 15 mg
◦◦ 2006: 52% of all intensive care units
-- 3.75 - 7.5 mg bolus-wise i.v., e.g. 3.75 mg i.v. 6 times
a day • Sedation must be monitored: Without monitoring of

176 General Part

 sedation, which is an absolutely simple measure (just • In the survey it is important to pay attention on the du-
determine RASS!), the mortality of the patient is incre- ration of the eye contact zu (10 seconds a very long!).
ased (i.a. Kastrup et al, JIMR 2008)! • goal:
-- during the day: RASS 0
-- at night: RASS -1
no monitoring of sedation → • The intensive curve resp. the PDMS should then show,
mortality ↑ for example, as an arrangement Propofol 1% accor-
ding to RASS (target during the day: 0, at night: -1).
• deviations:
Types -- RASS ≥ 1: agitation (agitated)
• sedation monitoring -- RASS -2 bis -5: sedation (sedated)
• analgesia monitoring
points term description
Sedation monitoring 4 combative violent, immediate danger for staff
• scores 3 very agitated aggressive (e.g. towards the
-- Ramsay-Sedation-Scale (RSS; according to Ram- stuff), pulls / removes catheters /
sey et al, Br Med J 1974) drainages
-- Richmond-Agitation-Sedation-Scale (RASS; accor- 2 agitated frequent nonpurpuseful move-
ding to Sessler et al, Am J Respir Crit Care Med ments, patient-ventilator dyssyn-
2002) chrony
-- Riker-Sedation-Agitation-Scale (RSAS; according to 1 restless anxious, apprehensive
Riker et al, Crit Care Med 1999) 0 alert an calm
-- GCS (Glasgow Coma Scale) modified according to -1 drowsy not fully alert, but has sustained
Cook and Palma (GCS-CP) awakening by voice with eye
-- Motor Activity Assessment Scale (MAAS) contact (> 10sec)
-- Vancouver Interaction and Calmness Scale (VICS) -2 light sedation awakens briefly with eye contact
-- Comfort-Scale by voice (< 10sec)
• instrumental method: EEG monitoring -3 moderatese- moving or eye opening by voice
dation but no eye contact
Ramsay-Sedation-Scale (RSS) -4 deep sedation no response to voice, movment or
• the most frequently used score for sedation monitoring eye opening on physical stimulus
in Germany formerly -5 unaraousable no response to voice or physical
• goal: stimulus (coma)
-- during the day: RSS 2
-- at night: RSS 3
EEG monitoring
• not to be recorded on a relaxed patient
• examples:
-- BIS (most common)
symptoms
-- EEG median frequency
1 anxious, agitated, complete awake
• no general recommendation
2 awake, cooperative, tolerant (ventilation), oriented,
• only additionally recommended for very deep sedation
calm
(Ramsay 5-6 or RASS ≤ -3)
3 drowsy, but response to command
4 asleep, but still a brisk response to stimulus (e.g. BIS
glabella tap or loud auditory stimulus) • BIS: bispectral index
• Covidien company
5 asleep, only sluggish response to stimulus
• Adhesive electrodes are sticked on the forehead. Then
6 no response to stimulus at all the degree of awareness is displayed on the BIS-mo-
nitor as als BIS-value.
• interpretation (BIS):
Richmond-Agitation-Sedation-Scale
-- 100: awake
(RASS)
-- 80: light sedation
• the best score for sedation monitoring (gold stan-
dard!) -- 60: moderate sedation
• the most frequently used score for sedation monitoring -- 40: deep sedation
in Germany today -- 20: burst suppression
• significant correlation with doses of sedatives (Ely et -- 0: flat-line EEG (isoelectric; no brain activity)
al, JAMA 2003) • Cerebral autonomic activities (e.g. epileptic seizure,
• also records agitation (RASS ≥ 1: p.d. agitation) status epilepticus) are not detectable with the BIS sys-
tem.

General Part 177

Fig. 298  monitoring of deep sedation (indication here: hy-
pothermia after resuscitation after myocardial infarction)
using BIS
Fig. 301  BIS (bispectral index) [11]

Analgesia monitoring
• assessment by the patient: self-assessment (would be
best, but usually not possible with ventilated patients)
• assessment by the staff (nurse, physician)

Assessment (by patient)

• numeric rating scale (NRS])
-- from 0 (= no pain) up to 10 (= most pain)
-- NRS > 3: additional analgesia required
• visual analogue scale (VAS; higher error rate [espe-
cially in older patients])
Fig. 299  BIS-monitor • verbal rating scale (VRS)

worst pain
no pain
imaginable
mild moderat severe

0 1 2 3 4 5 6 7 8 9 10
Fig. 302  NRS (numeric rating scale)

no pain worst pain

imaginable
Fig. 303  VAS (visual analogue scale)

Fig. 300  BIS (bispectral index) [11] no mild moderate strong very strong strongest
pain pain pain pain pain pain

Fig. 304  VRS (verbale rating scale)

Assessment (by staff)

• facial expression, movement
• physiological parameters:

178 General Part

 -- tear flow, sweat secretion
-- blood pressure, heart rate
-- respiratory rate
• scores:
-- Behavioral Pain Scale (BPS; according to Paysen et
al, Crit Care Med 2001; see infobox)
-- Critical-Care Pain Observation Tool (CPOT; accor-
ding to Gelinas et al, Am J Crit Care 2006; siehe in-
fobox); interpretation:
◦◦ 0-2 P.: no or little pain
◦◦ 3-6 P.: moderate pain
◦◦ 7-10 P.: severe pain
-- special scores: see infobox

Behavioral Pain Scale (BPS)

• necessary for all patients who are unable to res-
pond to pain (classically the ventilated patient)
• assessment of:
-- facial expression
-- movement of the upper extremity
-- adaptation to the ventilator (if ventilated) respec-
tively vocalization (if not ventilated)
• acquisition every 8 hours by the caregiver (once per
shift)
• goal: < 6 points

General Part 179

Delir Differential diagnosis
The most important differential diagnoses to delirium
are summarized in the acronym "I watch death" (ac-
cording to Wiese et al, American Psychiatric Press
Textbook of Neuropsychiatry 1986) zusammengefaßt.

Definition
• definitions:
-- ICD-10 (International Classification of Diseases):
etiologically unspecific organic brain syndrome cha-
racterized by simultaneous disorders of conscious-
ness, perception, thinking and memory
Epidemiology
-- DSM-5 (Diagnostic Manual of Mental Disorders): • most frequent psychiatric disorder in intensive care
acute disturbance of consciousness with signs of patients
attention deficit disorder, accompanied by at least • occurrence
one additional disorder of the following 4 domains: -- 32% of all intensive care patients (Ouimet et al,
orientation, short-term memory, speech or percep- Intensive Care Med 2006; Salluh et al, Crit Care
tion (e.g. hallucinations or delusions) with typically 2010 [DECCA study])
fluctuating course -- 64% of all long-term ventilated patients (Shehabi
• etymology Delir(ium): Latin for "madness" et al, Crit Care Med 2010)
• syn.:
-- OBS (organic brain syndrome) Types
-- ICU psychosis • hyperactive delirium (5% [The diagnosis would be ea-
• a secundary encephalopathy siest here, but it is the rarest!])
• neurotransmitter imbalance • hypoactive delirium (30%)
• organic cause -- especially older patients
• occurrence -- often overlooked
-- acute onset -- worst prognosis
-- more frequent under sedation with midazolam than • mixed form (65%)
with propofol
-- especially at night Risk factors
• average duration: 2-3 days • advanced age (most important)
• always an exclusion diagnosis - exclusion of • male gender
-- hypoxia (if necessary optimize ventilator settings) • previously known cognitive disorder (e.g. dementia)
-- fever • arterial hypertension, heart failure
-- metabolic derailment (especially hypoglycaemia) • high APACHE-II-score (see page <?>)
-- pain • chronic alcohol abuse (20% of all patients admitted to
-- withdrawal (e.g. opioids) intensive care are alcoholics!)
• If a delirium occurs, mortality is tripled (among others • drug abuse (e.g. benzodiazepines)
Ely, JAMA 2004; Lin, Crit Care Med 2004; Pisani et al, • fixation
Am J Resp Crit Care Med 2009)! Delirium should be • sleep disturbance
understood as organ failure of the brain, which should
• sedation
be taken seriously and treated in the same way as fai-
lure of other organs. -- depth of sedation: The deeper the sedation, the hig-

180 General Part

 her is the risk of delirium in the further course (espe-
cially in weaning)
-- duration of sedation: The longer the sedation, the
higher is the risk of delirium (especially in weaning).
-- type of sedation: benzodiazepines (are deliriogenic)
• depth of anaesthesia: The deeper the anaesthesia
during surgery, the higher is the risk of postoperative
delirium.
• deliriogenic drugs (especially pantoprazole, benzodia-
zepines, pethidine, meropenem, anticholinergic drugs
[e.g. tricyclic antidepressants])
• hip-TEP (surgery with the highest incidence of deliri-
um!)

Symptoms
• qualitative disturbance of consciousness (confusion,
disorientation)
• agitation
• delusion, hallucinations
• fear
• vegetative side effects: i.a. tachycardia, hypertensive
crisis
• disturbed day-night rhythm
• typically fluctuating during the day

Scores
• for screening with regard to delirium
• only used in 5-10% of cases on ICU
• assessment once per shift (according to guidelines;
more practical: once per 24h)
• Without a validated diagnostic 2/3 of the cases (es-
pecially hypoactive delirium) are not detected!
• types
-- CAM-ICU (best [according to German guidelines];
higher sensitivity)
-- ICDSC (intensive care delirium screening checklist;
Bergeron, Intensive Care Med 2001)
-- Nu-DESC (Nursing-delirium-Screeningskala), DDS
(delirium detection score), DRS (delirium rating scla-
le), CRS (confusion ratin scale) → not very helpful

CAM-ICU
• confusion assessment method (see infobox)
• rating:
-- 1st feature: acute change of vigilance or fluctuating
course
-- 2nd feature: inattention
-- 3rd feature: altered level of consciousness
-- 4th feature: unorganized thinking
• delirium, if 1st + 2nd and 3rd or 4th positive

General Part 181

Annotation: The implementation of the CAM-ICU is re-
commended in the guidelines. However, according to our
own surveys within the framework of our intensive care
courses, it has been shown that in reality almost no one
uses this test (in the last ten years, not a single person
reported to have ever used this test!) If you only imagi-
ne that you are an intensive care patient yourself and
someone comes every 8 hours and tells you about the
CASABLANCA several times or asks you if "elephants
live in the sea", it is quite possible that this will trigger a
delirium ("CAM-ICU is deliriogenic!"). On the other side it
has to admitted fairly, that without a validated diagnostic
2/3 of the cases are overlooked indeed.
Complications
• cardiac arrhythmia, stress-related myocardial ischa-
emia
• stress ulcer, ulcer bleeding
• accidental removal of accesses (especially CVC, tube;
especially in hyperactive delirium)
• gastrointestinal reflux ↑ ↓ enteral nutrition ↑, possibly
aspiration
• dysphagia → aspiration, possibly aspiration pneumo-
nia
• persistent cognitive deficit (i.a. Wolters et al, Crit Care
2014)
• renal replacement therapy (due to restlessness) dif-
ficult to control
delirium: not a harmless disease
(increased mortality!)
182 General Part
Therapy (symptom-oriented)
• agitation
-- lorazepam (Tavor; 0.5-1mg p.o./s.l./i.v.)
-- propofol at night as an add-on therapy
• sympathetic hyperactivity → α2-agonists (even if vaso-
pressors are necessary at the same time; cave: lowe-
ring of the seizure threshold ["Delirium and seizures
are good friends!"])
-- clonidine
-- dexmedetomidine
• productive-psychotic symptoms (excitation) → neuro-
leptics (cave: lowering of the seizure threshold ["Deli-
rium and seizures are good friends!"])
-- typical neuroleptics (contraindicated in M. Parkin-
son)
◦◦ high potency: haloperidol (Haldol)
◦◦ middle potency: melperone (Eunerpan)
◦◦ low potency: promethazine (Atosil)
-- atypical neuroleptics (also permitted in M. Parkin-
son)
◦◦ risperidone (Risperdal) 0.25-0.5mg p.o.
◦◦ olanzapine (Zyprexa) 25-50mg p.o. / i.m. (not i.v.)
◦◦ quetiapine (Seroquel) 50-100mg p.o.
◦◦ ziprasidone (Zeldox, Geodon):
▪▪ p.o.: 2 x 40mg
▪▪ i.m. (not i.v.): 10mg 1-4 times daily
• anxiety → benzodiazepine
-- lorazepam (Tavor; drug of choice): 0.5-1mg p.o./s.l./
i.v
-- lormetazepam (Sedalam)
-- midazolam (Dormicum)
• physostigmine (Anticholium):
-- only if anticholinergic syndrome (see page 1411) is
present (e.g. triggered by anticholinergic substances
such as TCA or neuroleptics)
-- If the delirium is unclear, the pseudocholinesterase
can be determined in the serum. If this is reduced,
this can be an indication of acetylcholine deficiency,
so that physostigmine can be started if necessary.
Several studies (e.g. Low preoperative plasma cho-
linesterase activity as a risk marker of postoperative
delirium in elderly patients; Cerejeira et al, J Br Ger
Soc 2011) have already been published on this to-
pic, but a general recommendation can certainly not
yet be given.
-- 1 amp. = 5ml = 2mg; 2mg as short infusion in 50ml
NaCl 0.9% over 30min
-- monitoring obligatory (as potentially severe brady-
cardias up to asystole are possible)
"Delirium and seizures are good
friends!"

for excitation: Haloperidol (Haldol; if M.
Parkinson: quetiapine [Seroquel])
for anxiety: Lorazepam (Tavor) or
Lormetazepam (Sedalam)
Haloperidol (Haldol)
• a highly potent neuroleptic
• a butyrophenone
• 1 amp. = 5 mg; e.g. 1-1-1
• max. 50 mg/d
• application
-- i.v.: cave QT interval prolongation (ECG monitoring
therefore obligatory, especially in combination with
clonidine [due to the decrease in heart rate relative
increase in QT interval]); approval for i.v. administ-
ration was withdrawn (off-label use; only if intramu-
scular administration is not possible [e.g. Marcumar
patient])
-- i.m.
-- p.o.
• side effects
-- extrapyramidal symptoms (EPS; in M. Parkinson
contraindicated [Haloperidol is a dopamin-antago-
nist!]; in M. Parkinson atypical neuroleptics such as
quetiapine [Seroquel 50-100mg p.o.] are possible)
-- neuroleptic malignant syndrome (NMS)
-- seizures
-- QT interval prolongation
◦◦ 0.4% of intensive care patients develop torsades
de pointes!)
◦◦ especially in combination with clonidine: The clo-
nidin-induced decrease of the heart rate leads to a
relative increase of the QT interval!
cave combination of haloperidol
and clonidin: QT interval ↑,
possibly torsades de pointes,
ventricular fibrillation
Melperone (Eunerpan)
• a middle potent neuroleptic
• a butyrophenone
• application: only p.o. / gastric tube (not i.v.)
-- juice (1ml = 5mg; 5-80 ml [25-400mg] daily)
-- pill (10mg, 25mg or 100mg; e.g. 25mg-0-50mg)
• not metioned S3-guideline 2015 "Analgesia, Sedation
and Delirium Management in Intensive Care"
Promethazine (Atosil)
• a lowly potent neuroleptic
• a phenothiazine
• especially suitable for older patients
• dosage: 1 amp. = 50 mg, 12.5-50 mg (max. 100 mg/d)
i.v. / i.m.; e.g. ½-1 amp. as short infusion
• side effects:
-- heart rate ↓ (cave: up to asystole)
-- dry mouth
-- increase of intraocular pressure (cave in glaucoma)
study
Effect of rivastigmine as an adjunct to usual care with halo-
peridol on duration of delirium and mortality in critically ill
patients: a multicenter, double-blind, placebo-controlled
randomized trial
van Eijk et al, Lancet 2010
• multicenter randomized controlled study
• 440 intensive care patients with delirium; standard the-
rapy (including haloperidol)
-- with rivastigmine
-- without rivastigmine (placebo)
• result: premature discontinuation due to excess mor-
tality in the rivastigmine-group
MIND-USA study
Haloperidol and Ziprasidone for Treatment of Delirium in
Critical Illness
Girard et al, N Engl J 2018
• MIND-USA: Modifying the Impact of ICU Associated
Neurological Dysfunction
• multicenter (16 centers) randomized controlled studiy
(USA)
• 1183 intensive care patients with delirium (89% hypoac-
tive, 11% hyperactive)
-- neuroleptic:
◦◦ haloperidol (a typical neuroleptic) or
◦◦ ziprasidone (an atypical neuroleptic)
-- Placebo
• results: no difference
-- primary endpoint (number of days alive without deliri-
um during the 14-day intervention period)
-- secondary endpoints (duration of delirium, ventilation
or ICU stay; mortality)
Prophylaxis
• non-pharmacological:
-- patient information (e.g. clock/calendar in the inten-
sive care room, explanation of procedures, introduc-
tion of the persons present, hanging up family pho-
tos, use of the usual perfume / aftershave)
-- acoustic and visual aids (hearing aid, glasses)
-- Reduction of noise, earplugs at night (including me-
ta-analysis Litton et al, Crit Care Med 2016: signifi-
cant reduction of the incidence of delirium), maybe
eye mask
General Part 183
 -- maintaining a day-night rhythm
-- if possible always the same team (nursing staff, phy-
sician)
-- explanation of the alarms (The permanent alarm
sounds [noise] may disturbe and unsettle the patient
["alarmitis"]. That´s why it is useful to explain him the
meaning and purpose of the alarms. The alarms in
the patient´s room should be set to mute at night.)
-- flexible (instead of rigid) visiting hours for family
members (open visiting hours; Rosa et al, JAMA
2019: no reduction the incidence of delirium)
-- mobilisation (early)
-- if possible no transfers to another room
-- as few fixation measures as possible
-- removal of the urinary catheter or drainages as soon
as possible
-- maybe ceratin of an ICU diary (through family mem-
bers or caregiver; Garrouste-Orgeas et al, JAMA
2019: no decrease of the risk for a PTDS)
-- possibly music (e.g. favourite music of the patient
via headphones: significant reduction of anxiety and
sedatives [Chlan et al, JAMA 2013])
• pharmacological:
-- from > 72h onwards, taper off analgesics (especially
opioids; no abrupt discontinuation); initial reduction
of 25%, then 10% per day
-- α2-agonist (e.g. clonidine) in the weaning phase
-- avoidance of anticholinergic medication (e.g. tricyc-
lic antidepressants should not be continued during
ventilation but discontinued instead)
-- possibly neuroleptics (olanzapine, haloperidol) →
no general recommendation (optional in case of a
high risk; no bedefit, however, in the HOPE-ICU stu-
dy 2013 [see box] and in the REDUCE study 2018
[see box])
-- statins: no benefit (MODUS study [Page et al, Lan-
cet Resp Med 2017)]
-- possibly melatonin
◦◦ promotion of the day-night rhythm for the prophy-
laxis of delirium
◦◦ the sleep hormone from the pineal gland (epiphy-
sis)
◦◦ The secretion is suppressed by light.
◦◦ dosage: 1 x 5mg p.o. at night
◦◦ especially in geriatric patients
◦◦ In a study on orthopaedic patients (Sultan et al,
Saudi J Anaesth 2010) the postoperative delirium
incidence could be reduced from 32.6% to 9.5%
by twice daily administration of melatonin 5mg.
Melatonin cannot yet be generally recommended
for delirium prophylaxis, current studies are ongo-
ing (e.g. de Jonghe et al, The effects of melatonin
versus placebo on delirium in hip fracture patients:
study protocol of a randomized, placebo-cont-
rolled, double blind trial; BMC Geriatrics).
184 General Part
study
Haloperidol prophylaxis decreases delirium incidence in
elderly patients after noncardiac surgery: a randomized
controlled trial
Wang et al, Crit Care Med 2012
• randomized controlled trial (2 centers)
• 457 postoperative patients (non-cardiosurgical)
-- haloperidol (0.5mg i.v. as bolus, then 0.1mg/h for 12h)
-- placebo
• results:
-- significantly lower incidence of delirium
-- significantly shorter ICU length of stay
-- no difference in mortality
HOPE-ICU study
Effect of intravenous haloperidol on the duration of delirium
and coma in critically ill patients
Page et al, Lancet Resp Med 2013
• HOPE-ICU: Haloperidol Effectiveness in ICU Delirium
• monocenter randomized controlled study
• 142 ventilated intensive care patients
-- haloperidol
-- placebo
• result: no difference in the primary endpoint (deliri-
um-free days)
REDUCE study
Effect of Haloperidol on Survival Among Critically Ill Adults
With a High Risk of Delirium
van den Boogaard et al, JAMA 2018
• multicenter randomized controlled study
• 1789 critically ill patients (at least 2 days in ICU) with a
hogh risk of delirium
-- haloperidol (1-2mg i.v. 3 x tägl.)
-- placebo
• results:
-- primary endpoint (surviving rate [after 28d]): no diffe-
rence
-- sedundary endpoints (i.a. incidence of delirium, du-
ration of ventilation, duration of ICU / hospital stay):
no difference
Fig. 305  We have installed a warning system (here Sound-
Ear2) in our intensive care unit at the base: If a certain noise
level is exceeded, the system emits a visual warning signal
(right picture; left picture: noise level o.k.). This should help
to sensitize both nurses and doctors to the noise they are
causing and then motivate them to reduce the noise.

General Part 185

 ◦◦ only suitable for heart rate and rhythm analysis,
HAEMODYNAMIC not suitable for analysis of ST segment changes
and thus myocardial ischemia
MONITORING ◦◦ poor-man´s V5: Here a modified ECG system is
used (according to Kaplan). The red electrode is
placed to the right of the upper sternum, the green
electrode at the lateral end of the left clavicle and
the yellow electrode in V5 position. Then the lead
I is derived: Here 80% of the ST depressions pre-
sent in a 12-lead ECG can be detected.
-- 5-electrode lead
◦◦ should be standard on the intensive care unit
◦◦ best lead for ST segment analysis: V5
• shock index (= heart rate / SBP) > 1: shock (introduced
by Allgöwer and Burri 1967; completely unreliable!)
• recapillarisation time (capillary refill time [CRT];
norm < 2s; very good and unfortunately much too ra-
rely used simple clinical parameter! i.a. equivalent to
the lactate ,onitoring [Andromeda-Shock study 2019])
• diuresis (goal: > 0.5 ml/kg/h): The kidney is a very
"sensitive and egotistical" organ. If its oxygen supply is
no longer sufficient, it stops working immediatly. This is
because the kidney has a relatively high oxygen con-
Definition sumption compared to other organs. Therefore, diure-
sis is a good parameter for hemodynamics.
• hemodynamic: theory of the flow of blood in the ves-
sels and in the heart • lactate
• Latin "monere": to warn, to alert -- An increased lactate is always a sign of a reduced
oxygen supply for the cell (e.g. as a consequence
• monitoring of the cardiovascular function
of a reduced CO [shock parameter], haemoglobin or
• guidelines: Consensus on circulatory shock and hemo-
SaO2): Under hypoxia, pyruvate can no longer be
dynamic monitoring - Task force of the European Soci-
introduced into the citric acid cycle (see page 728)
ety of Intensive Care Medicine; Cecconi et al, Intensive
via pyruvate dehydrogenase and is thus degraded
Care Med 2014
consecutively via lactate dehydrogenase (LDH) to
• classification lactate
-- basic monitoring -- conversion lactate (units): 1 mmol/l (SI-unit) = 9 mg/
-- advanced monitoring (p.d. determination of cardiac dl (conventional unit)
output [CO]) -- the most important laboratory shock parameter (i.a.
meanwhile according to the depsis-3-definition a
diagnostic criteria for the septic shock [laktate > 2
mmol/l respectively > 18 mg/dl])
-- lactate clearance (decrease > 10% within 2 hours)
as a very good parameter (i.a. Arnold et al, Shock
2009; LACTATES study [Jones et al, JAMA 2010];
Jansen et al, Am J Respir Crit Care Med 2010)
-- lactate level:
◦◦ venous and arterial lactate levels without any rele-
vant difference (i.e. arterial cannulation not abso-
lutely necessary); note.: For the determination
in the venous blood, the sample must be taken
without congestion (i.e. without tourniquet const-
riction), as otherwise false high values ​​can occur!
◦◦ in whole blood (haemolysed; determination in
Fig. 306  monitoring [14] the laboratory) 1.4 times higher than in BGA (not
haemolysed)
• oxygen saturation (SO2): proportion of hemoglobin in
Basic monitoring the total hemoglobin that is loaded with oxygen (for de-
finition also see page 81)
• blood pressure
-- arterial saturation: SaO2 (from arterial BGA)
• heart rate (not to be confused with pulse rate)
-- pulse oximetry measured saturation: SpO2
• EKG
-- venous saturation: SvO2
-- - 3-electrode lead

186 General Part

 ◦◦ central venous saturation: ScvO2 (BGA from CVC;
from superior vena cava)
◦◦ mixed venous saturation: SmvO2 (usually also
only SvO2; BGA from pulmonary artery catheter
[lumen PA-distal]; from pulmonary artery)
Fig. 307  Monitoring of the diuresis is part of the basic mo-
nitoring in the intensive care unit. Goal is a diuresis > 0.5
ml/kg/h.
lactate: the most important laboratory
parameter for a reduced oxygen
supply to the cell (i.a. due to a decrea-
sed CO: therefore even the most
important laboratory shock parameter)!
Blood pressure
Measurement
• non-invasive (NIP: non-invasive pressure; NIBP: non-
invasive blood pressure; oscillometric according to
the Italian physician Scipione Riva-Rocci [1863-1937;
"RR"])
• invasive (IP: invasive pressure; IBP: invasive blood
pressure)
Meaning
• systolic blood pressure (SBP, RRsys): afterload; annot:
SPV (systolic pressure variation; syn.: cardiac cycling
[for illustration see page <?>]: a parameter for volume
requirement [SPV > 10%])
• diastolic blood pressure (DBP, RRdias): coronary perfu-
sion (goal: DBP > 50 mmHg)
• mean blood pressure, exactly mean arterial pressure
(MAP): perfusion
-- Therefore, the MAP is also called perfusion pressu-
re.
-- goal: MAP > 65 mmHg
-- Some organs (brain, kidney) are (within certain li-
mits) independent of the perfusion pressure, i.e. de-
spite systemic hypotension, their perfusion is main-
tained (autoregulation).
-- formulas:
◦◦ MAP = RRdias + 1/3 (RRsys – RRdias) = (RRsys + 2x
RRdias) / 3
◦◦ MAP ~ CO x SVR (Ohm's equation; blood pres-
sure can thus be raised both by increasing the
cardiac output [CO] and by increasing systemic
vascular resistance [SVR].)
Pulse oximetry
Definition
• non-invasive percutaneous measurement of partial
oxygen saturation (percentage of O2-saturated [oxy-
genated] hemoglobin of total hemoglobin)
• via clip / adhesive sensor on the finger or earlobe
• principle of spectrophotometry:
-- developed by the Japan engineer Takuo Aoyagi in
1972
-- On the one side, the clip has two light sources that
emit light in two wavelengths: infrared light (940 nm)
and red light (660 nm). On the other side there is a
light sensor (photodetector).
-- Oxygenated haemoglobin absorbs less light than
deoxygenated haemoglobin.
-- The device measures the difference between the
minimum absorption in systole and the maximum
absorption in diastole.
-- The quotient (absorption ratio) of the absorption of
the read (940 nm) and the infrared (660 nm) light
determines the saturation.
◦◦ absorption ratio (660 nm/ 940nm) of 0.43 → satu-
ration 100%
◦◦ absorption ratio (660 nm/ 940nm) of 3.4 → satu-
ration 0%
• Large studies from the 1990s (e.g. Moller et al, Anes-
thesiology 1993) could not show any mortality benefit
from the use of pulse oximetry in intensive care pati-
ents.
• measured values:
-- SpO2 95% ≈ paO2 90 mmHg
-- SpO2 90% ≈ paO2 60 mmHg
• The pulse oximetry measured SO2 values correlate
well with arterial pO2 only if SO2 > 70%.
• For the assessment of oxygenation, the saturation
(pulse oximetry) is much more meaningful than the
pO2 value in the (arterial) BGA. Just think of a pleural
effusion: Here you find a high pO2 with low saturation.
General Part 187
 If the blood in the vascular system was to be replaced Oxygen supply
by a pleural effusion, one could not live despite a high
The oxygen enters the alveoli via the respiratory tract. By
pO2.
diffusion through the alveolo-capillary membrane it gets
into the blood. Because oxygen is (in contrast to carbon
Errors dioxide) extremely poorly water soluble, the transport in
• falsely too high measurements: the blood is predominantly (98.5%) chemically bound to
-- CO-Hb (carbon monoxide poisoning) hemoglobin. Only a small part of oxygen (1.5%) is physi-
-- Met-Hb (methaemoglobin formers poisoning [methe- cally dissolved in the blood. Via the blood (oxygen trans-
moglobinemia]) port) the oxygen is deliverd to the the tissue / cells. The
-- cyanide poisoning delivered amount of oxygen per time (oxygen delivery) is
the decisive determinant of the cell. The oxygen supply
• falsely too low measurements:
for the cell therefore depends on:
-- nail polish (blue, black, green; not red) • oxygen delivery (DO2: delivery of oxygen; norm: 1000
-- centralization (including shock, catecholamine the- ml/min [for survival at least 300 ml/min are necessa-
rapy, hypothermia) ry]): This in turn depends on
-- onychomycosis -- cardiac output (CO; the most important factor:
-- methylene blue Oxygen delivery DO2 depends on CO by 90%!)
• no influence: -- haemoglobin (Hb)
-- red nail polish -- arterial oxygen saturation (SaO2)
-- skin colour (e.g. black African) • oxygen consumption (VO2: volume per time of oxygen;
-- jaundice (absorption maximum of bilirubin is much norm: 200-250 ml/min); calculation:
lower [at 460 nm].) -- from the blood gases (BGA): VO2 = Hb x 1.39 x
(SaO2 - SmvO2) x 10 x CO (ml/min)
-- from the breathing gases: VO2 = RMV x (FiO2 - FEO2)
◦◦ RMV: respiratory minute volume
◦◦ FiO2: oxygen fraction inspiratory air
◦◦ FEO2: oxygen fraction expiratory air

Oxygen delivery DO2 depends on:

- CO
- Hb
- SaO2

DO2 ~ CO SaO2 Hb

Fig. 308  pulse oximetry for measuring oxygen saturation

[32] function: function: function:
heart lung blood

Fig. 310  The three determinants of oxygen delivery (DO2)

to the cell: the function of the heart (CO), the lung (arterial
oxygen saturation [SaO2]) and the blood (Hb).

The German physiologist Eduard Pflüger (1829-1910)

stated already in 1872: "The cardio-respiratory system
fulfills its physiological task in ensuring the cellular oxy-
gen supply.“

Fig. 309  pulse oximetry [32]

188 General Part


Fig. 311  The relationship should illustrated by a compari-
son with a train: The oxygen delivery for the cell can be
compared with the amount of coal supplied by a train (e.g.
for heating). In this comparison, CO corresponds to the en-
gine (power) of the locomotive (traction engine), the Hb to
the number of wagons and the SaO2 to the proportion of
the load volume of each wagon loaded with coal. The lar-
ger the individual parameters (i.e. stronger traction engine,
more wagons, wagons loaded with coal up to the ceiling if
possible), the more coal is ultimately delivered by the train
and can then be burned for energy generation
Fig. 312  normal oxygen delivery DO2: strong traction engi-
ne (CO), enough (iin the example here 4) number of wagons
(Hb), all of which are fully loaded (SaO2 = 100%).
Fig. 313  reduced oxygen delivery DO2: indeed a sufficient
number (Hb) of fully loaded (SaO2) wagons, but a to small
(too weak) traction engine (CO)
Fig. 314  reduced oxygen delivery DO2: indeed a strong
traction engine (CO) and a sufficient number (Hb) of wa-
gons (Hb), but which are underloaded (too little saturation
SaO2)
Fig. 315  reduced oxygen delivery DO2: indeed a strong
traction engine (CO) and fully loaded (SaO2) wagons, but
which are too few (only 2 instead of 4; Hb)
In shock, by definition the oxygen delivery is smaller than
the oxygen consumption.
shock: oxygen delivery DO2 <
oxygen consumption VO2
So in order to optimize the oxygen supply to the cell, the
following can be done:
• increase the oxygen delivery (DO2):
-- cardiac output (CO; the main determinant of DO2
[90%]):
◦◦ CO = stroke volume (SV) x heart rate (HR)
◦◦ stroke volume: optimization of preload, ejection
fraction (EF) and afterload (e.g. volume adminis-
tration, catecholamines)
-- hemoglobin (Hb): administration of red cell concen-
trates (RCC; the simplest and most effective); note:
In the case of anemia, the body automatically incre-
ases CO (usually by increasing of the heart rate) as
a compensation mechanism to ensure a sufficient
oxygen delivery.
-- arterial oxygen saturation: oxygen delivery (the most
importat emergency drug [is the fastest]!), begin-
nung respectively optimization of ventilation
• reduction of oxygen consumption (e.g. by deep anal-
gosedation, hypothermia; usually therapeutically only
little accessible)
oxygen: the most important emergency
drug!
An increase in arterial oxygen saturation from 85% to
99% by optimizing ventilation (this must first be achie-
ved) increases the oxygen delivery by (only) 14%. An
increase in the cardiac output from 3.0 to 3.5 l/min in-
creases the oxygen delivery by 16% and an increase in
haemoglobin by administration of RCC from 7 to 10 g/dl
(SI units: from 4.3 to 6.2 mmol/l) even by 43% (most ef-
fective and simplest [i.a. Langgartner et al, Intensiv- und
Notfallbehandlung 2008]). The higher the hemoglobin le-
vel, the lower saturation values can be tolerated. In case
of anemia (low hemoglobin level) there is often a tachy-
cardia: This is a physiological compensation mechanism.
By increasing the heart rate the cardiac output CO (CO
= SV x HR) is increased in order to supply a sufficient
oxygen delivery.
Venous oxygen saturation
Oxygen is mainly chemically bound (98.5%) to haemoglo-
bin in the blood and only a small part (1.5%) is physically
dissolved in the blood. The oxygen-loaded haemoglobin
is pumped by the heart (cardiac output) to the periphery
and there it is released again from oxygen. However, the
release (desaturation) is not complete, so that even in
venous blood the largest proportion of haemoglobin is
still loaded with oxygen. Under physiological conditions,
only about a quarter (25%) of the oxygen is released du-
ring passage through the tissue capillaries (oxygen ext-
General Part 189
raction ratio [O2-ER]). The proportion of oxygen-loaded
haemoglobin in venous blood is called venous oxygen
saturation (SvO2). It is a parameter for oxygen trans-
port and represents a balance between oxygen delivery
(DO2) and oxygen consumption (VO2). It is a surrogate
parameter for the cardiac output. ("poor man´s cardiac
output"). A decrease is an early sign of a reduced tissue
oxygenation. In shock the venous saturation is typically
decreased, hence both the oxygen consumption and the
oxygen extration ratio are increased.
SvO2 = (Hb x 1.36 x SaO2) - VO2 / CO
The oxygen extraction ratio (O2-ER) describes the relati-
onship between oxygen delivery and oxygen consump-
tion. Normally it is 25%, e.g. arterial saturation 97%, ve-
nous saturation 72%.
Fig. 316  The oxygen uptaken in the lung is bound to he-
moglobin and transported to the body tissue (cells). Only
about a quarter (25%) of the arterial blood is discharged
from oxygen (desaturated). In this example, the saturation
in the arterial blood (SaO2) is 100%, in the venous blood
(SvO2) 75%. The oxygen extraction ratio is 25%.
The venous saturation depends i.a. on the oxygen con-
sumption. During shock, centralization often occurs, re-
sulting in a decrease in oxygen consumption (reduced
oxygen extraction ratio). Consequently, venous satura-
tion is not reduced, i.e. normal, although there is a clear
pathological condition. The additional determination of
lactate is helpful here:
• normal venous saturation + non-increased lactate:
physiological
• normal venous saturation + increased lactate: patholo-
gical (patient in shock)
SvO2 decreased: pathological
(almost always)
SvO2 normal: physiological or
pathological
A normal venous saturation does not automatically mean
that everything is okay. The venous saturation is also
normal if either the oxygen delivery (DO2) is increased
(e.g. in the context of a hyperdynamic circulation in sep-
190 General Part
sis with a high cardiac output) or the oxygen consump-
tion VO2 is reduced (e.g. shock with centralization). For
this reason, the venous saturation (especially an normal
venous saturation) should never be considered alone (in
isolation), but only in conjunction with other parameters
(lactate, CO, SVR, etc.).
Central or mixed venous saturation
(especially if it is normal) must never
be considered in isolation!
The venous saturation SvO2 even depends (inversely
proportional) to the body temperature T:
• T ↓ → SvO2 ↑ (Under hypothermia the oxygen con-
sumption is reduced, so that the venous saturation in-
creases.)
• T ↑ → SvO2 ↓
For a long time, mixed venous saturation was considered
the standard in haemodynamics in intensive care medi-
cine. However, this requires a pulmonary artery catheter,
which today is rarely used for (daily) standard haemody-
namic monitoring in intensive care units. For this reason,
central venous saturation was investigated as a substitu-
te parameter for mixed venous saturation. For the cen-
tral venous saturation only a central venous catheter is
necessary, which (almost) every intensive care patient
has anyway. It was shown that central venous saturati-
on correlates very well with mixed venous saturation and
can be interpreted in the same way.
In healthy people (under physiological conditions) the
central venous saturation usually is 5% lower than the
mixed venous saturation, because the oxygen consump-
tion in the brain is high (superior vena cava) and hepatic,
splanchnic and renal oxygen consumption is low (due
to the high perfusion; inferior vena cava). In critically ill
patients (under pathological conditions) the perfusion of
heart and brain is increased at the expense of the hepatic,
splanchnic and renal perfusion. The hepatic, splanchnic
and renal oxygen extraction ratio is increased. Due to
the analgosedation in an intubated patient the cerebral
oxygen consumption is low, so that in critically ill patients
(pathological) in contrast to healthy persons (physiologi-
cal) the central venous saturation ist usually 5% higher
than the mixed venous saturation.
However, central venous saturation also has its limita-
tions: In critically ill patients it is often faslely too high
and therefore does not reflect the current hemodynamic
situation sufficiently. Critically ill patients in shock often
experience reduced perfusion with consecutive desatu-
ration in the splanchnic area. However, this is only shown
in mixed venous and not in central venous saturation,
since only blood from the upper half of the body (supe-
rior vena cava) is included in central venous saturatio.
Futhermore a shunt (e.g. left-to-right-shunt due to a ven-
tricular septal rupture [ventricular septal defect]) can only
be recognized in the mixed venous (noticeably too high,
i.e. > 80%) and not in the central venous saturation.
central venous saturation mixed venous saturation
Fig. 317  central venous saturation: saturation in the su-
perior vena cava (before the right heart; from CVC); mixed
venous saturation: saturation in the pulmonary artery (after
the right heart; from PAC) [30]
Central venous oxygen saturation (ScvO2)
• saturation in venous blood before the right heart (only
from superior vena cava)
• from central venous catheter (CVC; only if CVC is in
internal jugular or subclavian vein, not in femoral vein;
always take from the distal lumen)
• misinterpretation:
-- falsely low values with too low position of the CVC tip
near the coronary sinus (orifice of the coronary veins
into the right atrium; the blood in the coronary veins
is strongly desaturated!)
-- falsely high values:
◦◦ increases oxygen delivery DO2 (hyperdynamic cir-
culation in sepsis [high cardiac output])
◦◦ reduced oxygen consumption VO2 (with strong
centralization [e.g. shock])
• Central venous saturation is (in critically ill patients)
usually 5% higher than mixed venous saturation. Cen-
tral venous saturation is only the saturation in the su-
perior vena cava, mixed venous saturation is the sa-
turation from superior and inferior vena cava. In the
inferior vena cava (lower half of the body) oxygen
saturation is lower than in the superior vena cava in
critically ill patients. Furthermore, mixed-venous satu-
ration is accompanied by strongly desaturated blood
from the coronary sinus (orifice of the coronary veins).
• measurement:
-- discontinuous (BGA from CVC)
-- continuous (e.g. CeVOX probe)
• norm: 70-85%
CeVOX
• additional module of the PiCCO system from Pulsion
(now Maquet)
• continuous measurement of central venous saturation
ScvO2
• via the distal lumen of each CVC
• measuring method: spectrophotometry (as in all satu-
ration measurements; here via a fiberoptic probe in the
superior vena cava)
• sterile installation of the CeVOX probe is obligatory (It
is best to install it as part of the insertion of a central
venous catheter.)
• In our experience, the probe clotted relatively often.
Therefore we add 500ml Ringer + 5000IU of heparin
with an infusion rate of 10ml/h for clotting prophylaxis
via the probe.
ScvO2 LED
sensor
device optic module fiberoptic probe
Fig. 318  CeVOX: continuous measurement of central ve-
nous saturation spectrophotometrically using a special
probe in the superior vena cava [30]
Fig. 319  CeVOX probe: is placed over the distal lumen of
a CVC [30]
Mixed venous oxygen saturation (SmvO2)
• saturation in venous blood after the right heart (from
pulmonary artery)
• Only in the pulmonary artery is the complete venous
blood of all parts of the body is to be found!
• from pulmonary artery catheter (PAC; from lumen "PA
distal")
• norm: 65-80%
• In case of increased (> 80%) mixed venous saturation
(e.g. 93%) one should think of a left-right shunt (e.g.
ventricular septal rupture due to myocardial infarction)
Venous-arterial pCO2 difference (dCO2)
• more precisely: central venous-arterial pCO2 difference
• dCO2 = central venous pCO2 (BGA from CVC) and ar-
terial pCO2 (BGA from arterial line)
• norm: < 8mmHg
• It is directly proportional the carbon dioxide production
(e.g. increased in the context of shock [anaerobic me-
tabolism ↑] and inversely proportional to the cardiac
output (the lower the cardiac output, the higher the
DCO2).
• dCO2 > 8mmHg indicates reduced perfusion (shock)
• The higher the dCO2, the worse is microcirculation. An
elevated dCO2 is a good predictor for a disturbence of
the microcirculation (u.a. Ospina-Tascon et al, Intensi-
ve Care Med 2016).
• The pH value in the venous BGA (up to max. 0.02 hig-
her) also corresponds approximately to the pH value in
the arterial BGA. A venous-arterial pH difference > 0.1
is typical for shock.
General Part 191
 Advanced (syn. extended) monito-
ring
• pulmonary artery catheter (PAC)
• pulse contour analysis
-- PiCCO
-- EV1000 (analogous to PiCCO system from the Ed-
wards Lifescience company; minimal-invasive vari-
ant: FloTrac-Vigileo-system)
• echocardiography
-- TTE (transthoracic echocardiography)
-- TEE (transesophageal echocardiography)
• LiDCO
-- Lithium-Dilutions-Cardiac-Output
-- indicator dilution procedure (transpulmonary)
-- application of lithium via a peripheral access, then
measurement of the arterial lithium concentration via
a special probe
-- side effects (lithium):
◦◦ Tremor
◦◦ psoriasiform rash
◦◦ muscle weakness
◦◦ seizure (previously damaged CNS)
◦◦ polyuria (diabetes insipidus)
-- in pregnancy (1st trimester [increased risk of conge-
nital cardiac defects, especially Ebstein anomaly])
and lactation contraindicated
• oesophageal Doppler
-- special gastric tube (easy to apply)
-- example: CardioQ system
-- placement of the probe in the middle esophagus (35-
40cm from teeth row; best signal usually at the level
of thoracic vertrebrae T5-T6)
-- measurement of blood flow in the descending aorta
(with 4 MHz)
-- relatively well validated (numerous studies)
-- only possible in ventilated patients (otherwise not
tolerated)
• USCOM system (LEA Medizintechnik)
-- ultrasonic cardiac output monitor
-- continuous echocardiographic determination of car-
diac output non-invasively via paddles
• thoracic bio-impedance (application of high-frequency
alternating current via electrodes on the chest, measu-
rement of resistance; inaccurate)
• non-invasive method (via a double-finger clip) for con-
tinuous blood pressure measurement (i.a. from the
analysis of the pulse contour aslo calculation of the
cardiac output; "volume clamped"-method; no general
recommendation):
-- CNAP (continuous non-invasive arterial pressure;
Dräger company)
-- ClearSight (former Nexfin; Edwards Lifescience
company)

192 General Part

 • cardiac output (CO) = stroke volume (SV) x heart rate
(HR)
• CO ~ MAP/SVR (Ohm's equation)
-- MAP: mean arterial pressure
-- SVR: systemic vascular resistance
• norm: 4-8 l/min
• cardiac index (CI)
-- CI = CO/BSA (body surface area)
-- norm: 2.5-4.5 l/min/m2
• heart rate:
-- By increasing the heart rate, CO (product of stroke
volume and heart rate) can be increased. However,
from a heart rate of approx. 150-170/min there is a
decrease in stroke volume and thus also in cardiac
Fig. 320  Here lithium is applied peripherally and then the output, since on the one hand the reduced coronary
lithium concentration is measured with a special probe (an perfusion (relative shortening of the diastole in ta-
indicator dilution procedure) [35]. chycardia) reduces the contractility and on the other
hand the preload decreases due to the shortening of
the diastolic filling time.
-- Bowditch effect (syn.: staircase phenomenon, force-
frequency relationship): With increasing heart rate,
contractility also increases. However, in case of
heart failure (e.g. dilated cardiomyopathy) this me-
chanism is defective.
• Shock (mostly reduced cardiac output) is not detected
in half of the cases because the focus is often wrongly
placed on blood pressure. The cause is not the dis-
turbance of the macrocirculation, which can be recog-
nized by the blood pressure, but the disturbance of the
microcirculation. The quotation by A. Jansch from the
Deutsche Medizinische Wochenschrift in 1928 is still
valid today: "For the development of the theory of cir-
culation, it was certainly a fatality that the flow volume
[meaning here cardiac output] is relatively complica-
ted, but the blood pressure can be determined so ea-
sily: Therefore the blood pressure manometer gained
an almost fascinating influence, although most organs
do not need pressure, but flow volume". According to
Ohm's equation applies: MAP ~ HZV x SVR
-- In a sever sepsis or anaphylaxia the systemic vascu-
lar resistance is low (SVR ↓) and the cardiac output
is high (CO ↑), so that the blood pressue (MAP) is
normal, although the hemodynamic situation is de-
leterious.
-- In a cardiogenic shock or in a septic shock in the
endstage he cardiac output is low (CO) ↓ syste-
mic vascular resistance is high (SVR ↑), so that the
blood pressue (MAP) is normal, although the hemo-
dynamic situation is deleterious.

Fig. 321  USCOM (ultrasonic cardiac output monitor): con-

tinuous echocardiographic determination of cardiac output
non-invasively via paddles [36] A reduced cardiac output (CO) is not
recognized in half of the cases!!

Cardiac output (CO)

Definition
• the amount of blood the heart pumps through the body
every minute
• product of stroke volume and heart rate

General Part 193


The organs are not pressure-, but
flow-dependent! Therefore the flow
(perfusion) is much more important
than the pressure (blood flow instead
of blood pressure)!
Fig. 322  Especially for the diagnosis and therapy of shock,
blood pressure should not be used (alone) as a guide. Much
more important is an advanced hemodynamic monitoring
(including determination of cardiac output and systemic
vascular resistance)!
The three windows of perfusion:
- skin (cold, mottled)
- kidney (oliguria)
- brain (disturbance of consciousness)
Stroke volume (SV)
• amount of blood that is ejected per heartbeat
• difference between end-diastolic and end-systolic vo-
lume (SV = EDV - ESV)
• norm: 60-80ml
• The stroke volume of the right heart is equal to the
stroke volume of the left heart and not less.
• The stroke volume depends on 3 parameters (deter-
minants):
-- preload
-- afterload
-- contractility
load = wall tension of the ventricle
- end-diastolic: preload
- end-systolic: afterload
Preload
• end-diastolic wall tension of the ventricle
• simplified: ventricular end diastolic pressure
• end-diastolic fiber length (sarcomere)
• Frank-Starling mechanism (named after the German
physiologist Otto Frank [1865-1944] an the English
physiologist Ernest Starling [1866-1927]; syn.: force-
194 General Part
length relationship): The force of the individual heart
muscle fiber is proportional to the initial sarcomere
length (superposition [overlapping] of actin and myo-
sin filaments). The pre-stretching (longitudinal) of the
myocytes leads to an increased calcium influx and
consequently to an increase in inotropy. The contrac-
tion force of the heart muscle cells increases with their
pre-stretching. The optimal sarcomere length (length
of superposition) with the maximum force is 2.2 μm.
Beyond 2.6 μm there is overextension with a conse-
cutive reduction of the force. You can compare this
to a balloon: The further you inflate it, the greater its
pre-stretch and the faster the air will finally whistle out
when you release the opening.
• The pre-stretching cannot be measured in clinical
practice. As a surrogate parameter therefore the pres-
sure in the ventricle at the end of the diastole (end-
diastolic pressure; syn .: filling pressure) can be used:
The higher the pressure inside the ventricle at the end
of the filling phase (end-diastolic), the stronger the pre-
streching of the ventricle and thus the higher the pre-
load. The parameter for the left ventricular preload is
the left ventricular end-diastolic pressure (LVEDP), pa-
rameter for the right ventricular preload the right ventri-
cular end-diastolic pressure (RVEDP). However, as is
known today, the pressures do not correlate sufficiently
with the preload, so that today even other parameters
are used to estimate the preload (see page 216). The
estimation of the preload (volume dependency) is one
of the most common and at the same time one of the
most difficult questions in daily practice.
-- LVEDP; measurement:
◦◦ directly (arterial puncture): The LVEDP can be
measured directly only invasively in the cath lab
(cardiac catheterization laboratory): Therefore, the
pigtail catheter is retrogradly inserted from the as-
cending aorta via the aortic valve into the left ven-
tricle, where the pressure at the end of the diastole
then is measured.
◦◦ indirectly (venous puncture): In the intensive care
unit the LVEDP is only measured indirectly by the
measurement of the wedge pressure (= PCWP
[pulmonary capillary wedge pressure] with the pul-
monary artery catheter [PAC].)
-- RVEDP (The ZVD is often used here indirectly very
simplified. The RVEDP could certainly be measu-
red directly with the pulmonary artery catheter [right
heart catheter]. However, this is very rarely done in
daily clinical practice, since the perload of the right
ventricle is not so important: The right ventricle is
relatively insensitive to volume, so that the Frank-
Starling mechanism does not play a pronounced
role an the right heart. The right ventricle, however,
is extremely sensitive to pressure (afterload): If the
reight ventricular afterload increases [e.g. pulmona-
ry embolism], the right ventricular stroke volume de-
creases quickly.)
• options:
-- to increase the preload: volume administration
-- to decrease the preload: volume withdrawal (e.g.
loop diuretics, CVVH), nitrates (especially in low do-
sage venous vasodilation occurs)

Fig. 323  sarcomere with the contractile proteins (filaments)
myosin and actin: The larger the superposition, the higher
is the force. Optimal is a superposition of 2.2 µm.
stroke volume (SV)
1 2 3 increase of the afterload, physiologically the wall
preload
Fig. 324  relationship between preload and stroke volume:
Frank-Starling curve (= cardiac function curve = force-
length relationship). In section 1 of the curve, the stroke vo-
lume SV and thus the cardiac output CO (CO = SV x HR) can
be increased by volume administration (preload of myocy-
tes → increased calcium influx → increase in inotropy). In
section 2 of the curve (target corridor of therapy!), the vo-
lume status and thus the preload is optimal. In section 3,
the preload is too high (volume overload): Here, the preload
must be lowered and thus volume withdrawn in order to
increase cardiac output.
stroke volume (SV)
diastolic
heart failure
normal
systolic
heart failure
preload
Fig. 325  Heart failure causes a shift of the Frank-Starling
curve (normal [black]): in systolic heart failure (red; syn.:
HFREF [heart failure with reduced ejection fraction]) down-
wards, in diastolic heart failure (blue; syn.: HFPEF [heart
failure with preserved ejection fraction) rightwards.
Afterload
• end-systolic wall tension of the ventricle (during the
systolic ejection period)
• resistance that the left ventricle must overcome during
ejection into the aorta
• measure of the workload (stroke work, heart work) of
the ventricle
• Laplace's law: T = P x r / 2d (named after the French
physicist Pierre-Simon Laplace [1749-1827])
-- T: well tension
-- P: transmural pressure
◦◦ difference between the pressure inside and out-
side (= intrathoracic pressure) of the left ventricle
◦◦ The higher the transmural pressure, the higher is
the wall tension and therefore the afterload.
◦◦ Due to ventilation positive pressure is applied.
That leads zu an increase of intrathoracic pressu-
re, so that the pressure outside of the left ventricle
increases and therefore the transmural pressure
(difference of the pressure in- and outside) decre-
ases. Thus the afterload decreases.
◦◦ In case of a pressure load of the left ventricle (e.g.
arterial hypertension, aortic valve stenosis) the
pressure inside of the left ventricle and therefore
the transmural pressure (difference of the pressu-
re in- and outside) increases. In order to prevent
an increase of the wall tension and therefore an
thickness d increases. Left ventricular hypertrophy
occurs.
-- r: radius (The larger the diameter of the left ventricle
[dilatation of the left ventricle], the higher is the wall
tension.)
-- d: wall thickness (The thicker the wall [left ventricular
hypertrophy], the lower is the wall tension.)
• The higher the wall tension, the higher is the afterload
and thus the oxygen consumption and the lower the
stroke volume! The higher the wall tension, the lower
the contractility. This can be seen, for example, in a
pheochromocytoma crisis: As a result of the massively
increased blood pressure values, there is often a pro-
nounced decrease of the ejection fraction (EF < 20%).
• The wall tension cannot be measured in clinical practi-
ce. The surrogate parameters for the afterload are the
systolic blood pressure (SBP; simplified) and (better)
the systemic vascular resistance (SVR: systemic va-
scular resistance) for the left ventricle. The same ap-
plies to the right ventricle: pulmonary arterial pressure
(PAP) and pulmonary vascular resistance (PVR).
• The afterload is i.a. also increased in aortic valve ste-
nosis.
• vascular resistance:
-- produced by the tone (contraction) of the arterioles
(resistance vessels)
-- Ohm's law (from electrical engineering): R = U / I
◦◦ R: resistance (here: SVR)
◦◦ U: tension (here: MAP - CVP [The driving force is
the pressure difference between the aorta and the
right atrium.])
◦◦ I: current flow (here: CO)
General Part 195
• systemic vascular resistance (SVR) pressure outside
-- SVR = 80 x (MAP - CVP) / CO (intrathoracic
pressure)
-- standard values:
◦◦ SVR: 900-1400 dyn x sec x cm-5
◦◦ SVRI = SVR/BSA [body surface area]: 1700-2400 transmural
dyn x sec x cm-5 x m-2 pressure P
pressure radius r
-- The higher the systemic vascular resistance, the lo- inside
wer the stroke volume.
-- options:
◦◦ to increase the afterload (SVR ↑): vasoconstric-
tors (syn.: vasopressors; e.g. norepinephrine
[standard], vasopressin, possibly angiotensin II in
the future [ATHOS 3 study, Khanna et al, N Engl J wall thickness d
2017: Here, angiotensin II showed a higher MAP Fig. 326  Laplace´s law (T = P x r / 2d): The left ventricle (red)
compared to placebo in vasodilatory shock but wit- is simplified considered as a ball (sphere). The wall tension
hout any influence on the SOFA score or mortality.) and thus the afterload increases with increasing transmural
◦◦ to decrease the afterload (SVR ↓): vasodilators pressure P (difference of pressure inside and the perssure
outside [i.e. intrathoracic pressure] of the left ventricle) and
(e.g. nitrates [especially in higher dosage effect of
increasing radius r of the left ventricle and decreases with
arterial vasodilation], sodium nitroprusside [SNP]); an increasing wall thickness d.
example: patient with cardiogenic shock, BP 70/50
mmHg, SVRI with 3000 dyn x sec x cm-5 x m-2 mas-
sively increased: In this case the strokef volume
and thus the cardiac output (CO) can be increased
with a nitro-perfusor by reducing the afterload!
• pulmonary vascular resistance (PVR)
-- PVR = 80 x (mPAP - PCWP) / CO
◦◦ mPAP: mean pulmonary arterial pressure
◦◦ PCWP: pulmonary capillary wedge pressure wall tension wall tension wall tension
(wedg pressure) high normal low
-- norm: < 240 dyn x sec x cm-5 (< 3 Wood; 1 Wood = Fig. 327  Laplace´s law: If the left ventricle dilates, the wall
80 dyn x sec x cm-5) tension increases. If the left ventricle hypertrophies, the
wall tension decreases.
-- rules:
◦◦ mPAP < MAP / 3 (The mean pulmonary arterial
pressure should not exceed a third of the mean parameter for the afterload:
arterial pressure.) - left ventricle: SBP, SVR
◦◦ PVR < SVR / 5 (The pulmonary-vascular resis- - right ventricle: PAP, PVR
tance should not exceed one fifth of the systemic-
vascular resistance.)
-- options:
stroke volume (SV)

◦◦ to decrease the afterload (PVR ↓):

▪▪ drugs for the treatment of pulmonary hypertensi-
on: calcium channel blockers, PDE-5-inhibitors,
endothelin receptor antagonist (ERA), prostacy-
clin analogs, guanylate cyclase stimulator (rio-
ciguat), nitrates (glyceroltrinitrate [nitroglycerin])
▪▪ dobutamine, levosimendan, vasopressin
▪▪ reduktion of PEEP(if ventilated)
◦◦ to increase the afterload (PVR ↑): Therapeutic
measures that consciously increase right ventri-
cular afterload (PVR) play no role in daily clinical
practice. Unfortunately, what often increases PVR
in clinical practice is hypoxia of various origins (via
the Euler-Liljestrand reflex vasoconstriction of the systemic vascular resistance (SVR)
pulmonary arteries), ventilation with high PEEP
(too high PEEP → hyperinflation → compression Fig. 328  Relationship between afterload and stroke volu-
me: The higher the systemic vascular resistance (SVR), the
of the lung capillaries → right ventricular afterload
lower the stroke volume. The parameter for the afterload is
↑), hypercapnia (pCO2 ↑ → PVR ↑) and norepine- the systemic vascular resistance (SVR). The therapy prin-
phrine. ciple of course reaches its limits at some point, especially
when the perfusion pressure for the organs (especially
brain and kidney) is no longer sufficient.

196 General Part

Contractility Fig. 329  Hemodynamic pressure curves (Wiggers dia-
gram [named after the US-Amercinan physiologist Carl J.
• inotropy (pumping force) Wiggers, 1883-1963]): The pressure in the left atrium (LA
• best parameter: ejection fraction (esp. echocardiogra- pressure), in the left ventricle (LV pressure) and in the aorta
phy [for measurement see page 223]) is shown. The systole in the ECG extends from the top of
• options to increase contractility: inotropics the R wave to the end of the T wave, the diastole from the
end of the T wave to the top of the R wave. The systole is
-- dobutamine (first choice inotropic)
divided into a contraction phase (I; isovolumetric, i.e. the
-- levosimendan pressure rises, but the volume in the left ventricle does not
-- PDE III inhibitors (PDE: phosphodiesterase) decrease because the aortic valve is still closed, because
-- digitalis (positive inotropic due to inhibition of sodi- the perssure in the left ventricle does not yet exceed the
pressure in the aorta) and an ejection phase (II), the diasto-
um-potassium ATPase, negative lusitropic due to
le into a relaxation phase (III; isovolumetric, i.e. the pressu-
increased calcium overload) re decreases, but the volume of the left ventricle does not
increase because the mitral valve is still closed, because
the pressure in the left atrium does not yet exceed the pers-
sure in the left ventricle) and a filling phase (IV). All three
pressures can only be measured invasively in the cardiac
catheterization laboratory: LV pressure is measured via an
arterial puncture (femoral or radial artery) after retrograde
passage of the aortic valve with a pigtail catheter into the
left ventricle. After withdrawing the pigtail catheter into the
proximal ascending aorta, the pressure in the aorta is mea-
sured. Measuring LA pressure is even more complex: Via a
venous puncture of the femoral vein the catheter is inserted
in the right atrium and then (if there is no PFO) you have to
perform a transseptal puncture to get into the left atrium. In
the intensive care unit these pressures can only be measu-
red indirectly: For aortic pressure, the pressure in a peri-
pheral artery (e.g. radial artery, femoral artery) can be used
as part of the invasive blood pressure measurement. For
The basics for understanding hemodynamics are on the the LA pressure, the wedge pressure (PCWP) is used accor-
one hand the pressure curves and on the other hand the ding to the principle of communicating vessels, which can
working diagram (also called pressure-volume relation- be measured relatively easily with the pulmonary catheter.
ship) of the left ventricle. Regarding LV pressure, only the LVEDP can be measured
indirectly in the intensive care unit: The LVEDP (left ventri-
cular end-diastolic pressure; a measure of the pre-stretch
120 I II III IV
and thus of the preload of the left ventricle) is the perssure
in the left ventricle at the end of the diastole (top of the R
(mmHg)
pressure

aorta
wave in ECG.). This can also be measured indirectly via the
wedge pressure at the end of the diastole with the mitral
80 valve open using the pulmonary catheter.

left
left ventricular pressure

ventricle

40
left
atrium
LVEDP
0 C

systole diastole

D A

left ventricular volume

General Part 197

Fig. 330  Working diagram (pressure-volume loop) of the
left ventricle: Shown is the relationship between volume
and pressure. The area under the curve corresponds to the
stroke work (syn.: pressure-volume-work). The higher the
stroke work, the higher is the oxygen consumption. A: end
of diastole = beginning of systole; AB: contraction phase
(isovolumetric; phase I of systole); B: opening of the aortic
valve; BC: ejection phase (phase II of systole); C: end of
systole = beginning of diastole; CD: relaxation phase (iso-
volumetric; phase I of diastole); D: opening of the mitral
valve; DA: filling phase (phase II of diastole)
SV
pressure
C -- EV1000 (analog zum PiCCO-System von der Firma
afterload B
preload A with determination of the end-diastolic [EDV] and the
D
ESV EDV volume
Fig. 331  EDV (end diastolic volume): volume at point A;
ESV (end systolic volume): volume at point C; SV (stroke
volume): difference between EDV and ESV; preload: pres-
sure at point A; afterload: pressure at point B (If the after-
load increases, the end diastolic volume and thus the stro-
ke volume decreases.); EF (ejection fraction): quotient of
SV and EDV
Measurement (cardiac output))
Indications
Methods
• oxygen method according to Fick
• thermodilution: Cold saline solution (indicator) is injec-
ted into a catheter, that is inserted into the superior
198 General Part
cava vein (CVC) and the temperature rise (increase)
is measured further distally. The cardiac output is then
calculated from the temperature rise according to the
Stewart-Hamilton equation.
-- intrapulmonary (intrapulmonary thermodilution
[IPDT]: Here the temperature rise is already mea-
sured in the in the pulmonary circulation, i.e. in the
pulmonary artery.): pulmonary artery catheter (PAC)
-- transpulmonary (transpulmonary thermodilution
[TPTD]: Here the temperaturer rise is measured only
after the pulmonary circulation and after passage of
the left heart in a peripheral artery.):
◦◦ PiCCO (Pulsion v[now Maquet])
◦◦ VolumeView (EV1000; Edwards Lifescience com-
pany)
• pulse contour analysis
-- PiCCO (minimal-invasive Variante: PulsioFlex)
Edwards Lifescience; minimally invasive variant:
FloTrac-Vigileo)
-- PRAM (pressure recording analytical method; mini-
mally invasive variant of the Vytech company)
• laevocardiographic (ventriculography in the cath lab
end-systoliv [ESV] volume; stroke volume = SV = EDV
- ESV; CO = SV x HR)
• echocardiographic (see page <?>; using TTE [mostly
sufficient] or TEE): HZV = SV x Hf
-- stroke volume (SV) determination via volumes (Sim-
pson; determination of the end-diastolic [EDV] and
the end-systoliv [ESV] volume; stroke volume = SV
= EDV - ESV; CO = SV x HR)
-- stroke volume (SV) determination via velocity time
integral (VTI)
SCV
PA
RA RV LA LV
femoral
artery
Fig. 332  Difference between intra- and transpulmonary
thermodilution: In thermodilution, cold saline solution is
injected into a central venous catheter (CVC) in the superi-
or cava vein (SCV): There the temperatur is measured pro-
ximally. Another temperature measurement is then carried
out further distally. The cardiac output is then calculated
from the temperature rise. In intrapulmonary thermodiluti-
on (IPDT; pulmonary artery catheter [PAC]), the temperatur
is already measured in the pulmonary artery (PA), i.e. even
before passage of the lung. In transpulmonary thermodilu-
tion (TPTD; e.g. PiCCO) in contrast, the temperature is only
measured very distally in a peripheral artery (usually femo-
ral artery). The blood here completely passes the pulmona-
ry circulation, the left atrium (LA) and the left ventricle (LV).
Fick's method
Definition
• founded in 1870 by Adolf Fick (German physiologist;
1829-1901)
• an indicator dilution procedure with oxygen (as indi-
cator)
• principle: The same amount of oxygen VO2 (= oxygen
uptake), that is taken up into the blood via the pulmo-
nary tract per unit of time, must also be taken up via
breathing (ventilation) due to the principle of mass
maintenance. The amount of oxygen VO2 that is ab-
sorbed through the lungs per minute is therefore equal
to the difference between the pulmonary oxygen out-
flow (= pulmonary blood flow Q x oxygen content cO2
in a peripheral artery [after the lung; arterial, e.g. radial
artery, femoral artery]) and the pulmonary oxygen in-
flow (= pulmonary blood flow Q x oxygen content cO2 in
the pulmonary artery [before the lung; mixed-venous]).
The oxygen content is cO2 = Hb x SaO2 x 1.34.
-- VO2 = Q x cO2 arterial - Q x cO2 mixed venous
-- VO2 = Q x (cO2 arterial - cO2 mixed venous)
-- The cardiac output (CO) is equal at every point in the
circulation. There also the flow volume per minute in
the lung corresponds to the cardiac output, so that
the pulmonary blood flow Q can be equated with the
cardiac output: VO2 = CO x (cO2 arterial - cO2 mixed
venous)
-- After solving the equation to the CO you get: CO =
VO2 / (cO2 arterial - cO2 mixed venous)
-- The difference between the oxygen content cO2 ar-
terial and the oxygen content cO2 mixed venous is
called arteriovenous oxygen difference avDO2 be-
zeichnet, so the following applies: CO = VO2 / avDO2
• analogy: The uptake of oxygen VO2 can be compared
to the uptake of money (Euro €) V€ in a cash box of a
ticket office at the entrance of a football stadium. It was
found out (by an independent authority), that 20€ per
minute are taken up in the cash box. Before the cash
box every spectator has still 5€ in his purse (wallet),
after the cash box then only 1€. From this the inflow of
spectators Q into the stadium can be calculated:
-- V€ = (Q x content of purse before the cash box) - (Q
x content of purse after the cash box)
-- V€ = Q x (content of purse before the cash box - on-
tent of purse after the cash box) = Q x (5€ - 1€)
-- Since V€ is known (20€), the equation can be sol-
ved to Q: Q = V€ / 4€ = 20€ / 4€ = 5, i.e. the inflow
of spectators Q into the stadium is 5 persons per
minute. In this analogy, the flow of spectators corre-
sponds to the cardiac output.
Fick´s formula: HZV = VO2 / avDO2
• VO2: oxygen uptake (formula; nomogramm)
-- men: VO2 = BSA x (161 - age x 0.54) ml/min
-- women: VO2 = BSA x (147.5 - age x 0.47) ml/min
-- body surface area (BSA) = kg body weight x 0.425
x height [cm] x 0.725 x 0.007184 (DuBois formula;
also possible with table / normogram)
• avDO2 (arteriovenous oxygen difference) = Hb x 1.34*
x (SO2 arterial - SO2 central venous)
*Hüfner number (oxygen binding capacity): maximum
amount of oxygen that can be bound by 1g hemoglobin
(1.34 ml O2/g hemoglobin; in vivo value [in vitro value:
1.39 ml O2/g hemoglobin])
Once CO has been determined, the systemic vascular
resistance can also be easily calculated: SVR = 80 x
(MAP - CVP) / CO.
CO measurement according to Fick's
method: only BGA from artery and
CVC are necessary!
Example: 45-year-old man, height 180cm, weight 78kg
(According to the du Bois formula this results in a body
surface area of 1.97m².), hemoglobin (Hb) 12.4 g/dl; ar-
terial BGA arterial (from arterial line): SO2 96%, central
venous BGA (from central venous catheter) SO2 68%
• VO2 = 1.97 x (161 - 45 x 0.54) ml/min = 269.3 ml/min
(memo: "poin before line!")
• avDO2 (arteriovenous oxygen difference)
-- arterial oxygen content = 0.96 x 12.4 x 1.34 ml/100ml
= 15.95 ml
-- central venous oxygen content = 0.68 x 12.4 x 1.34
ml = 11.29 ml/100ml
-- difference: avDO2 = 15.95 ml - 11.29 ml = 4.66
ml/100ml
• CO = VO2 / 10 x avDO2 = 269.3 ml/min / 10 x 4.66 = 5.7
l/min; cardiac index CI = CO / BSA = 5.7 l/min / 1.97m2
= 2.89 l/min/m2
Assessment
• The measurement of cardiac output according to Fick's
method is an absolute standard in (nearly) every cath
lab, but unfortunately relatively little known in intensive
care medicine. It is very simple and should be used
much more often in the intensive care unit!
• Strictly speaking the mixed venous and not the cen-
tral venous saturation has to be used. However, for the
mixed venous saturation a pulmonary artery catheter
is necessary
• Strictly speaking the formula (nomogramm) for the
oxygen uptake VO2 is only valid for patients breathing
room air (FiO2 21%), i.e. it is actually not valid if additi-
onal oxygen is applied or the patient is even ventilated.
Here one would have to measure the oxygen uptake
VO2 directly (spirometrically) as the difference bet-
ween the inhaled and exhaled amount of oxygen. This
is possible, for example, with anesthesia respirators in
the operating room, but not usually with intensive care
respirators.
• source of error: In the case of anemia or arterial hypo-
xemia, one gets a falsely too high cardiac output (CO).
The lower the Hb level, the smaller the arteriovenous
oxygen difference and thus the higher the CO. In ane-
mia, hyperdynamic circulation is often found.
• also reliable in case of a severe tricuspid valve regur-
General Part 199
 gitation (The measurement of cardiac output via ther-
modilution is not permitted in case of severe tricuspid
valve regurgitation [often in intensive care, especially
when ventilating with high pressures], because cardiac
output is underestimated here! Due to tricuspid valve
regurgitation, the applied cold injectate solution is re-
peatedly thrown back into the right atrium, so that it
ultimately has more time to warm up: This results in a
greater temperature rise, so that a lower cardiac output
is measured. This applied to the intrapulmonary ther-
modilution (by pulmonary artery catheter), where the
temperature rise is already measured after the right
ventricle in the pulmonary artery. In transpulmonary
thermodilution (e.g. by PiCCO system), where the tem-
perature rise is only measured in a peripheral artery
[mostly femoral artery], this even applies to all severe
valve regurgitations [i.e. also for mitral valve- and aor-
Fig. 334  pulmonary artery catheter (5-lumen) [14]
tic valve regurgitation.])

no measurement of cardiac output

(CO) by thermodilution in severe
tricuspid valve regurgitation! CO is
underestimated here! Here, cardiac
output should be measured by Fick´s
method or by echocardiography!

Pulmonary artery catheter (PAC) Fig. 335  pulmonary artery catheter: With the help of the in-
flated balloon at the tip of the catheter, it is directed into the
Definition pulmonary artery following the blood flow and then closes
a branch of the pulmonary artery in wedge position [14].
• syn.:
-- Swan-Ganz catheter
History
-- flow-directed catheter
• The pulmonary artery catheter was introduced (i.a. N
-- right heart catheter
Engl J 1970) into clinical practice in 1970 by the Ame-
• instrument for hemodynamic and volumetric monito- rican cardiologists Harold James Charles (“Jeremy”)
ring Swan (1923-2005) und William Ganz (1919-2009).
• mostly 4 lumen, 7 Charr, made of PVC, length 110cm • anecdote: The American cardiologist H.J.C. Swan was
• note: "right-heart catheter of the little man": If the (inva- on the beach of Santa Monica with his children in 1963
sively measured) systolic BP increases by > 10 mmHg and observed sailing ships. He had the idea of atta-
after lifting the legs, there is a need for volume (Tren- ching a sail or balloon to the tip of a catheter, which
delenburg maneuver; passive leg raising; recruitment would then guide it into the pulmonary artery following
of approx. 300ml of blood). the strongest blood flow (analogous to the sail in the
wind current).

Measurements
• cardiac output (CO; using thermodilution method [int-
rapulmonal])
• mixed venous saturation (SmvO2)
• pulmonary capillary wedge pressure (PCWP)
• calculation of shunt volumes (left-right shunt)

Measurement of cardiac output (CO)

• thermodilution method (intrapulmonry, i.e. pulmonary
arterial [in contrast to PiCCO: transpulmonary])
• Cold saline solution is injected into the proximal lumen
and the temperature is measured there. The tempera-
Fig. 333  pulmonary artery catheter: composition [14] ture is also measured using a distal probe at the tip.

200 General Part

• calculation of the cardiac output (CO) according to the
Stewart-Hamilton equation (syn.: thermodilution equa-
tion) as area under the curve (AUC): The cardiac out-
put is inversely proportional to the area. The gerater
the area, the lower the CO.
• interpretation:
-- low temperature rise → high CO
-- high temperature rise → low CO
• CO measurement: always in PA position (not in
wedge position!)
• In the meantime, pulmonary artery catheters (e.g. Vi-
gilance 2 [Edwards]) have been developed, with which
the CO can also be measured continuously using the
principle of heat mass transfer (heating coil at the di-
stal end).
• In the case of a severe tricuspid valve regurgitation,
measurement of the cardiac output via thermodilution
is not possible or only possible to a very limited extent:
Due to the regurgitation over the tricuspid valve, the
blood is repeatedly thrown back from the right ventricle
into the right atrium, so that the blood has a long time
to warm up, i.e. the temperature increase is high and
the cardiac output is ultimately underestimated
TB-TI
CO = x VI x k
AUC
Fig. 336  Stewart-Hamilton equation (syn.: thermodilution
equation); CO: cardiac output; TB: blood temperature; TI:
injection temperature; VI: injection volume; k: calculation
constant; AUC: area under the curve
Temperatur
Zeit
Fig. 337  Various thermodilution curves are shown here:
green (normal cardiac output), blue (decreases cardiac out-
put [in most shock forms]) and red (increased cardiac out-
put [e.g. hyperdynamic phase of a septic shock).
Mixed venous oxygen saturation (SmvO2)
• saturation in blood after the right heart (from pulmo-
nary artery)
• in contrast to central venous oxygen saturation
-- from CVC (central venous catheter; from superior
vena cava)
-- saturation in blood before the right heart
-- Central venous saturation is (in critically ill patients)
usually about 5% higher than mixed venous satura-
tion.
• norm: 65-80%
-- < 65%: increased oxygen extraction
-- < 40%: tissue hypoxia
-- > 80%: %: left to right-shunt (e.g. ventricular septal
rupture, ruptured sinus valsalvae aneurysm), high
output
A mixed venous saturation > 80%
is always pathological (left to
right-shunt [e.g. infarction-VSD])!
Wedge pressure
Definition
• syn.:
-- pulmonary capillary wedge pressure (PCWP)
-- PAOP (pulmonary artery occlusion pressure)
• determination with the help of a balloon inflated behind
the catheter tip
• A branch of the pulmonary artery is closed like a wedge
by pushing the balloon forward.
• principle of communicating vessels: After a pulmonary
artery branch has been closed ("wedged") by the bal-
loon, a standing blood column arises from the closed
pulmonary artery branch via the pulmonary capillaries
and pulmonary veins to the left atrium. Since there is
no valve in between, the measured wedge pressure is
equal to the pressure in the left atrium and, when the
mitral valve is open (diastole), to the pressure in the
left ventricle. The wedge pressure then corresponds
to the left atrial pressure and at the end of the diastole
(open mitral valve) to the left ventricular end-diastolic
pressure (LVEDP). The LVEDP is the classic parame-
ter for the left ventricular preload!
• The PCWP (wedge pressure) is an indirectly measu-
red value of the:
-- pressure in the left atrium (LA pressure): The pres-
sure in the left atrium could also be measured direct-
ly, but this is very complex and only takes place in
the cath lab: Here you have to puncture transseptally
(atrial septum), which is relatively complex. Then the
pigtail catheter is pushed from the right into the left
atrium and the pressure is measured there. Since
the direct measurement of the LA pressure is so
complex, PCWP (wedge pressure) can be used as
an indirect measure of LA pressure in everyday cli-
nical practice.
-- pressure in the left ventricle at the end of diastole
(left ventricular end-diastolic pressure [LVEDP]; the
classic parameter for left ventricular preload): The
LVEDP can be measured directly only in the cath
lab by inserting a pigtail catheter retrograde from the
ascending aorta through the aortic valve into the left
ventricle and then measuring the pressure there at
the end of the diastole. With the pulmonary cathe-
ter, the LVEDP can be determined indirectly via the
General Part 201
 PCWP. The LVEDP and the PCWP correlate very
well to each other, so that they are equated as stan-
dard in hemodynamics (PCWP = LVEDP). However,
there are two important exceptions:
◦◦ mitral valve stenosis (high diastolic pressure in the
left atrium [PCWP ↑] and low pressure in the left
ventricle [LVEDP ↓]): PCWP > LVEDP
◦◦ aortic valve regurgitation (acute, severe; very high
diastolic pressure in the left ventricle [LVEDP ↑↑]):
PCWP < LVEDP
• norm < 15 mmHg, for ventilated patients < 20 mmHg;
goal: "optimal" wedge at 15-20 mmHg
• objective of PCWP pressure measurement:
-- measurement of LVEDP and thus information on left
ventricular function and left ventricular end-diastolic
volume (PCWP is the "classic" parameter for left
ventricular preload, but according to recent know-
ledge not very reliable. PiCCO parameters ITBV and
GEDV, for example, are better parameters for pre-
load than wedge pressure.)
-- estimation of the hydrostatic pulmonary capillary
pressure (for DD of pulmonary edema)
◦◦ PCWP increased: cardiac pulmonary edema
◦◦ PCWP not increased: non-cardiac pulmonary ede-
ma (permeability edema: typical e.g. in ARDS, in-
toxications)
• As the PCWP is dependent on intrathoracic pressure
fluctuations during breathing, it should be p.d. measu
end-expiratory.
• For a correct and trouble-free measurement the tip of
the PAC must be positioned in the zone III accoding
to West (see page 88). Only here the influence of
the alveolar pressure (This is the PEEP in ventilated
patients) on the measurement is very low and negli-
gible. In a location outside of zone III, the PCWP is
overestimated.
tral valve to bulge into the left atrium during systole,
which increases the pressure in the left atrium.)
-- v-wave: passive filling of the left atrium when the mi-
tral valve is closed (filling of the atrium by inflow of
blood via the pulmonary veins); high v-wave:
◦◦ early systolic: in severe (acute) mitral regurgitation
(classic)
◦◦ late systolic: in severe diastolic dysfunction ("refill
wave")
• descents (pressure drops in the left atrium):
-- x-descent: pressure drop due to downward move-
ment of the cardiac valvular plane (shift of the valvu-
lar plane); relaxation of the left atrium
◦◦ deep x-descent: pericardial tamponade
◦◦ flattened x-descent: atrial fibrillation, mitral regur-
gitation
-- y-descent: pressure drop due to blood inflow from
the left atrium into the left ventricle (relaxation of the
left ventricle)
◦◦ deep y-descent: hypervolemia, constrictive peri-
carditis, restrictive cardiomyopathy
◦◦ flattened y-descent: pericardial tamponade, mitral
stenosis
mmHg
a
10 c v
y
x

Measure of atrial pressures:

right atrial pressure: CVP
left atrial pressure: PCWP diastole systole diastole
Fig. 338  form of the PCWP curve (pressure curve left atri-
um; normal findings)
preload parameters:
left ventricle: PCWP (wedge)
Orientation by ECG:
right ventricle: CVP
a-wave: after the P-wave in the ECG
afterload parameter: SVR
v-wave: after the T-wave in the ECG

Waveform
mmHg

• waves (pressure increases in the left atrium):

-- a-wave: contraction of the left atrium (atrial)
◦◦ high a-wave: mitral stenosis; even giant / cannon a a a
10 c v
a-wave: AV dissociation (The left atrium contracts
against the closed mitral valve, which massively
increases the pressure in the left atrium).
◦◦ several a-waves: atrial flutter y
◦◦ missing a-wave: atrial fibrillation x
-- c-wave: contraction of the left ventricle (The contrac-
Fig. 339  PCWP curve (LA pressure) in atrial flutter: Several
tion of the left ventricle causes the leaflets of the mi- a-waves can be detected.

202 General Part

 Fig. 343  PCWP curve (LA pressure) in pericardial tampo-
mmHg nade: A reduction or loss of the y-descent (while retaining
the x-descent) is apparent: Due to the increased intraperi-
cardial pressure, the left ventricle can no longer fill in the
10 c v
diastole. Consequently, blood can no longer flow from the
left atrium into the left ventricle and there is no decrease in
pressure in the left atrium

Indications
y
In addition to the general indications for an expanded
hemodynamic monitoring (see page 198), the following
indications are to be mentioned especially for pulmonary
Fig. 340  PCWP curve (LA pressure) in atrial fibrillation: The artery catheter:
a-wave and x-descent are missing.
• acute right heart failure
-- e.g. acute pulmonary embolism, decompensated cor
v pulmonale
-- Since with the pulmonary catheter also the pressu-
mmHg

res in the pulmonary circulation (right atrium, right

ventricle, pulmonary artery [PAP]) can be measured
a (intrapulmonary thermodilution instead of only trans­
10 c
pulmonary thermdilution [e.g. PiCCO system]), it is
above all in acute right heart failure still a very good
x option today!
• cardiogenic shock
y
-- with right heart infarction
-- with use of IABP (PiCCO not applicable here, be-
Fig. 341  PCWP curve (LA pressure) in sever mitral regur- cause IABP disturbs the pulse contour analysis)
gitation: The high v-wave is visible. It is higher than the a- -- cardiac index < 1.2 l/min/m2 (very low output)
wave. Normally the v-wave is smaller than the a-wave. Fur- • decompensated aortic valve stenosis (but with caution)
thermore, the x-descent is reduced.

a The domain of the pulmonary catheter

is (still) the acute right heart failure!
mmHg

10 c Contraindications
v
• relative contraindications:
-- Marcumar (with INR > 2) or NOACs, thrombocytes
< 20000/μl
y
-- ventricular arrhythmias
x -- severe aortic valve stenosis (The hypertrophied
myocardium is very contact-vulnerable, so that the
Fig. 342  PCWP curve (LA pressure) in AV dissociation (e.g. risk of triggering ventricular tachycardia or ventricu-
third degree AV block): The left atrium contracts against the
lar fibrillation by touching the wall with the catheter
closed mitral valve, which massively increases the pressu-
re inside the left atrium. This results in a high a-wave (giant is increased).
/ cannon a-wave). • absolute contraindications:
-- latex allergy
-- tricuspid valve stenosis, pulmonary valve stenosis
mmHg

-- tumor / thrombus in the right atrium or ventricle

-- within 7 days after insertion of a temporary pace-
a maker (risk of dislocation; especially if the patient is
10 c v completely dependent on a pacemaker)

y Access routes
• internal jugular vein (standard)
• subclavian vein
x • femoral vein

General Part 203

Lumina Placement
• distal lumen ( "PA distal"): • first of all, insertion of a sheath (7F sufficient) as in the
-- measurement of pressures (RA pressure, RV pres- CVC using the Seldinger technique (preferably sono-
sure, PA perssure [PAP], PCWP graphically), fixation with sutures
-- measurement of the mixed venous oxygen saturati- • preparation of drugs for emergency use (epinephrine,
on (SmvO2) atropine, orciprenaline); stand-by for defibrillation
• balloon lumen ( balloon cap scc max ), with locking → • continuous ECG monitoring (switch on the systolic
Blocking the balloon tone)
• thermistor electrode ( thermodilution 110cm; with • control of the balloon (1-2 ml air)
plug): away from the catheter tip; for CO measurement • flushing of all lumina with NaCl 0.9%
• proximal lumen ("RA proximal“): • sterile protective sleeve for repositioning the catheter
-- 30cm away from the catheter tip without increasing the risk of contamination / infection
-- injection of NaCl 0.9% here for CO measurement • insertion of the PAC via the check valve of the airlock
-- measurement of CVP of the sheath blindly up to 30cm, so that the tip of the
PAC protrudes from the distal end of the sheath
-- measurement of central venous saturation (ScvO2)
• connection of the distal lumen with the pressure dome
• possibly RV lumen (not always available)
(pressure at "PA distal"), flushing, zeroing
-- 20cm away from the catheter tip
• inflation (blocking) of the balloon with 1-2ml air; advan-
-- This can be used to insert a pacemaker probe (e.g.
ce only in blocked state, retraction only in unblocked
in the case of a posterior myocardial infarction with
state
bradycardia.)
• advance without fluoroscopy a total of 40-60cm while
• infusions possible via "RA proximal" and "PA distal";
observing the pressure curves (RA, RV, PA) on the
in 5-lumen PAC, additional white lumen for infusions
monitor until the wedge curve ("curve flattens off") ap-
pears
• The current catheter position is therefore not determi-
balloon
ned by means of fluoroscopy, but by means of the typi-
thermistor cal pressure curves
electrode
• deflation (unblocking) of the balloon (After unblocking,
balloon- the wedge curve should change to the PA curve!)
lumen
PA • fixation of the PAC by means of screw caps on the
distal sterile sleeve
• X-ray control
-- correct position
-- exclusion of
RA
◦◦ pneumothorax
proximal
◦◦ knotting of the catheter
• CO measurement → 3 x 10 ml ice-cold NaCl 0.9%
(thermodilution)
• dwelling time: max. 5 days (in exceptional cases: 7
Fig. 344  pulmonary catheter: lumina
days) due to the risk of infection
distal lumen (PA) • It is also possible to carry out pulmonary angiography
(at the top) (e.g. question of pulmonary embolism) via the lying pul-
monary catheter. The catheter is placed in RV-position
balloon thermistor electrode (right ventricle) and then the contrast medium (40ml)
(5cm before the tip) is injected via PA-distal. In this way, a non-selective
pulmonary angiography is obtained.
proximal lumen
(RA)
(30cm before
the tip)
RV lumen
(20cm before the tip)

Fig. 345  pulmonary catheter in wedge position with the lu-

mina [14]

204 General Part

Fig. 346  flushing of the lumina Fig. 349  Advancing of the pulmonary catheter while obser-
ving the pressure curves (Here the tip of the pulmonary ca-
theter is located in the right ventricle.)

Fig. 347  testing of the balloon

Fig. 350  pulmonary catheter in PA position (pulmonary ar-

tery) [14]

Options for difficult installations

• If resistance is encountered 10-15cm after introduc-
tion of the PAC into the sheath, there is often an acute
angle of the jugular junction between the internal jugu-
lar vein and the subclavian vein. In this case you only
have to pull back the sheath a few cm.
• let the patient sit upright or turn to the right side (left
side up)
• advance under assistance of:
-- echocardiography
-- X-ray fluoroscopy

Fig. 348  insertion the pulmonary catheter through a sheath

General Part 205

 internal jugular vein

subclavian vein

Fig. 351  If resistance is suddenly felt after introduction

of the PAC (black) into the sheath (red) and the PAC can
no longer be pushed forward, there is often an excessi-
vely acute angle at which the internal jugular vein enters
the subclavian vein. In this case, one only has to pull the
sheath back a few centimetres.

internal jugular vein

subclavian vein Fig. 353  As an option in difficult PAC insertion, echocar-

diography is helpful for orientation and control: Here, for
example, the tip of the PAC is located in the right ventricle
(arrow).

Pressure curves
• superior vena cava (SVC) / right atrium (RA): typically
3-peaked, respiratory dependent, mean pressure 2-6
mmHg
internal jugular vein
• right ventricle (RV): systolic peaks 15-30 mmHg, dias-
tolic values towards 0 mmHg
• pulmonary artery (PA): same systolic pressure as in
right ventricle, but increased diastolic pressure
• wedge position: decrease of pressure levels (usually
slightly below the diastolic pressure of the pulmonary
subclavian vein artery [PAdias], flattening of the curve (disappearance
of systolic pressure peaks; curve appears "damped")
-- flat
-- respiratory dependent
• After unblocking the balloon, the pressure of the pul-
monary artery (PA) curve appears again.
Fig. 352  The pulmonary catheter usually has a preformed
bend. This should be observed when inserting it into the
sheath according to the course of the vessels, so that it
does not slip into the brachial veins.

206 General Part

pressure (mmHg) RA RV PA Wedge

30

25

20 Fig. 358  pressure curve of the pulmonary artery (PA): com-

pared to RV, same systolic but higher diastolic pressure
15

10

5
catheter depth (cm)

10 20 30 40 50
Fig. 354  the different pressure curves when the pulmonary
artery catheter is inserted (RA: right atrium; RV: right ven-
tricle; PA: pulmonary artery)
Fig. 359  pressure curve in wedge position: The curve is
flattened.

Fig. 360  lying pulmonary catheter: unblocked in PA posi-

tion (arrow)
Fig. 355  pulmonary catheter: pressure curves (top RA,
then RV; bottom PA, then wedge position [PAOP]) [14]
Standard values
• measurable values
• calculable values

Measurable values

mean value standard value

Fig. 356  pressure curve of the right atrium (RA): typical [mmHg] [mmHg]
triple peak, low pressures (2-6 mmHg) CVC 5-10
RA 5 2-10
RVsys 25 15-30
RVdias 2-8
PAPsys 23 5-30
PAPdias 9 4-12
PCWP 9 < 15 (if ventilated: < 20)
LA 9 5-12
LVsys 120 90-140
Fig. 357  pressure curve of the right ventricle (RV): systolic LVdias 9 5-12
pressures 15-30 mmHg, diastolic towards 0 mmHg (typical
SvO2 central 70-85%
for a ventricular pressure curve)
SvO2 mixed 65-80%

General Part 207

Plausibility criteria -- chest X-ray: Westermark sign (wedge-shaped sha-
The measured values are only plausible and therefore dowing of the lung beginning in the area of the ca-
usable if the following criteria ("The water cannot flow theter tip)
uphill!") are met: • dardiac arrhythmias (in 3% hemodynamically rele-
• PCWPmean ≤ PAdiast vant):
• PAsys ≤ RVsys -- atrial fibrillation (especially due to the cold bolus in-
• RAmean ≥ RVDEP jection)
-- sinus bradycardia (especially due to the cold bolus
Calculable values injection)
-- PAC (premature atrial contractions), PVC (prematu-
re ventricular contractions), salves, ventricular tachy-
cardia (VT) up to ventricular fibrillation (VF; therefore
always insert PAC under standby-defibrillation)
-- AV block (when the AV valve is passed)
-- RBBB (right bundle branch block; in 4%; cave in
case of already existing LBBB [left bundle branch
block] → total AV block!)
• knotting of the catheter
• thrombosis, pulmonary embolism
• venous spasms
• accidental intraarterial injection (The pulmonary artery
is also an artery!)
• balloon rupture (risk of air embolism; no further "inflati-
on attempts" in the event of a balloon rupture!)
• injuries of the tricuspid or pulmonary valve (petechial
bleeding, perforations)
• infections
-- catheter-associated sepsis, endocarditis
-- significant increase from the 4th day
• rupture of the pulmonary artery

Rupture of the pulmonary artery

Definition
• iatrogenic injury of the pulmonary artery in course of
the insertion of the PAC
• mechanisms:
-- over-wedging (excessive inflation of the balloon)
-- puncture of the vessel wall with the catheter tip
• imaging:
-- chest X-ray
-- chest CT
• mortality: 50%

Symptoms
• dyspnea
Complications • blood-tinged sputum, haemoptysis or if intubated, sud-
denly bloody suction
• complications due to the puncture (e.g. pneumothorax,
• danger of asphyxia
arterial puncture, air embolism)
• pulmonary infarction, infarct pneumonia Risk factors
-- causes • age > 60 years
◦◦ permanent wedge (You should never leave a PAC • female gender
with inflated balloon in wedge position for a longer
• chronic pulmonary hypertension
period of time, otherwise this can lead to a pulmo-
-- rigid and fragile vessels
nary infarction!)
-- But especially here the pulmonary catheter is the
◦◦ spontaneous wedge (unnoticed deep sliding of the
central and most important diagnostic tool!
actually defalted balloom with occlusion of a small
pulmonary artery branch) • hypothermia (e.g. cooling after resuscitation; e.g. du-
ring cardiothoracic surgery with heart-lung machine)

208 General Part

 → increased stiffness of the catheter
• steroid therapy
Therapy
• supportive:
-- immediately block the balloon of the pulmonary ca-
theter (to reduce the risk of asphyxia
-- haemodynamic stabilisation
-- generous intubation (risk of asphyxia), ventilation
with high PEEP, if necessary unilateral intubation
with a double-lumen tube
• causal; types (see also excursus "bronchial hemorrha-
ge" [page 723]):
-- interventional (occlusion of the perforation site with
5000 IU of thrombin via the distal lumen, then leave
the catheter insufflated for 6 hours [only casuistics])
-- operative
◦◦ surgical closure of the perforation site
◦◦ lung segment resection
the pulmonary artery catheter (right heart catheter) is
often used in cardiology (e.g. preoperatively for a se-
vere valve stenosis or regugitation, cardiomyopathies
etc.). Here the examination is usually performed in the
cardiac catheterization lab under fluoroscopy via the
femoral vein
• The ESC Tasc Force (Cecconi et al, Intensive Care
Med 2014) advises against routine use of the pulmo-
nary catheter during shock (Level 1), but recommends
it in therapy-refractory shock with right ventricular dys-
function (Level 2).
• The acute right heart failure is and remains the do-
main of the pulmonary artery catheter!
PiCCO

Assessment
• Squara et al, Chest 2002
-- Only 50% of intensive care physicians were able to
perform the measurements technically correct.
-- Only 35% of intensive care physicians were able to
interpret the parameters correctly
• There is no study that has demonstrated an improved
outcome by using a pulmonary artery catheter; i.a.:
-- PAC-Man study (Harvey et al, Lancet 2005): no ad-
vantage for pulmonary artery catheter
-- ESCAPE study (Stevensen et al, JAMA 2005): pa-
tients with severe heart failure → no advantage for Fig. 361  PiCCO monitor [30]
pulmonary artery catheter
• In the SUPPORT study (Connors et al, JAMA 1996)
the use of a pulmonary artery catheter led to a lon- Definition
ger hospital stay in intensive care, higher costs and • PiCCO: pulse invasive contour cardiac output (acro-
finally to increased mortality (by 24% excess mortali- nym)
ty!). However, this was a non-prospective study with • Pulsion Medical / Munich (The company has been ta-
a significant bias and significant statistical deficienci- ken over by Maquet in the meantime.)
es. The retrospective study by Murdoch (Br J Anaesth • developed in Munich in 1986 by Prof. Ulrich Pfeifer
2000) on 4182 patients could not confirm the results of
• clinically introduced in 1997
the SUPPORT study.
• monitoring:
• meta-analysis (Shah et al, JAMA 2005; 13 RCTs with
5051 patients): no increase in mortality (as in the SUP- -- haemodynamic (CO measurement)
PORT study), but finally no overall benefit at all (for -- volumetric (volume measurement)
various indications)
• no continuous haemodynamic monitoring possible Measurement methods
(new: truCCOMS system: pulmonary catheter with • discontinuous: thermodilution (transpulmonary [TPTD;
continuous CO measurement [heat mass transfer: in contrast to the pulmonary artery catheter, where the
Here, the blood temperature is raised slightly by a thermodilution is intrapulmonary [pulmonary arterial])
heating coil located about 20 cm proximal to the tip of • continuous: pulse contour analysis
the pulmonary catheter. Then the heating coil is swit-
ched off again so that the blood temperature, which is
Thermodilution
measured by a thermistor electrode at the tip of the
pulmonary catheter, drops again. Due to the integrated • 15-20ml cooled (< 8 °C) NaCl 0.9%, 3 measurements
heating coil, the continuously measuring pulmonary • After the central venous injection of the cooled saline
catheter is somewhat thicker]). solution (always via the distal lumen of the CVC) the
• Today the pulmonary artery catheter is rarely used in thermistor at the tip of the PiCCO arterial line measu-
intensive care medicine, in many places it has been res the temperature rise.
replaced by other systems (e.g. PiCCO). However, • calculation of the cardiac output (CO) according to the

General Part 209

 Stewart-Hamilton equation from the area under the curve
thermodilution curve (AUC [area under the curve]; ◦◦ DSt x CO = PTV (pulmonary thermal volume);
analogously to the pulmunary catheter) PTV = PBV (pulmonary blood volume) + EVLW
(extravascular lung water)

Fig. 364  pulse contour analysis according to Wesseling:

The hatched area below the systolic part of the pressure
curve is proportional to the stroke volume [30].

COPC = cal x HR x ∫ (Pt/SVR + Cp x dP/dt) dt

Fig. 362  principle of transpulmonary thermodilution [30]
COPC: the cardiac output determined from the pulse con-
tour analysis; cal: patient-specific calibration factor; HR.
heart rate; ∫: systole; Pt/SVR: area under the pressure
curve; Cp: compliance; dP/dt: shape of the pressure cur-
ve

Installation
For PiCCO you need on the one hand a conventional
Fig. 363  thermodilution curve: Cardiac output (CO) is cal- CVC, which almost every intensive care patient has any-
culated from the area under the curve according to the way, and on the other hand a special PiCCO artery: This
Stewart-Hamilton equation [30]. has the special feature that it can measure not only the
pressure, but also the temperature.
Pulse contour analysis
• The German physiologist Otto Frank (1865-1944) de- • usual central venous catheter (CVC)
scribed the principle of pulse contour analysis already -- at least 3 lumina
in 1899: "It is perhaps not without interest that one can
-- connection of the PiCCO system with the proximal
calculate the volume ejected by the heart from the ba-
lumen of the CVC
sic oscillation of the arterial system under certain as-
-- location: usually internal jugular or subclavian vein;
sumptions for the occurrence of the wave reflection if
measurements with the PiCCO system are also pos-
the pressure change of the pulse is known."
sible via a central venous catheter in the femoral
• continuous analysis ("beat by beat") of parameters de-
vein [but more sensitive to errors])
termined from the shape of the arterial pressure curve
• PiCCO arterial line (PiCCO "artery"; PULSIOCATH):
(according to pulse contour analysis of Wesseling)
thermodilution catheter with thermistor at the tip and
• The algorithm is capable of determining each individu-
arterial pressure transducer
al stroke volume (SV) after calibration with transpulmo-
-- femoral artery (standard): arterial thermodilution ca-
nary thermodilution.
theter 5F, 20 cm length
• Every 6h calibration by bolus administration is required
-- brachial artery: arterial thermodilution catheter 4F,
(according to manufacturer's specifications).
22 cm length
• The cardiac ouput is calculated according to the pul-
-- axillary artery: arterial thermodilution catheter 4F, 8
se contour analysis of Wesseling. Then a logarithmic
cm length
transformation of the transpulmonary thermodilution
curve is carried out. Form this you get two times, from -- radial artery: arterial thermodilution catheter 4F, 50
which you can again calculate two volumes by multi- cm length (only short-term use up to 3 days possible)
plying with the CO (cardiac output):
-- mean transit time (MTt)
◦◦ mean transit time of the indicator
◦◦ MTt x CO = ITTV (intrathoracic thermal volume);
ITTV = ITBV (intrathoracic blood volume) + EVLW
(extravascular lung water)
-- down-slope time (DSt; exponential fall time)
◦◦ time from the top to the end of the thermodilution

210 General Part

 -- corresponds to about half of the ejection fraction de-
termined echocardiographically (according to Simp-
son)
-- GEF = 4 x SV / GEDV
-- norm: 25-35%
-- for evaluation of cardiac function (contractility; like
echocardiography)

Intrathoracic volume
• intrathoracic gas volume (ITGV)
• intrathoracic blood volume (ITBV)
Fig. 365  PiCCO arterial line: Combination of pressure and -- blood in the heart (all 4 heart chambers: RA, RV, LA,
temperature measurement [30] LV): GEDV (global enddiastolic volume)
-- blood in the lung: PBV (pulmonary blood volume;
amounts to 25% of the enddiastolic blood volume;
PBV = 0.25 x GEDV)

Intrathoracic blood volume (ITBV)

Fig. 366  PiCCO arterial line: The inner lumen is not round
because it also contains the temperature probe (red). Only
the special PiCCO-Seldinger wire, which is also not round,
is therefore suitable for installation or replacement. A nor-
mal Seldinger wire, which is round, cannot be advanced!
• = sum of the volumes of all 4 heart chambers (GEDV) +
the volume contained in the pulmonary vessels (PBV)
• ITBV = GEDV + PBV
• ITBV = GEDV x 1.25
• norm: 850-1000 ml/m2
• very good parameter for cardiac preload (better
than CVP [right ventricular preload] and wedge pres-
sure [left ventricular preload])

Parameters
• parameters of thermodilution
• parameters of pulse contour analysis

Parameters of thermodilution
• haemodynamic parameters
-- CO (cardiac output) = SV (stroke volume) x HR;
norm: 4-8 l/min
-- CI (cardiac index) = CO/BSA; norm: 2.5-4.5 l/min/m2
• volumetric parameters (volumes) Fig. 367  ITBV: intrathoracic blood volume [30]
-- ITBV Global end diastolic volume (GEDV)
-- GEDV
• sum of the volumes of all 4 heart chambers
-- EVLW
• Norm: 680-800 ml/m2
• CFI:
• parameters for preload (as ITBV)
-- cardiac function index
• the best parameter for volume status (but not for
-- CFI = CI / GEDV volume responsiveness)
-- norm: 4.5-6.5/min
-- unit: 1/min
-- preload-independent cardiac performance index
• PVPI:
-- pulmonary vascular permeability index
-- PVPI = EVLW / PBV; norm: 1-3
-- for clarifying the aetiology of pulmonary oedema:
◦◦ > 3: non-cardiac pulmonary oedema (due to incre-
ased permeability; capillary leak; typical in ARDS/
toxic pulmonary oedema!)
◦◦ < 3: cardiac pulmonary edema (hydrostatic)
• GEF:
-- global ejection fraction Fig. 368  GEDV: global enddiastolic volume [30]

General Part 211

Extravascular lung water (EVLW)
• water in the lung tissue, i.e. outside the lung vessels
("water content of the lung")
• extravascular lung water index (EVLW related to body
weight [not to body surface area])
• norm: < 10 ml/kg
• good parameter for the detection of pulmonary oe-
dema
-- p.d. > 10 ml/kg
-- better than auscultation, SO2 or chest X-ray
• possibility to diagnose pulmonary edema with the
ELWI at the bedside
• ELWI detects an increase of water in the lung tissue
already from 20%, chest X-ray only from 200%.
• Correlation with the severity and mortality in ARDS
-- studies: Sakka et al, Chest 2002; Craig et al, Crit
Care Med 2010; Kushimoto et al, Crit Care 2013
-- ELWI is the hemodynamic parameter that corre-
lates best with mortality in ARDS!
• limitations:
-- major pulmonary arterial obstruction (e.g. pulmonary
embolism)
-- focal lung damage
-- after lung resection
-- note: pleural effusion → no disturbance
induced intrathoracic pressure changes (therefore only
possible with controlled ventilation)
• assessment: for estimation of volume responsive-
ness (= increase of CO by volume application [high
sensitivity!])
• types:
-- stroke volume variation (SVV)
-- pulse pressure variation (PPV; the pulse pressure
[syn.: blood pressure amplitude] is the difference
between systolic and diastolic blood pressure)
-- systolic pressure variation (SPV)
◦◦ quotient of the difference between the maximum
and minimum systolic blood pressure and the
mean systolic blood pressure
◦◦ SPV = (SBPmax - SBPmean) / SBPmean
◦◦ can be seen as "cardiac cycling" in the arterial
blood pressure curve [for picture see page 39])
• norm: < 10%; volume deficiency → increased, i.e. >
10%; > 10%: fluid responsiveness
• prerequisites: only applicable for
-- controlled ventilated patients (e.g. not with CPAP,
not with spontaneous breathing)
◦◦ VT ≥ 8 ml/kg (which should not be the case during
ARDS in the context of lung protection; however,
a study [Freitag et al, British Journal of Anesthesia
2013] showed a good correlation of SVV and VT of
only 6 ml/kg. In another study [Mallat et al, British
Journal of Anesthesia 2015] a decrease in SVV or
PPV showed a good correlation to volume sensiti-
vity even at low tidal volumes after a probatory test
administration of 100 ml of volume); tip: For the
measurement switch to VT 8 ml/kg briefly!)
◦◦ pressure gradient Δp from inspiratory pressure
and PEEP > 20 cmH2O (which should not actually
be the case during ARDS in the context of lung
protection)
◦◦ ratio heart rate / respiratory rate > 3.6
-- sinus rhythm (e.g. not in the case of atrial fibrillation)
-- unreliable in IABP (intra-aortic balloon pump)

SVmax
Fig. 369  EVLW: extravascular lung water [30] SVmin

SVmean
Parameters of pulse contour analysis
• COPC: CO by pulse contour (PC) analysis (measured
continuously; calculated from: CO = stroke volume x
Fig. 370  SVV: stroke volume variation [30]
heart rate)
• MAP (mean arterial pressure)
• HR (heart rate)
• SV (stroke volume), SVI (stroke volume index = stroke
volume / body surface area; norm: SVI > 35 ml/m²)
• functional parameters
• SVR
• dPmx (index of left ventricular contractility)

Functional parameters
• syn.: dynamic volume parameters, dynamic preload
parameters
• definition: parameters from the analysis of ventilation-

212 General Part

stroke volume (SV)

Fig. 374  dPmx: on the left, rapid increase of the pressure

curve (good contractility), on the right, slow increase of the
pressure curve (poor contractility) [30].

1 2 3
preload
volume volume
application application
Fig. 371  stroke volume variation: After volume application
in section 1 of the Frank-Starling curve, the stroke volume
increases significantly more than after volume application
in section 2, i.e. the change in stroke volume (= stroke volu-
me variation) after volume application is significantly grea-
ter in section 1 than in section.

Fig. 375  decision tree (starts with cardiac index CI < or >
3.0 l/min/m2) [30]

Fig. 372  PPV: pulse pressure variation [30]

Systemic vascular resistance (SVR)

• SVR = 80 x (MAP - CVP) / CO
• The SVR is the parameter for the afterload.
• This is the only reason why the CVP must be entered
into the PiCCO before measurement after zeroing.
• SVRI (systemic vascular resistance index): related to
the body surface area (BSA)
• standard values:
-- SVR 900-1400 dyn x sec x cm-5
-- SVRI: 1700 - 2400 dyn x sec x cm-5 x m-2

dPmx
• maximum rate of pressure increase
• measure of left ventricular contractility
• Maß für die linksventrikuläre Kontraktilität
• norm 900-1200 mmHg/s
-- reduced in cardiogenic shock
-- increased in the initial phase of septic (hyperdyna-
mic circulation)
Fig. 373  dPmx: The higher the rate of pressure increase,
the better the ejection fraction [30].
Products
• PiCCO classic (discontinued in 2008)
• PiCCO plus
• PiCCO2 (now standard)
Additional modules
• CeVOX probe (see page 191): for continuous mea-
surement of central venous oxygen saturation (ScvO2)
• LiMON module (see page 872): for measurement of
ICG clearance (indocyanide green) for diagnosis of
liver failure
• CiMON module (see page 867): for continuous int-
ragastral measurement of intra-abdominal pressure in
intra-abdominal compartment syndrome [IACS])

General Part 213

Comparison PiCCO / PAC
Advantages compared to PAC
• longer dwelling time (PAC max. 7 days)
• less invasive
• The volume parameters ITBV and GEDV (static pre-
load parameters) as well as the function parameters
SVV, PPV and SPV (dynamic preload parameters) are
better parameters for (left ventricular) preload than
wedge pressure (PCPW).
• easier handling and interpretation
• continuous haemodynamic monitoring (new: truC-
COMS system [e.g. Vigilance 2 from Edwards]: PAC
with continuous CO measurement [heat mass trans-
fer])
• also applicable in small children
Disadvantages compared to PAC
• no possibility of a differentiated analysis of the pressu-
res in the lungs (pulmonary arterial, pulmonary venous)
as measurement is only trans- and not intrapulmonary
• especially in cases of severe right ventricular load /
cardiogenic shock
Limitations
• arrhythmias (e.g. atrial fibrillation) → poorer pulse con-
tour analysis, especially dynamic preload parameters
(SVV, PPV, SPV) not usable
• aortic aneurysm (thoracic) → overestimation of the
static preload parameters (ITBV, GEDV)
• severe valve regurgitation (e.g. mitral od aortic valve
regurgitation) →
-- overestimation of ITBV, GEDV
-- Underestimation of the cardiac output when measu-
ring via thermodilution: Due to the valve regurgitati-
on, the applied cold injection solution is thrown back
again and again, so that it ultimately has more time
to warm up. The result is a greater temperature rise,
so that a lower cardiac output is measured. This ap-
plies to thermodilution using a pulmonary catheter, in
which the temperature rise is already measured after
the right ventricle in the pulmonary artery, only for
regurgitation of the tricuspid valve. In thermodilution,
however, using the PiCCO system, in which the tem-
perature rise is only measured in a peripheral artery
[mostly femoral artery], this applies to reurgitation of
all valves!
• tricuspid valve regurgitation (often in intensive care,
especially when ventilating with high pressures) →
underestimation of cardiac output (generally applies
to thermodilution: In case of a sever tricuspid val-
ve regurgitation, thermodilution (no matter if transpul-
monary or intrapulmonary) must not be used for the
determination of the CO, because in this case CO is
underestimated [Due to the regurgitation from the right
ventricle back to the right atrium, the blood now has
more time to warm up.]!)
• intracardiac shunt
-- right to left-shunt: falsely high CO (The blood takes a
214 General Part
"shortcut" here and thus has less time to be warmed
up, which leads to a too high cardiac output).
-- left to right-shunt: falsely low CO
• extracorporeal support devices:
-- IABP (intra-aortic balloon pump; interferes with pul-
se contour analysis; i.e. in cardiogenic shock with
IABP → possibly PAC instead of PiCCO)
-- ECMO
◦◦ pulse contour analysis: still usable
▪▪ provided that the initial calibration of the thermo-
dilution was performed correctly
▪▪ appies only to vv-ECMO (not to va-ECMO [in-
sufficiently validated data])
◦◦ thermodilution: not usable
-- Impella
◦◦ pulse contour analysis: not usable, since the turbi-
ne pump generates a laminar and not a pulsatile
flow
◦◦ thermodilution: usable with limitations (The tran-
spulmonary thermodilution overestimates the
cardiac output while the impella is running. The
preload parameter [ITBV, GEDV, EVLW] cannot
be used.)
• pulmonary hypertension / acute right heart failure (e.g.
in case of fulminant pulmonry embolism): no differenti-
ated measurement of intrapulmonary pressures possi-
ble with PiCCO → PAC
• obesity: often unreliable measurements
• very low output (CI < 1.3 l/min/m2; e.g. cardiogenic
shock) → often no more reliable measurements →
PAC
• decompensated (severe) aortic valve stenosis: with
PiCCO often only very limited monitoring (as here
mostly insufficient pulse contour analysis; but PAC
only with caution [contact vulnerable myocardium])
• no influence, i.e. the PiCCO measurements are not
disturbed by
-- pleural effusion: no disturbance (not perfused!)
-- prone position
-- renal replacement therapy (note: CVVH via a Shal-
don catheter in the internal jugular vein with high
dialysate flow and heating not switched on can dis-
turb the thermodilution by lowering the central body
temperature.)
-- hypothermia
Assessment
• The PiCCO-System is certainly very helpful and often
supports us in our daily clinical routine in therapeutic
decisions. However, the recommendations in the de-
cision tree shown on the PiCCO monitor are not the
"Ten Commandments"! It would be fatal to rely only
absolutely on the PiCCO values: These are only one of
many building blocks (including clinical, ultrasound, X-
ray) on which you base your decision. On no account
should one disregard the clinical examination in parti-
cular: Despite PiCCO, the patient may still be looked at
and clinically examined!
• A study that the mortality of critically ill patients could
be reduced by using the PiCCO system for haemody-
 namic monitoring does not exist here either (just as
with the pulmonary catheter (i.a. study of Zangh et al,
Intensive Care Med 2015 [see box]: no reduction of
mortality).

no blind orientation of the therapy

only on the PiCCO (no faithfulness in
measurements)! "PiCCO has no
brain - use your own!"

Fig. 376  PulsioFlex system [30]

"If technology is master
the disaster happens faster!"
FloTrac-Vigileo system
• combination of Vigileo-Monitor and FlowTracSensor
(Edwards Lifesciences company)
• minimally invasive sensor (only one arterial access
[mostly radial artery] necessary)
study • pulse contour analysis
• continuous measurement
-- CO, CI
-- SV (stroke volume), SVI (stroke volume index)
Effectiveness of treatment based on PiCCO parameters in
critically ill patients with septic shock and/or acute respira- -- SVV (stroke volume variation)
tory distress syndrome: a randomized controlled trial -- SVR (systemic-vascular resistance)
Zangh et al, Intensiv Care Med 2015

• 715 (planned) critically ill patients with septic shock or

ARDS; monitoring (control of fluid management) by me-
ans of
-- CVP
-- PiCCO
• results (premature termination of the study after 350
patients included, as no difference was observed at all)
-- primary endpoint: 28-day mortality → no difference
(in the subgroup of patients with ARDS, but without
septic shock even increases mortality!)
-- secondary endpoints: no difference
◦◦ duration of ICU stay
◦◦ vasopressor-free days
◦◦ ventilator-free days

Fig. 377  FloTrac-Vigileo system [14]

PulsioFlex
• "PiCCO-light"-variant (Pulsion company [now Maquet])
• mainly for perioperative monitoring
• minimally invasive sensor (only one arterial access
[mostly radial artery] necessary)
• pulse contour analysis
• continuous measurement
-- CO, CI
-- SV (stroke volume), SVI (stroke volume index) Fig. 378  EV1000 (analogous to the PiCCO system) with pul-
-- SVV (stroke volume variation) se contour analysis and transpulmonary thermodilution)
-- SVR (systemic-vascular resistance) from Edwards Lifesciences

General Part 215

Fluid (volume) responsiveness syndrome) are shown in the info box (i.a. Bagshaw et al,
Crit Care Med 2008; Boyd et al, Crit Care 2011; Lee et al,
(preload dependency) J Intern Med 2014). In the initial phase of a septic shock,
An often difficult question to ask oneself daily at the in- intensive volume administration is usually necessary.
tensive care bed is whether the patient benefits from fluid After stabilization (usually after 48 hours), however, the
administration, i.e. whether his cardiac output can be in- volume should then be applied restrictively (risk of hyper-
creased by administering volume (preload dependency) volemia), i.e. then the "water tap should be switched off"!
in accordance with the Frank-Starling mechanism (see
diagram page 195). For a long time, pressure was used
pressure ≠ volume!
as the basis for this: CVP (as a measure for right ventri-
hemodynamic monitoring: no more
cular preload) and PCWP (as a measure for left ventricu-
use of filling pressures (CVP, PCWP)!
lar preload). However, pressure is not to be equated with
CVP ≠ RVEDP, PCWP ≠ LVEDP
volume, and accordingly, only very limited statements
about volume can be made by determining pressures.
Especially in septic patients the filling pressures (CVP,
PCWP) hardly correlate with the blood volume (Osman
et al, Crit Care Med 2007). Accordingly, in a meta-ana- Approximately 50% of all critically ill
lysis (Marik et al, Crit Care 2009) the (dynamic) volume patients are fluid responsive, i.e. their
parameters SVV, SPV and PPV showed a significantly cardiac output can be increased by
better predictability of volume response than the CVP volume administration.
and PCWP. The CVP is not suitable for estimating vo-
lume response (i.a. meta-analysis Marik et al, Crit Care
Med 2013; meta-analysis Eskesen et al, Intensive Care
Med 2016). The global end-diastolic volume (GEDV) is
better suited for this purpose than the CVP (Michard et
al, Chest 2003). In haemodynamics, the CVP and PCWP
should no longer be used as a guide. Even the passive
leg raise (Trendelenburg maneuver) has a higher pre-
CVP
dictive power regarding volume responsiveness than the
CVP (i.a. Monnet et al, Crit Care Med 2006)! Even accor-
ding to the S3 guideline "Intravascular Volume Therapy"
2014 from the German Society of Anaesthesiology and
Intensive Care Medicine, the CVP should no longer be
used for this purpose (recommendation level A). Howe-
ver, since most patients already have a CVC in an in-
tensive care unit, measuring the CVD means at least no
additional invasiveness.
Fluid responsiveness must not be equated with fluid
requirement. Patients with ARDS, for example, who ty-
pically have too much fluid in the alveoli (permeability
pulmonary edema) are also often fluid responsive, but do
not need volume. On the contrary: Here you have to try
to extract the volume!

Fig. 379  The CVP should no longer be used to assess fluid

volume responsiveness ≠ volume responsiveness. The CVP is not suitable for this purpose
requirement! at all ("mission impossible"). You might as well flip a coin!

But also overhydration (hyperhydration, hypervolemia)

should be avoided. This is also easily possible in healthy
people, because our system is evolutionarily more orien-
ted towards water absorption than water excretion. Hu-
mans have no water reservoirs in their bodies ("We are
neither camels nor cacti!"). The ability of the kidneys to
excrete excess water by suppressing the RAAS (renin-
angiotensin-aldosterone system) adapts relatively slowly
(takes a few days). In half of all critically ill patients, vo-
lume administration is not indicated and is harmful. The
hyperhydration is mostly iatrogenic, the main cause is
the physician! The negative consequences of hyperhy-
dration (volume overload syndrome, "poly-compartment"

216 General Part

 -- reduced skin turgor (skin fold test), dry mucous
membranes, dry axilla, soft or sunken eye bulbs, oe-
dema (caution: Septic patients almost always have
oedema due to capillary leakage and still have a pro-
nounced fluid requirement!)
-- fluid challenge (volume challenge; volume test):
◦◦ test for fluid responsiveness (i.e. if the preload is
decreased and if the CO can be increased by fluid
administration)
◦◦ crystalloid 150-350ml (4 ml/kg) within 15min
-- Trendelenburg maneuver
• laborchemical (i.a. hematocrit [in case of lack of vo-
lume increased due to hemoconcentration], lactate
[especially lactate clearance, i.e. drop > 10% within 2
hours: very good parameter], base excess, central ve-
nous oxygen saturation)
• pulse-oxymetric: With the special pulse oximeter MA-
SIMO the PVI (pleth variability index) is determined
non-invasively via a sensor using plethysmography.
The higher the PVI, the greater the fluid responsive-
ness.
• radiological (i.a. signs of congestion, pleural effusions;
note: A normal chest X-ray does not rule out hypervo-
lemia! X-ray has only a sensitivity therefore of 50%,
i.e. 50% are fluid overloaded, even the x-ray is normal!
Especially in patients with COPD, pulmonary venous
congestion in the chest X-ray is often not visible.)
• sonographic
-- abdominal sonography: inferior vena cava
◦◦ measurement of the diameter directly (1-2cm)
below the diaphragmatic passage
◦◦ standard values:
▪▪ diameter < 21mm (often increased in adole-
scents / athletes: up to 27mm, but with regular
respiratory modulation)
▪▪ regular respiratory modulation, i.e. inspiratory
collapse > 50%
◦◦ Ventilation with PEEP always leads to a dilated in-
ferior vena cava → exspiration hold, if necessary
short-term disconnection
◦◦ variation of diameter > 12% (in the ventilated pati-
ent): regarding fluid responsiveness (Feissel et al,
Intensive Care Med 2004)
▪▪ positive predictive value: 93%
▪▪ negative predictive value: 92%
-- pleural sonography
◦◦ pleural effusions
◦◦ B-lines ("comet tail" artifacts, reverberations; see
page 380)
-- echocardiography (TTE [transthoracic echocardio-
graphy] sufficient, no TEE [transesophageal echo-
cardiography] usually necessary; for echocardiogra-
Fig. 380  Be ware of hyperhydration (hypervolemia): It can phic estimation of the filling pressure see schematic
have deleterious consequences (polycompartment syndro-
drawing); indications for an increased filling pressure
me)!
are:
◦◦ excessive E-wave (i.e. E-wave : A-wave > 2:1) in
The fluid responsiveness (= increase in CO due to volu- the transmittal inflow (An E-wave < 50 cm/s or E <
me addition; preload dependency) can be estimated as A [in case of a reduced ejection fraction] excludes
follows: an increased filling pressure)!
• clinical
◦◦ filling index E/E´ > 15 (tissue doppler; see page

General Part 217

 222)
◦◦ B-notch (syn.: B-bump; notch [shoulder] in the AC
segmet in mitral M-mode; see page 222)
◦◦ PVa-dur > A-dur (difference > 30ms) in pulmonary
vein Doppler (see page 226)
◦◦ PAP (pulmonary arterial pressure) > 35mmHg
◦◦ premature mitral valve closure (always an indica-
tion of increased left ventricular end-diastolic pres-
sure)
◦◦ LVEDAI (left ventricular enddiastolic area index)
▪▪ In the apical 4-chamber view the area of the left
ventricle is planimetered end-diastolically and
then related to the body surface area. .
▪▪ A LVEDAI < 7 cm2/m2 indicates a lack of volume
◦◦ VTI (velocity time integral): systolic VTI < 55% of
the sum of systolic and diastolic VTI → increased
filling pressure (> 15 mmHg; i.a. Kuecherer et al,
Circ 1990)
◦◦ "kissing papillaries"
▪▪ definition: The both papillary muscles of the left
ventricle touch each other during contraction
("kissing papillaries").
▪▪ assessment: This is repeatedly indicated as
a sign of a lack of volume and therefore a too
low preload, which is completely unreliable and
therefore completely nonsensical (was probably
always copied from one textbook to another).
This is usually a sign of a hyperkinetic (p.d.
ejection fraction> 70%) left ventricle and thus
a sign of volume load (i.e. exactly the opposite
of a lack of volume) due to a severe mitral or
aortic valve regurgitation or a ventricle septum
defect (e.g. ventricular septal rupture due to
myocardial infarction). In the case of a volume
load, volume administration is of course coun-
terproductive and kills the patient! Here volume
has to be extracted. If there is a lack of volume,
the preload is reduced so that, according to the
Frank-Starling mechanism, the inotropy decrea-
ses and does not increase! The sign "kissing pa-
pillaries" may only be regarded as a sign of lack
of volume if the inferior vena cava is narrow and
collaptic. But if the inferior vena cava is narrow
and collaptic, then it is already clear that there is
a lack of volume, so that the sign of the "kissing
papilleries" as a possible indication for a lack of
volume can also be completely avoided.
• ventilatory: EEO test
-- EEO: end-expiratory occlusion
-- rationale: In the ventilation cycle, the applied positive
pressure and thus the intrathoracic pressure is lo-
west at the end of expiration. If ventilation is stopped
by end-expiratory occlusion, more blood can flow
into the chest, i.e. the cardiac preload increases.
-- procedure: Press the "expiration hold" button on the
ventilator for 15 seconds in invasively ventilated pa-
tients.
-- Interpretation: If the invasively measured blood pres-
sure or (even better) the continuously measured CO
increases by more than 5%, there is fluid responsi-
veness.
218 General Part
• hemodynamic
-- pressures (CVP, PCWP): formerly the classic pre-
load parameters; but insufficient (poor correlation;
not recommended!)
-- volumes:
◦◦ static parameters (worse): GEDV, ITBV
◦◦ dynamic parameters (better): > 10% → volume
responsive
▪▪ SVV (stroke volume variation)
▪▪ PPV (puls pressure variation)
▪▪ SPV (systolic pressure variation)
"kissing papillaries": usually not a
sign of lack of volume, but of volume
load (hyperkinesia):
- left ventricle not dilated: severe
mitral valve regurgitation
- left ventricle dilated: severe
aortic valve regurgitation, VSD
Trendelenburg maneuver
• named after the German surgeon Friedrich Trendelen-
burg (1844-1924)
• syn.: autotransfusion, PLR (passive leg raising), "right
heart catheter of the little man"
• If the (invasively measured) systolic BP increases by
> 10 mmHg after raising the legs, there is a need for
volume (recruitment of approx. 300ml of blood).
• Before this, the upper body should be positioned at
45°. Finally, reversibility should also always be che-
cked.
• It is not uncommon to observe in everyday clinical
practice how the physician suddenly, without any war-
ning, pulls up the patient's legs while the patient lies
calm and relaxed in bed. Due to the reaction of shock
and pain, the blood pressure rises, but this has nothing
to do with a lack of volume! Therefore, instead of rai-
sing the legs, it is usually better to simply flip the bed
as a whole. .
• Strictly speaking, the increase in arterial blood pressu-
re alone is not valid and therefore unsuitable for pre-
dicting fluid responsiveness. Onlyif the difference bet-
ween MAP and CVP increases by more than 20mmHg,
then there is fluid responsiveness.
• modification (Strictly speaking, only these are valida-
ted and suitable to predict fluid responsiveness.):
-- increase of CO, SVV, PVV: If the patient is already
provided with advanced hemodynamic monitoring
(e.g. PiCCO), then you should also consider the
changes in stroke volume (especially cardiac out-
put: increase of CO >10%) and (if ventilated) the
dynamic preload parameters SVV and PPV during
the Trendelenburg maneuver. In daily clinical practi-
ce, however, this is precisely why a Trendelenburg
maneuver is performed in order to avoid an advan-
ced hemodynamic monitoring with its corresponding
invasiveness.
-- increase of VTI: It is also a good option to measure
 the VTI (velocity time integral) with the echo. If this
increases by more than 10% as a result of the Tren-
delenburg maneuver, there is fluid responsiveness.)
-- increase of ETCO2: If the end-tidal CO2 concentra-
tion displayed on the ventilator increases by more
than 5% during the Trendelenburg maneuver, there
is fluid responsiveness (a very simple test!)
• assessment: very well suited to predict fluid respon-
siveness (but this applies only to the increase of the
cardiac output, not to the incerase of the blood pers-
sure); i.a. meta-analysis Monnet et al, Intensiv Care
Med 2016:
-- sensitivity: 85%
-- specifity: 91%
• also reliable under (veno-venös [Guinot et al, Crit Care
2011])
Fig. 381  echocardiography: Derivation of the transmitral
• contraindications: flow profile with the pw Doppler: What is striking here is a
-- increased intracranial pressure (ICP) very high E wave compared to the A wave (typical sign of a
-- right heart failure (The maneuver leads to an increa- high filling pressure [LVEDP]!).
sed inflow of blood into the thorax and thus into the
right heart, so that the hemodynamic situation is ag-
gravated.) E/E´ < 8: no increased filling pressure
-- pericardial tamponade, restrictive cardiomyopathy, E/E´ > 15: increased filling pressure
constrictive pericarditis
-- cave (with Trendelenburg's positioning) in sponta-
neously breathing obese patients: Here, the apical E/E´ 8-15
displacement of the fat masses can lead to a reduc-
tion in lung volume and thus to acute respiratory in-
sufficiency. PAP < 35 mmHg PAP > 35 mmHg

Ranking order of priority:

1. functional parameters (SVV, PPV,
SPV)
2. volume parameters (GEDV, ITBV)
3.pressure parameters (CVP, PCWP)
FENICE study
no increased increased
filling pressure filling pressure
Fig. 382  echocardiographic estimation of the filling pres-
sure (= LVEDP) during normal left ventricular function (LV-
EF): At a filling index E/E' > 15, an increased filling pressure
has been proven, at a filling index E/E' < 8. an increased fil-
ling pressure is excluded. With a filling index E/E' between
8-15, the pulmonary arterial pressure (PAP) should also be
determined.

E:A < 1: no increased filling pressure

E:A > 2: increased filling pressure
Fluid challenges in intensive care
Cecconi et al, Intensiv Care Med 2015

• observation study
E:A 1-2
• 2213 critically ill patients with volume challenge (balan-
ced crystalloids)
E/E´ < 8 E/E´ > 15
• results:
PAP < 35 mmHg PAP > 35 mmHg
-- mean volume: 500ml
-- mean time: 24min
-- monitoring:
◦◦ without preload parameters: 44% no increased increased
◦◦ with preload parameters: filling pressure filling pressure
▪▪ static parameters: 36% Fig. 383  echocardiographic estimation of the filling pres-
▪▪ dynamic parameters: 22% sure (= LVEDP) with reduced left ventricular function (LV-
EF): At an E:A ratio in the transmitral inflow of < 1 an in-
creased filling pressure is excluded, at an E:A ratio > 2 an
increased filling pressure is proven. At an E:A ratio of 1-2,
the filling index E/E' and the pulmonary arterial pressure
(PAP) should also be measured.

General Part 219

Echocardiography be called in for consultation. The answer is that you can
then just as well write a consultation to the anaesthetist
for intubation.

unclear hemodynamic instability

→ always and immediately
perform echocardiography (TTE)!

transthoracic ecocardiography:
central role in hemodynamic monito-
ring in the intensive care unit!

Furthermore, echocardiography can also be used to esti-

mate the filling pressures very well. This could also be
demonstrated in a meta-analysis (Mandeville et al, Crit
Care Res Pract 2012; TTE good sensitivity [77-100%]
and specificity [88-99%] for fluid responsiveness). The
echo device should also be placed at the bedside during
any resuscitation in the emergency room or intensive
care unit. The echocardiographic finding often has an
immediate therapeutic consequence that cannot be post-
poned: You look for signs of pulmonary embolism (right
ventricular load; then immediately perform lysis), peri-
cardial tamponade (then immediately perform pericardi-
al puncture) and assess the volume status. In addition,
electromechanical dissociation can be easily recognized
by the lack of contractions (then immediately continue
thoracic compression). If necessary, you can also place
In this chapter, the role of echocardiography in intensi-
a pacemaker probe on the bedside under echo control.
ve care medicine (especially for monitoring the cardiac
In case of massive pulmonary embolism, a local lysis or
output) should be highlighted. The basics of echocardi-
local embolus fragmentation can be performed under
ography cannot be discussed here. This chapter is cer-
echo control with a pulmonary catheter (balloon blocked
tainly more suitable for advanced echocardiographs. The
with water instead of air).
basics of echocardiography should be solidly mastered
by every resident in internal medicine from the 3rd year
of training. Those who wish to acquire the knowledge For every resuscitation (emergen-
and practical skills in a compact form in a short period cy room, intensive care unit) the
of time in order to be able to perform echocardiography echo device belongs to the bed!
independently and solidly in everyday clinical practice
should refer to our echocardiography course Theory and
Practice in Regensburg in Germany (http://www.echo-
kardiographie-kurs.de). Every physician who practices
Whenever there is an unclear hemodynamic instability (internal) intensive medicine must be
in a patient, echocardiography should be performed im- able to solidly master echocardiogra-
mediately. This is also required in the S3 guideline "Intra- phy (a sine qua non condition)!
vascular volume therapy in adults" 2014 of the German
Society for Anaesthesia and Intensive Care Medicine (re-
commendation grade A). In this way, valuable informati-
on (ventricular function, right ventricular load, pericardial
tamponade, CO measurement, estimation of PCWP, re-
levant cardiac defects such as severe aortic valve steno-
sis or mitral valve regurgitation) can be obtained in the
critically ill patient in the shortest possible time. For this
purpose, the transthoracic echo (TTE) is completely suf-
ficient, only very rarely a transesophageal echo (TEE) is
necessary. In my opinion, intensive care medicine can
and should only be performed by those who solidly mas-
ter echocardiography (a sine qua non condition). The
mastery of echocardiography is just as imperative a pre-
requisite as the mastery of intubation. Some may object
that if an echocardiography is needed, a cardiologist can

220 General Part


• VTI (velocity time integral)
sector transducer
linear transducer
Fig. 384  In the meantime, portable miniaturized echo devi-
ces (handheld devices; here Vscan from the GE company
of both the old and the new generation [Vscan Extend])
have also become available, which can be brought to the
patient's bed immediately and without major effort. In ad-
dition, a dual transducer can be seen here, which consists
of a sector transducer (for echocardiography) and a linear
transducer (for vessels, especially for central venous ca-
theter insertion).
▪▪ apical 3-chamber view
◦◦ TEE:
▪▪ ME AV LAX (midesophageal aortic valve long
axis1)
▪▪ TG LAX (transgastric long axis)
▪▪ deep TG LAX (deep transgastric long axis; most
suitable!)
-- circular area = (d/2)2 x π
-- π = 3.14
-- distance covered by the erythrocyte during systole
-- computer-aided determination by tracing the enve-
lope of the Doppler signal (pw-Doppler) in the infun-
dibulum
◦◦ TTE: in 3- or 5-chamber view
◦◦ TEE: modified deep transgastric setting: deep
TG LAX (deep transgastric long axis; pw-Doppler
2mm below the aortic valve ring)
-- usually approx. 25 cm (VTI < 10 cm: highly reduced
pump function)
-- Since the area in the infundibulum of the same pa-
tient does not change, it is sufficient to indicate only
the VTI instead of the stroke volume in the futher
course.

Conzepts
• FEEL: focused echocardiography for life support (Ger-
many [especially for echocardiography])
• POCUS: point of care ultrasound (Germany [generally
for ultrasound in intensive care and emergency medi-
cine])
• FOCUS: focused cardiac ultrasound (USA)
• FATE: focus assessed transthoracic echocardiography
(Denmark) Fig. 385  determination of the diameter d of LVOT in the pa-
rasternal axis
Determination of cardiac output (CO)
The cardiac output (CO) is calculated from the formula
cardiac output = stroke volume SV x heart rate HR. The
heart rate is easy to determine (just feel the pulse or read
it on the monitor). The stroke volume can be determined
in two different ways by echocardiography:
• by determination of the velocity time integral (VTI; bet-
ter)
• by determination of the volumes (worse)

Stroke volume determination by VTI

SV = ALVOT (cm²) x VTI (cm)
• ALVOT: area LVOT (left ventricular outflow tract [syn.: in-
fundibulum], CSA [cross sectional area])
-- determination of the diameter d of the LVOT at the
level of the aortic valve ring (5mm before the aortic Fig. 386  The velocity time integral (VTI) is obtained by tra-
valve plane) cing the envelope of the pw-Doppler signal in LVOT (here
◦◦ TTE: apical 5-chamber view) with the trackball.
▪▪ parasternal long axis

General Part 221

 v = 0.70 m/s
VTILVOT > 20cm: normal stroke volume
(SV) and therefore normal cardiac
output (CO)

Stroke volume determination volumes

-- Stroke volume SV = EDV - ESV
◦◦ EDV: end-diastolic volume
◦◦ ESV: end-systolic volume
• measurement of volumes in the B-scan
• methods: v = 0.10 m/s
-- area-length method (Gibson method)
-- slice summation method (Simpson method; stan-
dard)

Systemic vascular resistance (SVR)

Once the cardiac output (CO) has been determined
echocardiographically, the systemic vascular resistance
(SVR) can be easily calculated:
SVR = 80 x (MAP - CVP) / CO
• CO echocardiographic determination
• MAP = (SBP + 2 x DBP) / 3
• CVP: simply measure via the CVC
PCWP
• Echocardiographic determination of wedge pressure
(PCWP; as a measure for LVEDP [= filling pressure]) is
also possible. It correlates very well with the so-called
filling index E/E´ (i.a. Ommen et al, Circulation 2000.
The level of the filling index E/E´ corresponds to the
PCWP in mmHg (exactly [Nagueh formula]: PCWP =
1.24 x E/E´+ 1.9).
• The filling index is the quotient of the transmitral inflow
velocity E and the mitral ring velocity E´:
-- E (transmitral inflow velocity): This is determined by
placing the pw-Doppler in the apical 4-chamber view
exactly between the two leaflets of the mitral valve.
-- E' (mitral ring velocity): This is determined by pla-
cing the tissue Doppler (switch to TDI [tissue doppler
imaging]) on the lateral or septal mitral ring.
• example:
-- E velocity 0.60 m/s
-- E' velocity 0.06 m/s
-- E/E' = 10 → PCWP = 10 mmHg
• explanation:
-- high E-wave: A high LVEDP (filling pressure) also
leads to an increase on the pressure in the left at-
rium (LA pressure). If the mitral valve opens at the
beginning of the diastole, the high pressure in the left
atrium causes the blood to flow rapidly into the left
ventricle, which explains the high velocity and thus
the high E-wave.
-- low E´-wave: The ventricle, however, is completely
rigid, so that almost no movement of the mitral ring
takes place, resulting in a very low E' wave.
Fig. 387  determination of the filling index E/E´: first deter-
mination of the velocity of the E-wave in the transmitral in-
flow (E = 0.46 m/s); then determination of of the velocity of
the E'-wave with the tissue Doppler (sample volume here on
the septal mitral ring; E'= 0.09 m/s). This results in a filling
index E/E´of 5 and thus a PCWP of 5 mmHg.
echocardiographic determination of the
wedge pressure: PCWP (LVEDP) =
E/E' filling pressure = filling index)
Other echocardiographic indications of increased LVEDP
(filling pressure) are :
• B-notch
-- syn.: B-bump, B-point
-- notch [shoulder] in the AC segmet in mitral M-mode
→ LVEDP > 20 mmHg (usually requiring intensive
care!)
-- corresponds to the 3rd heart tone in auscultation
• E >> A (E:A > 2:1) in the transmitral inflow profile
E
A
F
D C
Fig. 388  derivation of the movement pattern of the anteri-
or mitral leaflet (AML) in mitral M-mode in the parasternal
long axis: The B-bump (marked with a circle) is a notch in
the AC-segment. The evidence of a B-bump is indicative of
an increased LVEDP, so the patient should receive a loop
diuretic!

222 General Part

Left ventricular function because in laevocardiography contrast medium pene-
trates the trabeculae of the ventricle and in echocar-
• systolic left ventricular function (= ejection)
diography one often has the problem of the cut-off tip
• diastolic left ventricular function (= filling) (tangential sections). Accordingly, the echocardiogra-
phically determined EF is also smaller (by about 5%)
Systolic left ventricular function than the laevocardiographically determined EF.
• global (ejection fraction) • Gardin formula:
• regional (wall movement disorders) -- measurement of the maximal flow velocity vmax (in
cm/s) at the aortic root
Global systolic left ventricular function -- EF = (vmax - 25) / 1.62
• fractional shortening (FS)
Methods (volume determination)
• ejection fraction
• special parameters: • one-dimensional (M-mode): Teichholz-Formel
-- MAPSE, MASV -- volume determinations from the ventricular M-mode
in the parasteral long axis according to the formula:
-- left ventricular pressure rise rate dp/dtmax
volume = 7,0 / (2.4 + diameter) x diameter3 (ml)
-- isovolumetric contraction time (IVCT)
-- only insufficient consideration of the actual ventricu-
-- left ventricular ejection time (LVET; time of systolic lar geometry → suboptimal (In the ASE-/EACVI Gui-
aortic outflow) delines 2015 the determination of EF after Teichholz
-- aortic valve opening time is no longer recommended.)
-- globaler longitudinaler strain (GLS; recommended in • two-dimensional (B-mode):
the ASE-/EACVI Guidelines 2015!) -- area-length-method (Gibson method)
Fractional shortening (FS) -- slice summation method (Simpson method; Stan-
dard)
• Teichholz formula: FS = (LVEDD-LVESD) / LVEDD
• three-dimensional (3D volume model)
• norm: > 25%
• not applicable for regional wall motion abnormalities Gibson method
• misinterpretation possible in case of LBBB • syn.: area-length-method
• FS > 50%: hyperkinesia • volume determination by rotating the surface of the
• only very limited parameter ventricular cavity around its long axis
• Volume V = 0.85 x A2/l
Ejection fraction (EF) -- A: surface of the left ventricle in apical 4-/ 2-chamber
view (tracing the endocardial contour; possibly auto-
Definition matically [advanced automated contour trace])
• EF = (EDV - ESV) / EDV -- l: length of the left ventricular long axis (syn. longitu-
• stroke SV = EDV - ESV dinal axis of the ventricle; connection of the center of
• determination of volumes the mitral valve annulus to the apex)
-- section planes • determination of the volume in each case end diastolic
◦◦ parasternal short axis (height of papillary muscle) (EDV) and end systolic (ESV)
◦◦ apical 4-/2-chamber view • section planes:
-- standard values -- monoplane: 4-chamber view
◦◦ EDV < 55 ml/m2 BSA -- biplane: 4-chamber and 2-chamber view
◦◦ ESV < 18 ml/m2 BSA • EF = (EDV - ESV) / EDV
• improvement of endocardial visualization • computer-aided calculation of the EF (by the echocar-
-- harmonic imaging diography device)
-- contrast medium (left heart contrast medium [Levo- Simpson method
vist, Optison, SonoVue])
• named after the English mathematician Thomas Sim-
• assessment
pson (1710-1761; Simpson method: a method for nu-
-- normale EF: > 55% merical integration
-- reduced: • determination of volume by a certain number (usually
◦◦ low grade: 45-55% 20) of parallel slices of equal thickness
◦◦ moderate: 30-45% • Slices: flat cylinder with elliptical cross-section
◦◦ high grade: < 30% • formula: volume V = π/4 x h ∑ (n/1) x d2 (ml)
-- hyperkinetic: > 70% (e.g. severe mitral or aortic val- -- π: circle numer (3.14)
ve regurgitation, VSD, hyperthyroidism, AV-shunt, -- n: number of slices
initial stage of sepsis)
-- h: height of slices
• The echocardiographically determined volumes are
-- d: thickness of slices
smaller than the volumes determined by laevocardio-
• end-diastolic and end-systolic tracing of the endocardi-
graphy (echocardiographic volume underestimation),

General Part 223

 al contour (trackball; possibly automatically [advanced
automated contour trace])
• section planes:
-- monoplane: 4-chamber view
-- biplane: 4-chamber and 2-chamber view (If there are
no wall movement disorders, the monoplane deter-
mination is completely sufficient.)
• computer-aided calculation of the EF (by the echocar-
diography device)
• assessment:
-- advantage: also applicable in wall motion abnormali-
ties and irregularly shaped ventricles (most accurate
method)
Fig. 390  MAPSE: here with 7.8mm reduced as a sign of a
-- disadvantage: sometimes endocardium can only be
reduced systolic LV function
delimited insufficiently due to poor sound conditions
• In the ASE-/EACVI Guidelines 2015 (Recommenda-
tions for cardiac chamber quantification by echocardio- MAPSE: a relatively easy and espe-
graphy in adults: an update from the American Society cially well reproducible parameter for
of Echocardiography and the European Association of the systolic LV function!
Cardiovascular Imaging) the biplane determination of
the EF according to Simpson is considered the method
of first choice. MASV
• mitral annular systolic velocity
• derivation by tissue Doppler (TDI [tissue Doppler ima-
gin])
• placement of the sample volume on the lateral mitral
valve annulus
• norm > 10 cm/s

Fig. 389  measurement of the EF according to Simpson

(slice summation method)

MAPSE
• mitral annular plane systolic excursion Fig. 391  MASV: here with 7.8mm reduced as a sign of a
reduced systolic LV function
• M-mode in 4-chamber view
• placement of the line on the lateral mitral valve annulus
Regional systolic left ventricular function
• norm > 10 mm
Definition
• Analysis of wall motion abnormalities of individual seg-
ment
• normokinesia:
-- systolic inward movement and
-- wall thickness increase of the myocardium
• exception: basal antero-septal segment (no inward,
possibly even outward movement since it is fixed to
the aortic ring)
• wall motion abnormalities typical in coronary heart di-
sease (CHD)
• possibly compensatory hyperkinesia of contralateral
wall segments

224 General Part

Wall motion abnormalities
• types
-- hypokinesia: reduced but still present inward move-
ment
-- akinesia: absence of inward movement; occurrence:
◦◦ infarction scar (thin + hyperechogenic wall)
◦◦ acute ischemia
-- dyskinesia: systolic outward movement ("bulging");
occurrence: aneurysm (e.g. ventricular aneurysm
after infarction)
• causes
-- with ischemia (No.1; classic)
-- without ischemia
◦◦ Left bundle branch block
◦◦ status post cardiac surgery (e.g. paradoxical sep-
tal movement after valve replacement)
◦◦ WPW syndrome
◦◦ DCM
◦◦ right ventricular load (paradoxical septal move-
ment)
classical cause for wall motion
abnormality: stenosing CHD or acute
ischemia
Wall segments
• 16-segment model of the left ventricle according to
American Society of Echocardiography 1989
• updated classification (American Heart Association,
Circulation 2002): segment 17:
-- outermost tip of the ventricle ("cap")
-- only little used in clinical routine
• division of the left ventricle into 3 heights
-- basal segments (base of the ventricle)
-- mid segments (middle section of the ventricle)
-- apical segments (tip of the ventricle)
• circumferential designation
-- anterior / posterior
-- lateral / septal
-- inferior / superior
• can be assigned to the respective coronary vessels
Diastolic left ventricular function
E:A ratio
• placement of the sample volume exactly in the middle
of the leaflets of the mitral valve
• diastole:
-- E-wave (early): early filling phase (early diastolic)
due to the shift of the valvular plane (75% of blood
flow)
-- A-wave (atrial): late filling phase (late-diastolic) due
to the atrial contraction (25% of the blood flow)
• filling disorder → decrease of the velocity of the pri-
mary filling phase (E-wave) → compensatory increase
of the velocity of the secondary filling phase (A-wave)
• increase of the left ventricular pressure :
-- increase of the left ventricular pressure → A-wave ↓
→ E-wave ↑ (pseudo-normalization)
-- increase of the left atrial pressure → E-wave ↑↑ (A
high E-wave is always a sign of a high LA pressure!)
• normal E > A (up to 2:1)
• normal E : A ratio: 1.1-2.0
• at age > 65 years often minor relaxation abnormality
normal (E : A up to max. 0.8)
• E < A: diastolic relaxation abnormality
• E : A > 2:1 → restriction (e.g. constrictive pericarditis,
restrictive cardiomyopathy, decompensated heart fai-
lure)
• An excessive E-wave is always an indication of in-
creased filling pressure! When the mitral valve opens
at the beginning of the diastole, the high pressure in
the left atrium causes the blood to flow rapidly into the
left ventricle, which explains the high velocity and thus
the high E-wave.
• The parameter is not very reliable and has some dis-
advantages:
-- not possible in case of atrial fibrillation (no A-wave
present)
-- load-dependent
◦◦ preload (pretending a relaxation abnormality by
reduced preload (e.g. hypovolemia): E-wave ↓,
compensatory A-wave ↑)
◦◦ afterload (e.g. blood pressure)
• pseudonormal stage: The E:A ratio is pseudonormal
in grade II (but becomes pathological under Valsalva-
maneuver or nitroglycerin [unmasking!]).
Fig. 392  diastolic dysfunction: In the transmitral inflow
profile the E-wave is smaller than the A-wave.
Isovolumetric relaxation time (IVRT)
• positioning of the sample volume of the pw-Doppler
between LVOT and mitral inflow in apical 5- or 3-cham-
ber view
• IVRT = time between end of aortic outflow (aortic val-
ve closure) and beginning of transmitral inflow (mitral
valve opening)
• norm: 60-100 ms
• pathological:
-- > 100 ms: diastolic heart failure grade I/II
-- < 60 ms: diastolic heart failure grade III
General Part 225
 ◦◦ grade III: PVa-dur > A-dur (difference > 30ms; al-
ways an indication of increased LA pressure! The
high LVEDP leads to high LA pressure. Due to the
high LA pressure, the blood is pressed back into
the pulmonary veins over a longer period of time.)
• normal: PVs > PVd
• diastolic heart failure: PVs < PVd
• standard values:
-- PVs
◦◦ PVs1 (early systolic) > 0.5 m/s
◦◦ PVs2 (late systolic) > 0.6 m/s
-- PVd < 0.45 m/s
-- PVa < 0.2 m/s
• indications (pulmonary vein Doppler)
Fig. 393  determination of the isovolumetric relaxation time -- diastolic function
(IVRT) in apical 5-chamber view: time between the end of -- determination of the severity of mitral valve regur-
the aortic outflow and the beginning of the transmitral in-
gitation
flow (here 60ms)

Deceleration time (DT)

• time interval from peak to end of E-wave
• norm: 150-220 ms
• usually shortened only in cases of higher grade of dia-
stolic dysfunction (< 150 ms)
• also possible in atrial fibrillation

Fig. 395  normal pulmonary venous flow (TTE): PVs > PVd

Fig. 394  deceleration time (time from the peak to the end
of the E-wave)

Pulmonary venous flow (PVF)

• derivation
-- TTE (The right upper pulmonary vein may be pre-
sentable in the apical 4 chamber view.)
-- TEE (Here almost always the left upper pulmonary Fig. 396  normal pulmonary venous flow (TEE): PVs > PVd
vein is presentable next to the terminal crest.)
• pulmonary venous flow (normal):
-- 2 systolic portions (PVs); biphasic systole
-- 1 diastolic portion (PVd)
-- at the end of diastole atrial reflux occurs (PVa; re-
verse flow; atrial phase [The atrial contraction forces
blood from the left atrium back into the pulmonary
veins, in which there are no valves.])
◦◦ The duration (dur) of PVa is normally less than the
duration of the A-wave, i.e. PVa-dur < A-dur.
◦◦ grade II: PVa-dur ≈ A-dur

226 General Part


Fig. 397  pathological normal pulmonary venous flow (TTE):
PVs < PVd im TTE
Fig. 398  pathological normal pulmonary venous flow (TTE):
PVs < PVd im TEE
Mitral annulus velocity (MAV)
• tissue Doppler (TDI: tissue Doppler imaging)
• positioning of the sample volume of the pw tissue
doppler in the lateral or medial mitral valve annulus
(recommendation of the German Siciety of Cardiology
2007: mean value between septal and lateral measu-
rements [usually higher MAV])
• designation as in transmitral inflow, only E´ and A´, e´
and a´ or Em and Am
• normal values: E´
-- septal > 7 cm/s
-- lateral > 10 cm/s
• normal E´ > A´, pathological (in all 3 grades): E´ < A´
• advantages
-- even in the pseudonormal stage (grade II) E´ < A´ (in
contrast to: E > A); no pseudonormalization
-- also possible in atrial fibrillation (filling index)
-- load independent
• restriction (= grade III):
-- reversible: A´ > 0.05 m/s
-- irreversible: A´ < 0.05 m/s
• filling index: E / E´
-- < 8 → exclusion of diastolic dysfunction
-- >15 → detection of diastolic dysfunction
• In the early stage of diastolic dysfunction (grade I) the
quotient E/E´ is often falsely normal. Although there is
a decrease of E´, there is also a decrease of E, so that
the quotient E/E´ does not increase, although there is
already a diastolic dysfunction.
E´ A´
Fig. 399  derivation of the mitral annulus velocity using tis-
sue Doppler (here normal: E´ > A´)
Fig. 400  derivation of the mitral annulus velocity using tis-
sue Doppler (here pathological: E´ < A´)
best parameter for diagnosis of
diastolic dysfunction: filling index E / E´
Tei index
• according to Tei et al, J Cardiol 1995
• syn.:
-- MPI (myocardial performance index)
-- LIMP (left ventricular index of myocardial perfor-
mance)
• combined systolic and diastolic parameter (evaluation
of isovolumetric contraction and relaxation time)
• Tei index = (IVCT + IVRT) / ET
-- IVCT: isovolumetric contraction time
-- IVRT: isovolumetric relaxation time
-- ET: ejection time
• Tei index = (a - b) / b; parameters to be measured:
-- a = time span of the CD interval (= time between the
end and the beginning of a transmitral inflow profile
-- b = time of systolic aortic outflow (ejection time [ET])
• norm: < 0.5
General Part 227
• interpretation (increased Tei index, i.e. Tei index > 0.5)
-- CHD
◦◦ high sensitivity for cardiac ischemia
◦◦ good screening parameter for stenosing CHD
◦◦ prognostic factor after myocardial infarction: Tei
index > 0.55 → poor prognosis
-- chemotherapy (early indicator of toxic cardiomyopa-
thy)
-- diastolic heart failure

Fig. 401  derivation of the Tei index (left heart): (343ms -

228ms) / 228ms = 0.5

228 General Part

 • E/E´ > 14
• E´(septal) < 7 cm/s
• PAP > 31mmHg bzw. TRV > 2.8 m/s
• LAVI > 34 ml/m2

< 2 positive: 2 positive: > 2 positive:

no diastolic not determinable diastolic
dysfunktion dysfunktion
Fig. 402  procedure according to the ASE / EACVI guideli-
nes 2016 for normal ejection fraction (PAP: pulmonary arte-
rial pressure; TVR: tricuspid regurgitant velocity; LAVI: left
atrial volume index)

E/A ratio

E/A < 0.8 + E/A ≥ 2

E ≤ 50cm/s E/A 0,8-2
or E/A < 0.8 + E > 50cm/s

• E/E´ > 14
• PAP > 31mmHg bzw. TRV > 2.8 m/s
• LAVI > 34 ml/m2

2 negative 1 positive 2 positive

1 negative
LA pressure
not increased not LA pressure ↑ LA pressure ↑↑
diastolic determinable diastolic diastolic
dysfunction dysfunction dysfunction
grade I grade II grade III
Fig. 403  procedure according to the ASE / EACVI guide-
lines 2016 for reduced ejection fraction (PAP: pulmonary
arterial pressure; TVR: tricuspid regurgitant velocity; LAVI:
left atrial volume index); annot.: Axiomatically, it is assu-
med that patients with a reduced ejection fraction always
also have diastolic dysfunction.

transmitral inflow

E>A E<A

Valsalva
(to exclude
pseudonormalization)

E>A E<A
diastolic
no diastolic dysfunction
dysfunction
falls Vorhofflimmern: E/E´

Fig. 404  simplified (and also completely sufficient for prac-

tical everyday use) procedure for the question of diastolic
dysfunction

General Part 229

 S3 guideline "Intravascular volume therapy in adults"
CIRCULATORY THERAPY 2014 (DGAI [German Society of Anaesthesiology and
Intensive Care Medicine])
• volume therapy
• catecholamine therapy grade of re- type of recommen- vocabulary
commendation dation
strong recommen-
A dation must
B recommendation should
open recommenda-
0 tion can

Also infusion solutions (applies

especially to colloids) are drugs,
so that side effects, contraindica-
tions and maximum dosages
must be observed!

Crystalloid

VOLUME THERAPY Definition

• They contain dissolved salts that form crystals when
dry (hence the name).
• dominating salt: NaCl (sodium chloride)
• 75% migration into the interstitium (no intravascular
persistence), only 25% remain intravascular→ Infusi-
on in a ratio of 3:1 (e.g. blood loss 500ml → infusion of
2000ml of crystalloids)
• history: Crystalloids were developed in the 1830s for
the supportive therapy of cholera (e.g. first description
by Thomas Latta in the Lancet 1832; so-called Latta
solution: NaCl 0.9% + bicarbonate).

crystalloids → increase in extracellular

fluid
colloids → increase in plasma volume
("plasma expander")

Classification
• by ionicity:
-- balanced solutions (physiological electrolyte con-
tent; buffered)
-- unbalanced solutions (unphysiological electrolyte
content; unbuffered): mainly NaCl 0.9%
• by tonicity:
-- isotonic crystalloids
-- anisotonic crystalloids
◦◦ hypotonic crystalloids
◦◦ hypertonic crystalloids (e.g.a. NaCl 3%)

Isotonic crystalloids
• full electrolyte solutions (Na > 120 mM)
• two-thirds electrolyte solutions (Na 90-120 mM)
• half electrolyte solutions (Na 60-90 mM)
• one-third electrolyte solutions (Na < 60 mM)

230 General Part

Full electrolyte solutions
Na Cl K Ca Mg acetate lactate
NaCl 0.9%
Ringer´s
Tutofusin
Ionosteril
Sterofundin
Fig. 405  different crystalloids [8]
NaCl 0.9%
• NaCl 0.9% is also called "physiological isotonic" saline
solution, but is neither physiological nor isotonic:
-- ionicity (electrolyte content):
◦◦ high sodium content (154 mmol; 10% higher than
in extracellular fluid [supraphysiological]; 1000ml
NaCl 0.9% contain 9g NaCl; note: 154 mM = 145
mmol/l, i.e. 1 liter contains 154 mmol sodium, 1ml
accordingly 0.154 mmol sodium)
◦◦ high chloride content (154 mmol; 50% higher
than in extracellular fluid) → danger of hyperchlo-
remic acidosis (especially in cases of impaired re-
nal function); note: The pH value of 4.5-7.0 is also
significantly lower than the physiological pH value
(7.36-7.44) in the blood.
-- tonicity: NaCl 0.9% has a higher osmolarity (308
mmol/l) than serum, i.e. "isotonic" NaCl 0.9% is also
not isotonic but hypertonic. Therefore NaCl 0.9%
also has a (low) volume effect of 110%.
• assessment:
-- NaCl 0.9% is completely unphysiological (including
severe hyperchloremic acidosis) and should be ban-
ned from the intensive care unit as a standard infu-
sion.
-- Even in acute kidney failure with hyperkalemia,
Ringer's solution should paradoxically be used, alt-
hough it contains potassium: Due to hyperchloremic
acidosis, NaCl 0.9% can even exaggerate hyperka-
lemia via the H+/K+ exchanger (so-called Hambur-
ger shift). In any case, one litre of Ringer's solution
contains only a very small amount of potassium (4-5
mmol potassium), which is only about one twentieth
of the daily recommended dietary intake of potassi-
um. The organism contains 6500 mval of potassium,
1 liter of Ringer´s contains only 5 mval of potassium,
so this does not matter at all. Within the scope of a
kidney transplant it could be shown that with NaCl
0.9% the potassium levels were significantly high-
er than with Ringer's lactate (i.a. Khjavi et al, Ren
Fail 2008; Saudi et al, J Kidney Dis Transpl 2012).
"Physiological" saline solution can even trigger an
acute kidney failure or aggravate an existing renal
failure, as the chloride it contains is a strong renal
vasoconstrictor, which leads to reduced renal blood
flow! NaCl 0.9% is nephrotoxic!
-- A hyperchloremic acidosis leads to acute kidney
failure by reducing renal perfusion, glomerular filtra-
tion rate and urinary excretion! In addition, acidosis
also leads to hemodynamic instability, since the en-
dogenous catecholamines are no longer effective
here.
-- Today there are only the following indications for
NaCl 0.9%:
◦◦ hypovolemic hyponatremia
◦◦ strong vomiting with pronounced hypochloremia
◦◦ as a carrier solution for drugs (In Ringer's soluti-
on drugs must not be dissolved due to its calcium
content, as they may flocculate here.)
◦◦ filling fluid for the pressure bag in invasive blood
pressure measurement
-- Despite the disadvantages mentioned and known
for a long time, NaCl 0.9% is still the most widely
sold infusion solution, because it's just the cheapest.
• studies:
-- In one study (Yunos et al, JAMA 2012), the use of
NaCl 0.9% compared to balanced solutions showed
that critically ill patients experienced acute kidney
failure significantly more often and also significantly
more often the need for renal replacement therapy
was observed.
-- The SPLIT study (see box) did not show an incre-
ased rate of renal failure for NaCl 0.9% compared
to balanced solutions, although it should be noted
that the patients received only 2000ml of crystalloids
on average within 24h, so that the negative effects
(probably) did not occur.
-- In an observational study (Shaw et al, Ann Surg
2012) in patients after abdominal surgery, the use
of NaCl 0.9% instead of a balanced electrolyte so-
lution led to significantly more complications, more
frequent kidney failure and to an increased mortality.
-- meta-analysis (Krajewski et al, BJS 2014;see box)
-- Shaw et al, Crit Care 2015 (see box)
-- The SALT study (Semler et al, AJRCCM 2016; mo-
nocentric cluster randomized pilot study) showed
in 974 intensive care patients no increased rate of
renal failure when using NaCl 0.9% compared to a
balanced crystalloid.
-- The LICRA study (Mc Illroy et al, Intensive Care Med
2017), showed in 1136 cardiac thoracic surgery pa-
tients no increased rate of renal failure when using
NaCl 0.9% compared to a balanced crystalloi.
-- PLUS study: current ongoing large study in Australia
and New Zealand (NaCl 0.9% versus Plasma Lyte)
General Part 231
• guidelines:
-- S3 guideline "Intravascular volume therapy in adults"
2014 (DGAI): Isotonic saline solution should not be
used for volume replacement in intensive care (re- SPLIT study
commendation grade A).
-- sepsis guidelines:
◦◦ international (Surviving Sepsis Campaign 2016):
here NaCl 0.9% and balanced crystalloids still Effect of a Buffered Crystalloid Solution vs Saline on Acute
equivalent Kidney Injury Among Patients in the Intensive Care Unit
Young et al, JAMA 2015
◦◦ national (S3 guideline sepsis 2018 [German Sep-
sis Society]): NaCl 0.9% should no longer be used • randomized controlled trial (4 intensive care units in Aus-
in patients with sepsis (strong recommendation). tralia and New Zealand)
• 2278 critically ill patients
-- NaCl 0.9%
-- balanced crystalloid (Plasma-Lyte 148)
meta-analysis • results:
-- primary endpoint: acute kidney injury → no difference
-- secondary endpoints (need for renal replacement the-
rapy, duration of mechanical ventilation, mortality): no
Meta-analysis of high- versus low-chloride content in peri­ difference
operative and critical care fluid resuscitation • comments:
Krajewski et al, BJS 2014 -- relatively low disease severity (mean APACHE II
score only 14P.)
• 6253 intensive care patients; volume therapy with -- only low infusion volume (on average within 24h only
crystalloids: 2 liter/24h)
-- crystalloids with high chloride content: NaCl 0.9% -- the only randomized controlled trial however on this
(154 mM) topic
-- crystalloids with low chloride content (111 mM)
• results: NaCl 0.9%
-- mortality: no difference
-- significantly more frequent acute kidney failure (by
64%) SMART study
-- significantly more frequent metabolic acidosis (caused
by hyperchloremia)
-- significantly longer duration of ventilation
Balanced Crystalloids versus Saline in Critically Ill Adults
Semler et al, N Engl J 2018

• monocentre (5 intensive care units in one center) cluster

study randomized crossover study
• 15802 critically ill patients
-- NaCl 0.9%
-- balanced crystalloid (Ringer´s lactate, Plasma-Lyte A)
Impact of intravenous fluid composition on outcomes in pa- • results: NaCl 0.9%
tients with systemic inflammatory response syndrome -- primary endpoint (MAKE 30 [major adverse kidney
Shaw et al, Crit Care 2015 events]: death, renal replacement therapy [RRT],
persistent renal impairment [rise of creatinine to over
• cohort study (propensity-matched) 200% from baseline] after 30 days): significantly in-
• 3116 patients with SIRS; crystalloids creased (relatively by 10%, absolutely by 1%)
-- balanced -- secondary endpoints: i.a.
-- unbalanced (NaCl 0.9%) ◦◦ RRT-free days: signifikantly reduced
• results: NaCl 0.9% ◦◦ mortality: no difference (in the subgroup of patients
-- primary endpoint: mortality → significantly increased with sepsis: decreased)
secondary endpoints: i.a.
◦◦ prolonged hospitalization
◦◦ more frequent bleeding if possible no more use of NaCl
◦◦ more frequent cardiac events 0.9%!
◦◦ more frequent infections
◦◦ renal failure: no difference
Ringer's solution
• named after the British physician Sydney Ringer
(1834-1910)
• variants to the classical Ringer's solution: To avoid di-

232 General Part

 lution acidosis (dilution of bicarbonate with a consecu-
tive decrease of the bicarbonate concentration with a crystalloids: It is best to use buffered
larger volume application) and hyperchloremic acido- (= balanced) full electrolyte solutions!
sis (with a high chloride content of 156 mmol/l), the
solution is mixed with metabolisable anions (so-called
bicarbonate precursors]), which are then degraded to
Na Cl K Ca acetate lactate
bicarbonate. Bicarbonate itself is unstable in soluti-
on, hence industry offers bicarbonate precursors that Ringer´s 147 156 4.0 2.3 - -
remain stable in solution. The following are used as Ringer´s
metabolisable anions (bicarbonate precursors: lactate lactate 130 112 5.4 1 - 28
(lactic acid salt), acetate [acetic acid salt]), malate (salt Ringer´s
of malic acid) and gluconate (salt of gluconic acid). The acetate 130 112 5.4 1 28 -
buffered solutions are also called balanced solutions.
These should be used preferably Ringer´s Ringer´s
-- Ringer's lactate (lactate also contained in Sterofun- lactate acetate
din; osmolarity 276 mosm/l [slightly hypotonic, there- example Sterofundin Ionosteril
fore contraindicated in cases of increased intracrani- osmolarity (mosm/l) 276 296
al pressure, e.g. during traumatic brain injury!])
oxygen consumption higher lower
-- Ringer's acetate (acetate also contained in Io-
nosteril [annot.: Plasma-Lyte contains in addition to RQ (respiratory quoti-
ent) 0.67 0.50
the acetate also gluconate.]; better; osmolarity 296
mosm/l); advantages over Ringer's lactate: increase of blood gluco-
se (gluconeogenesis ↑) yes no
◦◦ lower oxygen consumption during metabolism
▪▪ lactate: 3 mol oxygen per formation of 1 mol bi- increase of lactate yes no
carbonate (Per liter Ringer's lactate the oxygen hypocalcaemia (setting
consumption of the patient is doubled for 7 mi- of ionized Ca2+) yes no
nutes!)
▪▪ ccetate: 2 mol oxygen per formation of 1 mol bi-
Ringer's acetate is clearly superi-
carbonate
or to Ringer's lactate!
◦◦ In contrast to lactate, acetate is metabolised in-
dependently of the liver. In hypoxia, the citric acid
cycle in the liver and thus the lactate degradation
is disturbed (utilization disturbance in hypoxia). no Ringer's lactate in shock, as
◦◦ no increase in lactate (marker for hypoxia) lactate cannot be utilized and oxygen
consumption is increased!
-- Ringer's malate: also metabolism independent of the
liver; only 1 mol of oxygen per formation of 1 mol of
bicarbonate
Hypotonic crystalloids
-- Ringer´s gluconate (Plasma-Lyte [In addition to glu-
conate, it also contains acetate.]) • indication:
• Electrolyte content of the classical Ringer's solution -- hypertonic dehydration
(i.e. without addition of metabolisable anions): -- hypernatremia (here administration of glucose 5%
-- cations: together with a crystalloid in a ratio of 1: 1)
◦◦ Na+ 147 mmol/l • representatives:
◦◦ K+ 4.0 mmol/l -- 0.45% NaCl solution
◦◦ Ca2+ 2.3 mmol/l -- Glucose 5% (rapid metabolism, "free water"; re-
mains almost not at all in the intravascular space,
▪▪ due to the calcium content caution with lar-
goes mainly intracellularly [cave cerebral edema];
ge-volume administration with patients taking
therefore restrictive use [at best still in hypernatre-
digitalis
mia])
▪▪ no dissolution of drugs (flocculation due to
the calcium content!)
▪▪ for Ringer's acetate and Ringer's lactate only 1 no infusion solutions containing
mmol/l (but still no dissolution of drugs) glucose (e.g. G5%) alone for volume
-- anions: therapy (cave brain edema)!
◦◦ Cl- 156 mmol/l (in Ringer's acetate and Ringer's
lactate only 112 mmol/l)
◦◦ lactate (Ringer's lactate): : 28 mmol/l Hypertonic crystalloids (NaCl 3%)
◦◦ acetate (Ringer´s acetate): 28 mmol/l • indication: hyponatremia
• preparation:
-- 1000 ml NaCl 0.9% + 7 amp. NaCl 20% a 20ml ( (9g
[1000ml NaCl 0.9%] + 7 x 4g [7 x NaCl 20% a 20ml]

General Part 233

 = 37g auf 1140ml → 3g in 100ml [3%]) or
-- 500 ml NaCl 0.9% + 3 ½ amp. NaCl 20% (a 20ml)
• 1-2 ml/kg/h according to sodium deficit
• 1ml NaCl 3% = 0.5 mmol sodium
Sodium deficit
sodium deficit = total body water x
(Nadesired - Nameasured)
• total body water (TBW; in liter):
-- men: 60% of body weight (kg x 0.6)
-- women: 50% of body weight (kg x 0.5)
• As desired sodium (Nadesired; target) usually is 142
mmol/l is used.
• example: 75 kg man, Nameasured 120 mmol/l, Nadesired
142 mmol/l → sodium deficit 900 mmol sodium; 1ml og
NaCl 0.9% contains 0.5 mmol sodium → Patient needs
1800ml NaCl 0.9% to compensate his sodium deficit.
Colloids
• Greek: "kolla" (glue)
• syn.: plasma expander
• intravascular persistence (almost no migration into the
interstitium [especially not in cases of intravascular hy-
povolemia; however, in patients with capillary leak, e.g.
during sepsis, colloids also migrate to a considerable
extent into the interstitium due to the disturbed vascu-
lar barrier])
• history: first use in 1915 by James Hogan in patients
with hemorrhagic shock (The intravenous use of collo-
idal [gelatine] solutions in shock; JAMA 1915)
• representatives:
-- artificial colloids
-- natural colloids
Artificial colloids
• hydroxyethyl starch
• gelatine
• dextrane
Hydroxyethyl starch (HES)
Definition
• a highly branched starch: amylopectin (polysaccharide
consisting of 1,4α-glycosidically linked glucose chains)
with hydroxyl groups at C2 and C6 (The hydroxylation
of the glucose molecules is done to modulate the phar-
macological degradation rate.)
• production from corn or potato starch
• types:
-- isooncotic: HES 6%
-- hyperoncotic: HES 10%
• molecular weight between 70000-450000 Dalton
• substitution degree:
-- proportion of glucose units that are hydroxylated
(e.g. 0.5: 50%)
-- between 0.4-0.7
234 General Part
-- The higher the degree of substitution, the lower the
rate of degradation and thus the longer the half-life.
• substitution pattern:
-- ratio of glucose units substituted in C2 and C6 posi-
tion
-- C2/C6-ratio: C2 compounds are cleaved slower than
C6 compounds by α amylase. The more C2 com-
pounds, the lower the rate of degradation and the
longer the half-life
• example HES 6% 130/0.4: solution with
-- HES concentration of 6%
-- molecular weight of 130000 D
-- substitution degree of 0.4
• maximum daily dose:
-- HES 10%: 20 ml/kg bw
-- HES 6%: 33 ml/kg bw
• contraindicated from creatinine > 2.0 mg/dl
• intravascular residence time: 4-5h (HES 6%)
Representatives
• isooncotic:
-- HES 6% 70/0.58 (Rheohes)
-- HES 6% 130/0.4 (Voluven)
-- HES 6% 200/0.5 (Hemohes 6%, HES-Steril 6%)
-- HES 6% 450/0.7 (Plasmasteril)
• hyperoncotic: HES 10% 200/0.5 (Hemohes 10%,
HES-Steril 10%): longer used today; cave: VISEP stu-
dy (ssee page 848): increased rate of acute kidney
failure
Fig. 406  HES 6% [8]
Side effects
• disturbance of platelet function (inhibition of platelet
aggregation ["coating"], acquired von Willebrand-Juer-
gens syndrome), possibly bleeding
• α-amylase­ ↑ (5-fold)
• falsely high measurement of fibrinogen (factor I)
• disturbance of renal function
-- pathomechanisms:
◦◦ reabsorption of HES macromolecules in the tu-
bular cells of the kidney with consecutive osmotic
nephrosis
◦◦ tubular damage by hyperviscosity of urine
-- contraindicated from creatinine > 2.0 mg/dl (half-life
increases from 36 to 88h!)
• allergic reaction (often difficult diagnosis; tryptase in
serum ↑)
• pruritus (with prolonged use; HES is stored in the reti-
culoendothelial system [RES])
Studies
• VISEP study (SepNet; see page 848): HES 10%
 200/0.5 was not better than the crystalloid Sterofundin
in sepsis, but led to significantly more acute kidney fai-
lure with the need for renal replacement therapy.
• CRYSTMAS study (Guidt et al, Crit Care 2012): HES
6% versus NaCl 0.9% in patients with severe sepsis
→ no difference (including rate of acute kidney injury)
• 6S study (see page 848): HES 6% 130/0.4 (Voluven)
led to an increased rate of acute kidney failure in seve-
re sepsis with the need for renal replacement therapy
as well as to increased mortality!
• CHEST study: see box
• CRISTAL study: see box
• In patients undergoing abdominal surgery, administra-
tion of HES showed a doubling of the bleeding rate
compared to Ringer's lactate. Significantly more blood
transfusions were necessary. Thombelastography
showed a significant lower clot strength (Rasmussen
et al, Annals of Surgery 2014).
• FLASH study (Futier et al, JAMA 2020): no difference
in the primary combined endpoint mortality and post-
operative complications between HES and NaCl 0.9%
in patients at increased risk of postoperative acute kid-
ney failure who underwent major abdominal surgery
CHEST study
Hydroxyethyl Starch or Saline for Fluid Resuscitation in
Intensive Care
Myburgh et al, N Engl J 2012
• CHEST: crystalloid versus hydroxyethyl starch trial
• multicenter prospective randomized trial
• 7000 intensive care patients - volume therapy
-- crystalloid: NaCl 0.9%
-- colloid: HES 6% 130/0.4
• results: HES 6% 130/0.4
-- mortality after 90 days: no difference
-- significantly more frequent increase in creatinine and
more frequent acute kidney failure with necessity of
renal replacement therapy
Assessment
Now that the 6S study (see page 848) has even shown
that the use of HES can cause excess mortality of 6%
in sepsis patients, the administration of HES should no
longer be used in severe sepsis or septic shock. Accor-
dingly, synthetic colloids such as HES for volume therapy
in sepsis are no longer recommended in the SSC gui-
delines 2012 and 2016. However, the partly emotional
discussion about the use of HES in intensive care units
must be conducted in a very objective and unemotional
manner: If there is a clear lack of volume (e.g. gastroin-
testinal bleeding), HES is still a good option! The advan-
tage of plasma expansion is greater than the disadvan-
tage of the slightly increased bleeding rate due to the
inhibition of platelet aggregation ("coating").
The Pharmacovigilance Risc Assessment Committee
(PRAC) of the European Medicines Agency (EMA) initi-
ated a pharmacovigilance procedure in 2012. After com-
pletion in 2013, PRAC has now also recommended that
HES should only be used in a limited patient population
(Restriction of Marketing Authorisation, red hand letter in
Germany 2013 [warning of risks]): HES is now only indi-
cated for the treatment of hypovolemia in acute bleeding
when the administration of crystalloids alone is conside-
red insufficient. In 2018. PRAC has recommended with-
drawing from the market with the (somewhat strange)
reason that HES has continued to be used in everyday
clinical practice in critically ill patients with sepsis. The
German Federal Institute for Drugs and Medical Devices
(BfArM) has also recommended to refrain from the use
of HES until the current procedure has been completed.
On March 27, 2019, the BfArM decided on a program
for "controlled access": Training courses (in particular
on the contraindications; e-learning of the European So-
ciety for Anesthesia [ESA]; annual repetition) are now
mandatory. From April 17th, 2019 a delivery may only
be made to accredited facilities. All users of the facility
must have completed the training. The British regulatory
authority MHRA has already withdrawn the approval for
HES in 2013. Following its review, the EMA (European
Medicines Agency) continued to maintain the approval
of HES as a plasma substitute. Peri-interventionally (e.g.
in the operating theatre) however, HES can be used
for the therapy of acute hypovolemia according to the
S3 guideline "Intravascular Volume Therapy in Adults"
2014 on an equal footing with gelatine or crystalloids.
It is then best to apply it as a pressure infusion (using
a compressible container). However, it should not be
used in the intensive care unit of critically ill patients.
CRISTAL studiy
Effects of Fluid Resuscitation With Colloids vs Crystalloids
on Mortality in Critically Ill Patients Presenting With Hypo­
volemic Shock: The CRISTAL Randomized Trial
Annane et al, JAMA 2013
• multicenter randomized study
• 2857 intensive care patients with hypovolemia
-- colloids (HES, gelatin, dextranes, human albumin)
-- crystalloids (isotonic saline solution, Ringer's solution)
• results:
-- primary endpoint (28-day mortality): no difference
-- secondary endpoints
◦◦ 90-day mortality: significantly lower in colloids
◦◦ need for renal replacement therapy: no difference
HES: only indicated for the
therapy of hypovolemia in acute
bleeding!
Contraindications
• renal failure (creatinine > 2.0 mg/dl [SI unit: 177 μmol/l;
half-life increases from 36 to 88h!]) or renal replace-
General Part 235
 ment therapy tation (Hahn et al, Resuscitation 2014; but no general
• sepsis (u.a. SSC-guidelines 2012 und 2016; German recommendation).
S3-guideline sepsis 2018)
• intracranial hemorrhage Gelatine
• burns
Definition
• severe coagulation disorders
• severe liver dysfunction • mixture of animal proteins (main component: denatu-
red collagen; obtained from bones, cartilage and ten-
dons)
Hyper-HES
• mostly derived from bovine bones
Definition • average molecular weight: 30000 D (relatively small
• NaCl 7.2% (hypertonic saline solution) + HES 6% molecular size)
200/0.6 (as Hyper-HES on the market) • only short intravascular residence time (only 2-3h;
• self-production of hypertonic saline solution (NaCl shortest duration of action among all artificial colloids)
7.2%): 250ml NaCl 0.9%, of which 85ml should be dis- • only small volume effect (smallest volume effect among
carded and replaced by 85ml NaCl 20% all artificial colloids
• hypertonic and hyperoncotic solution • excretion: mainly renal (to 80%; partly also via the in-
• molecular weight: 200000 Dalton testine and breakdown by peptidases)
• small volume resuscitation (lowers intracranial pres- • Due to contained NH2 groups, gelatine also has a cer-
sure; better outcome in patients with severe TBI and tain buffer capacity.
hypotension) • no storage in the reticuloendothelial system (RES; qui-
• 3-4 ml/kg within 2-3min (give 250ml as a bolus in 2min te in contrast to hydroxyethyl starch)
• maximum dose: 3-4 ml/kg • no dose limitation (in contrast to hydroxyethyl starch
and dextranes)
• not approved in children
• largely abandoned for a long time (i.a. taken from the
• cave:
US market due to safety deficiencies, among other
-- hypernatremia (per 250ml increase of sodium by things), now more frequently used again due to the re-
9mmol/l) strained use of hydroxyethyl starch
-- increase in serum osmolarity (Hyper-HES is one of
the osmotherapeutic agents.) Types
-- with rapid infusion BP ↓↓ Depending on the substance used to crosslink the
chains, different preparations are distinguished:
• SC-gelatine (succinylated; syn. polysuccinate gelatine,
modified liquid gelatine): e.g. Gelafundin 4%, Gelafu-
sal 4%
• OP-gelatine (oxypoly gelatine): e.g. Gelifundol 5.5%
• HV-gelatine (urea cross-linked; syn.: diisocyanate ge-
latine; high calcium content [cave therefore in patients
taking digitalis]): e.g. Haemaccel 3.5%

Fig. 407  Hyper-HES
Indications
• TBI
• increased intracranial pressure (osmotherapeutic
agent)
• trauma-induced hemorrhagic shock
• burns
• possibly resuscitation (to improve microcirculation in
the context of CPR): In a retrospective cohort study,
ROSC (return of spontaneous circulation) was signifi-
cantly more frequently achieved in patients who recei-
ved Hyper-HES (2 ml/kg over 10 min) during resusci-
Side effects
• allergic reaction (anaphylaxis; via histamine release)
• disturbance of platelet function (inhibition of platelet
aggregation ["coating"], acquired von Willebrand-Juer-
gens syndrome), possibly bleeding
• immunosuppression (via decrease of fibronectin level)
• nephrotoxicity (especially in septic patients [Bayer
et al, Crit Care Med 2012; see box])
Studies
• meta-analysis (Saw et al, Anaesth Intensive Care 2012
[see box])
• Bayer et al, Crit Care 2012 (see box)
• GENIUS study:
-- GENIUS: Gelatine in ICU and Sepsis
-- actually ongoing double-blind randomized study
-- gelatine (Gelaspan 4%) versus crystalloids (Stero-
fundin) in patients with severe sepsis / septic shock

236 General Part

 meta-analysis
Benefits and risks of using gelatine solution as a plasma
expander for perioperative and critically ill patients
Saw et al, Anaesth Intensive Care 2012
• 2709 patients (perioperative or intensive care)
• volume therapy
-- gelatine
-- other infusion solutions (crystalloid or other colloid)
• results: Gelatine
-- no advantage compared to crystalloids (i.a. no diffe-
rence in mortality)
-- increased risk of bleeding compared to human albu-
min
-- compared to HES less acute kidney failure
study
Renal effects of synthetic colloids and crystalloids in pa-
tients with severe sepsis: a prospective sequential com-
parison
Bayer et al, Crit Care Med 2012
• prospective comperative study
• volume therapy for 346 patients with severe sepsis
-- crystalloids
-- colloids:
◦◦ gelatine
◦◦ HES
• results: colloids
-- significantly more frequent acute kidney injury (HES:
70%; gelatine: 68%) than among crystalloids (47%)
-- significantly more frequent need for renal replace-
ment therapy (HES: 34%; gelatine: 34%) than among
crystalloids (20%)
meta-analysis
How safe is gelatin? A systematic review and meta-analy-
sis of gelatin-containing plasma expanders vs crystalloids
and albumin
Moeller et al, J Crit Care 2016
• gelatine versus crystalloids / human albumin for therapy
of hypovolemia
• results: gelatine
-- significantly more frequent acute kidney injury
-- significantly more frequent bleeding
-- significantly more frequent anaphylaxis
-- significantly increased mortality
• conclusion of the authors: cave gelatin, better use
crystalloids
Assessment
Due to the restrained use of hydroxyethyl starch, gelatine
is now used instead of HES in many places (gelatine as
a "governor" function for HES). There is almost no data
and no recommendation at all for this. Gelatine is also
nephrotoxic (especially in septic patients), so gelatine
should not or only carefully be used in patients with sep-
sis. According to the S3 guideline "Intravascular Volume
Therapy in Adults" 2014, gelatine (and human albumin)
can be used if, in the opinion of the physician, acute hy-
povolemia cannot be adequately treated with crystalloids
alone (recommendation grade 0). The sepsis guidelines
of the Surviving Sepsis Campaign 2016 place crystallo-
ids over gelatin in patients with sepsis. The German S3
guideline Sepsis 2018 makes a weak recommendation
for patients with septic shock who cannot be adequately
stabilized with crystalloids: Here human albumin (alter-
natively gelatin) can additionally be admistered.
Dextrane
Definition
• a polysaccharide of glucose molecules (1,6-glycosidi-
cally linked)
• extraction from bacteria (Leuconostoc mesenteroides)
from sucrose-containing solution
• little hyperosmotic
• pronounced volume effect
• solutions with 6-10%
• molecular weight: 40000-70000 Dalton
• maximum daily dose: 1.5 g/kg
• degradation by enzymatic breakdown (dextrase) and
predominantly renal excretion
• no storage in the reticuloendothelial system (RES; au-
ite in contrast to hydroxyethyl starch)
• due to considerable side effects today largely aban-
doned (no longer available in Germany)
General Part 237
Types outcome. It is multifactorial: dilution by volume, losses
• dextran 70 into the interstitium by increased capillary permeability,
liver synthesis disorder and increased proteolysis.
-- molecular weight: 70000 Dalton
• types:
-- high molecular weight
-- hypooncotic (human albumin 5%)
-- trade names: Macrodex, Onkovertin, Salvi Dextran,
Infukoll, Longasteril -- hyperoncotic (human albumin 20%; standard today)
-- concentration: 6% ◦◦ A bottle with 50ml contains 10g.
-- volume effect: 130% ◦◦ A bottle with100ml contains 20g.
-- intravascular residence time: 4-6h • Only the hyperoncotic human albumin (20%) is COP-
effective, therefore the hypooncotic human albumin
• dextran 40
(5%) is almost never used.
-- molecular weight: 40000 Dalton
• documentation obligation according to transfusion law
-- low molecular weight (blood product)
-- trade names: Rheomacrodex, Rheofusin, Onkover- • the best studied colloid in critically ill patients
tin, Infukoll, Longasteril
-- concentration: 10%
-- volume effect: 175%
-- intravascular residence time: 2-4h

Side effects
• allergic reaction (dextran anaphylaxis; frequent!)
-- by preformed IgG antibodies (e.g. sensitization as
cross-reaction with bacterial polysaccharides or food
components), which can then trigger an immune
complex anaphylaxis via cross-linking of the dextran
molecules
-- Therefore an allergic reaction is possible here even
with the first administration.
-- Before the first administration, a dextran hapten
(dextran 1 [trade name Promit]; amount: 20ml; mo-
lecular weight: 1000 D) should be given for neut-
ralization. Dextran should be given at the latest 20
minutes later. Fig. 408  human albumin 20%. 1 bottle = 100ml = 20g (also
known colloquially as "fruit dwarf")
• disturbance of platelet function (inhibition of platelet
aggregation ["coating"], acquired von Willebrand-Juer- Studies
gens syndrome), reduction in the activity of coagulati-
on factors (Factors II, V, VIII), possibly bleeding • Cochrane-analysis 1998 (Cochrane Injuries Group Al-
bumin Reviewers; BMJ)
• more difficult blood group determination after adminis-
tration of dextran -- 1419 patients, 32 studies
• increase in urinary viscosity, possibly oliguria and re- -- Human albumin administration led to excess morta-
duction in GFR (Therefore, dextran is contraindicated lity (46%; risk ratio: 1.46).
in renal failure!) -- „Humanalbumin kills!“
-- significant methodological errors
Natural colloids • SAFE study (Finfer et al, N Engl J 2004):
• human albumin -- SAFE: saline versus albumin fluid evaluation
• red cell concentrates (see chapter blood products -- Human albumin as a colloid in sepsis is safe (and
[page 1010]) expensive). But NaCl 0.9% is as good as albumin
(even in the presence of hypalbuminemia!).
Human albumin -- In the subgroup of patients with TBI an increased
mortality was observed (but only applied to human
Definition albumin 5%).
-- 1 liter of human albumin: approx. 300 €, 1 literNaCl
• protein from 580 amino acids
0.9%: approx. 5 €
• molecular weight: 66000 Dalton
• SOAP study (Vincent et al, Crit Care Med 2006): hu-
• introduced as a volume expander in the 1940s
man albumin → increased mortality
• maintenance of colloid-osmotic (syn. oncotic) pressure
• CRYCO study (Schortgen et al, Intensive Care Med
(COP: pressureswhich ensures that water remains in
2008): Human albumin in critically ill patients
the vessel)
-- human albumin 20% → increased mortality
• Hypalbuminemia is common in critically ill patients
-- human albumin 5% → decreased mortality
(especially in patients with septic shock [in 95%]) and
represents an independent prognostic factor for a poor • meta-analysis 2011 (The role of albumin as a resusci-

238 General Part

 tation fluid for patients with sepsis: A systematic review
and meta-analysis; Delaney et al): In 1977 patients the only remaining colloid in sepsis:
with sepsis in the human albumin group showed a re- human albumin!
duced mortality compared to the group with another
fluid therapy
• meta-analysis (Patel et al, BMJ 2014): human albumin Side effects
in sepsis → no reduction in mortality
• allergic reactions
• EARSS study (Charpentier et al, Int Care Med 2011;
EARSS: early albumin resuscitation during septic • infections
shock): no mortality benefit for human albumin in pa- -- especially with viruses (Human albumin is a blood
tients in septic shock (results still not yet completely product!)
published [only in abstract form], but presented at the -- but overall very low risk of infection
ESICM Congress 2011) • plasma protein binding (Especially acidic drugs [e.g.
• ALBIOS studiy (Niven et al, N Engl J 2014; ALBIOS: antibiotocs] can be bound and thus become ineffec-
Albumin Italian Outcome Sepsis): In this largest mul- tive.)
ticenter study to date on human albumin in sepsis
(1818 patients with severe sepsis and septic shock),
the additional administration of human albumin 20% CATECHOLAMINE THERAPY
(with a target albumin of 30 g/l) showed no reduction in
mortality compared to the administration of crystalloids
alone. In the subgroup analysis, however, which only
considered patients with septic shock, a significant re-
duction in mortality was shown. From a scientific point
of view, however, this is as a result of a subgroup ana-
lysis only hypothesis-generating and must first be con-
firmed by a randomized controlled trial.
• ARISS study: actually ongoing study in patients with
septic shock

Indications
• plasma substitute
-- not better than NaCl 0.9% (not even for hypalbumi-
nemia)
-- The SSC guidelines 2012 and 2016 recommend hu-
man albumin for volume therapy in sepsis optionally Definition
in addition to crystalloids if larger amounts of crystal-
loids have already been given. • cardiovascular active substances, which all together
-- optionally in addition to crystalloids in hypalbumine- contain the molecular structure catechol (dihydro-
mia (albumin < 25 g/l) xybenzene) and a common amine (phentol-amine),
hence name: "catechol-amines"
• replacement after ascites puncture
• agonists at receptors of the cardiovascular system
-- per drained litre of ascites 6-8g human albumin
(adrenoceptors, syn.: catecholamine receptors [see
-- However, with a puncture quantity < 5 litres (so- infobox])
called small volume paracentesis) no substitution is
• degradation by the enzyme monoaminooxidase (MAO)
necessary!
-- not recommended for malignant ascites
• spontaneous bacterial peritonitis
-- human albumin 1.5g/kg on day 1 and 1g/kg on day
3; according to the revised S2k-guidelines 2019
„complications of liver cirrhosis“ of the German So-
ciety for Gastroenterology (DGVS) aslo low-dose
possible, i.e. 1.0 g/kg on day 1 und 0.5 g/kg on day 3
(equal [de Araujo et al, Gut 2012])
-- especially with risk factors (i.e. creatinine > 1 mg/dl
[SI-unit: 88.5 μmol/l] and bilirubin > 4 mg/dl)
• hepatorenal syndrome type I
• no indications for the administration of human albumin:
-- synthesis disorder (e.g. liver cirrhosis) Fig. 409  Here the two components of a catecholamine are
-- hypalbuminemia without clinical consequences illustrated: firstly the catechol (yellow): A catechol is a
benzene (= ring of 6 hydrocarbon atoms) with 2 hydroxyl
-- mobilization of fluid from the third space (e.g. pleural groups (OH); secondly the amine (blue): An amine is a com-
effusion) pound of a hydrocarbon with ammonia (NH3).

General Part 239

 Tyrosine O Adrenaline OH

OH
OH

NH2
OH HN
OH CH3
Tyrosine hydroxylase
Fig. 410  Synthesis of catecholamines (biosynthesis of na-
tural catecholamines): The starting substance is the amino
acid tyrosine. By hydroxylation (addition of an OH group)
L-DOPA L-DOPA (dihydroxyphenylalanine) is formed, from which
dopamine is formed by decarboxylation (removal of a CO2
(Dihydroxyphenylalanine) O group). After another hydroxylation noradrenaline (norepi-
nephrine) is formed and finally methylation (addition of a
OH methyl group [CH3]) produces adrenaline (epinephrine).
OH

NH2
OH
DOPA decarboxylase
(= aromatic L-amino acid
decarboxylase)

Dopamine

OH

NH2
OH

Dopamine hydroxylase

Noradrenaline OH

OH

NH2
OH
Phenyletholamin-
N-methyl transferase

240 General Part


Effects
α1 α2 β1 β2
Adrenaline
Noradrenaline
Dobutamine
Application
• via Perfusor
• Perfusor syringes should always be clearly labelled
(preferably with standardised syringe labels).
• If a perfusor syringe becomes empty, the change (es-
pecially with high catecholamine doses) should always
be made with an overlap, i.e. with two syringes.
• always with flow (NaCl 0.9% 10ml/h)
• catecholamine line:
-- It is always recommended to choose the distal CVC
lumen as the catecholamine line, because in this
way fluid doses via the proximal lumen cannot lead
to unwanted catecholamine boluses. Probably it
does not matter whether the distal or proximal lumen
is chosen, because the distance between the exit
openings is only minimal.
-- Catecholamines should always be connected direct-
ly to the hub. Infusion extension lines (e.g. Heidel-
berg extension line) should be avoided (dangerous
dead spaces!).
-- no additional medication via the catecholamine line
• always invasive BP measurement, preferably always
advanced haemodynamic monitoring ("no blind flight")
• The dosage (e.g. for transfers) should always be gi-
ven in mg/h and not in ml/h, as the perfusors are often
drawn up differently (e.g. noradrenaline 0.1mg/ml or
0.5mg/ml).
• attenuation of effect in an acidic environment (The lo-
wer the pH, the lower the catecholamine effect.)
• There are generally no formal dose limits for catechol-
amines ("upper limits", "maximum doses"): As long as
they work, they can be increased.
Fig. 411  Perfusor [8]
Side effects
• cardiac:
-- arrhythmia (atrial fibrillation)
-- tachycardia
-- increase in myocardial oxygen consumption (MVO2),
angina pectoris, myocardial ischemia
-- Tako-Tsubo cardiomyopathy (In 7% of cases of Ta-
ko-Tsubo cardiomyopathy a cardiogenic shock de-
velops: Catecholamines are contraindicated in this
case [see page 394]!)
• endocrinological:
-- hyperglycaemia (The stimulation of β2-receptors in
the liver leads to an increase in glycogenolysis.)
-- hypocalcaemia, hypomagnesaemia
-- hypothyroidism
-- lactate ↑ (endogenously increased lactate produc-
tion through the increased glycogenolysis mediated
via the β2-receptors)
• renal: acute kidney injury (by vasoconstriction)
• intestinal:
-- inhibition of peristalsis (gastrointestinal atony)
-- intestinal ischemia (by vasoconstriction; possibly
lactate ↑)
◦◦ small intestine: NEC (necrotizing enterocolitis)
◦◦ large intestine: ischemic colitis
• immunological:
-- immunosuppressive (inhibition of phagocytosis)
-- pro-inflammatory
-- development of tolerance (tachyphylaxis; through
down regulation of receptors)
No uncritical use of catecholamines!
They have considerable side effects!
No "drug executions" (classic:
norepinephrine in cardiogenic shock
with high SVR and low BP)
General Part 241
 • deterioration of the splanchnic perfusion (intestinal
Catecholamines only after exclusion of perfusion ↓, possibly lactate ↑)
hypovolemia (conditio sine qua non)!
• no combination with dobutamine, as the positive
Catecholamines mask a lack of
inotropic effect is partly cancelled out
volume! Caution: vasoconstrictor-
• adrenaline reversal: This means the reverse effect of
masked hypovolemia!
adrenaline on blood pressure, namely a drop instead
of a rise in blood pressure. This is the case when adre-
naline is given to patients under permanent medication
A lack of volume is treated with with an α-blocker (e.g. doxazosin, prazosin). Vessels
volume (and not with catecholami- are equipped on the one hand with α1-receptors (ef-
nes)! fect: vasoconstriction) and on the other hand with β2-
receptors (effect: vasodilation). Since the α1-receptors
are blocked here, adrenalin cannot bind to them and
thus cannot cause an increase in blood pressure. Ad-
Types renaline can only bind to the vessels at β2-receptors:
• adrenaline (epinephrine; Suprarenin) Stimulation of the β2 receptors causes vasodilatation
• noradrenaline (norepinephrine; arterenol) and thus a decrease in blood pressure.
• dobutamine (Dobutrex)
• dopamine
• isoprenalin, orciprenalin (Alupent; stimulation of
β-receptors)
• Akrinor (theoadrenaline, cafedrine):
-- 1 amp. = 2ml = 10mg theodrenaline [theophylline +
noradrenaline] + 200mg cafedrine
-- is often given in course of induction of anesthesia
(e.g. 1-2ml) to compensate for the anesthesia indu-
ced drop in blood pressure
-- also i.m. application possible

Adrenaline (epinephrine; Suprarenin) Fig. 412  small ampoule adrenaline (1ml = 1mg)

Definition
• a natural catecholamine (synthesis in the adrenal me-
dulla [Latin "ad-renes": adrenal gland], function as a
hormone)
• agonist at the α1α2β1β2-receptor
• the strongest positive inotropic substance
• an inopressor: positive inotrope (via stimulation of
β1-receptors) + vasopressor (via stimulation of α1-
receptors)
• effect:
-- in lower dose: especially β-adrenergic
-- in higher dose: especially α-adrenergic
• T½ = 2-3min
• ampoules (vials): Fig. 413  large ampoule adrenaline (25ml = 25mg): It is clas-
-- small ampoule: 1 amp. = 1ml = 1mg sically used for resuscitation.
-- large ampoule (e.g. for resuscitation): 1 amp. = 25ml
= 25mg Indications
• perfusor: • i.v.:
-- 5 amp. a 1mg a 1ml + 45ml NaCl 0.9% → 0.1 mg/ml -- as bolus:
-- according to MAP (target > 60 mmHg); 4-16 ml/h ◦◦ resuscitation (Here one is taking advantage of the
• dosage: extremely strong bathmotropic effect of adrenali-
-- 0.05-0.5 μg/kg/min (only relative upper limit) ne!)
-- 70kg: low (0.05 μg/kg/min) 2.1 ml/h, medium (0.2 μg/ ◦◦ anaphylactic shock (due to a mast cell stabilizing
kg/min) 8.4 ml/h, high (0.4 μg/kg/min) 16.8 ml/h; for effect; means of choice here: i.m. [not i.v., even
90kg: 2.7 / 10.8 / 21.6 ml/h if an i.v. access exists due to more side effects;
also not s.c.; only in case of oral anticoagulants
• improvement of coronary and cerebral perfusion pres-
not i.m.])
sure

242 General Part

 -- as perfusor:
◦◦ pronounced hemodynamic instability (e.g. if not
stabilizable under dobutamine + noradrenaline;
whether this actually has any positive effect is un-
clear ["permanent reanimation", "prefinal"])
◦◦ preclinical (as an emergency physician) in cardio-
genic shock, when dobutamine (usually not on the
emergency vehicle in Germany) is not available
(noradrenaline, however, better here than adrena-
line [Levy et al, Crit Care Med 2011; CardShock
study 2016; for studies see page 404])
• bronchial obstruction (Adrenaline also has a broncho-
dilatory effect via the stimulation of β2-receptors.)
indication of adrenaline: only resusci-
tation and anaphylaxis!
with reduced skin circulation, the resorption of
the s.c. low molecular weight heparin is no longer
safe.
• side effects (specific): :
-- reflex bradycardia: Norepinephrine per se has a
positive chronotropic effect as a catecholamine. The
increase in blood pressure caused by norepineph-
rine stimulates baroreceptors, so that the positive
chronotropic effect is reversed, leading to the same
remaining heart rate under norepinephrine.
-- intestinal ischemia
-- tremor
-- marked increase in pulmonary arterial pressure
(PAP) and pulmonary vascular resistance (cave in
acute right heart failure!)

Noradrenaline (norepinephrine, artere-

nol)
• a natural catecholamine (synthesis in the adrenal me-
dulla [function as hormone] and in postsynaptic neu-
rons of the sympathetic nervous system [function as
neurotransmitter])
• agonist at the α1/α2-receptor (also little effect at β1-
receptor [This is mainly the case in higher doses, so
that noradrenaline then also has a positive inotropic
effect here.])
• T½ = 2-3min Fig. 414  ampoule noradrenaline (1ml = 1mg)
• ampoules:
-- small ampoule: 1 amp. = 1ml = 1mg Dopamine
-- large ampoule: 1 amp. = 25ml = 25mg
• vasoconstriction (first choice vasopressor), increase Definition
in afterload (increase in systemic vascular resistance
• a natural catecholamine (synthesis in dopaminergic
[SVR ↑])
neurons of the CNS [main function as a neurotrans-
• increase in coronary perfusion (through an increase in mitter])
diastolic blood pressure)
• effect via dopamine receptors (in higher doses then
• decreased cadriac output (especially poor ejection also via adrenoceptors [β- and α-receptors])
fraction) → combination with dobutamine
-- D1-receptor:
• perfusor:
◦◦ presynaptic
-- 0.1 mg/ml („thin“, "watery"): 5 amp. a 1mg a 1ml +
◦◦ effect via stimulating G-proteins (Gs)
45ml NaCl 0.9%
◦◦ mesenteric, renal, cerebral and coronary vasodi-
-- 0.5 mg/ml („thick“, "turbid"):): 25 amp. a 1mg a 1ml
lation
+ 25ml NaCl 09%
-- D2-receptor:
• dosage:
◦◦ postsynaptic
-- 0.2-2.0 μg/kg/min (only relative upper limit)
◦◦ effect via inhibitory G-proteins (Gi)
-- 70kg (perfusor drawn up with 0.1 mg/ml): low (0.05
◦◦ D2-receptors are mainly located in the CNS (ex-
μg/kg/min) 2.1 ml/h, medium (0.2 μg/kg/min) 8.4
trapyramidal motor system [dopamine deficiency
ml/h, high (0.4 μg/kg/min) 16.8 ml/h; for 90kg: 2.7 /
→ Parkinson's syndrome]): Dopamine inhibits the
10.8 / 21.6 ml/h
release of acetylcholine and glutamate. Exoge-
• At a high dosage of noradrenalin (> 1 mg/h) we addi-
nously applied dopamine does not pass the blood-
tionally give:
brain barrier (only L-DOPA).
-- hydrocortisone perfusor (to increase catecholamine
• T½ = 5min
sensitivity; 200mg/24h)
• perfusor:
-- heparin perfusor (UFH) instead of LMWH for throm-
-- purely drawn up
bosis prophylaxis
-- 1 amp. = 50ml = 250mg
◦◦ dosage: UFH 400 IU/h without PTT control (in
case of thrombocytopenia < 50000/μl → 200 IU/h)
◦◦ reason: Due to the pronounced vasoconstriction

General Part 243


Fig. 415  ampoule dopamine (50ml = 250mg)
Dosage
• low dose ("renal dose"):
-- 0.5-5 μg/kg/min
-- stimulation of dopamine receptors (D1/D2)
-- effect: vasodilation
• medium dose ("cardiac dose"):
-- 5-10 μg/kg/min
-- stimulation of β-receptors
-- effect: increase in contractility (inotropic)
• high dose ("vascular dose"):
-- 10-20 μg/kg/min
-- stimulation of α-receptors
-- effect: vasoconstriction
Side effects
• gastrointestinal perfusion ↓ (i.a. intestinal ischemia)
• blockade of oxygen-dependent receptors → decrease
of respiratory drive
• suppression of the hormones of the pituitary gland and
hypothalamus
-- low T3-syndrome
-- STH ↓ (hyposomatropism, possibly catabolism)
-- prolactin ↓ → immunosuppression
Assessment
• "Dopamine in renal dose"
-- no benefit in acute kidney injury
-- not nephroprotective (Bellomo et al, Lancet 2000)
• ROSE-AHF study (Chen et al, JAMA 2013): dopamine
in acute heart failure and renal failure → no improve-
ment in renal function (see page 408)
• increased mortality (excess mortality) in septic
(Sakr et al, Crit Care Med 2006) and cardiogenic shock
(SOAP II study, de Backer et al, N Engl J 2010 [see
box])
• meta-analysis (Avni et al, PLoS One 2015): Dopami-
ne compared to noradrenaline in septic shock leads
to an increased rate of arrythmias and to an increased
mortality.
• guidelines:
-- European: In the ESC-guidelines 2016 "For the di-
agnosis and treatment of acute and chronic heart
244 General Part
failure" dopamine is still listed, but norepinephrine
should be preferred.
-- German: According to the German-Austrian S3 gui-
deline 2011 + 2018 "Infarction-related cardiogenic
shock - diagnosis, monitoring and therapy", dopami-
ne should not be used for the treatment of cardioge-
nic shock.
• the only remaining indication in intensive care medi-
cine: donor conditioning (in brain-dead patients; and
also here only optional [according to the current DSO
guidelines no longer recommended])
SOAP II study
Comparison of Dopamine and Norepinephrine in the Treat-
ment of Shock
de Backer et al, N Engl J 2010
• multicenter randomized trial
• 1679 patients with shock (i.a. 62% septic, 17% cardioge-
nic, 16% hypovolemic)
-- 821 patients: noradrenaline
-- 858 patients: dopamine
• results
-- primary endpoint (28-day mortality): no difference
(subgroup cardiogenic shock: Dopamine caused ex-
cess mortality!)
-- secondary endpoints: i.a. dopamine → doubled inci-
dence of arrhythmia
Dopamine: completely obsolete
("bad medicine")!
Dobutamine (Dobutrex)
• agonist at the β1β2-receptor (especially β1)
• T½ = 2-3min
• 1 amp.= 50ml = 250mg
• a synthetic catecholamine (in contrast to dopamine,
norepinephrine and adrenaline)
• positive inotropic, (low) peripheral vasodilation (via sti-
mulation of the β2-receptors; SVR [systemic vascular
resistance] ↓, afterload ↓), PAP (pulmonary arterial
pressure) ↓, PVR (pulmonary vascular resistance) ↓
• inotropic of choice
• increase of renal, hepatic and gastrointestinal perfu-
sion
• perfusor (purely drwan up): 5 mg/ml; 2-10 ml/h, max.
10 ml/h (maximum dose [only relative]) or up to a heart
rate of 120/min
• dosage: 2-20 μg/kg/min (only relative upper limit)
-- low: 3 μg/kg/min (70kg: 2.5 ml/h; 90kg: 3 ml/h)
-- medium: 6 μg/kg/min (70kg: 5 ml/h; 90kg: 6.5 ml/h)
-- high: 12 μg/kg/min (70kg: 10 ml/h; 90kg: 13 ml/h)
• If the patient was previously treated with β-blocker,
 higher doses are necessary.
• occasional tachyphylaxis (reduction of effectiveness
[by downregulation of the β receptors]) after 48h
• indications:
-- acute left heart failure, cardiogenic shock (means of
choice)
-- septic cardiomyopathy
-- hemodynamic instability with reduced cardiac output
(especially due to a reduced contractility)
-- acute right heart failure (dobutamine → PAP ↓, PVR
↓)
• The mechanism of centralization is used to maintain
circulation is reduced when the cardiac output decre-
ases (centralization). There is no cutaneous autoregu-
lation. The skin is the organ with the highest density
of vasoconstrictor receptors. Although the monitoring
of microcirculation by means of imaging is already
technically possible today (e.g. orthogonal polarisation
spectral imaging [OPS], sidestream dark field imaging
[SDF], incident dark field [ICD]), it is far from being a
clinical routine. A good and easily to measure surroga-
te parameter for a disturbed microcirculation is an in-
creased veno-arterial pCO2 difference dCO2 (see page
199).
blood flow and thus oxygenation of vital organs.

Assessment of the skin

• mottling (Ait-Oufella et al [Intensive Care Med 2011]
even established a mottling score [see infobox] and
could show that mortality from [septic] shock increases
with increasing mottling score.)
• cold (centralisation), sweating ("cold sweat")
• acrocyanosis
• extended capillary refill time (> 2sec; nail bed
sample)

Fig. 416  ampulle dobutamine (50ml = 250mg)

Shock

Definition
• exactly: circulatory shock
• circulatory disorder with a disproportion between oxy-
Fig. 417  mottling of the skin: classic sign of shock (distur-
gen delivery and oxygen consumption: The oxygen
bed vasomotion)
delivery DO2 is less than the oxygen consumption VO2.
• critical reduction of microcirculation with consecutive
tissue hypoxia and metabolic disorders
• The disturbance of microcirculation leads to mi-
crothrombi with consecutive failure of various organs
(so-called shock organs).
• etymology: French "choc" (term introduced in 1737 by
the French surgeon Henry Francois Le Dran for the ty-
pical symptomatology that occurred after major trauma
as a result of gunshot wounds)
• every third intensive care patient
• Shock is not recognized in 50% of cases because
people often focus only on blood pressure and do not
consider cardiac output. The patient may be in shock
despite a normal blood pressure (tip: central venous
saturation [good and simple surrogate parameter for
CO] simply determine by BGA from CVC and lactate)! always assess the skin if shock might
• The decisive factor is not the disturbance of the macro- be an issue (not only blood pressure!)
circulation, which can be recognized e.g. by the blood
pressure, but the disturbance of the microcirculation
(i.e. the circulation in vessels with a diameter < 100 μm
[arterioles, capillaries, venules]): This can be clinically
Consequences ("shock organs")
assessed most easily by assessing the skin (classic • skin (the skin is the first organ affected by shock!)
shock organ!). The skin is the first organ whose blood -- mottling (disturbed vasomotion)

General Part 245

 -- acrocyanosis
• kidney: acute kidney injury (oliguria, anuria) Goals in shock therapy: maintai-
• lung: ARDS ning an adequate oxygen delivery
• liver: shock liver (syn. hypoxic hepatitis; see page (DO2) and of a sufficient perfusion
442) pressure (MAP)!
• heart: decreased coronary perfusion, heart failure
• coagulation: disseminated intravascular coagulation
(DIC) Hypovolemic shock
• CNS: decreased cerebral perfusion with disturbance of
consciousness or agitation Causes
• intestine: non-occlusive mesenteric ischemia (NOMI; • hemorrhage (hemorrhagic shock)
see page 951) -- external (e.g. polytrauma, post partum)
-- internal (e.g. oesophageal variceal bleeding, splenic
Types rupture, pelvic fracture)
• hypovolemic shock (volume deficiency) • fluid sequestration (e.g. peritonitis, pancreatitis, ileus)
• anaphylactic shock (allergic reaction) • exsiccosis
• septic shock (see chapter Sepsis [page 820]) • vomiting, diarrhoea
-- most common shock form • burns
-- shock form with the highest mortality (50%)
-- only shock form with a not reduced (possibly
even increased) cardiac output (For all other shock
forms the cardiac output is reduced!)
• cardiogenic shock (see chapter cardiogenic shock
[see page 357]; for a long time considered the shock
with the highest mortality; however, the mortality rate
of cardiogenic shock has decreased to 42% in recent
years. The shock form with the highest mortality now
is septic shock!)
• neurogenic shock:
-- failure of the regulation of circulation and vascular
tone in lesions of the spinal cord (e.g. acute paraple-
gia [spinal shock], Guillain-Barré syndrome) or the
brain (e.g. traumatic brain injury, meningoencepha-
litis)
-- only shock form without tachycardia (mostly bra-
dycardia)!
-- a vasodilatory shock (therapy: noradrenaline)

Fig. 418  splenic hematoma after a skiing accident

246 General Part


Fig. 419  rupture of the spleen after a scooter accident
(note: A splenic rupture is mostly treated conservatively
today!)
Classification
• hypovolemic shock in the broader sense:
-- traumatic haemorrhagic shock with tissue damage
(e.g. polytrauma with severe soft tissue injury)
-- haemorrhagic shock (acute bleeding without tissue
damage; e.g. oesophageal variceal bleeding, post-
partum hemorrhages due to uterine atony)
-- traumatic hypovolemic shock (pronounced tissue
damage, no bleeding; e.g. burns)
• hypovolemic shock in the narrow sense: fluid sequest-
ration into the third space (e.g. peritonitis, pancreatitis,
ileus)
Therapy
• causal (i.a. endoscopic haemostasis, polytrauma care
according to the criteria of ATLS [Advanced Trauma
Life Support])
• symptomatic
-- volume administration
◦◦ A hypovolemic shock is treated with volume
(and not with catecholamines)! This also applies
to dialysis patients or patients with heart failure!
Catecholamines only mask volume deficiency!!
◦◦ In individual cases, however, it may be necessary
to use catecholamines temporarily at short notice
to generate a sufficient blood pressure until the re-
quired volume has been applied in sufficient quan-
tity and has become effective. Furthermore a drop
of diastolic blood pressure can lead to a critical
reduction in coronary perfusion and possibly to
ventricular fibrillation. In addition, traumatic hypo-
volemic shock (polytrauma) often leads to vasodi-
latation (i.a. caused by analgosedation with loss
of sympathetic tone, inflammation due to trauma
or injury to the spinal cord), so that a vasopressor
(usually norepinephrine) is necessary.
-- safeguarding and restoration of vital functions
-- shock psoition (passive leg raising)
-- if necessary administration of red cell concentrates
(RCC)
◦◦ In the case of acute bleeding, the indication for
RCC administration is based less on the hemo-
globin value and more on the clinically estimated
blood loss!
◦◦ Use of rapid infusion systems if necessary (e.g.
Level 1)
Anaphylactic shock
Definition
• severe allergic reaction (hypersensitivity reaction) with
circulatory failure
• a distributive shock (disturbance of distribution)
• etymology: Greek "phylaxia": "protection", anaphylaxis
"without protection, defencelessness" (term introduced
by Richet in 1902, after dogs died suddenly as a result
of the injection of a toxin of the sea anemone)
• incidence: 10-20/100000 (increasing)
Pathophysiology
• previous antigen contact obligatory (sensitization)
• reactions:
-- IgE-mediated (immediate reaction; type I according
to Coombs and Gell)
-- IgG-mediated (late reaction; type III according to
Coombs and Gell; in 25% additionally [biphasic
course] occurring as second reaction after the first
event, on average after 10h; therefore patients
should always be admitted to the hospital)
• release of mediators (histamine, leukotrienes, prosta-
glandins, bradykinin, PAF [platelet activating factor])
from basophilic granulocytes and mast cells; conse-
quences:
-- vasodilation
-- increased capillary permeability → marked loss of
volume due to extravasation of the intravascular lu-
men)
-- bronchospasm
Causes
• food (No.1)
-- 5% of all adults have food allergy.
-- mainly nuts (especially in children; cave mainly "hid-
den" nuts in chocolate or bars), fish, eggs, shellfish,
soy, flour, cereals (oats, rye, wheat), ingredients/ad-
ditives
-- can also be triggered by inhalation (e.g. haze when
cooking fish) in very highly sensitized people
• medication (No.2), i.a.
-- antibiotics, i.a.:
◦◦ penicillin
▪▪ most frequent cause of a drug-induced aller-
gic reaction
▪▪ In 90%, however, it is not a penicillin allergy
(only unspecific reaction), so that unfortunately
antibiotics that are too broad and less effective
are often used in everyday clinical practice due
to an alleged penicillin allergy.
▪▪ note: Carbapenems such as imipenem or mero-
penem are permitted in cases of penicillin aller-
gy.
◦◦ cephalosporins
General Part 247
 -- analgesics (ASA, NSAID [e.g. diclofenac]; second -- stridor:
most frequent cause of a drug-induced allergic re- ◦◦ expiratory (bronchospasm)
action ◦◦ inspiratory (laryngeal edema, syn.: glottis edema
-- X-ray contrast agent [most frequent cause of death!])
-- immunoglobulins -- cyanosis
-- anesthetics (especially muscle relaxants [succhinyl- • cardiac:
choline!], local anesthetics, hypnotics) -- hypotension, tachycardia
-- cytostatics -- arrhythmia
-- blood products -- chest pain
-- colloids: All colloids (especially gelatine and dextra- • gastrointestinal:
nes) can cause an allergic reaction!
-- dysphagia, salivation ( warning sign [indication
• insect bites for intubation]: If a patient is no no longer able to
-- wasp (most frequent; 3% of all Germans have a swallow his saliva, one must already assume a
wasp venom allergy) pronounced swelling. At the latest now the patient
-- bee should be intubated!)
-- bumblebee -- nausea, vomiting, diarrhea
• puncture of an echinococcus cyst (e.g. percutaneous -- abdominal pain (colicky; classic especially in
liver puncture; a septated liver cyst must never be children!)
punctured; puncture only after negative serology) • neurological:
• physical stress (exertion-induced anaphylaxis; e.g. -- headache
jogging; mostly unknown wheat allergy; the allergens -- dizziness
are absorbed more quickly by stress)
-- loss of consciousness
• idiopathic (no cause to be determined; 30%)
◦◦ qualitative (delirium)
◦◦ quantitative (somnolence, coma)
-- seizure
-- syncope

Fig. 420  CT abdomen: echinococcal cyst of the spleen

Symptoms
• dermatological:
-- urticaria ("hives")
-- flush
-- itching (beginning mostly plantar and palmar)
-- swelling of the lips, tongue, uvula
-- angioedema
-- Rhinorrhoe
-- erythema exsudativum multiforme
-- possibly Stevens-Johnson syndrome, Lyell syndro-
me (syn.: toxic epidermal necrolysis [TEN], scal-
ded skin syndrome; especially on medication; like
second-degree burns; classic: hemorrhagic cheilitis
[bloody lip inflammation; only found here!])
• pulmonary:
-- hoarseness, coughing
-- dyspnea, tachypnea

248 General Part


Fig. 421  Urticaria (various examples)
Fig. 422  Erythema exsudativum multiforme
Fig. 423  Lyell syndrome
Fig. 424  Stevens-Johnson syndrome: Pathognomonic is
the hemorrhagic cheilitis (inflammation of the lips). It is
usually an allergic reaction to medication (most common:
allopurinol [esp. in redeuced renal function])
Laryngeal edema: most frequent
cause of death in anaphylaxis!
Differential diagnosis
• mastocytosis (diagnosis: tryptase in serum; methyl imi-
dazole acetic acid and methyl histamine in urine)
• carcinoid (diagnosis: 5-hydroxyindole acetic acid in
urine)
• angioedema (Quincke's edema)
• pheochromocytoma
• panic attack (hyperventilation)
Therapy
• stop further antigen supply
• sufficient administration of volume (crystalloids)
-- adults: 500-1000ml
-- children: 20 ml/kg
• adrenaline (Suprarenin):
-- catecholamine of choice in anaphylactic shock
-- catecholamine of choice in anaphylactic shock
- the most important drug in anaphylaxis (always in-
dicated when the symptoms of an allergic reaction
go beyond a skin rash, i.e. from grade II; is often
forgotten or administered far too late; it is much more
effective than the usual "triple cocktail" of prednisolo-
ne, H1- and H2-blockers!
-- application:
◦◦ i.m. (not s.c.; even better than i.v. because of less
side effects); not i.m. in case of VKA [Vitamin K
antagonist] or NOAK (here s.c. or i.v. [better])
▪▪ for patients not requiring resuscitation me-
ans of first choice
General Part 249
 ▪▪ location: outside of thigh or upper arm
▪▪ dosage (1:1000, i.e. 1 amp. = 1ml = 1mg pu-
rely drwan up with a insulin syringe): adults +
children > 12 years: 500μg (0.50ml), children
6-12 years: 300μg (0.30ml), children 6 years -
6 months: 150μg (0.15ml), < 6 months: 50μg
(0.05ml)
◦◦ i.v.
▪▪ in patients requiring resuscitation or in case of
a insufficient response to or contraindications
(VKA, NOAK) against the i.m. administration
▪▪ Dosage: 1:100000 (1 vial of adrenaline a 1mg in
100ml NaCl 0.9% → repetitive milliliter-wise i.v.
application)
◦◦ endobronchial (triple dose)
• antiallergic ("triple cocktail"; critical note on effective-
ness: This "triple cocktail" is almost always given,
although the effectiveness has not been proven. Ste-
roids have no effect at all in the acute phase, they only
reduce the risk of a late reaction, i.e. a biphasic course.
H1-blockers only have an effect against itching and urti-
caria, but not for example against bronchospasm, gas-
trointestinal symptoms or shock. Ultimately, no effect
at all is proven for H2-blockers):
-- prednisolone 250-500mg i.v., then for prophylaxis
of late reaction for two days 1 x 50mg p.o. each day
(e.g. outpatient [most practical])
-- Antihistamines: Always apply H1-blockers prior
to H2-blockers, otherwise coronary vasoconstriction,
bradycardia and reduction of inotropy may occur
[known from animal experimental data [Felix et al,
Agents Actions 1991])!
◦◦ H1-blocker, e.g. dimetindene (Fenistil) 4mg i.v.
◦◦ H2-blocker, e.g. ranitidine (Zantic; note: recalled by
the German Federal Institute for Drugs and Medi-
cal Devices [BfArM] in 2019 due to potential con-
tamination with the carcinogenic substance NMDA
[nitrosodimethylamine]) 200mg i.v. or famotidine
(Pepcid, Pepdul) 20mg i.v.
• glucagon if necessary:
-- If patients on β blocker medication suffer an ana-
phylactic shock, the possibility of endogenous coun-
terregulation is limited. These patients should there-
fore receive glucagon (in case of a life-threatening
allergic reaction).
-- mechanism of action: increase of the intracellular
cAMP concentration → inotropy ↑, chronotropy ↑
-- dosage: 50 μg/kg as bolus, then 70 μg/kg/h i.v., also
possible i.m. or intranasally (e.g. via MAD)
• anti-obstructive therapy if necessary (e.g. nebulisation
with Berodual, adrenaline; e.g. theophylline as a short
infusion [no longer generally recommended])
• others:
-- Patients who are under the following pre-medication
have an increased risk:
◦◦ β-blocker (reduced ability for endogenous coun-
terregulation; furthermore, adrenaline in this case
is ineffective at the ß-receptors because they are
blocked) → glucagon
◦◦ ACE inhibitors (inhibition of kinase II → reduced
250 General Part
degradation of mediators → prolonged allergic re-
action)
-- After an insect bite, tetanus immunity must be che-
cked and, if necessary, a booster vaccination must
be injected (is often forgotten!).
-- possibly hyposensibilization after allergic reaction
after insect bite in the winter months (after the end of
the insect flight); annot.:
◦◦ determination of the specific IgE
◦◦ After allergic reaction by hornet, hyposensibiliza-
tion with wasp venom takes place, after allergic
reaction by bumblebee, hyposensibilization with
bee venom occurs.
-- in unclear cases allergy testing in the interval (possi-
ble after 4 weeks at the earliest)
-- If the allergic genesis is unclear, tryptase can be de-
termined in serum and thus retrospectively the aller-
gic genesis can be confirmed.
-- making out of an allergy passport
-- if necessary handing out an emergency set
◦◦ auto-injector for adrenaline
▪▪ most important part of the emergency set
▪▪ dosage: < 30kg: 0.15mg; > 30kg: 0.30mg
▪▪ examples: Fastinjekt, Anapen, Jext
▪▪ costs: 80€ (in USA: 800$)
▪▪ not only handing out, but also training how it
works!
◦◦ possibly also antihistamine (e.g. Cetirizine AL
10mg/ml drops, e.g. Fenistil drops), betamethaso-
ne (e.g. Celestamine Liqu.), inhalative β2 sympa-
thomimetic (e.g. salbutamol)
most important therapy in
anaphylaxis: adrenaline i.m. (even
prior to the "triple cocktail")
in 25% late reaction (biphasic
course) → therefore always
hospital admission!
Angioedema
Definition
• syn.:
-- Quincke's edema (named after the German internist
Heinrich Irenaeus Quincke [1842-1922])
-- angioneurotic edema
• acute circumscribed swelling of the skin/mucosa in the
head area (mostly in the face), but also in the neck,
extremities or genitals
-- especially lips, eyelids, tongue, glottis
-- Angioedema is never generalized! This is the
most important distinguishing feature from anaphy-
laxis!
• often also involvement of the gastrointestinal tract
Types
• histamine-mediated (via mast cells) angioedema
-- allergic (most common; IgE mediated)
-- physical (pressure, cold, vibrations)
• bradykinin-mediated angioedema
-- C1 esterase inhibitor deficiency (The C1 esterase
inhibitor inhibits the conversion from pre-kallikrein
to kallikrein. Kallikrein stimulates the synthesis of
bradykinin. The C1 esterase inhibitor also inhibits
the activation of factor XII. The activated factor XII
stimulates the conversion from pre-kallikrein to kal-
likrein.)
-- ACE inhibitor / Angiotensin receptor blockers (ARB)
◦◦ RAAS-inhibitor induced angioedema (RAE)
◦◦ by inhibiting the degradation of bradykinin
◦◦ frequently (risk for the occurrence of angioedema
under ACE inhibitors: 0.4%)
◦◦ possible even after years (on average only occur-
ring after 3 years, not immediately!)
◦◦ always in the face, almost never peripherally
◦◦ Note: Angioedema can also occur under minoxidil.
◦◦ If you switch (e.g. in course of a heart failure the-
rapy) from an ACE inhibitor to an ARNI (angio-
tensin-receptor-neprilysin-inhibitor; e.g. Entresto
[sabucitril + valsartan]), the ACE inhibitor must be
discontinued at least 36 hours before, otherwise
the risk of angioedema is significantly increased.
This is not necessary in case of an angiotensin
receptor blocker: Here you can start with an ARNI
immediately after stopping the ARB.
• leukotriene-mediated angioedema
-- pseudoallergy (intolerance)
-- typical examples: ASA, diclofenac
-- inhibition of cyclooxygenase (COX) in arachidonic
acid metabolism → increased formation of leukot-
rienes
Angioedema in a patient with ACE
inhibitors on medication is
considered ACE-induced angio-
edema until proven otherwise!
C1-esterase inhibitor deficiency
• congenital (hereditary angioedema [HAE])
-- autosomal dominant (mutation of C1-INH gene on
chromosome 11; classically positive family history)
-- deficiency of C1-esterase inhibitor → activation of
the complement system (resulting in consumption
of complement factor C4 [is always reduced, even
during intervals; good screening parameter!])
-- types:
◦◦ type I (80%): C1-esterase inhibitor deficiency (fur-
thermore also complement factor C4 decreased)
◦◦ type II (15%): C1-esterase inhibitor functional de-
fect (C1-esterase inhibitor level usually increased,
complement factor C4 however decreased)
◦◦ type III (5%): mutation in the gene for factor XII
(Hageman factor) → reduced bradykinin degra-
dation (depending on estrogen, therefore almost
exclusively women)
-- prevalence: 1:50000
-- m = w
-- usually occurs before the age of 20 (typically comp-
laints since childhood)
-- recurrent localized swelling of the skin or mucosa
with restitutio ad integrum after 3-5 days
-- gastrointestinal attacks
◦◦ recurrent colicky abdominal pain
◦◦ nausea, vomiting, diarrhea
◦◦ pseudoperitonitis ("appendectomy scar")
◦◦ possibly even ascites (usually spontaneously re-
gressive)
-- frequent triggers for the attacks: stress (psychologi-
cal [e.g. stress], physical), surgery (e.g. tooth ext-
raction), trauma, infection, menstruation, pregnancy,
estrogens (especially in type III)
-- oedema
-- typically no urticaria, no itching, no rash
-- no allergic reaction → therefore antiallergic the-
rapy not effective
• acquired: acquired angioedema (AAE)
-- type I: by consumption of C1-esterase (especially
lymphomas, MGUS [monoclonal gammopathy of
undetermined significance], M. Waldenström, CLL,
cryoglobulinemia, SLE, Churg-Strauss syndrome
[EGPA: eosinophilic granulomatosis with polyangii-
tis])
-- type II: by auto-antobodies against C1-esterase in-
hibitor
Symptoms
• swelling (localized; never generalized)
-- in the face (lips, eyelids)
-- limbs
-- in the genital area
• in hereditary angioedema typically no itching
• glottis oedema → inspiratory stridor and dyspnea
• urticaria (typically absent in C1-esterase inhibitor defi-
ciency and in angioedema caused by ACE inhibitors)
• Pseudoperitonitis ("appendectomy scar"); usually
severe abdominal cramps
General Part 251

Fig. 425  angioedema with pronounced swelling of the ton-
gue
Trigger
• infections
• menstruation
• trauma, anaesthesia, operations (classic case: sud-
denly increasing swelling of the tongue in the posta-
naesthesia recovery room after surgery)
• heavy physical strain (including sports)
• medication: mainly antibiotics, antidiabetics, ACE inhi-
bitors, estrogens, alteplase (Actilyse; in 2% oropharyn-
geal angioedema)
◦◦ officially approved for HAE (hereditary angioe-
dema), but also effective in RAE (RAAS-inhibitor
induced angioedema [i.a. study Bas et al, N Engl
J 2015: see box]; note: The extension of the ap-
proval for RAE was planned, but the application
for a corresponding extension of the approval was
withdrawn because the data were not sufficient for
a positive benefit-risk assessment.)
◦◦ relatively expensive (approx. 1700 € per injection;
however, if you can avoid intubation with an inten-
sive care stay of several days, which will probably
cost even more overall, the costs are relativized)
◦◦ effective onset on average after approx. 2h (com-
plete regression of the angioedema on average
after 8h)
◦◦ i.a. since 2011 already approved for self-medica-
tion in patients with hereditary angioedema
-- Since it is not allergic, an anti-allergic therapy is
also ineffective! Nevertheless, in everyday clinical
practice it is usually the case that antiallergic thera-
py (H1-blocker, H2-blocker, steroid) is administered,
because in an emergency situation, unless the pati-
ent is familiar with it, you can never distinguish with
certainty between a histamine and a bradykinin me-
diated angioedema.

Laboratory (C1-esterase inhibitor deficiency)

• complement C4 ↓ (as screening; C4 is always reduced
[also during interval], since the deficiency of C1-este-
rase inhibitor leads to permanent uncontrolled comple-
ment activation) Fig. 426  Icatibant (Firazyr): should be available (in the
• determination of C1-esterase inhibitor (concentration, emergency room or intensive care unit) for severe cases of
activity) HAE / RAE (e.g. shortly before intubation)

Classification
• with urticaria: mostly histamine-mediated (steroids, HAE / RAE: Steroids, H1- and
H1-/H2-blockers effective) H2-blockers are ineffective!
• without urticaria: mostly bradykinin-mediated (steroids,
H1-/H2-blockers ineffective)

Therapy Emergency therapy of C1 estera-

se inhibitor deficiency: admini-
• if necessary early protective intubation (preferably stration of FFP, Berinert, possibly
bronchoscopically) to secure the airways icatibant (if available)!
• histamine-mediated angioedema → antiallergic thera-
py
-- prednisolone
-- H1-blocker, H2-blocker
-- adrenaline (from grad II)
• C1-esterase inhibitor deficiency:
-- FFP (also contains C1-esterase inhibitor)
-- C1-esterase-inhibitor (Berinert, Cinryze): 20 E/kg i.v.
-- Icatibant (Firazyr) s.c.:
◦◦ Bradykinin receptor antagonist
◦◦ a synthetic nonapeptide
◦◦ dosage: 1 amp. = 3ml = 30mg s.c.

252 General Part

 study

A randomized trial of icatibant in ACE-inhibitor-induced an-

gioedema
Bas et al, N Engl J 2015

• multicenter double-blind randomized trial

• 27 patients with ACE inhibitor-induced angioedema
(RAE)
-- icatibant 30mg s.c.
-- prednisolone 500mg + clemastine 2mg
• results: icatibant
-- significantly shorter time to symptom relief (2h versus
12h)
-- significantly shorter time to complete resolution of an-
gioedema (8h versus 27h)

Prophylaxis
• androgen derivatives: danazol, stanazol
• tranexamic acid (less effective)
• icatibant (Firazyr)
• C1-esterase-inhibitor (Berinert, Cinryze; 60 IE/kg s.c.
every 3-4 days for 14 weeks)
• lanadelumab (Takhzyro):
-- a recombinant antibody against pre-kallikrein
-- reduction of HAE attacks by 87%
-- pre-filled syringe a 300mg s.c. every 2 weeks for 26
weeks
• ACE inhibitor/ ARB (angiotensin receptor blocker)/
ARNI (angiotensin receptor neprilysin inhibitor): cont-
raindicated

General Part 253

 al, Crit Care 2013). However, there are two exceptions:
NUTRITION acute pancreatitis and acute liver failure.

Every third inpatient is malnourished!

Nutritional nihilism! Sad reality in the

intensive care unit!
Nutrition: an integral part of intensive
care medicine!

Consequences
• increased infectious complications
• increased wound healing disorders
• more frequent decubital ulcers
Guidelines • longer ICU- and hospital stay
• delayed rehabilitation
• national (DGEM [German Society for Nutritional Medi- • higher costs
cine]) S2k-guideline „Clinical Nutrition in Critical Care
• increased mortality (twice as high [Mogensen et al, crit
Medicine" 2018
Care Med 2015]
• international
• As a complication of nutritional therapy of malnouris-
-- European: ESPEN (European Society for clinical nu- hed patients refeeding syndrome can occur (see page
trition and metabolism) 270) auftreten. The most important marker for this is
-- American: ASPEN (American Society for Parenteral hypophosphataemia. Therefore, the calorie count for
and Enteral Nutrition) malnutrition is best based on the phosphate level (see
page 280).

Malnutrition

Definition study
• The term malnutrition covers the following three enti-
ties:
-- disease-related and involuntary weight loss Nutrition therapy in the critical care setting: What is „best
-- protein deficiency achievable“ practice? An international multicenter observa-
-- specific nutrient deficiency (especially vitamins) tional study
• malnutrition should not be confused with undernou- Cahill et al, Crit Care Med 2010
rishment (p.d. BMI < 18.5 kg/m2). Malnutrition can
• observational study in 158 intensive care units (20 coun-
even be present in obese patients! The majority (60%) tries), 2946 patients
of all obese patients in the intensive care unit are even • median time to start enteral nutrition: 46.5h (according to
malnourished (Robinson et al, Crit Care Med 2015)! guidelines: < 24h!)
• only in 13% start of nutrition < 24h (clearly recommen-
Epidemiology ded!)
• normocaloric nutrition takes place in only 59% (41% hy-
• 30% of all inpatients (especially geriatric and onco-
pocaloric)
logical patients) are malnourished.
• in 20% of patients no nutrition at all
• 38% of all patients who were hospitalized with a nor-
mal nutritional status develop malnutrition during their
hospital stay (Kirkland et al, AJM 2018).
Estimation (nutritional status)
• 40% of ICU-patients without any nutrition, in 58% too
little nutrition (hypocaloric) • anamnesis (unintended weight loss within the last 3
months)
• nutrition: stepchild in intensive care!
• body-mass-Index (BMI): weight in kg / height in m to
• In contrast, obese intensive care patients paradoxi- square < 18.5 kg/m2
cally have a survival advantage over normal weight in-
• laboratory parameters
tensive care patients (probably due to the larger energy
reserves; so-called obesity paradox). This could also • scores
be shown in patients with septic shock (Wacharasin et

254 General Part

 MUST
When admitted to the ICU, the
patient's nutritional status should
always be estimated!

Laboratory parameters
• albumin < 30-35 g/l (hypoalbuminemia: Proteins are
broken down in a catabolic metabolic state, e.g. also
functional proteins such as albumin.)
• pre-albumin < 140-160 mg/l
• lymphocytes < 1200/mm³
• cholesterol < 100 mg/dl
• triglycerides < 50 mg/dl
• creatinine < 0.5 mg/dl (decreased muscle mass so that
the synthesis of creatine is reduced)
• urea / creatinine > 40 (sign of catabolism [Proteins
are broken down in a catabolic metabolic state. This
creates ammonia, which is converted to urea in the
liver so that the urea level rises.])
• Bistrian-index (syn.: catabolism index, creatinine-
height-index; 24-hour urine collection) < 80% (sign of
catabolism)
-- Ratio of the measured to the ideal creatinine excre-
tion
-- formula:
◦◦ men: urin volume x creatinine in urine (mg/dl) / 23
x (height in cm - 100)
◦◦ women: urin volume x creatinine in urine (mg/dl) /
18 x (height in cm - 100)

Increased urea with normal creatinine

is usually a sign of malnutrition
(catabolism) and not of acute kidney
injury!

Scores
• MUST (malnutrition universal screening tool; see info-
box, according to Kondrup et al, Clinical Nutrition 2003)
-- BMI Hackl-Score
-- weight loss
unwanted catabo-
-- acute disease weight loss albu- lism
• score according to Hackl (see table) - The sum of the in % last 3 min urea/ crea-
points gives the indication for nutritional therapy: BMI months g/l tinine points
-- ≤ 2P.: not indicated 25-19 <3 > 35 <30 0
-- 3-4P.: recommended 19-17 3-5 30-35 30-50 1
-- ≥ 5P.: obligatory 17-16 5-10 25-30 50-70 2
• NRS 2002 (nutritional risk screening):
<16 > 10 < 25 > 70 4
-- score for screening for malnutrition (see infobox)
-- recommended in the ESPEN guidelines
-- according to Kondrup et al, Clinical Nutrition 2003 days points
• MNA (mini nutritional assessment) ≤2 0
• SGA (subjective global assessment) 2-7 1
long-term 5

General Part 255

 patients with liver cirrhosis: these patients have no re-
serves at all and become catabolic without nutrition in
a very short time. For this reason, nutrition should start
within the first 12 hours. A patient with liver cirrhosis
should never be left without food for a long time!
• studies:
-- EPaNIC study (see box)
-- SPN study (Heidegger et al, Lancet 2013): In pati-
ents in whom enteral nutrition > 60% of the target va-
lue was not possible by day 3, additional parenteral
nutrition led to a reduction in the rate of nosocomial
infections and the duration of ventilation. A mortality
benefit was not found.
-- EARLY-PN study (Doig et al, JAMA 2013): Patients
in whom enteral nutrition was contraindicated were
randomized to early and late parenteral nutrition.
Early parenteral nutrition reduced ventilation dura-
tion and coagulation failure. A mortality benefit was
not found.
-- PermiT study (Arabi et al, N Engl J 2015): A reduced
calorie intake ("permissive underfeeding"; but no re-
duction of proteins) showed no difference in mortality
compared to normal calorie intake.
-- A hypocaloric nutrition during the first week in criti-
cally ill patients led to an increased rate of nosoco-
mial infections compared to a normalcaloric nutrition
(Petros et al, JPEN 2016).
-- EAT-ICU study (see box)
-- meta-analyses:
◦◦ Marik et al, Crit Care 2001
◦◦ Doig et al, Intensiv Care Med 2009 (see box)
• gradual start:
-- enteral: 25% of the target infusion rate
-- parenteral: 50% of the target infusion rate
• According to current recommendations (i.a. Casear et
al, N Engl J 2014) critically ill patients should only be
given hypocaloric nutrition ("permissive underfeeding",
i.e. only 10-15 kcal/kg instead of 25 kcal/kg) in the first
Timing 7 days, provided there is no malnutrition.
• With the NUTRIC-Score (Heyland et al, Crit Care 2011;
see infoxox) it can be estimated in which patients hy-
pocaloric nutrition is still possible (low risk: 0-4P.) and
in which patients a normocaloric nutrition is indicated
from the beginning (high risk: 5-9P.).
• The S2k-guideline of the DGEM 2018 recommends
(deviating from from the ASPEN and SSC guidelines)
to start with 75% of the calorie target (i.e. 18 kcal/kg)
in the acute phase.

• early start of nutrition (i.e. within the first 24 hours;

after stabilization of circulation): The nutrition should
be enteral. Early parenteral nutrition is not recommen-
ded (SSC-guidelines 2016).
• Early start of nutrition is important, especially for

256 General Part

 EPaNIC study
Early versus Late Parenteral Nutrition in Critically Ill Adults
Casaer et al, N Engl J 2011
• multicenter randomized study
• 4640 intensive care patients in whom sufficient enteral
nutrition could not be achieved
-- early parenteral nutrition (i.e. within 48h after admissi-
on; according to European guidelines)
-- late parenteral nutrition (i.e. only from day 8; accor-
ding to American and Canadian guidelines)
• results: early parenteral nutrition
-- longer ventilation duration
-- longer hospital stay
-- longer renal replacement therapy
-- more cholestasis
-- more infections
-- higher costs
-- mortality (90 days): no difference
EPaNIC study
notes
• The probability of being discharged alive earlier is, in my
opinion, a very unusual primary endpoint. The mortality
itself did not differ at all.
• In the early parenteral nutrition group, patients were
partly overfed with an energy content of 35 kcal/kg. It is
known that hyperalimentation is absolutely harmful (e.g.
Dissanaike et al, Crit Care 2007).
• The median duration of intensive care in these patients
was relatively short at 4 days. After 3 days 40% were al-
ready discharged from the intensive care unit. According
to the current guidelines, however, artificial nutrition is
only necessary if the patients cannot be fed orally after
3-5 days. It can be assumed that many patients in this
study would not have needed artificial nutrition at all.
• Conclusion: "Do not panic about EPaNIC?"
• In any case, due to this study, the (at least early) paren-
teral nutrition was almost completely out for a long time.
meta-analysis
Early enteral nutrition, provided within 24 h of injury or in-
tensive care unit admission, significantly reduces mortal-
ity in critically ill patients: a meta-analysis of randomized
controlled trials
Doig et al, Journal of Intensive Care Medicine 2009
• 234 intensive care patients (6 randomized controlled
trials)
-- early (< 24h) enteral nutrition
-- standard nutrition
• results: early (< 24h) enteral nutrition
-- - significant reduction of the pneumonia rate
-- significant reduction of mortality
EAT-ICU study
Early goal-directed nutrition versus standard of care in
adult intensive care patients
Allingstrup et al, Intensive Care Med 2017
• monocentric randomized trial
• 203 ventilated intensive care patients with an expected
length of intensive care > 3 days
-- early goal directed nutrition (EGDN): full calories from
the beginning (energy requirement calculated accor-
ding to indirect calorimetry and urea balance; if this
was not possible enterally alone, then additionally pa-
renterally)
-- standard group: slow increase in calorie intake (full
calorie [25 kcal/kg] only on the 7th day; slow enteral
diet build-up)
• results: early goal directed nutrition
-- primary endpoint (physical function after 6 months
[PCS: physical component score]): no difference
-- secondary endpoints (i.a. mortality, organ failure,
length of ICU / hospital stay, infections): no difference
General Part 257
 Nutrition in the intensive care unit is best done using a
standardized protocol (nutritional protocol). In the AC-
CEPT studiy (Clifford et al, Crit Care Resusc 2010) the
duration of intensive care was shortened and the morta-
lity tended to be lower.

Nutritional therapy: use of a protocol

(nutritional protocol) in the intensive
care unit!

Stress metabolism

Definition
• syn.: post aggression syndrome
• physiological reaction of the body to a sudden onset of
early (especially enteral) start of a serious disease or surgery to provide the substrates
nutrition („early goal directed nutriti- and energy necessary for reconvalescence
on“): within 24 hours after admission / • increase in metabolism
stabilization -- gluconeogenesia ­↑ → glucose ↑ ­
-- reduction of storage depots
◦◦ lipolysis
The principle of "early goal directed nutrition" (EGDN)
in nutritional medicine has come into criticism in the ◦◦ proteolysis
same way as the principle of "early goal directed the- ◦◦ glycogenolysis
rapy" (EGDT) in sepsis therapy. However, both (EGDN • insulin resistance
and EGDT) still apply, only the targets ("goals") have • activation of sympathetic nervous system → stress
changed. In my opinion this term should be maintained, hormones (catecholamines [adrenaline, noradrenali-
hence it finally succeeded in bringing nutrition from its ne], cortisol, glucagon) ↑
shadowy existence into the focus of everyday activity in • release of cytokines (e.g. TNFα, Il-1)
the intensive care unit. The goal to start start nutrition
early, namely enteral nutrition, still remains, however with Phases (according to Cuthbertson and
the goal of trophic nutrition (i.e. 250 ml/d; "villi food"; "mi-
Moore)
nimal enteral feeding") with the goal to preserve the in-
testinal mucosa, i.e. to avoid villi atrophy in the intestine • acute phase
with consecutive translocation of the bacteria. The goal • flow phase
is certainly no longer to reach the full number of calories • reparation phase
(normocaloric) right from the first day. This can even be
dangerous (especially refeeding syndrome)! In the initial Acute phase
phase of a severe illness (aggression phase), externally • syn.:
added calories cannot be utilized at all anyway. It is com- -- aggression phase
pletely sufficient to increase the number of calories slow- -- ebb phase
ly. In principle, in the first week, as long as there is no
• duration: hours (12-24h; 1st day)
malnutrition, you should only nourish hypocalorically (i.e.
• The acute phase is usually rarely found in internal in-
10-15 kcal/kg). Only after about a week a fullcaloric nutri-
tensive care patients: The disease process (e.g. pneu-
tion (i.e. 25 kcal/kg) should be offered. Hyperalimentation
monia) often goes on for several days, so that this
is harmful and should definitely be avoided. Another goal
phase is often already over when the intensive care
is to make sure you have a sufficient protein intake to
dependency arises. However, the acute phase is of-
avoid catabolism.
ten found in postoperative intensive care patients (e.g.

258 General Part

 traffic accident with polytrauma; e.g. after appendecto- amount of calories (hypocaloric; approx. 500-1000
my inacute perforated appendicitis). kcal or 10-15 kcal/kg) is performed.
• Due to evolution, the organism assumes shortly after
a life-threatening acute event that it will temporarily no Reparation phase
longer be possible take up food. After a severe injury, • syn.: convalescence metabolism
the stone age man couldn't leave his cave to collect • replenishment of resources
or hunt anymore. The organism prepares itself for the • duration: weeks to months
fact that the body's reserves must now be utilized. To • There is an increased release of insulin. Insulin is a
ensure survival (e.g. to fight or flight), quickly availab- classic anabolic hormone: It promotes the build-up
le energy sources are provided, especially for energy of fat, glycogen and protein. The release of catabolic
supply to glucose-dependent organs (especially the hormones (catecholamines, glucagon, cortisol) is re-
brain): Most of these sources are glucose and free duced.
fatty acids. This is achieved by massive release of ca-
• Own energy recources are no longer available at all
tabolic hormones ("anti-insulinary" hormones, stress
(because they are used up), so that nutrition is com-
hormones: catecholamines [especially adrenaline],
pletely necessary. Externally supplied calories are
glucagon, cortisol [syn.: hydrocortisone]). This leads
completely utilizable now. There is no more insulin re-
to an increased glycogenolysis, and gluconeogenesis
sistance. In this phase, a nutrition with a full amount of
and thus to hyperglycemia. Furthermore, lipolysis and
calories (full- / normocaloric; approx. 1500-2000 kcal
proteolysis are increased. A release of amino acids
or 25 kcal/kg) is performed.
from the skeletal muscles provides glucoplastic amino
• positive nitrogen balance (due to protein synthesis;
acids. These are used for gluconeogenesis in the liver.
anabolic)
As a result of an increased ADH release, water retenti-
on with edema occurs.
• hypermetabolism: glycogenolysis, lipolysis, proteolysis acute flow reparation
phase phase phase
• The release of insulin, an anabolic hormone, is sup-
pressed. duration hours days weeks

• supply from our own energy resources (e.g. glyco- adrenaline ↑↑ ↑ ↓

genolysis, gluconeogenesis, lipolysis with the release glucagon ↑↑ ↑ ↓
of free fatty acids, proteolysis)
cortisol ↑↑ ↑ ↓
• negative nitrogen balance (due to protein degradation;
catabolic) insulin ↓↓ ↓ ↑

• In this phase no nutrition is indicated! nitrogen

balance negative equal positive
-- The body is inundated with its own substrates any-
way! nutrition none half full
-- Externally supplied calories are not utilizable here,
because the insulin release is suppressed (missing Fluid requirement
insulin response, insulin resistence with disturbance
of glucose utilization; "stress diabetes" of the criti- • 30 ml/kg bw
cally ill patient; „metabolic paralysis“). They can only • loss through perspiratio insensibilis: 0.5 ml/kg/h
be metabolized if insulin is admistered externally at • in case of fever additionally 10 ml/kg per degree Celsi-
the same time. us > 37°Celsius (or 99° Fahrenheit)
-- Nutrition is even harmful here, since hyperglycemia • means of choice: crystalloids crystalloids
and hypertriglyceridaemia with fatty liver can deve-
lop.
-- In contrast to the hunger metabolism, the aggression
metabolism cannot be broken through nutrition.
• In the acute phase, no nutrition is performed. He only
gets fluid and electrolytes.

Flow phase
• syn.:
-- post aggression phase
-- transition phase
• duration: days (usually approx. 10 days)
• decrease of the catabolic hormones (catecholamines,
glucagon, cortisol) and increase of the anabolic hor-
mone (insulin)
• equal nitrogen balance
• Your own energy resources are no longer sufficient,
so that supplementary nutrition ("metabolic support")
is necessary. In this phase, a nutrition with a reduced

General Part 259

 -- energy requirement = oxygen uptake x caloric equi-
valent
-- determination of the respiratory quotient RQ = VCO2/
VO2 (norm: 0.83)
-- indirect Fick's principle
-- limitations
◦◦ beyond a FiO2 > 60% in ventilated patients no lon-
ger reliable
◦◦ ECMO (The CO2 is removed extracoprorally here.)
-- no clinical routine (academic)
-- EAT-ICU study (Allingstrup et al, Intensive Care Med
2017): no advantages of a caloric intake guided by
indirect calorimetry and measurement of urea excre-
tion in the urine compared to standard nutrition with
25 kcal/kg

Calorie requirement: 25 kcal/kg bw

Orientation on the ideal (not actual)

weight; important especially in case of
under- or overweight!

Harris-Benedikt
formula

Energy requirement

Basal metabolic rate

• definition: energy turnover per day in resting (therefore
Total energy turnover
syn.: resting metabolic rate)
• total energy turnover = basal metabolic rate x PAL
• estimation: formula
• PAL: physical activity level
-- 20-25 kcal/kg bw (exactly: women 20 kcal/kg,
men 25 kcal/kg, i.e. approx. 1500-2000 kcal/day)
◦◦ For underweight (BMI < 18.5 kg/m2) and moderate
overweight (BMI 25-30 kg/m2), the ideal and not
the actual weight is taken as a basis.
◦◦ For pronounced overweight (BMI > 30 kg/m2) the
formula applies: ideal weight x 1.3. According to
the S2k guideline of DGEM 2018 with regard to
obesity the following is recommended: BMI 30-50
kg/m2 → 11-14 kcal/kg real weight, BMI > 50 kg/m2
→ 22-25 kcal/kg ideal weight
-- S2k guideline DGEM 2018: 24 kcal/kg (a pragmatic
recommendation: If you feed enterally with standard
tube food [1 kcal/ml] for 24 hours a day, the infusion
rate of the pump corresponds to the patient's current
weigh.t)
-- Harris-Benedict (see box; the formula according to
Harris-Benedict dates back to 1919 and was deter-
mined on healthy volunteers.)
• measurement: indirect calorimetry

260 General Part

 Both hypo- and hyperalimentation
should be avoided!

Special cases
• liver cirrhosis: high energy requirement (35 kcal/kg
(30-35 kcal/kg [based on real weight; in patients with
ascites based on ideal weight])
• hypothermia: low energy requirement (um 30% redu-
ziert)
• obesity (see infobox)

nutrition in obese patients: hypoca-

loric + high-protein!

Contraindications (nutrition [PN/ EN])

• Acute phase of a disease, immediately after surge-
ry / trauma: No nutrition is indicated here, as externally
supplied calories cannot be utilized and can only harm
here.
• shock of any kind (no nutrition in a state of shock!
nutrition only after stabilization of circulation; however,
minimal enteral feeding [MEF] possible and quite ad-
visable!)
• severe acidosis (pH < 7.2)
• severe hypoxia / hypoxemia (paO2 < 50mmHg)

no "shock nutrition": no (full-caloric)

nutrition in shock (applies to both
parenteral and enteral nutrition); only
MEF (minimal enteral feeding)!

Types
• parenteral nutrition (PN)
• enteral nutrition (EN)

enteral parenteral

central

oral

gastral
jejunal
peripheral

General Part 261

Fig. 427  the different access routes for nutrition: First Indications
choice is the enteral access. If the patient can eat (e.g.
monitoring in the ICU after PTCA after a myocardial in- • necessity of nutrition and impossibility / contraindica-
farction), the nutrition is oral. It should be startet within 24 tion for enteral nutrition
hours of admission to the ICU. If an oral nutrition is not • overlapping until sufficient enteral nutrition is possible
possible within three days, a gastral nutrition is performed
(via a gastric tube). Jejunal nutrition is only indicated in
exceptional cases, if the gastric residual volume (GRV) is
Indications for a long-term parenteral
> 500ml/d despite administration of prokinetics (metoclo- nutrition
pramide, erythromycin). The parenteral access is the se- • short bowel syndrome
cond choice. Parenteral nutrition is usually performed via
a central venous access (CVC) and mostly supplementary -- anatomical
to enteral nutrition in order to achieve the required number -- functional
of calories. The amount of calories of the enteral nutrition • chronic inflammatory bowel diseases (CIBD)
is increased and the amount of calories of the parenteral • oncological diseases
nutrition is reduced every day.
• intestinal transit disorders
• HIV
Parenteral nutrition • cystic fibrosis

Components
• macronutrients:
-- carbohydrates (50-60%)
-- fats (30-35%)
-- amino acdis (15-20%)
• micronutrients:
-- electrolytes
-- vitamins
-- trace elements (minerals)

Definition
• supply of the necessary nutrients via a venous access
• less physiological than enteral nutrition
• approx. 8 times more expensive than enteral nutrition
Types
• supplemental parenteral nutrition (SPE): parenteral
nutrition is in addition to enteral nutrition (usually the
case).
• total parenteral nutrition (TPE): parenteral nutrition
alone without any ohne enteral nutrition (rarely the
case [There are actually no contraindications anymore
against additional minimal enteral feeding, i.e. 250ml
tube food per day, so that this should always be per-
formed!]).
Accesses
• central-venous (CVC; mostly)
• peripheral-venous; allowed (almost everything!):
-- fats
-- amino acids
-- glucose (only up to glucose 10% [At a concentrati-
on of glucose 20% and 40% effect like a "sclerosing
agent"])
Carbohydrates
• main energy supplier (main substrate for energy pro-
duction)
• Only glucose and no sugar substitutes such as e.g.
xylitol, sorbitol or fructose should be used as carbo-
hydrates.
• daily requirement: 4 g/kg bw (max. 5 g/kg bw), mini-
mum intake 150 g/d
• calorific value: 4 kcal/g
• concentrations:
-- glucose 5%: 0.2 kcal/ml (osmolarity: 277 mosm/l)
-- glucose 10%: 0.4 kcal/ml (osmolarity: 555 mosm/l)
-- glucose 20%: 0.8 kcal/ml (500ml G20%: 400 kcal;
osmolarity: 1110 mosm/l)
-- glucose 40%: 1.6 kcal/ml (500ml G40%: 800 kcal;
osmolarity: 2200 mosm/l)
-- glucose 70%: 2.8 kcal/ml (osmolarity: 3885 mosm/l)
• RQ (respiratory quotient): 1.0
• monitoring: blood sugar concentration (BSC)
-- target BSC < 180 mg/dl (BSC > 180 mg/dl in intensi-
ve care patients → increased mortality; but no more
intensive insulin therapy recommended, only gluco-
se control!)
-- if necessary insulin perfusor
◦◦ max. initially up to 6 IU/h (S2k-Leitlinie DGEM
2018: only up to 4 IE/h; note: In patients with
known diabetes mellitus, higher doses may be
necessary.), then first reduction of glucose and in-
crease of fats, if necessary reduction / discontinu-
ation of steroid therapy; only then further increase
of insulin perfusor

262 General Part

 ◦◦ control of the amount of calories on day 2 accor- ◦◦ dialysis: 2 g/h (Per hour of dialysis the body loses
ding to the running time of the insulin perfusor on 2g amino acids!)
day 1 (on day 1 75% [i.e. 18 kcal/kg]; according to ◦◦ CVVH (i.a. also auch during SLED): per litre of filt-
the S2k guideline DGEM 2018) rate x 0.2 g/kg amino acids
▪▪ 0-1 IE/h: 100% (i.e. 24 kcal/kg) -- fistulas (increased amino acid losses)
▪▪ 2-4 IE/h: 50% (i.e. 12 kcal/kg) -- drainages (e.g. with an open abdomen; increased
▪▪ > 4 IE/h: 25% (i.e. 6 kcal/d) amino acid losses [15-30g per liter of exudate])
• restriction:
-- chronic kidney disease (without renal replacement
therapy): 0.8 g/kg bw
-- liver cirrhosis with hepatic encephalopathy: In the
past a protein restriction was recommended (for 3d
20-30 g/d, then increase to 1 g/kg). But in the me-
antime this is no longer recommended (i.a. Cordo-
ba et al, J Hepatology 2004), hence this would only
intensify the catabolism already existing in cirrhosis
patients .
• The only clinical situation in which amino acids are
contraindicated, is the peracute liver failure, because
here amino acids are released from the liver itself.
• special forms:
-- AS Nephro in creatinine > 3 mg/dl (without renal re-
placement therapy
-- branched-chain amino acids (especially in liver cir-
rhosis with hepatic encephalopathy)
Fig. 428  glucose 40% 500ml

Amino acids
• daily requirement (proteins): 1.0-1.5 g/kg bw (approx.
100 g/d; is mostly underestimated; max. 2 g/kg bw)
• In the amino acid solutions the protein content is 17%
lower than in the formed protein, so that the calculated
amount has to be multiplied by 1.2.
• calorific value: 4 kcal/g
-- AS 10% 500 ml → 50g → 200 kcal
-- AS 10% 1000 ml → 100g → 400 kcal
• RQ (respiratory quotient): 0.8
• no protein storage in the body (The body has no pro-
tein storage!)
• Amino acids are not used for energy production, but for
substrate metabolism: They are the building blocks for
body proteins ("building blocks of life"). They are only
used for energy production in threatening exceptional
Fig. 429  AS 10% 500ml
situations (acute phase: e.g. stress, hunger).
• low energy gain, especially for the reduction of the
Branched-chain amino acids
disease-related catabolism
• Amino acids are not taken into account in the calculati- • rationale: In liver cirrhosis there are too many aro-
on of the supplied energy (convention [note: According matic and too few branched-chain amino acids (Val,
to the S2k guideline of DGEM 2018. they should alrea- Leu, Iso). The latter would be beneficial, as they would
dy be taken into account.]). inhibit protein degradation and thus the formation of
ammonia.
• monitoring: If the BUN (blood urea nitrogen; the mount
of nitrogen bound to urea in the blood; BUN = urea x • application:
0.47) increases by > 30 mg/dl per day or if the urea -- enteral: Falkamin 3 x 1 sachet (1.5g/kg)
increases by more than 60 mg/dl per day, the amino -- parenteral: Amino hepar 5% (500ml: 100 kcal) or
acid supply should be reduced. 10% (500ml: 200 kcal)
• increased need: • indications:
-- decubitus -- hepatic encephalopathy grade III/IV
-- renal replacement therapy (loss of proteins and thus -- after gastrointestinal bleeding (e.g. esophageal
amino acids): variceal bleeding) in patients with liver cirrhosis

General Part 263

 administered via transfusions (RCC, FFP), so that
the calculation is relatively unreliable and faulty and
therefore only plays a minor role in everyday clini-
cal practice. More suitable and more practical is the
urea production rate (UPR; see infobox).
• taregt: The nitrogen balance should be equal. The me-
tabolic status can be evaluated very well from the nit-
rogen balance:
-- A negative nitrogen balance indicates a catabolic
metabolism (protein degradation [breakdown]). This
is harmful because also important functional proteins
are also broken down: Due to the increased break-
down of albumin, for example, the oncotic (syn. col-
loidosmotic pressure) is reduced and edema occur.
-- Furthermore, an increased breakdown of functional
proteins can result in wound healing disorders and
a decrease in immune defense. In the severe acute
phase of the stress metabolism, negative nitrogen
balances of -30 to -40 g/day can occur.
-- A positive nitrogen balance indicates an anabolic
metabolism (protein synthesis [build-up]). This is fa-
Fig. 430  Amino hepar
vorable.
Nitrogen balance
• definition: difference between the amount of nitrogen
taken up with food or nutrition (with amino acids) and
the amount of nitrogen excreted (via urea in the urine)
• physiology: Nitrogen (N: Nitrogenium) only occurs in
proteins (amino acids). The proportion of nitrogen in
proteins is 16%, i.e. 1g protein contains 160mg nitro-
gen. Proteins are normally not used for energy pro-
duction. In catabolic situations (acute phase of stress
metabolism), however, proteins als also needed for
energy production and are degraded, so that nitrogen
arises. Nitrogen is present in the form of ammonia
(NH3), from which urea is formed in the liver in the
urea cycle. Urea consists of 2 molecules NH3 (ammo-
nia) and 1 molecule CO2 (carbon dioxide) and contains
2 atoms of nitrogen (formula: CH4N2O). Urea is well
water-soluble and is excreted in the urine via the kid-
ney.
• UN: urea nitrogen (the nitrogen bound to urea)
-- BUN: blood urea nitrogen (the nitrogen bound to Fats
urea in the blood; BUN = urea x 0.47)
• daily requirement: 0.5-1.5 g/kg bw (max. 1.8 g/kg bw
-- UUN: urine urea nitrogen (the nitrogen bound to
• energy storage in the body
urea in the urine)
• calorific value: 9 kcal/g (highest calorie content among
• determination:
all macronutrients)
-- nitrogen excretion: The amount of nitrogen bound to
• RQ (respiratory quotient) 0.7
urea (UUN: urine urea nitrogen) is measured in the
24-hour urine collection. • preparations from soy and olive oil (possibly additional
fish oil and coconut oil)
-- nitrogen uptake: either simply read the nitrogen con-
tent from the amino acid infusion bottle that the pati- • triglycerides (neutral fats; consisting of one molecule
ent received or calculate it (nitrogen in gram = amino glycerin and three fatty acids; mostly mixed solutions)
acids in gram / 6; the nitrogen content in proteins is -- 50% LCT (long-chain triglycerides)
16%) -- 35% MCT (medium-chain triglycerides)
-- calculation: nitrogen balance in g/day = protein up- • types:
take in g/day / 6 minus (urine urea nitrogen in 24h- -- fat solution 10%: 1.0 kcal/ml
urine in g/day plus 4g/day) (Approximately 4g nitro- -- fat solution 20%: 2.0 kcal/ml (e.g. Clinoleic 20%
gen per day are not excreted via the urin [urea] but 250ml: 500 kcal)
via the bowel) • monitoring:
-- Assessment: Among other things, nitrogen is also -- control of triglycerides twice a week
lost through bleeding and wound secretions and

264 General Part

 -- If the triglyceride level increases > 400 mg/dl (> 4.6 • contraindications:
mmol/l) or 3-fold from the initial value, the fat intake -- immediately postoperative
should be reduced (i.e. only given every second -- hypertriglyceridemia (> 1000 mg/dl)
day). If triglyceride level increases > 1000 mg/dl, -- DIC stage III
the fat intake should be completely stopped (cave
-- shock
especially acute pancreatitis with triglycerides >
1000 mg/dl). -- severe metabolic acidosis (pH < 7.2)
• classification of fatty acids: -- soy allergy
-- according to structure: • Fats should always be administered slowly (at least
over 12h, but not longer than 24h; also recommended
◦◦ saturated fatty acids: no double bond present
in ESPEN-guideline) when administered parenterally,
◦◦ unsaturated fatty acids (= Ωn-fatty acids [Ω: Ome-
as too fast administration leads to an overload of the
ga]): double bond present (The number n indica-
clearance function and thus particularly respiratory de-
tes the position of the first double bond.)
terioration can occur (worsening of oxygenation with
▪▪ mono-unsaturated fatty acids: only one double a decrease in Horovitz quotient paO2/FiO2 [Suchner et
bond present al, Crit Care Med 2001; Lekka et al, Am J Respir Crit
▪▪ poly-unsaturated fatty acids: more than one Care Med 2004]). On the other hand, they should not
double bond present be given too slowly (i.e. not > 24h), otherwise bacteria
-- according to synthesis: can accumulate.
◦◦ non-essential fatty acids: fatty acids that the body • If high doses of Propofol are applied, this should be
can produce itself included in the calculation (example Propofol 2%: 0.1
◦◦ essential fatty acids: fatty acids that the body can- g fat/ml, flow rate 10 ml/h → 240 ml/d, i.e. 24 g fat per
not produce itself, i.e. relies on the exogenous day → 216 kcal/d).
supply. The both essential fatty acids are:
▪▪ α-linolenic acid (ALA; a Ω3-fatty acid)
▪▪ linoleic acid (LA; a Ω6-fatty acid)
• Ωn-fatty acids (unsaturated fatty acids):
-- Ω3-fatty acids
◦◦ types:
▪▪ α-linolenic acid (ALA; contained in vegetable oil)
▪▪ eicosapentaenoic acid (EPA; contained in fish
oil)
▪▪ docosahexaenoic acid (DHA; contained in fish
oil)
◦◦ effect: anti-inflammatory (by decrease of the syn-
thesis of prostaglandin E3, leukotriene B5 and re-
solvins)
-- Ω6-fatty acids
◦◦ types:
▪▪ linoleic acid (LA)
▪▪ γ-linolenic acid (GLA [gamma linolenic acid]also
called dihomo-γ-linolenic acid [DGLA])
▪▪ arachidonic acid (AA)
Fig. 431  20% fat solution 250ml (here SMOFlipid [Fresenius
◦◦ effect: pro-inflammatory (by increase of the syn- Kabi]); SMOF is an abbreviation for: soybean oil + medium
thesis of prostaglandin E3, leukotriene B5 and re- chain triglycerides + olive oil + fish oil
solvins)
-- target: ratio Ω3-fatty acids : Ω6-fatty acids > 5:1 ( A
reduced content of Ω6-fatty acids is recommended,
since meta-analyses showed a higher morbidity [es-
pecially more infections] but no higher mortality com-
pared to Ω3-fatty acids.)
• examples (lipid emulsions):
-- Intralipid (Baxter)
-- Clinoleic (Baxter)
-- SMOFlipid (Fresenius Kabi)
-- Omegaven (Fresenius Kabi)
-- Structolipid (Fresenius Kabi)
-- Lipofundin (Braun)
-- Liposyn (Hospira)
Fig. 432  the three classic components of parenteral nutriti-
on: glucose, amino acids and fats [8]

General Part 265


carbohydrates, fats: especially for
energy metabolism
proteins: especially for substrae
metabolism
Principle in nutritional therapy:
Adjustment of the nutrition on the one
hand to the phase of the disease
(stress metabolism) and on the other
hand to the individual metabolic
tolerance of the patient!
Trace elements
• definition: elements that occur in the body only in a
very small amount (just in "traces")
• representatives: iron, copper, manganese, zinc, fluo-
rine, iodine, chromium, bromine, selenium, molybde-
num, cobalt
• examples (solutions):
266 General Part
-- Tracitans (Fresenius Kabi)
-- Tracutil (Braun)
-- Inzolen (Köhler; with impaired renal function)
Fig. 433  trace elements (here example Tracutil; 1 amp. =
10ml)
Zinc deficiency
• definition: zinc level in serum < 0.70 mg/l
• occurrence: frequent in intensive care units (every
10th intensive care patient [Duncan et al, J Crit Care
2012]; especially in sepsis [Besecker et al, Am J Clin
Nutr 2011])
• causes:
-- sepsis
-- catabolism
-- diabetes mellitus
-- liver cirrhosis (80% of all patients with liver cirrhosis
have a zinc deficiency [Grungreiff et al, Ann Hepatol
2016]!)
-- renal replacement therapy
-- reduced absorption (i.a. anastomosis insufficiency,
intestinal fistulas, Crohn's disease)
-- drugs: especially D-penicillamine, steroids
• symptoms:
-- diarrhoea (always exclude zinc deficiency in case of
unclear diarrhoea!)
-- skin changes: i.a. acrodermatitis (erythematous, pa-
pulopustular changes), wound healing disorders
-- immunodeficiency (increased rate of infections)
• substitution: Ob dies tatsächlich was nützt, ist unklar.
In a meta-analysis (Heyland et al, J Parenter Enteral
Nutr 2008) the zinc sub-situation in zinc deficiency
showed neither a shortening of ICU stay nor a reduc-
tion in mortality.
-- parenteral: Unizink (zinc aspartate; 1 amp. = 10ml =
30mg; mostly 1 amp. daily)
-- enteral: zinc orotate (1 tabl. = 25mg; mostly 2 tabl.
daily)
• annotation: A high-dose parenteral zinc therapy (3 x
30mg i.v.) is carried out in many places for the therapy
of COVID-19, because zinc may inhibit virus replica-
tion by inhibiting the RNA polymerase of SARS-CoV-2.
However, there is no evidence for this.
Selenium
• see esp. page 858
• dosage
-- Selenase (sodium selenite) 1 ampoule = 500 μg
-- 2000 μg as loading-dose within 30min, then 1000
μg/day for a total of 14 days (high-dose therapy)
• indications (formerly)
-- severe sepsis
-- septic shock
• guidelines: no longer recommended -- Most preparations do not contain vitamin K (konaki-
-- SSC-guideline 2012 + 2016 on), so this has to be given extra (1 ampoule of 10
mg vitamin K twice a week)
-- S2k-guideline DGEM 2018
-- for vitamin D deficiency see page 769
-- S3-guideline sepsis 2018

Vitamins

Fig. 434  Vitamin preparation FrekaVit: on the left side the

ampoule with the water-soluble vitamins and on the right
• types side the ampoule with the fat-soluble vitamins.
-- water-soluble vitamins:
◦◦ B-vitamins: vitamin B1 (thiamine [daily require-
ment: 3.4 mg/kg]), B2 (possibly orange discolora-
tion of the urine]), B6 (pyridoxine), B9 (folic acid),
B12 (cyanocobalamin)
◦◦ vitamin C (ascorbic acid)
◦◦ folic acid
-- fat-soluble vitamins: vitamin A, D, E, K ("ADEK")
• preparations (examples)
-- Vitalipid (Baxter; all fat-soluble vitamins)
-- Soluvit (Baxter; all water-soluble vitamins) Fig. 435  Vitamin preparation Cernevit (contains all water
and fat-soluble [except vitamin K] vitamins) [6]
-- Cernevit (Baxter; all vitamins except vitamin K)
-- FrekaVit (Fresenius Kabi; all vitamins in twi ampou-
les) If patients are nutrished (mainly)
-- Multibionta (Merck; all vitamins except vitamin B12, parenterally, vitamins and trace
K and folic acid) elements must always be added!
• annotations:
-- Only if a patient has to be nourished complete-
ly parenterally (by means of TPN), which is rather Calorific values
rare in internal intensive care medicine, the vitamins • glucose: 4 kcal/g
must also be given parenterally. If enteral nutrition is • amino acids: 4 kcal/g
possible, the vitamins can also be administered via
• fats: 9 kcal/g ( highest energy output of all macro-
the gastric tube (e.g. multivitamin drops 3 times a
nutrients)
day 8 gtt each), which is considerably cheaper. From
a tube feeding quantity of approx. 1500ml (depen-
ding on body weight), the intake of the recommen-
ded daily doses of vitamins and trace elements is
completely covered by the tube feeding alone, so
that neither vitamins nor trace elements nor additio-
nal administration is necessary.
-- Under renal replacement therapy there is an in-
creased loss of water-soluble vitamins: Therefore,
the dose of water-soluble vitamins must be doubled
here!
-- Numerous vitamins are sensitive to light and oxy-
gen. Therefore, they should always be admistered
under light protection and quickly (i.e. as a short in-
fusion over 30min).

General Part 267

Application types
• single-chamber bag (The individual components such
as glucose, amino acids or fats run separately.)
-- former standard
-- separate control of the infusion rates of the individual
components is possible
-- cheaper
• multi-chamber bag (esp. three-chamber bag; ready-
to-use solutions)
-- today's standard ( also recommended by the S2k-
guideline DGEM 2018 empfohlen)
-- significantly less bacteremia (especially EPICOS-
studiy [see box], IMPROVE study [a retrospective
Fig. 437  various three-chamber bags (here SmofKabiven
analysis of a US database; Turpin et al, Parenteral
[Fresenius Kabi]): on the left side SmofKabiven central
Enteral Nutrition 2012]) (only via central venous catheter), on the right side Smof-
-- more expensive Kabiven peripheral (also possibe via a peripheral venous
-- Some can also be applied by peripheral venous ca- catheter)
theter: e.g. Olimel 2.2% 1500ml (900 kcal), Smofka-
biven peripher 1500ml (1000 kcal). Immunonutrition

Definition
EPICOS study • syn.: pharmaconutrition
• enteral or parenteral supply of immunomodulating sub-
stances
• nutrition to improve the immune defense
Influence of parenteral nutrition delivery system on the de- • supplement:
velopment of bloodstream infections in critically ill patients -- amino acids (arginine, glutamine, glycine)
Pontes-Arruda et al, JPEN (J Parenter Enteral Nutr) 2012 -- omega-3 fatty acids (fish oil; anti-inflammatory ef-
fect)
• multicener international double-blind prospective rando-
mized study -- nucleotides
• 406 critically ill patients; parenteral nutrition -- antioxidants
-- single-chamber bag • immunomodulating tube feeding (nucleotides, argini-
• multi-chamber bag ne, omega-3-fatty acids) recommended peri- and post-
• results: multi-chamber bag operatively in elective surgery patients with gastroin-
-- significantly fewer bloodstream infections and testinal tumours or polytrauma patients who are fed via
catheter-associated infections (CVC) enteral nutrition
-- no difference in mortality, organ failure or length of
ICU stay Examples
• OxEPA
-- Omega-3 fatty acids + antioxidants
-- grade A recommendation for ARDS in the previous
guidelines
-- Omega study (see page 734): no benefit (Here
the administration of omega-3 fatty acids in patients
with ALI did not lead to a reduction in mortality on
the one hand, and on the other hand even to fewer
ventilator-free and therapy-free days, so that a more
harmful effect was shown here!)
-- SSC-guideline 2016 und S3-guideline sepsis 2018:
no more recommended
• arginine
-- a basic amino acid (conditionally essential)
-- recommendation
◦◦ only recommended for elective surgical patients
with malnutrition, major tumor surgery (especially
esophagectomy, gastrectomy, partial duodeno-
pancreatectomy) or after severe trauma (ESPEN
Olimel-Packshot.indd 1 03.03.10 14:18
guideline)
Fig. 436  three-chamber bag [6]

268 General Part

 ◦◦ otherwise not recommended, especially not in Care 2005)
sepsis (Arginine even led to excess mortality in -- recent studies: no reduction in mortality
severe sepsis/septic shock [Galban et al, Crit Care ◦◦ SIGNET study (Andrews et al, BMJ 2011):
Med 2000] and is therefore no longer recommen- ◦◦ SGT study (Scandinavian Glutamin Trial; Werner-
ded for these patients. The main problem is the mann et al, Acta Anaesthesiol Scan 2011)
NO release by arginine, which leads to a deterio-
◦◦ REDOX study (Heyland et al, N Engl J 2013 [siehe
ration of the haemodynamic situation! It can only
box]): even increase in mortality
be warned against an uncritical use of arginine!)
• previous recommendation of DGEM (German Society
◦◦ SSC-guideline 2016: no more recommended
for Nutritional Medicine) (only) from the fifth day of
• glutamine
a purely parenteral nutrition (which is extremely rare in
internal intensive care medicine!)
• When administered early (already within 24h), critically
study ill patients with multi-organ failure even showed an in-
creased mortality (REDOXS study: Heyland et al, N
Engl J 2013 [see box]).
• Glutamine should not be given in shock or multiorgan
High-protein enteral nutrition enriched with immunemodu-
failure.
lating nutrients vs standard high-protein enteral nutrition • Ideally, level determinations should be performed
and nosocomial infections in the ICU: a randomized clini- (gosl: 430-930 μmol/l).
cal trial • previously recommended for severe sepsis / septic
van Zanten et al, JAMA 2014 shock with long-term parenteral nutrition
• multicenter randomized study • ASPEN-guidelines 2016 and sepsis guidelines
• intensive care patients (ventilated); enteral nutrition: (SSC [Surviving Sepsis Campaign] 2016, S3-guideline
-- standard tube feeding sepsis 2018): no longer recommended (neither paren-
-- immunonutrition tube feeding (with glutamine, ome-
teral nor enteral); note: The S2k-guideline of the Ger-
ga-3 fatty acids, antioxidants) man Society for Nutritional Medicine (DGEM; "Clinical
Nutrition in Intensive Care Medicine") 2018 speaks
• results: immunonutrition tube feeding
only against enteral administration of gutamine and
-- no difference in rate of nosocomial infections
continues to adhere to the option of parenteral admi-
-- no difference in mortality (even significantly increased
in the subgroup of internal intensive care patients) nistration, provided there is no severe liver, kidney or
multi-organ failure (but still only in case of long-term
purely parenteral nutrition).
Glutamine
• L-alanyl-L-glutamine
• the most highly concentrated amino acid in the body
(60% of the total amino acid content)
• amino acid which under certain conditions (e.g. sepsis)
can no longer be produced in the body and thus beco-
mes an essential amino acid
• preferred energy substrate especially for cells with a
high proliferation rate (especially enterocytes [here es-
pecially important for the maintenance of the intestinal
mucosa barrier to prevent bacterial translocation], fib-
roblasts and lymphocytes
• important nitrogen carrier
• unstable as a mono-substance in aqueous solution for
parenteral nutrition, therefore synthetically produced
dipeptide solution (Dipeptamin)
• application:
-- parenteral (Dipeptamin; most frequent form of appli-
cation; 1 bottle = 100ml = 200mg, perfusor: 5 ml/h)
-- enteral (Adamin; only recommended in burn and
trauma patients, otherwise enteral administration not Fig. 438  glutamine (Dipeptamin)
recommended)
• duration: 3-5 days (as long as parenteral nutrition
• studies:
-- previous studies: significant reduction in mortality
(Griffith et al, Nutrition 1997; Goeters et al, Crit Care
Med 2002; meta-analysis Novak et al, Crit Care Med
2002; meta-analysis Heyland et al, Curr Op Crit

General Part 269

 translocation → SIRS, sepsis ("intestine as motor of
multi organ failure"; therefore whenever possible over-
lapping minimal enteral feeding [MEF; "villi feeding"])
REDOXS study • refeeding syndrome (especially in previously malnou-
rished patients)

Refeeding syndrome
A randomized trial of Glutamin and antioxidants in critically
ill patients Definition
Heyland et al, N Engl J 2013
• complication of nutritional therapy for malnourished
• multicenter (40 intensive care units) randomized (2 x 2 patients
design) study • This was first observed after the liberation of Japane-
• 1223 intensive care patients (ventilated) with multiorgan se prisoners of war and concentration camp inmates
failure in World War II, when they were subsequently hospi-
• within 24h start with: talized and immediately fed full calories in a well-me-
-- glutamine aning manner. This resulted in numerous deaths.
-- antioxidant (especially selenium) • life-threatening metabolic disorders of the fluid and
-- placebo electrolyte balance
• results:
-- glutamine: increased mortality (hospital and Risk factors
6-month-mortality) • malnutrition
-- antioxidant: no reduction in mortality • alcoholics
• anorexia nervosa
• patients with cancer
• malabsorption syndromes
meta-analysis • prolonged fasting, hunger strike

The effects of glutamine therapy on outcomes in critically
ill patients: a meta-analysis of randomized controlled trials
Chen et al, Critical Care 2014
• 3383 critically ill patients, 18 RCT
• results: glutamine
-- no difference in mortality (neither hospital mortality
nor after 6 months; in higher doses [> 0.5 g/kg/d] even
increased mortality)
-- significantly less nosocomial infections (especially in
surgical patients)
-- no difference in hospitalization time
Laboratory
• lactic acidosis (Due to malnutrition, vitamin B1 [thiami-
ne] is missing: This is an important coenzyme of pyru-
vate dehydrogenase, which links pyruvate to the citric
acid cycle [see diagram page 728]. If glucose is now
added, pyruvate cannot be linked and is degraded to
lactate.)
• hyperglycemia
• electrolyte disorders
-- hypernatremia (sodium retention; edema [pro-
nounced])
-- hypokalemia, hypocalcemia, hypomagnesemia, hy-
pophosphatemia (most important marker)

most important marker for the

Complications
• catheter complications
-- thromboses
-- infections
• electrolyte imbalances (especially hypophosphatemia
→ CIP/CIM)
• hypertriglyceridemia (cave acute pancreatitis with tri-
glycerides > 1000 mg/dl)
• liver dysfunction ("fat overloading syndrome"): fatty
liver (possibly even steatohepatitis), cholestasis (intra-
hepatic
-- transaminases ↑, bilirubin ↑, alkaline phosphatase ↑­
-- thrombocytopenia, possibly bleeding
• acalculous cholecystitis
• hyperglycemia, possibly hyperosmolar coma
• hydropic decompensation due to volume overload
• degradation of the intestinal mucosa and bacterial
refeeding syndrome: hypophos-
phataemia!
Complications
• neurological: seizures, paresis, encephalopathy, cen-
tral pontine myelinolysis
• muscular: muscle weakness. rhabdomyolysis
• cardiac: heart failure, arrhythmia
• renal: acute kidney injury
Prophylaxis
• As a prophylaxis, nutritional therapy should be started
slowly (e.g. with 10 kcal/kg) in malnourished patients.
It is best to guide the calorie number by the phosphate
level (note: not possible in chronic renal insufficiency
[hence here often hyperphosphataemia] and in renal
replacement therapy):

270 General Part

 -- day 1: 16 kcal/kg (i.e. 75% of the goal)
-- day 2:
◦◦ phosphate > 0.65 mmol/l: 25 kcal/kg (i.e. 100% of
the goal)
◦◦ phosphate < 0.65 mmol/l: 6 kcal/kg + phosphate
substitution (40-80 mval); only if phosphate > 0.65
mmol/l: increase in calorie numbers by 4 kcal/kg
per day (up to maximum 25 kcal/kg)
• close electrolyte control
• thiamine substitution (vitamin B1; first day 3 x 100mg
i.v., then 1 x 100mg)
in patients with risc factors
(especially malnutrition): slow
cost build-up + thiamine!
Enteral nutrition
History
• already described in the 12th century (oral substrate
supply via a silver cannula inserted into the oropharynx
in a patient with esophageal cancer)
• development of astronaut food by the company Pfrim-
mer Nutricia GmbH in the early 1960s on behalf of
NASA (aim: food requiring as little storage space as
possible)
Definition
• Enteral nutrition is more physiological than parenteral
nutrition.
• Enteral nutrition preserves the intestinal mucosa so
that no villous atrophy and thus no bacterial translo-
cation occurs.
• Enteral nutrition is almost always feasible in intensive
care patients, total parenteral nutrition (TPN) is rarely
necessary. Even with parenteral nutrition, at least a mi-
nimum amount of enteral nutrition (250ml/d; minimal-
enteral feeding [MEF], trophic / villi feeding, "trickle
feed") should always be offered to avoid villous atro-
phy in the intestine with consecutive translocation of
bacteria. Even from a visceral surgical point of view,
there is actually no longer any contraindication for mi-
nimal enteral nutrition.
• Enteral nutrition has clear advantages (including fewer
infections [SPN-study Heidegger Lancet 2013], lower
rate of septic shock, cheaper) over parenteral nutrition
(meta-analysis Simpson et al, Crit Care Med 2005),
but shows no difference in mortality (meta-analyses
Peter et al, Crit Care Med 2005; Heidegger et al, Crit
Care 2006; Elke et al, Crit Care 2016; CALORIES stu-
dy [see box]). TPN therefore does not stand for "total
poisoning nutrition", as might be assumed!
• early initiation of nutrition (within 48h [Artinian et al,
Chest 2006: significant reduction of mortality]); new:
within 24h ("early goal-directed nutrition"; e.g. meta-
analysis Doig et al, Int Care Med 2009 → significant
reduction of mortality)
• Unfortunately, in reality only 70% of the enteral ca-
lories prescribed by the physician are actually supplied
to the patient (e.g. interruption for mobilisation, transfer
to CT etc., prone position, etc. [i.a. Faisy et al, Br J
Nutr 2009]). Enteral nutrition can also be carried out at
night: The day-night rhythm does not necessarily have
to be taken into account.
CALORIES study
Trial of the route of early nutritional support in critically ill
adults
Harvey et al, N Engl J 2014
• multicenter prospective randomized study
• 2388 intensive care patients; nutrition (start within 36h
after admission for at least 5 days; i.a. the same intake
of calories and protein):
-- parenteral
-- enteral
• results: enteral nutrition
-- primary endpoint (mortality after 30 days): no diffe-
rence
-- secondary endpoints: i.a.
◦◦ rate of hypoglycemia: significantly increased
◦◦ rate of vomiting: significantly increased
◦◦ ◦ infectious complications: no difference
◦◦ duration of ventilation: no difference
◦◦ mortality after 90 days: no difference
Proceed
• application via feeding pump
• elevated upper body position by 30-45º recommen-
ded during enteral feeding
• In internal intensive care patients (in contrast to pa-
tients who have just undergone abdominal surgery),
enteral feeding (250-500ml tube feeding) can almost
always be started on the first day. Then, as a rule, the
amount of tube feeding is increased by 250ml daily un-
til the goal of 1500ml is reached. Then you have usu-
ally reached the required number of calories (25 kcal/
kg; for a standard patient with 70kg: 1500kcal; 1ml of
tube feeding: 1 kcal). Supplemental parenteral nutriti-
on (SPN) is used to provide the patient with a normo-
caloric nutrition during the increase phase. This over-
General Part 271
 lap is only dispensable in patients who do not suffer
from malnutrition (e.g. recently resuscitated 50-year-
old tennis player). In most cases, however, the patients
are already suffering from malnutrition, so that supple-
mentary parenteral nutrition is usually necessary to
achieve the sufficient calorie amount. To identify mal-
nutrition, there are numerous scores (see page 255).
Fig. 439  feeding pump (arrow) mit tube feeding
Fig. 440  feeding pump [8]
infusion rate of enteral nutrition
according to body weight: kg = ml/h
Physiology
• normal regulation of metabolic utilizationN
• utrients reach the liver directly.
• stimulation of gastrointestinal hormones
• nutrient supply of the intestinal mucosa
-- villous atrophy ↓
-- preservation of the intestinal barrier, bacterial trans-
location ↓ (preservation of the barrier function)
• buffering of gastric acid (physiological ulcer prophy-
laxis!
• maintenance of peristalsis
272 General Part
If the gut works, use it!
If you use the gut, it works!
gastrointestinal tract: "Use it or loose
it"!
Indications
• pre-existing / imminent malnutrition
• inadequate oral food intake probably > 7 days
• ventilated patients
• swallowing/transit disorder
• short bowel syndrome
• acute exacerbation of Crohn's disease
• anorexia nervosa, bulimia
• consuming diseases (e.g. malignancy, tuberculosis)
Contraindications
• rejection
• shock (in case of hemodynamic instability [e.g. high-
dose catecholamine therapy])
-- This applies to both enteral and parenteral nutrition.
External calories can not be used anyway here and
only harm (acute phase of the stress metabolism).
-- here only minimal enteral feeding (MEF)
-- NUTRIREA-2 study (Reignier et al, Lancet 2017 [see
box]: increased intestinal ischemia with full-calorie
enteral nutrition in shock)
• Polytrauma
• metabolic acidosis (pH < 7.20)
• acute metabolic imbalance (diabetic/hepatic coma)
• high risk of aspiration
• bowel obstruction (mechanical ileus)
• Ogilvie syndrome (pseudoobstruction)
• intestinal ischemia (especially acute mesenteric ische-
mia)
• gastrointestinal bleeding (especially in case of inter-
vention or hemodynamic instability)
• acute abdomen
• intra-abdominal compartment syndrome (IACS)
• perforation
• peritonitis
• high-output fistula (e.g. small intestine) / -stoma (wit-
hout distal access to nutrition)
• no contraindication (i.e. enteral nutrition possible
here):
-- hypothermia (But the energy requirement is reduced
by 30%.)
-- prone position (tube feeding up to max. 20 ml/h; al-
ways here measurement of the gastric residual vo-
lume)
-- open abdomen ("burst" abdomej)
-- ECMO
-- upper gastrointestinal bleeding: If there was no in-
tervention in course of the emergency EGD and the
patient is hemodynamically stable (no shock), ente-
 ral nutrition can certainly be offered.
-- NIV: Non-invasive ventilation per se is not a contra-
indication for enteral nutrition. However, since one
must always reckon with a respiratory deterioration
of the patient so that he has to be intubated, one
should be cautious with enteral nutrition here. Fur-
thermore, gastric hyperinflation can lead to vomiting
and even (if the patient is also somnolent due to the
CO2 anesthetic) to aspiration.
NUTRIREA-2 study
Enteral versus parenteral early nutrition in ventilated adults
with shock
Reignier et al, Lancet 2017
• multicenter prospective randomized controlled study
• 2410 ventilated intensive care patients in shock: early
(already within 24 hours after intubation) fullcaloric (20-
25 kcal/ kg)nutrition
-- enteral
-- parenteral
• results: enteral nutrition
-- no difference in mortality (primary endpoint)
-- increased gastrointestinal side effects (especially
vomiting, intestinal ischemia and pseudo-obstructions
[Ogilvie syndrome])
Complications
• diarrhea
• nausea, vomiting
• tube-feeding syndrome: dehydration with prerenal
acute kidney injury due to hyperosmolarity
• aspiration, possibly aspiration pneumonia
-- main complication of enteral nutrition
-- For prophylaxis of aspiration the gastric residual vo-
lume (GRV; see page 885) should be < 500ml.
• bacterial contamination
• pressure lesions of the probes (esophagogastroduo-
denal ulcers)
• ischemic intestinal necroses (mortality: 60%)
• dumping (especially in nasojejunal feeding due to loss
of pyloric function [analogous to dumping after Billroth
gastric resection BI / BII, falling of the contents from
the stomach into the small intestine])
-- early dumping:
◦◦ immediately after administration of tube feeding
◦◦ especially after nasojejunal bolus administration of
high molecular tube feeding (If you feed via a na-
sojejunal tube, the tube feeding should therefore
only be applied continuously [via a pump] and not
in bolus form.)
◦◦ The hyperosmolarity causes fluid to flow into the
intestinal lumen with distension pain, pallor, nau-
sea, vomiting, diarrhea and vasomotoric disorders
with tachycardia and drop in blood pressure (up
to shock).
-- late dumping:
◦◦ only 2-3h after administration of tube feeding
◦◦ Due to the lack of pre-digestion in the stomach in
course of nasojejunal nutrition, the carbohydrates
get into the jejunum, which are quickly absorbed
there and cause an increase blood sugar. A reacti-
ve excess of insulin release can then lead to hypo-
glycemia with the corresponding symptoms (inclu-
ding sweating, loss of consciousness, seizures).
Application (according to location)
• oral (sip feeding; high-calorific); cave dysphagia (dys-
phagia; see excursus)
• transnasal probes
-- syn.: enteral probes
-- They can be in the patient for up to 4 weeks.
Then a routine change should be made.
• percutaneous probes
-- syn.: enterostomy
-- with estimated duration of enteral nutrition > 4 weeks
Transnasal (enteral) probes
• nasogastrale Sonde (Magensonde; Standard)
-- limitation: gastroparesis (GRV: gastric residual vo-
lume: this should be a maximum of 500ml per day
[Monteso et al, Int Care Med 2010: up to 600ml even
possible without problems])
-- Gastric tubes are made of PVC (polyvinyl chloride).
However, they are not suitable for the long-term ap-
plication of tube feeding (PVC: plasticizer; change in
material properties). In this case gastric tubes made
of polyurethane or silicone should be used.
-- insertion:
◦◦ blind (usually the case; usually by the nurse; con-
trol of the correct position by auscultation [note:
also possible by ultrasound])
◦◦ targeted:
▪▪ laryngoscopic
▪▪ endoscopic
-- complications:
◦◦ reflux esophagitis
◦◦ pressure ulcer, possibly ipper gastrointestinal
bleeding
• nasojejunal tube (indicated only in individual cases)
Fig. 441  nasogastric tube [8]
General Part 273
 company), Tiger Tube (Cook Medical company):
◦◦ 155cm, 14F, 5 side ports, lateral plastic appenda-
ges (alternating cilia-like flaps)
◦◦ self-penetrating
◦◦ insertion: The probe is provided with lubricant and
then inserted nasally like a conventional gastric
tube 50-70cm into the stomach. Then it is manu-
ally advanced 10cm every hour until the 100cm
mark is reached. Finally, abdiminal X-ray is perfor-
med to confirm the position in the small intestine.
◦◦ disadvantages:
▪▪ takes much longer (approx. 10 hours) until the
probe is in position compared to the endoscopic
insertion (JEvery internist or every senior phy-
sician working in an internal intensive care unit
should be familiar with EGD. Endoscopically,
the jejunal probe is placed within 15-20 minutes!
If one really cannot perform an EGD, then the
Fig. 442  blind insertion of a gastric tube: After being provi- Tiger Tube probe is certainly an option!)
ded with gel, it is inserted transnasally into the stomach via ▪▪ additional administration of prokinetics neces-
the esophagus. The position is checked by auscultation. sary
Finally, it is attached to the nose with a plaster strip. ▪▪ significantly lower success rate (only in 67%
correct position [Holzinger et al, ICM 2009])
Endoscopic insertion of a gastric tube
▪▪ mucous membrane injuries due to the lateral
Indication for an endoscopic placement of a gastric tube plastic processes
is, on the one hand, the case when it is not possible to
place a gastric tube blindly despite several attempts. On
the other hand, this is also indicated in the case of eso-
phageal varices: In this case one is afraid of lacerating
the varices or the applied ligatures. For this purpose,
the thin endoscope ("paediatric") is used to perform a
transnasal endoscopy to the distal stomach. A wire (e.g.
zebra wire 4m long with a soft end at the tip; spray it with
silicone beforehand) is then advanced over the working
channel. Then the endoscope is pulled back while the
assistant simultaneously advances the wire. When the
endoscope is removed, the gastric tube is pushed over
the wire (tip: First rinse the inside with olive oil, apply
plenty of gel on the outside. Before that, insert a hole with
the needle at the tip of the stomach tube [usually there
are only holes at the sides!]). An X-ray is not necessary
for this procedure.
Nasojejunal tube Fig. 443  Tiger Tube

• definition: feeding tube placed post-pyloric in the jejun-

um (post-pyloric feeding)
• indication: It is indicated if the gastric residual volu-
me (GRV) continues to exceed 500ml/24h despite all
measures (e.g. erythromycin, metoclopramide). The
nasojejunal tube can reduce the rate of aspiration and
ventilator associated pneumonia (i.a. meta-analysis Al-
hazzani et al, Crit Care 2013 [see box]).
• appication of the tube feeding only continuous (via a
pump) and not boluswise, since this would lead to ear-
ly dumping
• insertion:
-- targeted
◦◦ endoscopic (standard; via guidewire)
◦◦ electromagnetic-visualised (e.g. CORFLO probe
[CORPAK MedSystems])
-- blind; examples: Bengmark probe (Pfrimmer Nutricia

274 General Part


study
A multicenter, randomized controlled trial comparing early
nasojejunal with nasogastric nutrition in critical illness
Davies et al, Crit Care Med 2012
• multicenter retrospective randomized study (Australia)
• 181 patients with enteral nutrition via a nasogastric
tube and increased gastric residual volume (GRV >
500ml/12h or 1 x > 150ml)
-- switch to nasojejunal tube
-- no switch to nasojejunal tube (further enteral nutrition
via gastric tube)
• results: nasojejunal tube
-- no reduction of the frequency of vomiting
-- no reduction of VAP rate
• note: study with clear limitations and controversial de-
sign
meta-analysis
Small bowel feeding and risk of pneumonia in adult criti-
cally ill patients
Alhazzani et al, Crit Care 2013
• meta-analysis (19 RCT)
• 1394 critically ill patients; enteral nutrition:
-- nasogastric tube
-- nasojejunal tube
• results: nasojejunal tube
-- significant reduction in pneumonia rate (absolutely by
2.5%)
-- no difference in mortality, duration of ventilation,
length ICU stay or vomiting
Percutaneous tubes (enterostomy)
• PEG (percutaneous endoscopic gastroenterostomy)
• PEJ (percutaneous endoscopic jejunoenterostomy)
PEG
• placement (implantation):
-- indirect (thread pulling method; standard)
◦◦ previously antibiotic prophylaxis (e.g. amoxicillin/
clavulanic acid 1.2g i.v. 30min before intervention)
◦◦ two physicians necessary: one performs the endo-
scopy (EGD), the other one the puncture
◦◦ puncture site: anterior wall of stomach
◦◦ procedure: gastroscopy with diaphanoscopy (This
is obligatory! To improve this, you can on the one
hand set the energy of the light source to maxi-
mum and on the other hand put the duvet over it
to completely darken the site.), after puncture with
the needle retraction of the steel stylet, leaving the
plastic cannula, advancement of the thread over
the plastic cannula into the stomach, grasping the
therad with pliers over the gastroscope, removal
of the gastroscope, stab incision at the puncture
site, stringing the PEG tube (feeding tube; usually
15 Fr [in case of decompression-PEG / relief-PEG
e.g. in peritoneal carcinomatosis: 20 Fr]) onto the
thread, pulling through, light (not to firm [cave de-
creased perfusion of the gastric mucosa due to
the increased pressure]) tightening of the retaining
plate
◦◦ After 24 hours (as part of the first dressing
change), the external fixation plate must then be
loosened and a free play of 5-10mm be allowed,
otherwise it will cause on the one hand ischemia
and possibly infection (peritonitis) or ulcer and on
the other hand the internal fixation plate may grow
into the gastric wall (burried bumper syndrome).
The adhesion of the stomach and abdominal wall
and the formation of the stoma channel take place
very quickly anyway, i.e. within 12-24h.
◦◦ start of feeding 12h after placement possible
-- direct (very rare): A PEG system via direct puncture
(e.g. Freka Pexact) is only carried out in (rare) cases
in which the patient has a relevant constriction in the
mouth and throat area (e.g. carcinoma of the mouth
floor, burns). My personal experience, however, is
that if you can overcome the constricted area with
the thin gastroscope ("pediatric"), you can usually
also advance the conventional PEG tube (15 Ch)
including the PEG plate over the constriction using
the thread pulling method. The plate is flexible. It is
different with a decompression-PEG, which is much
larger (20 Ch).
• Contraindication:
-- peritonitis
-- coagulation disorders
◦◦ platelets < 50000/μl
◦◦ Quick < 40% or INR > 1.8
◦◦ note: DAPT (dual antiplatelet therapy; e.g. ASA +
clopidogrel) is not a contraindication. In the event
of bleeding, there is compression between the sto-
mach wall and the tightened PEG plate..
-- missing diaphanoscopy ("no stitching without light";
alternatively, a wire can be implanted with CT-
guidance)
-- peritoneal carcinomatosis (but only a contraindi-
cation if thereby a diaphanoscopy is not possible;
otherwise no contraindication per se; among other
things a frequent indication for a decompression-
PEG [20 Ch])
-- ascites (a frequent contraindication for a decom-
pression-PEG! However, if the ascites is punctured
beforehand, the PEG can be applied).
-- gastric ulcer (depending on the location)
-- prefinal condition / ethical aspects
• complications:
-- haemorrhage
-- injury to intraabdominal vessels or organs
-- perforation
General Part 275
 -- colocutaneous fistula
-- ischemia (due to a decreased perfusion as a result
of a too strong and too long pull between the inter-
nal and external fixation plate), ulcer (possibly with
bleeding)
-- local wound infection (15%), systemic infection, pos-
sibly necrotizing fasciitis
-- pneumoperitoneum (relatively frequent immediately
after application with 40%; free air under the right
diaphragm is then visible in the x-ray image; in the
absence of peritoneal signs usually no therapeutic
consequence; free air may be present [immediately
after PEG-insertion, but not later]!)
-- peristomal leakage
-- Sondendysfunktion (i.a. always purge the PEG tube
with 20 ml water after administration of tube feeding
or drugs)
-- burried-bumper-Syndrom
Fig. 445  Upper GI bleeding occurred just two days after the
◦◦ ingrowth of the internal fixation plate PEG implantation. There was an ulcer (see arrow) under the
◦◦ Therefore the PEG has to be mobilized regularly internal fixation plate. The cause of the ulcer was a reduced
◦◦ If the PEG here has to be removed (e.g. in case of perfusion due to too strong and too long pull between the
infection or obstructed tube) it has to be removed extrenal and internal fixation plate. Therefore, you should
only use a light pull and only use it for 24 hours. Then the
surgically. Alternatively one can try to cut out the
external fixation plate should be loosened.
ingrown PEG endoscopically with a needle knife.
-- tube dislocation (possibly even foreign body ileus
[e.g. due to obstruction of the ileocecal valve])
• sizes: standard 15F (decompression-PEG: 20F)
• change every 6 months (optional only)
• If the PEG is no longer needed, it can usually be remo-
ved without any problems by gastroscopy with a sling
if it is not ingrown.

Fig. 444  PEG

Fig. 446  Free air after recent PEG-implantation (see ar-

rows: air crescent inferior to the right diaphragm) is com-
pletely normal and has no further therapeutic consequence
at all in the absence of peritoneal signs. Here, too, the gui-
ding principle applies: The symptoms lead! No therapeutic
actionism!

276 General Part

 (and feeding administered not too fast)
• rules:
-- Due to the risk of constipation, medication must ne-
ver be given via a PEJ or the jejunal port of a Jet-
PEG. These may only be applied via the gastric port.
Only food may be administered via the jejunal port.
-- The PEJ must be purged daily with saline solution
or water. However, it is extremely important that the
syringe is not simply attached to the jejunal hub: The
pressure of the plunger can cause the PEJ tube to
detach from the socket and dislocate. This error is by
far the most common reason for the necessity of a
new endoscopic PEJ insertion. Before irrigation, the
connectors of the PEJ must be unscrewed and the
PEJ tube must be held in place during irrigation, or
at least it must be checked that it does not dislocate
during irrigation.

Fig. 447  CT abdomen: Hollow organ injury (perforation)

within the scope of a PEG implantation with contrast medi-
um leakage (see arrows)

Fig. 449  PEJ probe: The tip is distal to the ligament of

Treitz.

Fig. 448  Placement of a PEG tube in direct puncture tech-

nique (rare; direct placement of a balloon tube over gastro-
pexy; here Freka Pexact)

PEJ
• placement (implantation):
-- surgical (intraoperatively if abdominal surgery is per-
formed anyway; mostly as fine needle catheter jeju-
nostomy [FNCJ])
-- interventional (extension of an already existing PEG Fig. 450  PEJ
[Jet-PEG]: This is performed in our clinic under ra-
diological control and EGD.
• indication: continued aspiration despite PEG in place

General Part 277

 Application (according to duration)
• boluswise
-- 30-50ml initially every 2-4h, then every 4-6h
-- maximum quantity: 100ml every hour or 200ml every
2h
-- more physiological (We don't eat continuously all
day!))
-- standard in nasogastric feeding (It is always cont-
roversial whether it should be fed boluswisely or
continuously via a gastric tube. According to the S2k
guideline of the DGEM 2018. both is possible.)
-- If you decide for the boluswise application, the tube
feeding should already be drwan up in the pump for
hygienic reasons and the boluses should then be ap-
plied via the pump. Otherwise, bacterial contamina-
Fig. 451  A PEJ must never be purged (flushed) in this way,
as the pressure of the plunger can cause the PEJ hose to
tion can occur if the tube feeding is left to stand for a
dislocate from the attachment point. long time and drawn up again.
• continuous (via pump)
-- 30-60 ml/h (infusion rate ovre 24h)
-- standard in nasojejunal feeding (A boluswise appli-
cation [especially of high molecular tube feeding]
would lead to early dumping.)

Tube feeding

Composition
• macronutrients (in a standard tube feeding):
-- 65% carbohydrates (60-70g in 500ml)
-- 20% fats (20g in 500ml)
-- 15% proteins (15g in 500ml)
• micronutrients: containing all vitamins and trace ele-
ments

Types
according to molecular weight
• nutrient-defined diet (NDD)
-- high molecular
-- standard
-- carbohydrate: maltodextrin; protein: milk / soy pro-
tein
• chemically-defined diet (CDD)
-- low molecular (i.e. the nutrients are already present
in cleaved form)
-- higher osmolarity than NDD, therefore usually less
well tolerated
-- only rarely indicated in special cases (e.g. short
bowel syndrome, enzyme deficiency, exocrine pan-
Fig. 452  Before purging, the two plugs are disconnected so creatic insufficiency, severe necrotizing pancrea-
that the PEJ hose is exposed. The PEJ hose should then be titis (as exocrine pancreatic insufficiency is usually
held in place during purging. After purging, the two plugs present anyway), severe malassimilation, severe
are screwed together again. chronic inflammatory bowel disease)
-- examples:
Purging of the PEJ: always ◦◦ Survimed (Fresenius Kabi)
disconnect beforehand and hold ◦◦ Peptisorb (Nutricia)
tight the PEJ hose! ◦◦ Salvipeptid (Nestle)

278 General Part

according to calorie content
• Start / Pre (0.8 kcal/ml, enteral nutrition can be started
with this)
• Standard: 1 kcal/ml (water content: 80%)
• Energy (1.5 kcal/ml; advantageous especially in terms
of saving volume [especially in decompensated heart
or kidney failure])
• Concentrated (2 kcal/ml; advantageous especially in
terms of saving volume; ; high osmolarity, must not be
administered into the jejunum [otherwise early dum-
ping])

according to dietary fibre

• without dietary fibre (fibre-free): standard
• with dietary fibre (fibre-enriched): They are indicated
in diarrhea under fibre-free tube feeding (and without Fig. 454  standard tube feeding (1ml = 1 kcal; here Fresubin
Original)
other reasons for the diarrhea such as clostridia). How-
ever, it should not be administered in ileostomy, recent
colon anastomosis or in short bowel syndrome.

according to companies
• Nutrison (Nutricia)
• Isosource (Nestle Health Science)
• Fresubin (Fresenius Kabi)
• Osmolite (Abbott)
• Nutricomp (Braun)
• drinking and tube feeding (Hipp)

Special preparations (formulas)

• for diabetics: Here the carbohydrate composition is
modified with a low glycemic index (measure for the
velocity of the increase of blood sugar after application
of nutrition). Various preparations exist depending on Fig. 455  Energy preparates (1ml = 1,5 kcal; here example
the company: Fresubin Energy): On the one hand, they are suitable due
-- Diason (Nutricia) to their higher calorie content for saving volume (e.g. in the
case of decompensated heart failure). On the other hand,
-- Diben (Fresenius Kabi)
the carbohydrate content in energy preparations is reduced
-- Novasource Diabetes (Nestle Health Science) and the fat content increased, so that they are very suitable
-- Salvimulsin Diabetes (Braun) for the enteral nutrition of ventilated COPD patients (espe-
• for dialysis patients (e.g. Restoric nephro [Vitasyn]): cially in weaning), since less CO2 is produced during meta-
bolism, so that the work of breathing decreases.
These are highcaloric (2 kcal/ml; for saving volume)
with a reduced content of potassium and phosphate.
Due to the high osmolarity, they must not be given jeju-
nally. However, they are not intended for acute kidney
injury.

Fig. 453  tube feeding [8]

Fig. 456  Diben as an example of a special preparation for
tube feeding in diabetics

General Part 279


Fig. 457  fibre-enriched preparations (here Fresubin Fibre):
They contain dietary fibres and are mainly indicated in the
case of diarrhea (with no other cause) under the standard
tube feeding, which is fibre-free.
Fig. 458  In the Internal Medicine we administer low mole-
cular tube feeding (chemically-defined diet [CDD]) as here
for example Survimed most common in severe necrotizing
pancreatitis with exocrine pancreatic insufficiency, since
the nutrients are already broken down in this preparation.
Excursus: Dysphagia
Definition
• difficulty in swallowing
• disturbance of absorption, crushing and transport of
fluids (incl. saliva) or food during deglutition
• often in intensive care (50% of all long-term ventilated
patients)
280 General Part
Fig. 459  The main problem with dysphagia is aspiration.
Etiology
• neurological (most frequent cause; especially stroke,
CIP / CIM, multiple sclerosis, amyotrophic lateral scle-
rosis, myasthenia gravis)
• mechanical (disturbance of swallowing by endotrache-
al tube, tracheal cannula [40% of all tracheotomized
patients have dysphagia!], gastric tube; surgery or
trauma in the neck area)
• medicative (especially sedatives, antidepressants,
neuroleptics)
• psychogenic (especially delirium)
Diagnostic
• swallowing trial (food and liquid trial; sitting): If within
five minutes after drinking of 5 x 10ml of water (water
test) or thickened food (e.g. jelly; better than water!)
there is coughing, chocking, harrumphing, change in
voice quality or a decrease in oxygen saturation, as-
piration is present. If a tracheal cannula is present, it
should be unblocked for the swallowing trial, as the
blocked cuff can lead to compression of the esopha-
gus and thus to difficulty in swallowing. The blocking
of the cannula does not provide sufficient aspiration
protection anyway.
• colored water test (Evan´s Blue Dye test): Here 5 drops
of a blue dye (e.g. methylene blue) are applied to the
back of the tongue. The cuff of the tracheal cannula is
unblocked. If now coloured secretion is coughed up,
aspiration due to dysphagia is present
• videofluoroscopy (X-ray; nowadays only rarely used
since in cannot be performed at the bedside)
• endoscopy (FEES: fiberoptic endoscopic evaluati-
on of swallowing):
-- During swallowing (first liquid [e.g. unsweetened
tea], then mushy) transnasal endoscopy is perfor-
med (without local anesthesia; position of the endo-
scope: level of the tip of the uvula; patient sitting)
and it is checked if something gets into the trachea
via the larynx. If this is the case, aspiration is obvi-
ous. For better visualization, the sample can also be
mixed with a dye (e.g. methylene blue). If the dye is
then visible endobronchially, aspiration can be dia-
gnosed.This examination has the great advantage
that it can also be performed at the bedside.
-- FEES is very simple and can be performed in any in-
 tensive care unit where a bronchoscope is available.
-- our procedure: In a semi-seated position (without
analgosedation) the bronchoscope is entered trans-
nasally until the glottis can be visualized. the pati-
ent is given jelly over a teaspoon and it is observed
whether anything enters the trachea via the glottis.
Next, the patient is given water stained with methyle-
ne blue over a cup to drink, and it is again assessed
whether something is passing through the glottis into
the trachea. Then local anaesthesia is administered
in the larynx (10ml xylocaine 1% on the glottis via
the working channel of the bronchoscope). Finally,
further endoscopic examination is performed into the
trachea via the glottis and an assessment is made
as to whether blue colour is visible here as evidence
of aspiration. Fig. 461  After drinking water stained with methylene blue,
-- assessment: Penetration Aspiration Scale (PAS) ac- blue stained tracheal secretion can be seen in the trachea,
which ultimately proves that aspiration has taken place and
cording to (see infobox)
thus dysphagia is present.

Before starting oral nutrition in a Scores

patient with a tracheal cannula: always
carry out dysphagia diagnostics first!
• PAS (Penetration Aspiration Scale)
• BODS (Bogenhausen Dysphagy Score)
• FOIS (Functional Oral Intake Scale)
• MASA (Mann Assessment of Swallowing Ability)
• DOSS (Dysphagie Outcome and Severity Scale)

Fig. 460  For endoscopic dysphagia diagnosis (FEES) we

use a cup of water stained with methylene blue, which is
given to the patient to drink, and another cup of jelly (alrea-
dy green coloured anyway), which is given to the patient to
eat with a teaspoon.

General Part 281

 DYNAMICS study

Dysphagia in Mechanically Ventilated ICU Patients: A Pro-

spective Observational Trial
Schefold et al, Crit Care Med 2017

• monocenter prospective observational study (cohort stu-

dy)
• DYNAMICS: Dysphagia in Mechanically Ventilated ICU
Patients
• 1304 intesive care patients; within 3h nach after extuba-
tion (mechanical ventilation) screening (by a trained nur-
se) for dysphagia using water swallowing test; if positive
(i.e. coughing, chocking, harrumphing) → assessment
by a specialist (trained physical therapist / speech the-
rapist) within 24h
• frequency dysphagia:
-- screening in 12% positive, in 87% conformed by the
specialist
-- incidence of dysphagia when discharged from the
ICU: 10% (60% of them also when discharged
fromhospital)
• consequences dysphagia:
-- prolonged ICU stay
-- longer duration of ventilation
-- onger duration of enteral nutrition (via gastric tube)
-- increases mortality (dysphagia as an independent
risk factor for increased mortality!)

Complications
• sspiration, possibly aspiration pneumonia (Therefore
always rule out swallowing disorders before starting
an oral nutrition!)
• dehydration
• malnutrition

Therapy
• If aspiration is proven, oralization (oral food intake) is
contraindicated (NPO: nil per os).
• swallowing training (already in the intensive care unit,
not only in rehabilitation; i.a. restitution, adaptation;
FOTT: facial oral tract therapy)
• interdisciplinary (especially speech therapy, ENT, phy-
sical therapy)
• if necessary, scopolamine patch as an anticholinergic
in large saliva lakes above the larynx to reduce saliva
production
• if necessary PEG implantation (not too early!)

282 General Part


RESUSCITATION
• resuscitation of children
• resuscitation of adults
RESUSCITATION OF [90%] caused by an obstruction, so that there is al-
CHILDREN
Definition
• terminology:
-- newborn (neonate): first 4 weeks
-- infant: 4 weeks - 1 year
-- toddler: 1-4 years
-- child: > 4 years
• approx. 4000 paediatric resuscitations per year in Ger-
many (of which approx. 1000 preclinical; approx. one
paediatric resuscitation per emergency physician loca-
tion per year in Germany; as an emergency doctor on
average every ten years one paediatric resuscitation)
• A cardiac arrest in children is almost exclusively caused
respiratory (in contrast to adults: here mainly cardiac).
• Therefore the leading arrhythmia in pediatric resusci-
tation is bradycardia (in contrast to adults: tachycardia
[i.e. ventricular fibrillation]).
• At 6 ml/kg/min, newborns have an oxygen consumpti-
on twice as high as adults (only 3 ml/kg/min).
• There is almost no ability to compensate for hypoxia
and almost no apnea tolerance; reasons:
-- low functional residual capacity (newborns: 100ml)
and thus only low intrapulmonary oxygen storage
-- high oxygen consumption (6 ml/kg/min)
• A decrease in oxygen saturation occurs much earlier
(already after about 20sec) than in adults (only after
about 60sec).
• The main cause of cardiac arrest in the 1st year of life is
sudden infant death syndrome (SIDS), after the 1st (up
to the 40th) year of life polytrauma is the main cause.
• dysfunction:
-- primary: respiratory
-- secondary: circulatory
• symptoms of dyspnea in infants:
-- Nasenflügeln (Zeichen für eine erhöhte Atemarbeit;
immer ein kritisches Zeichen), Kopfnicken
-- nasal flaring (signs for an increased work of brea-
thing; always a critical sign!); nodding of the head
-- moaning
-- stridor (Respiratory disorders in children are mainly
most always a stridor! In a respiratory disorder with­
out stridor one should consider the following:
◦◦ pneumonia, sepsis
◦◦ ketoacidosis (e.g. diabetic)
◦◦ pneumothorax
-- retractions (due to negative pleural pressure; espe-
cially jugular, subcostal, intercostal, sternal)
-- tachypnea (cave: A sudden drop in the respiratory
rate is a sign of exhaustion and decompensation!)
-- cyanosis (cave: Cyanosis [central] is a late sign [pre-
final], i.e. immediately afterwards ensuing cardiac
arrest!)
• A blood pressure is rarely sufficiently measurable in an
infant. The best parameter for assessing hemodyna-
mics is the recapillarisation time (standard value: < 2s;
best to be measured centrally on the skin [on the chest
or forehead]).
• typs:
-- NLS: newborn life support
-- PLS: pediatric life support
• Severe pediatric emergencies are rare. But this also
means that one lacks the practice in this subject. Very
good and (especially for emergency physicians) abso-
lutely recommendable are simulation trainings of pedi-
atric emergencies (e.g. PAEDSIM).
• There are several apps for the i-phone (especially for
emergency physicians; e.g. "Pedi Safe". However,
these only come from private providers. Not a single
tested app is actually error-free (sometimes serious
errors), so they should be used with caution.
• The medication for children is weight-adapted: weight
(kg) = 2 x (age + 4)
• Parents should be present during resuscitation if pos-
sible (if they wish, i.e. do not send them outside), as
this allows for better coping in case their child dies.
General Part 283
• Since children's resuscitation (no matter how it ends)
is extremely stressful for the medical staff, a debriefing
should always follow (i.a. for better coping).

The cause of bradycardia in

newborns is always hypoxia!

Fig. 462  special adapter cable for pulse oximetry in infants

(here Masimo lNCS Neo-3) for the finger or the sole of the
foot (If this is not availabe, you can alternatively attach the
clip of the adult pulse oximeter to the child's big toe.

Children are not small adults: Otherwi-

se they would be dwarfs!

The smaller the children, the bigger

the problems!

Fig. 463  pediatric blood pressure cuff

284 General Part

Procedure
• examination
• general measures
• ventilation (indication: heart rate < 100/min; in cont-
rast to adults, in children first ventilation and then chest
compression [almost exclusively respiratory emergen-
cies])
• chest compression (Indication: heart rate < 60/min
[but only if the heart rate has not increased after ade-
quate ventilation, which is relatively rare])
• access (i.v., i.o.)
• drugs
• defibrillation

Examination
• full-term (mature) newborn
-- skin:
◦◦ consistence: firm
◦◦ color: pink / rosy (so it should be), pale or blue
(cyanotic [Peripheral cyanosis is physiological,
central cyanosis is pathological.])
-- nipples / glandular body: palpable
-- ear: helix formed, spontaneous repositioning
-- sole of the foot: plication
-- genitals:
◦◦ boys: testes in the scrotum
◦◦ girls: labia majora larger than labia minora
• amniotic fluid
-- should be clear
-- A greenish and pea-like amniotic fluid is indicative for
meconium in the amniotic fluid. The newborn´s first
stool is called meconium. If hypoxia occurs as part of
a perinatal emergency, meconium is reactively pre-
maturely excreted as a stress reaction, which can
then also be aspirated (meconium aspiration).
• spontaneous respiration / crying
• muscle tone: should be present
• Apgar index (named after the US-American anesthe-
siologist and surgeon Virginia Apgar [1909-1974]; AP-
GAR can also be used as a memoric for: Appearance,
Pulse, Grimace [reflex irritability], activity [muscle tone]
and Respiration)
• Pulse palpation (brachial, radial or femoral arteriy);
Tip: it is easier to auscultate the heart or record an
ECG than to palpate the pulse in newborns! The ea- Fig. 464  Palpating the pulse of newborns is quite difficult.
siest way is to pay attention to vital signs: Is the baby It is much easier to determine the heart rate by auscultation
moving/coughing/choking? of the heart!

General measures
• tactile stimulation
• drying
• suctioning
-- only if the airways are blocked (not routine!)
-- caution: vagal bradycardia (especially when tou-
ching the back wall of the throat)
-- only orally, not nasally (too high risk of injury)
-- only in the front (not in the back [caution: laryngo-
spasm]) mouth area

General Part 285

 -- suctioning for max. 5 sec
-- maximum suction: 0.2 mbar
• keep warm (wrap in a warmed towel; switch on the
heating on the neonatal crash cart [37.5°C]; after suc-
cessful resuscitation, however, switch off the heating in
the post-resuscitation phase)
• no shaking (cave shaking trauma with rupture of the
bridging veins and consecutive subdural hematoma)
• cutting the cord after 1 min at the earliest (10cm away
from the child)
• in therapy refractory cases consider extracorporeal life
support at an early stage
Fig. 465  neonatal crash cart
Fig. 466  suction: only if the airways are blocked, only oral-
ly (not nasally) and only in the anterior part of the mouth!
286 General Part
Chest compression
• indication: heart rate < 60/min (despite adequate
ventilation) and absence of vital signs (applies until
puberty)
• techniques:
-- two-thumb technique (both thumbs; more effecti-
ve [Udassi et al, Resuscitation 2010]!)
-- two-finger technique
• pressure point: lower third of the sternum
• depth of pressure:
-- 1/3 of the diameter of the chest
-- depth 4-5cm (< 12 months: 4cm, > 12 months: 5cm)
-- One must always press relatively deeply ("tennis
ball"-deep). Mostly, out of fear of hurting the child,
unfortunately only much too shallow pressure is ap-
plied! The chest of newborns is very elastic.
• ratio chest compression / ventilation:
-- newborns (first 4 weeks): 3:1 (note: According to the
recommendation of the GRC [German Resuscitati-
on Council], the ratio 3:1 should only be applied im-
mediately postpartum, i.e. in the delivery room or in
the case of a home birth. Otherwise, the ratio 15:2
should also be applied in the newborn age.)
-- children (from 4 weeks [or from leaving the delivery
room] until puberty [12-14 years]): 15:2
-- from puberty signs (e.g. pubic hair, breast develop-
ment): 30:2 (like adults)
• even when intubated stop chest compressions du-
ring ventilation (no chest compressions during venti-
lation)
• frequency:
-- newborns: 120/min (2 times per second)
-- infants / children: 100-120/min (like adults)
The most important thing in resuscitati-
on of newborns is ventilation and not
chest compression! Therefore the ratio
chest compression / ventilation with
3:1 instead of 15:2 is also shifted in
favor of ventilation!
 soft before the lense goes out"). In premature ba-
bies, however, ventilation should only be performed
with room air or a maximum FiO2 of 30%.
-- but after ROSC reduction of FiO2
• contraindications:
-- meconium-stained amniotic fluid: If the amniotic fluid
contains meconium (fluid is not clear, but greenish
and pea-like), mask ventilation is contraindicated!
Mask ventilation increases the risk that meconium,
which may only be in the oropharynx or trachea, is
pressed further distally into the lower airways and
alveoli, so that a meconium aspiration syndrome
(MAS) can occur.
-- diaphragmatic hernia

Fig. 467  The two techniques of chest compressions in ne-

wborns: in the first picture two-thumb technique, in the se-
cond picture two-finger technique.

In resuscitation of children it is mostly

pressed too flat and too fast!
Fig. 468  Rendell Baker masks (left size 2, right size 3) [33]

Ventilation
Mask ventilation
• BMV (bag mask ventilation)
• start of resuscitation with 5 initial rescue breaths (Ini-
tially the positive inflation pressure should be maintai-
ned for 2-3s. In most cases this will cause the heart
rate to rise again)
• Rendell-Baker mask
• The mask should seal mouth and nose.
• positioning: "sniffing position" (Tip: Put a 2cm thick to-
wel [neck roll] or a diaper under the shoulders!) Fig. 469  example of the optimum position
• inspiratory time: 1 second (as for adults)
• C-grip (EC-technique), if necessary double C-grip
(EO-technique) with the help of a second person
• Esmarch maneuver (often required for sufficient mask
ventilation)
• During mask ventilation, care should be taken that the
third finger below the chin does not compress the air-
way. The third finger should touch the bones of the lo-
wer jaw (manible) and not the soft tissues of the neck.
• Mask ventilation is always effective when the chest is
raised. This is the most important control sign! There-
fore, children should always be undressed in order to
be able to adequately assess the chest raise.
• Mask ventilation in children (especially newborns and
infants) can lead to stomach hyperinflation and thus
diaphragmatic elevation due to air insufflation in the
stomach. The extrathoracic restriction reduces pulmo-
nary compliance, making ventilation difficult or impos- Fig. 470  BMV (bag mask ventilation)
sible. Therefore, a gastric tube should always be
inserted in mask ventilation!
• respiratory rate (ventilation): 30/min The first choice for ventilation in
children is mask ventilation and not
• maximum oxygen administration
intubation! in newborns and infants
-- In this situation the risk of developing retrolental fi- always insert gastric tube additionally!
broplasia of the eye is secondary ("The brain get's

General Part 287

Intubation
• only rarely necessary (As an emergency physician it
happens on average every 6 years that a child > 1 year
needs to be intubated and only every 13 years that an
infant [i.e. child < 1 year] needs to be intubated [Eich
et al, Resuscitation 2009]. Therefore, it is definitely not
possible to learn these skills only through the emer-
gency medical service!) Intubation of children (espe-
cially under preclinical conditions) should only be per-
formed with caution and only if expertise is available.
• However, intubation is not absolutely necessary: Suf-
ficient mask ventilation is just as good. Regarding mor-
tality, intubation does not show any advantage. The
risk of aspiration under mask ventilation is only very
low. Another good option is the use of intubation alter-
natives (especially the laryngeal mask or nasopharyn-
geal CPAP).
• Do not overstretch the head ("sniffing position"; neutral Fig. 471  straight laryngoscope blade (Foregger blade)
position), because the trachea is short and soft and
would otherwise be bent!
• straight laryngoscope blade (Foregger)
• The epiglottis is lifted on the blade (in contrast to the
adult).
• orotracheal (for non-pediatricians)
• tube
-- unblocked (blocked tubes are also possible, but usu-
ally not necessary in children under 8 years of age
[exception e.g. status asthmaticus, where higher
ventilation pressures are necessary]); S1-guideline
"Prehospital airway management" 2019 of the The
German Society of Anaesthesiology and Intensi-
ve Care Medicin: Prehospital only blockable tubes
should be used in children, since this can reduce the
risk of dislocation of the tube, which is higher pre-
hospital than inhospital.)
-- size in newborns: 3.5
• tube marking at 9-10 cm from the alveolar ridge (cave: Fig. 472  unblocked tube (size 3.0)
only short trachea [3-4cm]), fixation with plaster strips
• formulas:
-- tube size ~ thickness of the little finger (of the child)
-- inner diameter in mm = week of pregnancy / 10 (for
newborns)
-- inner diameter in mm = 4 + age/4 (with blocked tu-
bes 0.5 smaller)
-- tube depth (cm) = 3 x inner diameter
• after ROSC connection to the ventilator (e.g. Dräger
Babylog 2000; ventilation mode IPPV, max. pressure
25 mbar)
• Mask ventilation often causes a pronounced hyper-
inflation of the stomach, so that after intubation the
ventilation may be difficult (extrathoracic restriction).
herefore, a gastric tube should generously be placed
immediately after intubation (especially if mask ventila-
tion has taken place beforehand)!

288 General Part

 Fig. 475  ventilator for children (here as an example Baby-
log 2000, Dräger)

Intubation alternatives
• non-invasive:
-- laryngeal mask (very simple and effective option) -
sizes: :
◦◦ < 5kg (e.g. newborns): size 1 (filling volume: 4ml)
◦◦ 5-10kg: size 1.5 (filling volume: 6ml)
◦◦ 10-20kg: size 2 (filling volume: 10ml)
◦◦ 20-30kg: size 2.5 (filling volume: 14ml)
-- laryngeal tube: not suitable for infants, as the la-
rynx is too high (not recommended for children < 2J.)
-- nasopharyngeal CPAP (good especially for infants):
A normal tube (e.g. size 3.5) is inserted blindly (i.e.
without laryngoscope) through a nostril (lubricated
with silicone beforehand) 5cm wide. The end of the
tube is then approximately at the level of the soft
palate (supraglottic). Then the other nostril and the
Fig. 473  intubation of a newborne
mouth is covered and the patient is ventilated via the
tube adapter. If the stomach gets hyperinflated du-
ring ventilation, the tube is too deep in the esopha-
gus so that it should be pulled back a few centime-
ters. The insertion depth corresponds to the distance
from the earlobe to the tip of the nose.
• invasive:
-- transtracheal puncture
-- coniotomy: In the newborn there is almost no space
between the cricoid and the thyroid cartilage, so that
a coniotomy in newborns is usually not possible. If
necessary, a tracheotomy must then be performed.

Fig. 474  ventilator for children (here as an example Puritan

Bennett 840) [11]

General Part 289

 Accesses
very simple and effective alternatives
• intravenous: peripheral (needles of size 24Gy, 26Gy)
to intubation (besides bag mask
ventilation) in the newborn: laryngeal
mask or nasopharyngeal CPAP!!
• intraosseous (if no i.v. access possible within 60s;
Fig. 476  laryngeal mask size 1 (is blocked with 4ml of air): a
very good alternative to intubation in the newborn
Fig. 477  I-Gel-mask
• umbilical vein catheter
• endotracheal: no longer recommended
Fig. 478  nasopharyngeal CPAP: a very elegant and effecti-
ve alternative to intubation
Ranking of the importance of ventilati-
on in children:
1. BMV (bag mask ventilation)
2. laryngeal mask, nasophyryngeal
CPAP
3. intubation (only in the last place!)
290 General Part
-- dorsum of the hand (usually best)
-- cubital fossa
-- inner ankle
-- head (scalp)
-- neck (external jugular vein)
in the case of resuscitation of an infant, the non-paedi-
atrician should choose the intraosseous approach im-
mediately!); two intraosseous accesses are also pos-
sible; always rinse after administration of medication!
-- sites:
◦◦ tibia
▪▪ proximal tibia (medial; about a hand's breadth
[of the infant] below the tibial tuberosity; cave:
epiphyseal joint)
▪▪ distal tibia (cranial to the medial malleolus; es-
pecially in children > 6 years of age, as the corti-
cal bone of the proximal tibia is already relatively
thick and therefore difficult to pierce)
◦◦ sternum: contraindicated in children < 12 years
-- types:
◦◦ Cook needle
▪▪ < 18 months: 18G
▪▪ > 18 months: 16G (suitable until 8 years of age)
◦◦ EZ-IO power driver (best! [pink needle; see page
308])
◦◦ in premature infants (and very small newborns)
best: butterfly needle
-- The umbilical cord contains two arteries and one
vein.
-- umbilical vein catheter: 2.5F, 3.5 Ch, 5cm
-- If no umbilical vein catheter is available, an intrave-
nous cannula can be inserted into the umbilical vein.
-- sterile insertion mandatory
-- advance max. 5cm
-- Ideally the procedure is carried out in pairs in pairs:
One uses two tweezers to spread the umbilical cord,
the other pushes the catheter forward.
-- first choice access especially for newborn resuscita-
tion in the delivery room
The intraosseous approach is the
first choice approach for resusci-
tation of a newborn (no more
attempt of an i.v. approach)!
 epiphysis

Fig. 479  puncture site: proximal tibia (first choice) [28]

Fig. 480  puncture site: distal tibia [28]

Fig. 483  Ultrasound imaging of the umbilical cord intraute-

rine: first B-mode, then color Doppler and finally spectral
Doppler (pw; here the resistance index RI is determined by
default: RI = (vsyst - vdiast) / vsyst. The standard value depends
on the respective week of pregnancy.)

Fig. 481  Cook needle in the proximal tibia Medication (drugs)

Fig. 482  schematic illustration of the umbilical cord (com-

parable to a "smiley"): It contains two arteries (red; thick
wall; "eyes" of the smiley) and one vein (blue; thin wall;
"mouth" of the smiley). A catheter can be inserted into the
vein.

General Part 291

• adrenaline Defibrillation
-- 1 amp. Adrenalin = 1ml = 1mg (1:1000) • very rarely necessary ("Children's hearts do not fibrilla-
-- 10 μg/kg i.v. / i.o. (endobronchial: 100 μg/kg [no lon- te"; possibly in children with congenital cardiac defects
ger recommended]) such as tetralogy of Fallot)
-- tip for dosage: • only necessary in 3.8% of all newborn resuscitations
◦◦ 1 amp. adrenaline in 10ml NaCl 0.9%, i.e. 1ml • coupling:
adrenaline + 9ml NaCl 0.9% (1:10000) → thereof -- electrode paddels: Up to a body weight of 10kg pedi-
give 0.1 ml/kg (at weight 3kg: 0.3 ml); remove 1 atric paddles should be used, from 10kg on the nor-
ml of this with 1 ml syringe (insulin syringe mal adult paddles can be used.
◦◦ 1 amp. adrenaline in 100ml NaCl 0.9%, i.e. 1ml -- adhesive electrodes (at best; meanwhile there are
adrenaline + 99ml NaCl 0.9% (1:100000) → the- also special adhesive electrodes for children)
reof give 1 ml/kg (at weight 3kg: 3 ml) • position: preferably anterior-posterior ("sandwich"-
-- In the meantime there are also ready-to-use syrin- tequnique)
ges on the market (e.g. Adrenalin Fresenius ready • energy dose: 4 J/kg (for all shocks [according to
for injection 2mg/ml). ERC; correspondent to AHA initially 2 J/kg, then 4 J/
-- is often overdosed unfortunately kg]); note: energy dose for electrical cardioversion (R-
• volume spikes triggered): initially 1 J/kg (ERC 2015; earlier re-
-- crystalloids (Ringer's acetate; E148 G1 PAD) commendation: 0.5 J/kg), then 2 J/kg
◦◦ newborns: 10 ml/kg, infants / children: 20 ml/kg • single shock (no series of three)
◦◦ e.g. give 30ml via 10ml-syringes manually (Do not • AED (automatic external defibrillation) < 1year: not re-
administer it as an infusion! Tip for application: commended
three-way stopcock with i.v.-line to the infusion
bottle and perfusor syringe)
-- colloids (HES 6%) 5 ml/kg
-- no sugar-containing infusion solutions for volume
therapy (such as G5%; cave cerebral edema!)
• atropine
-- dosage: 20 μg/kg
-- no significance in neonatal resuscitation (Brady-
cardia in newborns is almost exclusively respiratory
induced! Atropine also causes hypoxia to be bela-
tedly detected, as the increase in heart rate obscu-
res the hypoxia-induced bradycardia!)
• amiodarone
-- after the 3rd unsuccessful defibrillation (and again
then after the 5th unsuccessful defibrillation)
-- dosage: 5 mg/kg
• sodium bicarbonate 8.4% 1-2ml (diluted to 1:1; howe-
ver, routine administration not recommended)
• glucose Fig. 484  pediatric electrode paddles: They are integrated
-- indication: BSC < 35 mg/dl into the adult paddles! You should know on your defibrilla-
tor where the children's paddles are mounted!
◦◦ no routine administration during resuscitation, but
only if hypoglycemia is detected
◦◦ However, hypoglycaemia is common in newborns
(especially premature babies) because they have
very low glycogen storages. The blood sugar
should be checked closely!
-- application:
◦◦ glucose 10% 4 ml/kg or glucose 20% 2 ml/kg i.v.
◦◦ glucose 40% p.o.: fill a 2ml syringe, then adminis-
ter dropwise on the tongue or in the mouth
• naloxon (Narcanti)
-- indication: maternal anesthesia with opioids during
emergency Cesarean section
-- dosage (1 amp. = 1ml = 0.4mg): 0.01 mg/kg
• magnesium:
-- indication: Torsades de pointes
-- dosage: 50 mg/kg i.v.

292 General Part

 THAPCA study

Therapeutic Hypothermia after Out-of-Hospital Cardiac Ar-

rest in Children
Moler et al, N Engl J 2015

• 295 successfully resuscitated children (older than 2

Fig. 485  pediatric adhesive electrodes
days, younger than 18 years) with out-of-hospital car-
diac arrest
-- hypothermia (32-34°C)
-- normothermia (36.0-37.5°C)
• primary endpoint (survival with good neurological
outcome after 1 year): no difference

Excursus: Foreign body aspiration

Definition
• inhalation of a foreign body (mostly peanut; often pie-
ces of apple / carrot) in the trachea / bronchi
• main age: 2-3 yeras
• m:w = 2:1
• dangerous (mortality: 3%)
• observed from the parents only in 50%
• foreign body ingestion:
-- orale Aufnahme (schlucken)
-- The following are particularly dangerous:
◦◦ button cells (e.g. batteries in toys or mobile pho-
ne): Due to the current flow (cathode with hydro-
chloric acid, anode with sodium hydroxide), hyd-
rolysis can quickly cause chemical burns (alkali;
pH 11) with necrosis (colliquation necrosis) of the
esophageal or gastric mucosa and even perforati-
on, so that EGD with salvage immediately should
immediately pe performed. In X-ray the button cell
can be distinguished from a harmless coin by the
typical ring-shaped double contour. It is recom-
mended here (especially preclinically) to give 10ml
honey every 10 minutes (up to max. 60ml) until the
Fig. 486  transport incubator button cells have been removed (Battery Ingestion
Triage and Treatment Guideline 2018 from the Na-
Therapeutic hypothermia tional Capital Poison Center [USA]).
◦◦ magnets (several): The magnetic effect can com-
• cooling after successful resuscitation recommended
press the intestinal loops with intestinal wall ne-
for babies around estimated date of delivery (> 36th
crosis or ileus.
week of pregnancy; especially in perinatal asphyxia)
• S2k-guideline 2015 "interdisciplinary care of children
• Both mild hypothermia (32-34°C) and controlled nor-
after foreign body aspiration and foreign body inges-
mothermia (36.0-37.5°C) are possible (THAPCA study
tion" of the German Society of Anaesthesiology and
[see box]).
Intensive Care Medicine
• Immediately after the successful resuscitation, you
should at least switch off the heating on the neonatal
crash card.
• In many places therapeutic hypothermia is not perfor-
med in children due to the lack of data. In any case,
fever should be consistently avoided or treated in the
first three days after resuscitation.

General Part 293

 Therapy
• pre-hospital (first measures):
-- conscious patient:
◦◦ 5 back slaps (between the shoulder blades)
◦◦ 5 thrusts (compressions)
▪▪ > 12 months: upper abdomen (Heimlich maneu-
ver [grasping the upper abdomen from behind
with both arms with the fist epigastric; not in
infants because of the risk of abdominal organ
injury])
▪▪ < 12 months (infant): chest
-- unconscious patient:
◦◦ open airways, if necessary laryngoscopy (if neces-
sary grasp the foreign body with Magill forceps)
◦◦ ventilation
▪▪ mask: high ventilation pressures necessary (air
must be pressed past the foreign body; tip: take
an adult bag mask valve [Ambu bag])
Fig. 487  Button cells cause hydrolysis and therefore che-
mical burns (caustic burns with colliquation necrosis) and ▪▪ if necessary intubation: high ventilation pressu-
even perforation (here the effects on the ham are shown res also necessary here; use smaller endotra-
after just 20 minutes of exposure). cheal tube and insert completely into the non-
obstructed main bronchus (unilateral intubation)
◦◦ chest compressions (manual support during expi-
ration by compressing the thorax to reduce overin-
flation)
◦◦ resuscitation: chest compression
◦◦ alternating with ventilation (15:2)
◦◦ conio- / tracheotomy: never indicated!
• in-hospital: bronchoscopy (immediately [do not wait for
Fig. 488  X ray: It could also be a harmless coin. The reco-
sobriety])
gnizable double contour on the edge, however, speaks for
the button cell. -- diagnostic: flexible bronchoscopy (only if unclear)
-- therapeutic (foreign body extraktion): rigid broncho-
Symptoms scopy
• sudden onset
• cough (massive)
• dyspnea
• stridor
• hypersalivation
• possibly cyanosis
• typically no fever

Diagnostics
• clinical examination, especially auscultation: unilateral
wheezing, unilateral weakened breathing sound, stri-
dor
• Chest x-ray:
-- foreign bodies mostly not radiopaque
-- one-sided (unilateral) hyperinflation
-- mediastinal shift to the opposite side
-- possibly infiltrate (secondary pneumonia)
• bronchoscopy (flexible)

in doubt always bronchoscopy (the

only way to exclude)!

294 General Part


RESUSCITATION OF
ADULTS
Societies
• ILCOR: International Liaison Committee on Resuscita-
tion (parent organisation)
-- ERC: European Resuscitation Council (Europe); i.a.
ERC Guidelines for resuscitation 2015
-- AHA: American Heart Association (America); i.a.
AHA Guidelines for Cardiopulmonary Resuscitation
and Emergency Cardiovascular Care 2020
• GRC (German Resuscitation Council): For the Ger-
man recommendations the guidelines of the ERC were
adopted,
• "Father of resuscitation": Peter Safar (1924-2003;
American anaesthesiologist)
Epidemiology
• sudden cardiac death (SCD); see especially page
38); prevalence:
-- in Germany: annually 150000-200000
-- in Europae: annually aprrox. 700000 (approx. 1000
people daily; the frequency of SCD in Europe corre-
sponds approximately to the crash of two full jumbo
jets per day)
• incidence resuscitations:
-- 69/100000 (German Resuscitation Register 2018)
-- 73/100000 (German Resuscitation Register 2019)
• ROSC (return of spontaneous circulation) in 45%
(primarily successful resuscitation)
• overall survival rate: 10% (without hypothermia;
with hypothermia however today: 50% [Nielsen et al,
N Engl J 2013])
• The most common causes of death by age are:
-- < 1 year: SIDS (sudden infant death syndrome)
-- 1-40 years: polytrauma
-- > 40 years: CHD (especially myocardial infarction)
• 4% of all emergency medical interventions are resus-
citations.
Causes
Causes (according to organ)
• cardiac (60%)
-- myocardial infarction (No.1)
-- pulmonary embolism (No.2)
-- valvular heart disease (e.g. aortic valve stenosis)
-- cardiomyopathies (especially DCM [dilated cardio-
myopathy], HOCM [hypertrophic obstructive cardio-
myopathy], ARRVD [arrhythmogenic right ventricular
dysplasia])
-- myocarditis
-- ion channel diseases (e.g. Brugada syndrome, long-
QT syndrome, short-QT syndrome)
-- WPW syndrome
• respiratory (e.g. aspiration, airway obstruction, asphy-
xia, drowning)
• circulatory (shock of any genesis)
• metabolic (electrolyte disorders [e.g. hyperkalaemia])
• traumatic (TCA [traumatic cardiac arrest]; No.1 < 40J.)
• toxic (intoxication)
• physico-chemical (e.g. electrical accidents, burns)
Causes (according to age)
• younger patients (< 40 years)
-- HOCM (hypertrophic obstructive cardiomyopathy;
No.1)
-- coronary anomalies (No.2; prevalence 0.1-0.3%, es-
pecially RCA; diagnosis: CT angiography)
-- ARRVD (arrhythmogenic right ventricular dysplasia;
syn.: ARVC [arrhythmogenic right ventricular cardi-
omyopathy])
-- ion channel diseases (e.g. Brugada syndrome)
-- WPW syndrome
-- myocarditis
-- idiopathic ventricular tachycardia
• elderly patients (> 40 years)
-- CHD (especiall myocardial infarction; No.1)
-- pulmonary embolism (No.2)
-- DCM (dilated cardiomyopathy)
General Part 295
 Symptoms (cardiac arrest)
• unconsciousness (response, shaking of the shoulders,
pain stimulus)
• respiratory arrest (look, listen, feel) / agonal respirati-
on (in 15% agonal respiration, better prognosis than
in respiratory arrest as considerable tidal volumes are
still present!)
• pulselessness (palpate carotid artery for 5 seconds per
side)

Annotations
• The symptoms of cardiovascular arrest should always
be checked despite of all the hectic, because only here
chest compression should be performed! Otherwise,
it may be that patients with a seizure, for example,
are resuscitated (including chest compression), which
is unfortunately not seldom in-hospital. A resuscitati-
on with the alleged "ROSC after two minutes" is then
typically reported: This is only because the ECG was
connected then and it is noticed that there is no cardi-
ovascular arrest at all.
• Wide pupils are no sign of already occurred brain da-
mage!
-- side effect of adrenalin
-- after 30sec already dilated during cardiac arrest

Dilated pupils during resuscitation are

resting completely normal (no sign of brain
damage that has already occurred!)
and therefore no reason to terminate
resuscitation prematurely (frequent
error!)

Forms
• shockable rhythms:
-- ventricular fibrillation (80%; note: very high energy
consumption)
-- pulseless ventricular tachycardia (PVT)
• non-shockable rhythms:
exercising
-- asystole (10%; every ventricular fibrillation degene-
rates into asystole at some point)
-- pulseless electrical activity (PEA), syn.: electrome-
chanical dissociation (EMD): frequent HITS (see
infobox)!

Note: If one considers only out-of-hospital resuscitations,

only 21% of the cases are ventricular fibrillation (mostly
already degenerated into asystole), i.e. only every fifth
patient has a shockable rhythm!
Fig. 489  Most common cause of sudden cardiac death
(SCD) in the age group < 40 years is the hypertrophic ob-
structive cardiomyopathy (HOCM). Echocardiography
shows the pronounced septal hypertrophy (here 35mm) in
the B-mode and the SAM sign (systolic anterior movement
[see arrow]) in the mitral M-mode. At rest, a pressure gradi-
ent of pmax 62mmHg can be determinded, which almost dou-
bles under exercising (10 squats) (pmax 118mmHg). The cw
Doppler spectrum persents the characteristic saber shape.

296 General Part

 electromechanical dissociation
(EMD): always remember the HITT
/ 4H & 4T (reversible causes)!

HITT
reversible causes

Fig. 490  ventricular fibrillation

Fig. 491  Every ventricular fibrillation finally degenerates

into asystole.

Fig. 492  electromechanical dissociation (EMD)

Electromechanical dissociation (EMD)

• especially during resuscitation (almost always!): 4H & 4T
The repetitively applied adrenalin classically leads to reversible causes
electrical actions ("sparks"; electrical twitches) at the
heart, which are almost never accompanied by mecha-
nical actions.
• frequently HITS (alternative: 4H & 4T; see each info-
box) as cause ( most common cause of EMD: hy-
povolemia)
• It must always be verified whether the electrical action
(ECG) is followed by a mechanical action. Only then
chest compression may be stopped!
• verification of mechanical action:
-- Palpation of the pulse (This is often very unreliable
and not very sensitive. Tip: You should already find
a site during chest compressions [e.g. in the groin]
where you can palpate the pulse well. This way it
will be faster during the interruption of chest com-
pression.)
EMD: Always check whether the
-- echocardiography (heart contractions present?)
electrical action is accompanied by
-- invasive BP measurement (arterial curve present du- mechanical action (this is almost
ring the QRS complexes in the ECG?) never the case)! Only then chest
• Care must also be taken with patients with a pace- compression may be stopped
maker: here the missing cardiac ejection is often not (frequent error)!
detected or only relatively late, because a deceptive
heart rate of 60/min appears on the monitor. This is
only the pacemaker stimulation. Here, therefore, chest
compression should have been initiated long ago.
Here it is essential to palpate the pulse and, ideally,
verify whether there is any ejection at all by means of
echocardiography or an invasive BP measurement!

General Part 297


bei innerklinischen Reanimationen
immer BGA machen (v.a. z.A. Hypo-/
Hyperkaliämie und Hypoglycämie)
Diagnostics
• unconsciousness (response, shaking of the shoulders,
pain stimulus)
• respiratory arrest (look, listen, feel)
• pulselessness (palpate carotid artery for 5 seconds per
side)
Measures
• basic life support (BLS; basic measures; most impor-
tant; ROSC [return of spontaneous circulation] occurs
in 75% only through the basic measures)
• advanced life support (ALS; advanced measures)
Basic life support (BLS)
• A: Airway
• B: Breathing
• C: Circulation (cardiopulmonary resuscitation; chest
compression)
A: Airway
• clear airway and keep the airway clear (i.a. opening of
the mouth, inspection of the mouth/throat area, suction
if necessary)
• jaw-thrust-maneuver (Esmarch maneuver):
-- tilt the head and pull the lower jaw forward and up-
wards
-- The tongue obstructs the airway.
-- not to be performed in case of cervical trauma
• pharyngeal tubes (see chapter airway management
[page 42])
B: Breathing
(see especially chapter airway management [page
44])
• mask ventilation (BMV [bag mask ventilation])
• dndotracheal ventilation (An intubation should if
possible always be performed in course of resuscita-
tion, as the lower esophageal occlusion pressure is
greatly reduced and thus the risk of aspiration is signi-
ficantly increased!)
• For intubation, chest compression should not be in-
terrupted. Only for the glottis passage of the tube it
should be stopped briefly (< 5s).
• Capnometry / Capnography is obligatory (to con-
trol and monitor the tube position as well as the qua-
lity of cardiopulmonary resuscitation [goal: ETCO2 >
10mmHg]; furthermore, capnography shows an early
ROSC [return of spontaneous circulation] due to a sud-
den increase in ETCO2)!
• inspiratory time: 1 second
• respiratory rate (ventilation): 10/min
298 General Part
• Hyperventilation with consecutive hypocapnia should
be avoided. Hypocapnia causes cerebral and coronary
vasoconstriction. Rather, a low respiratory minute vo-
lume should be aimed for.
• ventilation in bystander cardiopulmonary resuscitation
(i.e. mouth to mouth ventilation [The oxygen concen-
tration in the inhaled air is 21% and still 16% in the
exhaled air.] → not recommended (too high rejection
rate [i.a. SOS-KANTO study, Lancet 2007]; only chest
compression in bystander CPR!); in the EuReCa TWO
study (Graesner et al, Resuscitation 2020), however,
a significantly higher survival rate was found when
bystander CPR was performed with ventilation (14%
versus 8%)
• During resuscitation, the patient should be venti-
lated by hand and not connected to a ventilator (e.g.
Oxylog) in the emergency vehicle / emergency room.
When resuscitating an already ventilated patient in
the intensive care unit, the patient should also be dis-
connected from the ventilator and ventilation should
be continued by hand. The reason for this is that the
intrathoracic pressures and thus also the pressures
measured by the ventilator increase massively due to
chest compression, so that the upper pressure limit
is exceeded and the ventilator no longer delivers any
mandatory breaths. Alternatively, it is also possible to
leave the patient on the ventilator, adjust the alarm li-
mits upwards and switch from pressure-controlled to
volume-controlled ventilation, but this is often not con-
sidered in the context of the hectic pace of resuscitati-
on! In the case of ventricular fibrillation, one must also
note that there is no high PEEP set at the ventilator:
The higher the PEEP, the higher the transthoracic im-
pedance and the lower the likelihood of defibrillation
success! Therefore you should set the lowest possible
(or no PEEP at all; best to ventilate with your hand).
• possibly supraglottic airway management (e.g. laryn-
geal mask, laryngeal tube; often already placed pre-
clinically by the first arriving rescue service personnel
within the scope of emergency competence; but at the
latest in the emergency room, the patient should be
intubated); studies:
-- AIRWAYS-2 study (Benger et al, JAMA 2018): laryn-
geal mask (i-gel) equivalent to endotracheal intubati-
on (modified ranking scale)
-- PART study (Wang et al, JAMA 2018): laryngeal tube
even superior to endotracheal intubation (significant-
ly higher survival rate)
• possibly passive oxygen inflation during chest com-
pression between mask ventilation (MICR: minimal in-
terruption of the cardiopulmonary resuscitation)
The best "ventilator" for resuscitation is
the hand!
C: Cardiopulmonary resuscitation (CPR)
Definition
• chest compression (CC)
-- This is the absolutely pivotal part of resuscitation,
 not the intubation! In case of disgust / inability to • if necessary, use of feedback systems
ventilate (e.g. bystander CPR) chest compression -- measurement of chest compression quality during
should be performed alone (chest-compression only resuscitation
[but not in children: Here ventilation is obligatory!]). . -- example: TrueCPR system (Physiocontrol company)
-- syn.: heart massage (The term is actually a little un- -- however, no improvement in the outcome
fortunate: "Massage" implies something tender, but • telephone CPR (T-CPR): Here the layman is instructed
that is absolutely out of place for resuscitation. A by telephone to perform chest compressions via the
coarse chest compression must be performed here!) rescue control center. This is a highly effective measu-
• kneeling at the side of the patient with streched arms re with an NNT of only 7! According to the German Re-
with both hands and the ball of the thumb of one hand suscitation Register 2018. this was performed in 22%.
• immediate start with chest compression, then ventilati- • In individual cases also a successful open (internal)
on (in contrast to resuscitation in children: there first 5 heart massage (bimanual) after anterolateral thora-
initial rescue ventilations); no initial 2 ventilations any cotomy (uni- or bilateral [clamshell thoracotomy; see
longer (exception: asphyxia [e.g. drowning]) page 320; but only an option in traumatic cardiac
• as early as possible arrest]; possibly with rib spreader) has been reported
• Every interruption (hands-off time; no-flow time) (especially in the case of penetrating chest trauma).
worsens the prognosis! The goal is to minimize the However, this can certainly not be generally recom-
hands-off times (ERC 2015: for defibrillation or intuba- mended.
tion for max. 5 seconds)! • resuscitation strategies in OHCA (out-of-hospital car-
• reality: In 50% of the time there are no chest com- diac arrest):
pressions! -- "stay & play": The resuscitation is carried out on site.
• mode of action You have the competent rescue service staff and all
-- direct: cardiac compression the equipment on site and you can perform the chest
-- indirect: thoracic pump mechanism compressions sufficiently. The transport only takes
place when ROSC has occurred (post-ROSC trans-
• achievable systolic BP: 60-80 mmHg, achievable car-
port).
diac output: 20% of the normal value
-- "load & go" (syn.: "scoop & run"): The patient is
• frequency: 100-120/min (practical tip: rhythm like the
transported to the hospital with ongoing resuscitati-
song "Staying Alive" by the Bee Gees)
on (pre-ROSC transport). However, sufficient chest
• compression depth: 1/3 of the chest size (ERC 2015: compression is often not possible while driving. In
5cm [maximum 6cm]; the deeper the better! Note: In a a study (Grunau et al, JAMA 2020 [see box]), the
study [Stiell et al, Circ 2014] on 9136 patients the opti- "stay & play" strategy was accordingly superior to
mal compression depth was determined to be 4.5cm). the "load & go" strategy. However, this was only a
• pressure point: middle sternum prospective cohort study.
• If an invasive BP measurement is available, the dia-
stolic blood pressure (crucial for coronary perfusion)
should be above 25mmHg.
• decompression (release):
-- The decompression (release) phase should be as
along as the comperssion phase.
-- The higher the cardiac compression release velocity
(CCRV), the better the survival and neurological out-
come (Kovacs et al, Resuscitation 2015). An incre-
asing fatigue often leads to leaning on the sternum
in the release phase, what should be avoided (no
"leaning").
• ratio chest compressions: ventilation
-- prior to intubation: 30:2
-- after intubation: independent; note: If a supraglottic
airway device (e.g. laryngeal mask, laryngeal tube [is
often already placed preclinically by the first arriving
rescue service personnel as part of the emergen-
cy competence] instead of an endotracheal tube is
used, the ratio 30:2 should be maintained. However,
according to the ERC guidelines 2015, this is only
necessary if there is a pronounced leakage with con-
secutive inadequate ventilation. In one study (Trial of
continuous or interrupted chest compression during
CPR; Nichol et al, N Engl J 2015) neither an advan-
Fig. 493  chest compression: Compression point is the cen-
tage nor a disadvantage was found when chest com-
ter of the sternum. It is important for an adequate power
pression is interrupted for ventilation or not. transmission that the arms are stretched.

General Part 299


in 50% of the resuscitation time no
chest compressions are performed →
minimize hands-off times!
Fig. 494  True-CPR (Physiocontrol company): a feedback
system, whoch should improve the quality of resuscitation
study
Association of Intra-arrest Transport vs Continued On-
Scene Resuscitation With Survival to Hospital Discharge
Among Patients With Out-of-Hospital Cardiac Arrest
Grunau et al, JAMA 2020
• prospective cohort study (propensity analysis)
• analysisof the data of the Resuscitation Outcomes Con-
sortium (ROC) Cardiac Epidemiologic Registry (USA,
canada)
• 27705 patients with out-of-hospital cardiac arrest
(OHCA)
-- "stay & play": The resuscitation is carried out on site.
The transport only takes place when ROSC has oc-
curred (post-ROSC transport).
-- The patient is transported to the hospital with ongoing
resuscitation (pre-ROSC transport).
• results: "stay & play"
-- significantly higher survival rate (primary endpoint)
-- significantly more often favorable (mRS <3) neurolo-
gical outcome
300 General Part
Complications (chest compression)
• thoracic injury (chest compression causes thoracic
trauma 100 times per minute!):
-- fractures:
◦◦ rib fractures (based on previous data in 33%; pos-
sibly with consecutive fat embolism); sternal frac-
ture (based on previous data in 19%); based on
recent data (Kralj et al, Resuscitation 2015): rib
fractures in 77% (men) resp. 85% (women), ster-
nal fracture in 59% (men) resp. 73% (women)
◦◦ vertebral fracture
-- pneumothorax ( possibly even tension pneumo-
thorax → thoracic drainage!), hematothorax
-- cardiac contusion (contusio cordis)
• abdominal injury:
-- liver rupture (2.4%)
-- splenic rupture
-- stomach rupture
chest compression: severe
thoracic trauma 100 times per
minute !
Bystander CPR ("first aid")
• Unfortunately, the proportion of resuscitations al-
ready started by laymen is only 22% in Germany (last
place in international comparison in Europe). In Scan-
dinavian countries, on the other hand, 73% of resus-
citations are started by laymen. One reason why the
rate of bystander CPR in Germany is so low is the fact
that in first aid courses nonsense with mouth-to-mouth
resuscitation is still taught, which leads to a high re-
jection rate. Laymen should only perform chest com-
pressions!
• Bystander CPR (first aid; i.e. chest compression
before the arrival of the rescue service) is extremely
effective: It doubles the probability of survival (Hassel-
qvist-Ax et al, N Engl J 2015)!
• The greatest potential for improvement of resuscitati-
on lies in the promotion and expansion of bystander
CPR (e.g. through training [e.g. in Denmark mandato-
ry resuscitation training at schools; "kids save lives"],
advertising, campaigns) and not in the preclinical im-
plementation of ECMO. The campaign "Save a Life"
has already been launched by the German Society for
Anaesthesiology and Intensive Care Medicine (DGAI).
Bystander CPR is a "civic duty"! The first successes
have already been recorded: According to data from
the German Resuscitation Register, the rate of bystan-
der CPR has increased from 16% in 2008 to 37% in
2016 and to 42% in 2017. Germany has now left last
place in the European ranking, but is still in the lower
third.
• In Denmark a compulsory resuscitation training was
introduced in schools in 2005 with very good results:
Bystander CPR rate increased from 21% to 45% bet-
ween 2001 and 2010. The rate of patients reaching the
hospital alive increased from 8% to 22%. The one-year
survival rate increased from 3% to 10% (Association
 of National Initiatives to Improve Cardiac Arrest Ma-
nagement With Rates of Bystander Intervention and
Patient Survival After Out-of-Hospital Cardiac Arrest;
Wissenberg et al; JAMA 2013). Also in Germany, the
School Committee of the Standing Conference of the
Ministers of Education and Cultural Affairs has now re-
commended that all pupils from the 7th grade onwards
should carry out a resuscitation training (one double
lesson) annually.
• To support correct chest compressions (especially with
regard to compression position and depth), auxiliary
systems (including Cardio First Angel [CFA]) are now
commercially available for private use. Fig. 495  LUCAS

Resuscitation alternatives
Types
• interposed abdominal counterpulsation (IAC)
-- compression of the abdomen during chest recoil (re-
lease phase)
-- improvement of diastolic coronary perfusion
-- manual / mechanical (Lifestick)
• active compression-decompression (ACD)
-- examples: Cardiopump, Animax
-- In a meta-analysis (Reynolds et al, Annals of Emer-
gency Medicine 2013) the use of ACD systems
showed neither reduced mortality nor improved neu-
rological outcome compared to conventional chest
compressions
• Vest-CPR Fig. 496  result after protracted mechanical resuscitation
• Autopulse (Zoll) with LUCAS
-- band (LifeBand) around the chest (load distributing
band [LDB])
-- studies:
◦◦ ASPIRE study (Hallstrom et al,JAMA 2006): no
benefit
◦◦ CIRC study (Rubertsson et al, JAMA 2014): equi-
valent effectiveness to manual chest compressi-
ons, but no benefit in mortality
• LUCAS (Physiocontrol)
-- LUCAS: Lund University Cardiac Arrest System
-- electrically driven
-- presternal positioned stamp
-- studies:
◦◦ Steen et al, Resusc 2004: significant advantages
compared to manual CPR
◦◦ However, the LINC Study 2014 (see box) and PA-
RAMEDIC Study 2014 (see box) did not show any
advantage compared to manual CPR.
• impendance valve (ITV [inspiratory impedance
threshold valve])
• Corpuls CPR system (electrically operated, stamp with
pivoting arm; no artifacts in x-ray)
• MIDCM-DFIB (minimally invasive direct cardiac mas- Fig. 497  Autopuls [34]
sage and defibrillation) via thoracotomy 5th ICR (aban-
doned)

General Part 301

 LINC study

Mechanical chest compressions and simultaneous defi-

brillation vs conventional cardiopulmonary resuscitation
in out-of-hospital cardiac arrest: the LINC randomized trial
Rubertson et al, JAMA 2014

• multicenter randomized study

• 2589 patients with cardiac arrest (out-of-hospital)
-- manual CPR
-- mechanical CPR (LUCAS)
• results: mechanical CPR (LUCAS)
-- survival after 4h: no difference
-- survival with good neurological outcome after 6
months: no difference
Fig. 498  Animax [1]

PARAMEDIC study

Mechanical versus manual chest compression for out-of-

hospital cardial arrest (PARAMEDIC): a pragmatic, cluster
randomized controlled trial
Perkins et al, Lancet 2014

• multicenter randomized study

• 4471 patients with cardiac arrest (out-of-hospital)
-- manual CPR
-- mechanical CPR (LUCAS)
• results: mechanical CPR (LUCAS)
-- survival after 30d: no difference
Fig. 499  Corpuls CPR
-- survival with good neurological outcome after 6
Assessment months: even decreased!
• All studies comparing mechanical resuscitation alter-
natives with conventional (manual) resuscitation were
negative. This may be due to the fact that it has always
been compared with high-quality manual CPR, which
is certainly not always and everywhere performed. The
problem with mechanical resuscitation alternatives is
certainly the fact that it often takes some time (30-60
seconds) until they are functionally attached to the pa-
tient, so that no chest compressions take place during
this time (loss of time).
• ERC guidelines 2015: not a general recommendation,
but recommended in specific situations (e.g. LUCAS
or Autopulse:
-- in-hospital: resuscitation during PTCA as part of
cardiac catheterization (here, among others also to
reduce radiation exposure for personnel who would
otherwise have to perform chest compressions du-
ring fluoroscopy), CT, with prolonged resuscitation
(e.g. hypothermia), bridging until ECMO implantation Fig. 500  In special situations (as here during the rescue
-- out-of-hospital: for transport (e.g. ambulance, heli- with the turntable ladder of the fire brigade under ongoing
copter) resuscitation) mechanical resuscitation alternatives (here
example LUCAS [see arrow]) are absolutely useful

302 General Part

Advanced life support (ALS)
• D: drugs (medication)
• E: electrical therapy
-- defibrillation
-- pacemaker
Drugs
• adrenaline
• vasopressin
• atropine
• amiodarone
• lidcaine
• sodium bicarbonate
• magnesium
• theophylline
• fibrinolytics (thrombolysis)
• steroids: no routine recommendation (ERC 2015)
• possibly sedation (e.g. propofol during resuscitation:
The AWARE study [Parnia et al, Resuscitation 2014]
showed that 56% of successfully resuscitated patients
had memories of resuscitation and 2% could even re-
member everything completely. Among others, 9% of
all patients reported near-death experiences. In the
so-called "Cologne case" [Ulrichs et al, Resuscitation
2013], a 24-year-old resuscitated patient was reported
who was apparently fully conscious during resuscita-
tion and was then able to reproduce the doctors' con-
versations verbatim. This raises the question whether
patients should not be routinely sedated during resus-
citation, because the brain is perfused too. Furthermo-
re, chest compression (100 thoracic trauma per minu-
te) also causes considerable pain, so that analgesia
should also be considered. I personally generously
administer fentanyl and propofol for analgosedation
during resuscitation.
Adrenaline (Suprarenin)
• means of choice for resuscitation
• effects:
-- agonist at α- and β-receptor
-- The α-adrenergic effect with increase of coronary
and cerebral perfusion pressure is decisive for re-
suscitation. For ROSC (return of spontaneous cir-
culation) a coronary perfusion pressure of at least
15mmHg is necessary (Paradis et al, JAMA 1990).
The diastolic blood pressure is crucial for corona-
ry perfusion: To achieve sufficient coronary flow, it
must be higher than the pressure in the right heart
(simplified as the CVP). The diastolic blood pressure
should be at least 15mmHg.
-- During resuscitation, the extremely strong bathmo-
tropic effect of adrenaline is used, i.e. the excitability
of the heart is increased by adrenaline!
• studies: Although adrenaline has been an integral part
of every resuscitation for decades, its usefulness was
only proven in 2011 (study by Jacobs; see box). How-
ever, three other studies (Olasveengen et al, Resc
2012; Hagihara et al, JAMA 2012, Dumas et al, J Am
Coll Cardiol 2014), all of which are only observational
studies, questioned the benefit of adrenaline: A higher
ROSC rate was found, but long-term survival was re-
duced. The benefit has now been demonstrated again
in the largest randomized-controlled study to date (PA-
RAMEDIC-2 study [see box]), which was also reques-
ted by the ILCOR (International Liaison Committee on
Resuscitation).
• procedure:
-- non-shockable rhythm (asystole, electromechanical
dissociation): immediate administration (The faster
adrenalin is applied, the better the chances of survi-
val [i.a. Donnino et al, BMJ 2014].)
-- shockable rhythm (ventricular fibrillation): after
the 3rd defibrillation (together with amiodarone)
• dosage: 1mg i.v. every 3-5 min
• ampoules (vials):
-- small ampoule: 1 amp. = 1ml = 1mg (1:1000)
-- large ampoule (especially for resuscitation): 1 amp.
= 25ml = 25mg
study
Effect of adrenaline on survival in out-of-hospital cardiac
arrest: A randomized double-blind placebo-controlled trial
Jacobs et al, Resuscitation 2011
• multicenter randomized study
• 535 patients with cardiac arrest
-- adrenaline
-- placebo
• results: adrenaline
-- significantly higher ROSC rate (23.5% versus 8.4%)
-- significantly higher survival rate (until discharge; 4.0%
versus 1.9%)
General Part 303
 PARAMEDIC-2 study
A Randomized Trial of Epinephrine in Out-of-Hospital Car-
diac Arrest
Perkins et al, N Engl J 2018
• multicenter randomized placebo controlled trial (UK)
• required by the ILCOR (International Liaison Committee
on Resuscitation)
• 8014 patients with out-of-hospital cardiac arrest (OHCA)
-- adrenaline
-- placebo (NaCl 0.9%)
• results: adrenaline
-- primary endpoint: survival after 30d → significant-
ly increased (with an absolute risk reduction of only
0.8%, however, only a marginal effect; NNT 112 [very
high compared to other measures, e.g. bystander
CPR NNT only 15, e.g. early defibrillation NNT only 5)
-- secondary endpoints: i.a.
◦◦ ROSC rate: significantly increased
◦◦ survival after 3 months: significantly increased
◦◦ survival at hospital discharge with a good neurolo-
gical outcome (mRS ≤ 3): no difference due to an
increased (twice as often!) bad neurological out-
come (mRS > 3; possible explanation: i.a. stimula-
tion of the α-receptors → activation of platelets →
cerebral ischemia)
Vasopressin (Pitressin)
• as a possible alternative to adrenaline
• agonist at the α-receptor
• 1 amp. = 20 IU
• significantly better than adrenaline in asystole (Wen-
zel et al, N Engl J 2004: significantly lower mortality
of resuscitation in asystole with vasopressin than with
adrenaline)
• ERC 2015: Vasopressin should not be used instead
of adrenaline in cardiac arrest.
304 General Part
study
Vasopressin, Epinephrine and Corticosteroids for In-Hos-
pital Cardiac Arrest
Mentzelopoulos et al, Archives of Internal Medicine 2009
Note: republished under the title "Vasopressin, steroids
and epinephrine and neurologically favorable survival after
in-hospital cardiac arrest" in JAMA 2013
• prospective randomized double-blind study
• 100 patients with cardiac arrest on ICU (All patients re-
ceived adrenaline-)
• 3 arms:
-- additionally vasopressin (20 IU) per cycle versus pla-
cebo
-- additionally methylprednisolone (40mg) versus place-
bo
-- circulatory shock within 4h after resuscitation: hydro-
cortisone over 7d (high dose: 300 mg/d) versus pla-
cebo
• result (additional vasopressin, methylprednisolone and
hydrocortisone):
-- significantly more frequent ROSC
-- significantly higher survival rate
• note: not yet included in the guidelines
Atropine
• 1 amp. = 0.5 mg
• dosage: 3 mg (6 amp.) i.v.
• optional for asystole and PEA; ERC guidelines 2010
and 2015: no longer recommended (only for higher-
grade bradycardia / higher degree AV block)
Amiodarone (Cordarex)
• indication: ventricular fibrillation (or pulseless ventricu-
lar tachycardia) after the 3rd unsuccessful defibrillation
• dosage: 2 ampoules a 150mg as an i.v. bolus, then
continuously 900 mg/24h
• Amiodarone leads to an increase in the stimulation
threshold. After successful resuscitation of a patient
wearing a pacemaker or an AICD, the pacemaker or
AICD may no longer function. For example, a patient
successfully resuscitated in ventricular fibrillation who
is completely dependent on a pacemaker may become
completely asystolic in the course of the procedure
due to the increased stimulation threshold (due to defi-
brillation and amiodarone).
• contraindications: i.a.
-- pregnancy (in case of resuscitation, however, only
relatively ["A dead mother does not help the child!"])
-- torsade de pointes (Amiodarone leads to a QT-inter-
val prolongation!)
-- Otherwise there are no contraindications for amioda-
rone in an emergency!

meta-analysis
Antiarrhythmia drugs for cardiac arrest: a systemic review
and meta-analysis
Huang et al, Crit Care 2013
• meta-analysis of 10 randomized controlled trials and
7 observational studies regarding the benefit of antiar-
rhythmic drugs (especially amiodarone, lidocaine, mag-
nesium) during resuscitation
• results:
-- increase of the ROSC rate (especially amiodarone)
-- no reduction of mortality
ALPS study
Amiodarone, Lidocaine or Placebo in Out-of-Hospital Car-
diac Arrest
Kudenchuk et al, N Engl J 2016
• randomized, placebo-controlled double-blind study
• ALPS: Amiodarone, Lidocaine or Placebo Study
• 3026 (out-of hospital) resuscitated patients with ventri-
cular fibrillation or pulseless VT (after unsuccessful de-
fibrillation)
-- antiarrhythmics (amiodarone or lidocaine)
-- placebo
• results: antiarrhythmics
-- hospital mortality (primary endpoint): no difference
(note: In the subgroup of patients where the cardiac
arrest was observed [3/4 of patients], however, a sig-
nificant reduction in hospital mortality could be shown
[applied to both amiodarone and lidocaine].)
-- neurological outcome: no difference
Lidocaine (Xylocain)
• indication: ventricular fibrillation (or pulseless ventricu-
lar tachycardia) after the 3rd unsuccessful defibrillation
• While lidocaine was previously only recommended
if no amiodarone was available, it is now (according to
the results of the ALPS study) recommended as equi-
valent to amiodarone (ERC update 2018, AHA guide-
lines 2020).
• dosage:
-- fisrt dose: 1,0-1,5 mg/kg
-- second dose: 0,50-0,75 mg/kg
Sodium bicarbonate (Nabic 8.4%)
• ERC guidelines 2010 and 2015: no longer recommen-
ded, as no survival benefit was shown in the studies
(even disadvantageous [Kawano et al, Resuscitation
2017, see box]
• A not critical buffering (even at pH values> 7.1) neutra-
lizes the Bohr effect (see page 781) and therefore re-
duces oxygen delivery to the tissue (i.a. recognizable
by the increase in lactate) and aggravates the shock!
• indications (only):
-- severe metabolic acidosis (pH < 7.1)
-- hyperkalemia
-- intoxication with tricyclic antidepressants and QRS-
widening
• dosage: 50 mmol
study
Prehospital Sodium Bicarbonate Use Could Worsen Long
Term Survival with Favorable Neurological Recovery
among Patients with Out-of-Hospital Cardiac Arrest
Kawano et al, Resuscitation 2017
• prospective observational study
• 13865 patients (out-of hospital resuscitation)
-- with buffering (Nabic)
-- without buffering
• results: buffering (Nabic)
-- significantly worse neurological outcome
-- significantly lower probability of survival
Magnesium
• indications:
-- torsade de pointes
-- digitalis intoxication (not in bradycardia / higher de-
gree AV block)
-- shock refractory ventricular fibrillation in suspected
hypomagnesemia (often in hypokalemia)
• dosage:
-- 2g (= 8 mmol = 4 ml magnesium sulfate 50%) in
1-2min
-- repetition if necessary after 10-15min
Calcium gluconate
• indications:
-- hyperkalemia (calcium gluconate: fastest effect in
hyperkalemia! does not reduce the potassium level,
but acts as a direct antagonist, especially on the
myocardium, thus largely inhibiting the toxic effect of
potassium on the myocardium)
-- intoxication with calcium channel blockers
• dosage: 10ml of calcium gluconate 10% over 10min
("rule of 10")
• never administer to patients taking digitalis!
Theophylline
• dosage: 5 mg/kg
• formerly optional for persistent asystole, currently no
longer recommended
• ERC 2015: second choice (100-200mg slowly i.v.) due
to:
-- inferior wall mypcardial infarction
General Part 305
 -- heart transplantation
-- spinal cord injury

Small volume resuscitation (SVR) TROICA study

• NaCl 7.2% (hypertonic saline solution) + HES 6%
200/0.6 (The combination is on the market as Hyper-
HES.)
• self-production of hypertonic saline solution (NaCl Thrombolysis during Resuscitation for Out-of-Hospital Car-
7.2%): 250ml NaCl 0.9%, thereof discard 85ml and re- diac Arrest
place with 85ml of NaCl 20% Böttiger et al, N Engl J 2008
• to improve microcirculation in the context of CPR Content
• studies: • TROICA: thrombolysis in cardiac arrest
-- In a feasibility study (Bender et al, Resuscitati- • large European double-blind multicenter study
on 2007) in 66 patients, the administration of SVR • 1300 patients (only 1050 patients included because of
(Hyper-HES: 2 ml/kg NaCl 7.2% in HES 6%) ver- early discontinuation)
sus HES alone during resuscitation showed a trend • standard + placebo versus standard + lysis (tenectepla-
towards an increased ROSC rate and an increased se)
hospital discharge rate. Inclusion criteria
-- In a retrospective cohort study, patients who recei- • resuscitation in ventricular fibrillation / VT / EMD (asysto-
ved SVR (Hyper-HES: 2 ml/kg NaCl 7.2% in HES le was excluded afterwards)
6% over 10 min during resuscitation were signifi- • start of resuscitation < 10min
cantly more likely to achieve ROSC (Hahn et al, Re-
suscitation 2014). Results
• no general recommendation • survival
-- at hospital admission: no difference
-- after 30 days: no difference
Lysis (thrombolysis, fibrinolytic therapy)
• bleeding: no difference
• ROSC: no difference
• neurological outcome: no difference
• increased rate of intracerebral hemorrhage in the lysis
group (2.7% versus 0.4%)

Annotations
• Survival was surprisingly high in both groups with 20%
(in Germany otherwise only 10% for ventricular fibrillati-
on [only 0.5% for asystole]).
• point of criticism: lysis patients did not receive heparin/
ASA!
• subgroup analysis: sysis in pulmonary embolism → sig-
nificant mortality advantage

Substances (fibrinolytics)
• alteplase (Actilyse; dosage for resuscitation: 50mg as
a bolus i.v.)
Definition • tenecteplase (Metalyse; according to TROICA study;
• 70% of all cardiovascular arrests are caused by throm- single-shot):
botic vascular occlusion (most frequent causes: No.1 -- < 60 kg: 30mg
acute myocardial infarction, No.2 pulmonary embo- -- 60-70 kg: 35mg
lism) -- 70-80 kg: 40mg
• An ongoing resuscitation is not a contraindication, but -- 80-90 kg: 45mg
possibly an indication for lysis! -- > 90kg: 50mg
• TROICA study (see box): Thrombolysis showed no be-
nefit in survival! Intralipid
• ILCOR 2005: Lysis in CPR recommended
-- in suspected pulmonary embolism Definition
-- in initial failure • 20% lipid emulsion
• ERC 2010 and 2015 • "lipid resuscitation", "lipid rescue therapy"
-- only recommended in suspected pulmonary embo- • effect: modulation of the protein binding of the toxin
lism (not as ultima ratio in suspected myocardial in- • ROSC within a few seconds ("the new miracle drug"
farction) for resuscitation?)
-- preparate and dosage: alteplase (Actilyse) 50mg

306 General Part

• dosage: 100ml of Intralipid 20% as a bolus, then ad- • The aspirated blood can also be used for diagnostics
ministration of the remaining 400ml over 20min (Note: (e.g. laboratory, BGA [corresponds to a central venous
Any other 20% fat solution can also be used!) BGA], blood cultures).
• only very low complication rate (most frequent compli-
Indications (optional) cation: osteomyelitis)
• cardiac arrest after application of local anaesthetics
Sites
(ERC 2015: recommended!)
• intoxications • tibia
-- psychotropic drugs -- proximal (fisrt choice)
◦◦ tricyclic antidepressants (ERC 2015: recommen- -- distal (malleolus medialis)
ded!) • femur (distal)
◦◦ quetiapine (Seroquel [neuroleptic]) • humerus (proximal; humeral head)
◦◦ sertraline (Zoloft [antidepressant]) • radial bone
◦◦ bupropion (Zyban [antidepressant, i.a. for smoking • spina iliaca anterior superior
cessation]) • sternum (extremely rare; contraindicated in children <
◦◦ lamotrigine (Lamictal, Desitin [antiepileptic]) 12 years)
-- cardiacs
◦◦ β-blocker
◦◦ calcium channel blocker

Accesses
• intravenous
• intraosseous (second choice)
• endobronchial
-- Adrenalin dose endobronchial = triple of the intrave-
nous dose
-- ERC 2010 and 2015: not even recommended as ul-
tima ratio any longer (totally unreliable absorption)

Intravenous access
• peripheral:
-- cubital fossa, forearm, back of the hand, external ju-
gular vein
-- irrigation with 20ml liquid
• central: via an already inserted CVC; note: The instal- Fig. 501  puncture site: proximal tibia (1st choice) [28]
lation of a CVC during resuscitation is almost never in-
dicated: The achievable flow rate with a white venous
cannula (17 G) is as high as with a central venous ca-
theter (flow rate approx. 120 ml/min), with a grey (16G)
and orange venous cannula (14G) even higher. CVC
installation only leads to loss of time! It is not uncom-
mon to observe that a CVC is only placed to distract
from the fact that one has no idea what is actually the
patient's problem..

Intraosseous access
Definition
• parenteral access to the bone marrow (well supplied
with blood)
• In the context of soldier care during World War II, in-
traosseous access was by far the most frequently used
access route.
• The dose for the i.o. application corresponds to the Fig. 502  puncture site: distal tibia (malleolus medialis) [28]
dose for the i.v. application (identical dose as i.v.).
• always rinse with 20ml NaCl 0.9%
• All drugs may be administered (exception: bicarbonate
[only possible as diluted infusion] and Hyper-HES).

General Part 307


Fig. 503  puncture site: humerus [28]
Products
• Cook needle (Cook Medical):
-- sizes:
◦◦ < 18 months: 18G
◦◦ > 18 months: 16G (suitable until the age of 8)
-- modifications:
◦◦ Dieckmann needle (with sideports)
◦◦ Sussmann Raszynski needle (with screw thread)
• Bone-Injection-Gun (B.I.G.; Waismed):
-- spring mechanism (is "shot" into bone)
-- place vertically on puncture site
-- remove red safety pin, then pull off
-- preset depth: medial tibia (adjustable to malleolus
medialis and radius by rotating the needle)
-- two needle sizes
◦◦ red: for children
◦◦ blue: for adults
• EZ-IO (standard today)
• FASTR (First Access Shock and Trauma; Pyng Medi-
cal):
-- only for puncture of the manubrium sterni
-- approved for adults and children > 12 years
Fig. 504  Cook needle [10]
308 General Part
Fig. 505  B.I.G.: Bone Injection Gun
Fig. 506  B.I.G. (Bone Injection Gun): The spring mecha-
nism is illustrated here.
EZ-IO
• Vidacare (now Teleflex)
• power drill
• attachable needles of various sizes:
-- 15 (pink; PD; for children [1-39kg])
-- 25 (blue; AD; for normal weight adults)
-- 45 (yellow; for obese adults; note: For puncture of
the proximal humerus, the yellow needle should also
be used in non-obese patients.)
• procedure (installation):
-- skin disinfection
-- puncture the skin with the needle and place it firm-
ly on the bone, then drill (if possible, only with low
contact pressure, the work is done by the power drill
itself)
-- removing the trocar (turn out counterclockwise)
-- connect a three-way stopcock to the check valve
(The blue plastic part of the check valve can be ea-
sily pushed in.)
-- Aspiration, as read over and over again, should be
avoided. On the one hand, even if the position is cor-
rect, aspiration will only be successful in 50% any-
way, so that a missing aspiration possibility is not the
same as an incorrect position and thus the necessity
of re-installation. On the other hand, the aspiration
maneuvre can lead to blockage of the access by as-
pirated bone marrow. Furthermore, aspiration is also
extremely painful.
-- 10ml bolus NaCl 0.9% (can cause injection pain; the
set contains a sterile local anaesthetic gel which can
be applied beforehand)
-- connect the connecting line, infuse crystalloid soluti-
on over it (pressure infusion may be necessary)
• not MRI-compatible
• maximum dwell time: 72h (new approval; previously
only 24h)
• removal: attach a Luer-Lock syringe, then turn clock-
wise
 Fig. 508  EZ-IO [28]

Fig. 507  EZ-IO power drill

Fig. 509  EZ-IO: intraosseous access

Contraindications
• fracture (i.o. access must not be placed distal to the
fracture)
• infection at i.o. puncture site
• previous orthopedic interventions at the i.o. puncture
site
• osteoporosis (depending on system)

Defibrillation
• precordial thump recommended in case of observed
ventricular fibrillation (e.g. on monitor in the intensive
care unit)
• inventor of defibrillation and cardioversion: American
cardiologist Bernhard Lawn (born 1921; still alive)
• indication:
-- ventricular fibrillation
-- pulseless VT

General Part 309

• once, then resume chest compressions without pulse/
ECG control; immediately resume chest compressions
(even if a rhythm has been restored, it still takes some
time to restore post-shock circulation sufficient for per-
fusion!)
• A 3-series (three-shock therapy), as previously recom-
mended, should now only be performed in exceptional
cases of monitor-observed ventricular fibrillation in the
intensive care unit, in the cardiac catheterization lab or
in the early postoperative phase after cardiac surgery.
• Direct current (not alternating current) is used for defi-
brillation or cardioversion. Direct current is less dange-
rous than alternating current, as only a single impulse
is generated. With alternating current (standard in Eu-
rope: 50 Hertz) there are 100 pulses per second, so
the probability that a shock falls in the vulnerable pha-
se (ascending phase of the T-wave) and thus causes
ventricular fibrillation is much higher here. If alternating
current would used for cardioversion, the risk that the
VT would ultimately change into ventricular fibrillation
would be very high.
• energy:
-- monophasic: 360 Joule
-- biphasic (almost all devices today; significantly bet-
ter): first shock 150 Joule, then increase to 150-360
Joule
• contact pressure of the paddles: 8kg
• coupling:
-- paddels
-- adhesive electrodes: significantly better (ERC
2015: recommended)!
• start:
-- observed (e.g. in-hospital): immediately
-- not observed (e.g. out-of-hospital): in the previous
guidelines first 2min of chest compressions (to re-
gain coronary perfusion) recommended; ERC guide-
lines 2010 and 2015: immediately
• Per minute time delay, the probability of success de-
creases by 10%!
• Chest compressions must be continued during char-
ging (no interruption of chest compressions during
charging; only briefly for discharging)! Chest compres-
sions may be paused for a maximum of 5 seconds.
• The often given command "all away from the patient"
during discharge is probably unnecessary, because
despite contact with the patient (especially when wea-
ring plastic gloves), almost nothing happens. However,
I have not tried it myself yet.
• positioning:
-- sternal-apical
◦◦ 1st paddle: below the right clavicle
◦◦ 2nd paddle: in the anterior axillary line on the left at
the level of the 5th ICS above the apex of the heart
-- anterior-posterior ("sandwich" technique)
• pacemaker carrier:
-- If, as usual, the aggregate was implanted pectorally
on the right, the positioning of the paddles is mirror-
inverted, i.e. the 1st paddle below the left clavicle and
the 2nd paddle in the anterior axillary line on the right
at the level of the 5th ICS above the apex of the heart.
310 General Part
Alternatively, anterior-posterior ("sandwich" tech-
nique) positioning of the paddles is also possible. If
the aggregate is located pectorally on the left (e.g.
in the case of an AICD), the paddles are positioned
as usual.
-- After defibrillation, the stimulation threshold often ri-
ses significantly with a possible exit block. In a com-
pletely pacemaker-dependent patient, this can lead
to successful termination of ventricular fibrillation,
but the patient is now asystole. Therefore, pacema-
ker control is mandatory! If an exit block occurs, the
output (pulse amplitude and pulse duration) must be
increased via the programming device.
• possible errors:
-- wetness (self-protection)
-- gel bridges (do not apply too much gel)
-- nitro patch
-- oxygen (risk of fire)
-- High PEEP: The higher the PEEP, the higher the
transthoracic impedance and the lower the probabi-
lity of success of defibrillation. You should therefore
set the lowest (to none at all) PEEP as possible du-
ring defibrillation. The best thing to do during a re-
suscitation is to take the patient by the machine and
bag it manually.
• Each ventricular fibrillation degenerates after a certain
time into asystole.
Relevant pre- and post-shock pauses
of chest compressions must absolu-
tely be avoided!
Fig. 510  Lifepak 20
Public Access Defibrillation (PAD)
• syn.: automatic external defibrillators (AED)
• suitable locations for PAD programs: cardiac arrest at
least once in 2 years (e.g. airports, train stations, shop-
ping centres)
• systems: AED Plus, Lifepak CR Plus, Heartsave PAD,
Philips HS1/2, Lifeline VIEW, PowerHeart G5, Fred
Easy Life, Cardiolife AED 2100
• limitations:
-- 80% of all arrests occur at home and only 20%
in public places.
-- Only 20% of all patients with (out-of-hospital) cardiac
arrest have a defibrillable rhythm (ventricular fibril-
lation).
• only very poorly accepted and used (only used in 1.7%
of all [out-of-hospital] cardiac arrests [Deakin et al,
Heart 2014])
• Under no circumstances, however, chest compression
should be interrupted to get an AED. It must be conti-
nued and the AED brought by a second person. If this
second person is not available, chest compression is
continued without AED.
• only recommended for laymen, not for professionals
(because it just takes too long; i.a. in-hospital: AED →
even worse prognosis)
Fig. 511  examples of different AED
Pacemakers
• external pacemaker (transthoracic)
• indication: ventricular asystole (i.e. still existing P-
waves in the absence of QRS complexes; in case of
a complete [i.e. atrial + ventricular] asystole without
recognizable P-waves: no indication)
• set to synchronization mode (SYNC)
• electrode positioning: as in defibrillation
-- sternal-apical or
-- anterior-posterior („sandwich“ technique)
• - select stimulation frequency (approx. 60-90/min)
• select energy (120-200 mA)
• pulse control
• see also page 488
study
Out-of hospital advanced life support with or without a phy-
sician: effects on quality of CPR and outcome
Olasveengen et al, Resuscitation 2009
• prospective observational study (Oslo [Norway])
• resuscitation in 977 patients with cardiac arrest
-- without physician
-- with physician (anesthesiologist)
• results (with physician):
-- significantly better CPR quality (less hands-off times)
-- no difference in mortality
Extracorporeal life support (ECLS)
Extracorporeal procedures (syn.: eCPR [extracorporeal
cardiopulmonary resuscitation], mini-ECC (extracorpo-
real circulation), pCPS [percutaneous cardiopulmonary
support], ECPB [extracorporeal cardio-pulmonary by-
pass]) can be used to restore circulation and save time:
For example, coronary angiography with PCI in the case
of acute myocardial infarction or lysis or embolectomy
in the case of pulmonary embolism can be performed.
The cannulation is veno-arterial (va-ECMO). There are
various options for this:
• Lifebridge (Lifebridge medical technology)
-- mobile heart-lung machine (including centrifugal
pump and oxygenator)
-- 2 sheaths (installation possible without a cardiac
technician)
◦◦ femoral artery (17F)
◦◦ femoral vein (19F)
-- weight: 18kg
• MECC (minimized extracorporeal circulation; Maquet)
-- was the first mini ECLS system
-- centrifugal pump (Rotaflow; blood flow 4.0-4.5 l/min)
+ oxygenator (Quadrox; surface 2.4m2)
• Cardiohelp (Maquet)
• Life-Box (Sorin)
• Resting-Heart-System (Medtronic)
Within the scope of in-hospital resuscitation it has alrea-
dy been shown that the survival rate through ECMO is
significantly higher than through a purely conventional
resuscitation (i.a. Chen et al, Lancet 2008). Also in a me-
ta-analysis (Ouweneel et al, Intensive Care Med 2016),
ECMO showed an improvement in survival and the neu-
rological outcome. However, there are no randomized
controlled studies for ECMO in resuscitation, so that the
method can currently only be regarded as experimental.
Large studies on this topic are ongoing currently (espe-
cially EROCA, INCEPTION, Prague-OACA, ACPAR-2).
The practical feasibility with excellent results (in selected
patients) could be shown in the CHEER study (see box).
In a French register study (Bougouin et al, EHJ 2019), no
benefit in survival could be shown.
General Part 311
 The duration of cannulation (veno-arterial; mostly bife-
moral) and ECMO connection is approx. 10-15min. At
best, the cannulation is performed ultrasound-guided.
CHEER study 5000IU of heparin is administered intravenously. From
then on circulation with a cardiac output of 4-6 l/min is
available again and the patient is transported to the cli-
nic There, coronary angiography is usually performed
Refractory cardiac arrest treated with mechanical CPR, hy- (especially if CHD is suspected) immediately, unless
pothermia, ECMO and early reperfusion another clear cause (such as pulmonary embolism) for
Stub et al, Resuscitation 2015 cardiac arrest is found. Hypothermia can be started im-
mediately after connection of the ECMO system. ECMO
• prospective single-center observational study (Mel- also increases coronary perfusion. However, in the case
bourne [Australia]) of hypoxemic resuscitation (e.g. non-observed cardiac
• 26 patients with refractory cardiac arrest: i.a. therapeutic arrest with a correspondingly unclear duration of hypo-
hypothermia (with cold saline solution) and implantation
xia), the use of ECMO is certainly questionable: It can
of a va-ECMO
usually restore circulation, but ultimately the whole thing
-- 15 patients: IHCA (in-hospital cardiac arrest)
usually ends in pronounced brain damage. In this con-
-- 11 patients: OHCA (out-of-hospital cardiac arrest)
text, attention should also be paid to harlequin syndrome
• Ergebnisse:
(harlequin: stage character of the fool; syn.: watershed
-- results:
phenomenon, differential hypoxia phenomenon; "blue
◦◦ median age: 52 years
head & red legs", "north-south"-syndrome): This syndro-
◦◦ mean time to initiation of ECMO
me occurs when a va-ECMO has been implemented in
▪▪ from collapse: 56min
the context of cardiac arrest and suddenly ROSC (return
▪▪ from arrival: 20min
of spontaneous circulation) occurs with the patient's own
-- median ECMO duration: 2 days
cardiac actions restarting: In this case there is a compe-
-- ROSC: in 96% ting blood flow from the retrograde flow of va-ECMO and
-- survival with good neurological outcome: 54% the antegrade flow of the own heart. A watershed then
usually is formed in the area of the distal aortic arch. The
result is that the legs are well perfused with blood ("red
legs"), but the coronaries and the head ("blue head") are
not. Myocardial ischemia and hypoxemic brain damage
study may occur.

Extracorporeal cardiopulmonary resuscitation in out-of-

hospital cardiac arrest
Bougouin et al, EHJ 2019

• prospective registry study (in Paris [France])

• 13191 patients with out-of-hospital cardiac arrest
(OHCA)
-- with eCPR (525 patients [only 4%])
-- without eCPR (12666 patients [96%])
• result: no difference in survival at hospital discharge
(survival rate only 8%)

ECMO is usually installed with ongoing resuscitation in

the emergency room of the target clinic. It is also already
possible to implant ECMO out-of-hospital. Correspon-
ding projects are currently already being carried out, in-
cluding the RECA study (Regensburg ECLS for Cardiac
Arrest): Here, in the event of a cardiac arrest, the ECMO
team (anesthesiologist and perfusionist) is already called
oiz in the emergency medical services in parallel with the
emergency physician. Indications for preclinical ECMO
implantation here are:
• observed cardiac arrest incl. already performed by-
stander CPR
• still no ROSC after 5-10min of CPR
• age < 70 years (relative; the biological age is decisive)

312 General Part

Fig. 512  preclinical implantation (in the emergency vehicle)
of a va-ECMO (Cardiohelp [Maquet]; cannulation of the fe-
moral artery and vein on the right) during resuscitation of a
42-year-old man. With ECMO a sufficient circulation could
be established despite patient's cardiac arrest. Coronary
angiography showed proximal LAD occlusion. ROSC oc-
curred a few minutes after recanalization. The patient survi-
ved without any neurological damage.

General Part 313

If the asystole persists while va-ECMO is running, the
blood in the left ventricle completely stops moving. This
may lead to ballooning (possibly myocardial ischemia)
and to a reversal low into the pulmonary tract with con-
secutive pulmonary edema. Furthermore, thrombosis of
the left ventricle and of the ascending aorta can occur.
Therefore, cardiocompression (press 5 times) should be
performed every five minutes to relieve the left ventricle
and to generate blood flow in the left ventricle and the
ascending aorta to prevent thrombus formation. It is also
suitable to insert a temporary pacemaker at an early sta-
ge if the asystole persists.

In the consensus paper 2018 "Recommendations for

extracorporeal cardiopulmonary resuscitation (eCPR)"
from various German societies (German Society for
Internal Intensive Care Medicine and Emergency Me-
dicine [DGIIN], German Society for Cardiology [DGK],
German Society for Thoracic, Cardiac and Vascular Sur-
gery [DGTHG], German Society for Cardiac Technique
[DGfK], German Society for Anaesthesiology and Inten-
sive Care Medicine [DGAI], German Interdisciplinary
Association for Intensive Care and Emergency medicine
[DIVI] and German Resuscitation Council [GRC]) pro
and contra criteria were defined for the use of eCPR (va-
ECMO implantation during resuscitation), that are shown
(slightly modified) in the info box. These criteria should
help to decide whether va-ECMO should be installed or
not in the emergency room of a corresponding center, if a
patient with OHCA (out-of-hospital cardiac arrest) is de-
livered into the emergency room with ongoing CPR. The
criteria can also be applied analogously for an IHCA (in-
hospital cardiac arrest). If you decide to install a va-EC-
MO (eCPR) during resuscitation, this should be perfor-
med within 60 minutes after the onset of cardiovascular
arrest (collapse). The corresponding center should offer
eCPR standby completely (i.e. 24h / 7 days / 365 days). The following procedures should
There should also be the option of an advanced therapy always be considered during resuscita-
(e.g. implantation of an LVAD system). tion:
- mechanical resuscitation alternative
- echocardiography
- thrombolysis
- cardiac catheterization (under
ongoing CPR)
- va-ECMO (ECLS)

Termination
• individual decision of the attending physician
• existence of advance healthcare directive
• no generally valid guideline
• TOR: Termination of Resuscitation Rules
• Dilated pupils during resuscitation are completely
normal (i.a. adrenaline effect; no indication of brain da-
mage) and therefore no reason to stop resuscitation!
• generally accepted:
-- continuation of CPR as long as ventricular fibrillation
or spontaneous breathing activities persist
-- termination in case of asystole, which in case of a
non reversible cause lasts longer than 20 min despi-
te ALS measures (exception: hypothermia ["Nobody

314 General Part

 is dead until warm and dead"!]) and the cardiac ar-
rest was not observed
• exact documentation of the times
• confirmation of death (postmortem Examination):
may only be made when certain signs of death (e.g.
postmortem lividity, rigor mortis) are present (i.e. not
immediately after termination of resuscitation!)
Special situations
• resuscitation in pregnancy
• resuscitation in case of trauma (traumatic cardiac ar-
rest [TCA])
• resuscitation in case of drowning accidents (see page
1539)
• resuscitation in case of hypothermia ( see page 1546)
Resuscitation in pregnancy
Causes
• pulmonary embolism
-- incidence: 10-15/100000 pregnancies; in 3.5% lethal
-- most frequent cause of death in pregnancy
-- especially in the last trimester and in the first 6 weeks
postpartum
-- for pulmonary embolism in pregnancy see also page
579
• bleeding (second most frequent cause of death in
pregnancy)
-- prepartum (especially during late pregnancy)
◦◦ placental abruption (most frequent; severe ab-
dominal pain [acute abdomen in late pregnancy;
"rigid abdomen"] and severe vaginal bleeding [lea-
ding symptom: painful bleeding])
◦◦ placenta praevia (usually included in the maternal
passport; only minor abdominal pain and minor
vaginal bleeding [leading symptom: painless blee-
ding])
◦◦ uterine rupture (previous strongest contractions
["hyperactive labor"], almost always pre-operated
women [after section, after surgery due to myo-
ma], then sudden deceptive calm, patient in shock)
◦◦ velamentous cord insertion (insertion anomaly of
the umbilical cord; when the bladder ruptures, the
vessels rupture with heavy vaginal bleeding)
-- postpartum (atonic after-bleeding; uterine atony):
◦◦ torrential bleeding with frequently fulminant course
◦◦ therapy: Oxytocin (1 amp. = 1ml = 10IE; 5IU i.v.,
then 40IU as short infusion over 30min), tranexa-
mic acid (very effective and life-saving [WOMAN
study 2017])
• amniotic fluid embolism (only peripartum; incidence:
2/100000 births; see page 588)
• cardiovascular:
-- peripartum cardiomyopathy (most frequent cardiac
cause of death in pregnancy; see page 392)
-- myocardial infarction (recanalization of first choice in
case of STEMI in pregnancy: PTCA)
-- aortic dissection (increased risk during pregnancy
due to the relatively soft connective tissue; i.a. also
coronary dissection with consecutive myocardial in-
farction)
-- congenital cardiac defect
• EPH gestosis (E: edema, P: proteinuria [> 300
mg/24h], H: hypertension [BP > 140/90 mmHg; The
main cause of death is intracranial hemorrhage as a
result of a hypertensive crisis!])
-- pre-eclampsia
-- eclampsia (tonic-clonic seizure; mortality 10%; the-
rapy: magnesium sulfate + diazepam)
-- HELLP syndrome (see page 1057)
• extrauterine gravidity (EUG; only in early pregnancy;
often spotting prior to pregnancy [does not exclude
pregnancy!], unilateral lower abdominal pain; patient
pale ["white"] and in shock)
• inferior vena cava syndrome: compression of the in-
ferior vena cava by the uterus in supine position with
hypotension and reduced cardiac output; relevant from
the 20th week of pregnancy; therefore left-sided posi-
tion)
• sepsis
-- common (in 25%) cause of death in pregnancy
-- trigger: e.g. pneumonia, urinary tract infection, ne-
crotizing fasciitis, endometritis, septic abortion, mas-
titis, amniotic infection syndrome
• polytrauma (e.g. severe traffic accident)
• anaphylaxis
• subarachnoid hemorrhage
• suicide
General Part 315

• defibrillation:
• drugs:
• emergency c-section (c: cesarean; emergency hyste-
Therapy
• guiding principle: The life of the mother has priority
over the life of the unborn child ("first the mother, then
the child"). A dead mother does not help the child eit-
her!
• From the 24th WOP (week of pregnancy) onwards, the
children are able to survive. The gestational age can
be looked up in the pregnancy passport; if unknown: If
the uterine fundus is palpable from the outside above
the navel, the child is at least in the 24th WOP and thus
able to survive.
• alert the obstetrician and neonatologist at an early sta-
ge and bring them along (if resuscitation is carried out
in-hospital)
• positioning:
-- from the 20th WOP onwards, manual movement of
the uterus to the left and a slight (15-30°) left-sided
position during resuscitation, so that the uterus does
not compress the inferior vena cava
-- However, sufficient chest compressions must be gu-
aranteed (therefore only slight left-sided positioning).
• Due to the elevated diaphragm, the compression point
during chest compression is 2-3cm higher than usual.
• intubation:
-- early (due to the increased intra-abdominal pressure
massively increased risk of aspiration)
-- Due to the increased intra-abdominal pressure,
pregnant women have a lower functional residual
capacity (FRC) and thus also a significantly lower
hypoxia tolerance.
-- often difficult intubation (difficult airway)
-- tube size: choose an inner diameter that is 0.5-1.0
mm smaller than in non-pregnant women, as the
airways are often swollen and thus significantly nar-
rower
316 General Part
-- Physiologically, pregnant women have hypocapnia
(pCO2 28-32mmHg), which should also be left un-
changed on ventilation.
-- usual positioning of the paddles (as in non-pregnant
women)
-- The attachment of the paddles is often difficult due
to the left position and the enlarged breasts during
pregnancy, so it is best to use adhesive electrodes.
-- usual energy dose (as in non-pregnant women; no
increased thoracic impedance during pregnancy)
-- type and dosage as for non-pregnant women (Note:
Amiodarone, which is officially contraindicated in
pregnancy, is also permitted and also necessary for
resuscitation in pregnancy in the case of therapy-
refractory ventricular fibrillation).
-- if necessary, lysis
◦◦ especially for (suspicion of) pulmonary embolism
◦◦ not contraindicated in pregnancy (relatively safe:
In a review [Ahearn et al, Arch Intern Med 2002]
of 200 cases with massive pulmonary embolism
during pregnancy with lysis performed, a very low
maternal mortality rate of 1% was found.)
rotomy; "perimortem" cesarean section [PMCS], Sec-
tio in mortua)
-- cesarean section with continuous resuscitation of
the mother
-- should be carried out quickly (the child must be de-
livered within 5 minutes after the beginning of the
mother's cardiac arrest, from a time delay of more
than 5 minutes the chances of survival of the child
are almost zero! The incision must be made within
4 minutes after cardiac arrest (duration of the pro-
cedure: 1 minute), i.e. in plain language: You can-
not wait in a clinic without obstetrics until a gyne-
cologist / obstetrician comes to the rescue. Neither
is it possible for an emergency doctor to drive from
the scene of the accident to the target hospital, but
rather [unfortunately] he has to do this himself on
site! In the case of a clear injury to the mother that is
no longer compatible with her life, and from the 34th
WOP onwards, preclinical Cesarean section at the
emergency site is certainly a good option, because
after the birth the child breathes spontaneously and
does not need further complex care. Prior to the 34th
WOP, however, it is probably better to drive to the
target hospital with ongoing resuscitation of the mo-
ther, with advance notice in the shock room and then
section performed in-hospital by the gynecologist /
obstetrician with standby of the pediatrician / neona-
tologist. This is because prior to the 34th WOP there
is still no lung maturity and very few emergency phy-
sicians will be able to provide sufficient care for the
child (e.g. 27th WOP) after a successful preclinical
section. If the mother survives, a second emergency
team will be necessary, which will arrive at the emer-
gency site with a certain delay of time.
-- either out-of-hospital by the emergency doctor (the
absolute "worst case" for an emergency doctor!) or
 in-hospital by the gynecologist / obstetrician (in the
emergency room; do not drive into the operating the- resuscitation of a pregnant
atre!) woman: from 24th WOP emergen-
-- procedure: cy section (within 4min!)
◦◦ cross section: standard for a normal c-section
(technique according to Misgav-Ladach): Here a
cross section is performed in the lower abdomen
Post-Resuscitation phase (pregnancy)
(2 transverse fingers above the symphysis). After
spreading the rectus muscle apart, straight trans- • Therapeutic hypothermia (e.g. after successful resus-
verse incision of the uterus is performed. citation in early pregnancy) is possible during preg-
nancy and also obligatory! The unborn child should be
◦◦ longitudinal incision: In a perimortem section (pre-
monitored during hypothermia using CTG (cardiotoco-
clinical) it is best to perform a longitudinal incisi-
gram).
on, because this way you have the most space:
median (through the navel) longitudinal incision on • In the event of resuscitation due to ventricular arrhyth-
the abdomen completely from top to bottom (from mia / ventricular fibrillation without a recognizable
the symphysis to the costal arch), then open the cause (including no cardiac ischemia), pregnant wo-
uterus at the bottom with a scalpel or scissors by a men should be provided with an AICD. The discharges
longitudinal incision (caution: Do not cut the baby!) do not lead to fetal damage (Natale et al, Circulation
1997); good alternative: defibrillator vest (e.g. LifeVest)
-- necessary material: only scalpel and scissors
during pregnancy and AICD implantation only postpar-
-- From the 34th WOP onwards, the lungs are mature,
tum
i.e. the child usually breathes on its own after cesa-
rean section and does not need any further complex
treatment. Resuscitation in trauma
-- The C-section does not only increase the survival
rate of the child (survival rate of the children: 62.5%;
i.a. increased oxygen affinity of the fetal hemoglo-
bin), but also that of the mother: By relieving the
pressure on the inferior vena cava resuscitation con-
ditions and ROSC chances are significantly impro-
ved! In a case series of 38 cases where emergency
C-section was performed during cardiopulmonary
resuscitation, 34% of the mothers and 90% of the
children survived (Katz et al, Am J Obstet Gynecol
2005).
-- goals:
◦◦ < 20th WOP: no indication for emergency section
◦◦ 20th - 23th WOP: indication for emergency section
with the aim of saving the life of the mothter (not of
the child: this is not viable here)
◦◦ ≥ 24th WOP: Indication for emergency section with
the aim of saving the life of the mother and the Definition
child • syn.:
-- TRCA (trauma related cardiac arrest), TCA (trauma-
tic cardiac arrest)
-- "Trauma-Rea"
• polytrauma:
-- most common cause of death between the ages of
1-40 years
-- mortality: 15%
-- procedure according to the ABCDE scheme (see in-
fobox) according to nach ATLS (Advanced Trauma
Life Support)
-- S3 guideline "polytrauma" of the German Society for
Fig. 513  If the week of pregnancy is unclear (e.g. pregnant Trauma Surgery 2016
women no longer approachable, no mother's passport),
• A traumatic cardiac arrest has an extremely poor pro-
you can roughly estimate it: If the uterine fundus is palpa-
ted above the navel, as here, then the 24th week of pregnan- gnosis (survival rate only 5.6% [of which again only
cy has passed and the child is able to survive. 1.6% with good neurological outcome]).
• most frequent cause of death: bleeding with hypovo-
lemic shock
• most frequent rhythm: asystole (not ventricular fibril-

General Part 317

 lation: This is always primarily indicative of an acute
internal disease!)
• Cardiac arrest in penetrating trauma has a (slightly)
better prognosis than in blunt trauma.
• Despite the poor prognosis of the traumatic cardiac ar-
rest, one should not make the mistake of not initiating
any resuscitation measures at all if cardiac arrest and
an accident occur simultaneously. The primary cause
may have been an acute internal or neurological ill-
ness (e.g. heart attack with ventricular fibrillation while
driving, hypoglycemia, stroke, seizure), which then led
secundary to the accident with possibly only minimal
trauma, which has nothing at all to do with the cardiac
arrest. Ventricular fibrillation in a trauma-related cardi-
ac arrest is an absolute rarity (e.g. cardiac contusion)
and is primarily considered a sign of an acute coronary
syndrome!
• Overall, a general renunciation of the beginning of re-
suscitation measures in traumatic cardiac arrest, as
recommended by some professional societies (e.g.
American College of Surgeons, National Association
of EMS Physicians) for certain indications (e.g. apneic
and pulseless patient after blunt trauma with unorga-
nized heart rhythm), should therefore certainly be vie-
wed very critically here.
• In the case of an externally recognizable injury pattern
that is no longer compatible with life (e.g. decapitation,
severing or fragmentation of the trunk), no more resus-
citation emasures need to be initiated for sure
• Since polytrauma patients are mostly hypovolemic, the
lowest possible PEEP (or no PEEP) should be set for
ventilation
• The key is to recognize and treat reversible causes at
as early as possible ("golden hour of shock")!
• if necessary, emergency thoracotomy

Reversible (and therefore treatable) cau-

ses
• bleeding ( with 45% the most common cause of
traumatic cardiac arrest [Kleber et al, Resuscitation
2014]; "exsanguination")
-- lokale Stillung
◦◦ manuelle Kompression
◦◦ compression bandage, tourniquet (especially
for arterial extremity bleeding; very effective)
◦◦ pelvic binder (e.g. pelvic ring fracture with "open-
book"-injury; cave massive blood loss, hence

318 General Part

 compression of the pelvis from outside at the level
of the greater trochanter to reduce the intrapelvic
volume)
◦◦ maybe hemostatic agents (dressings; e.g. Quik-
Clot, Celox)
◦◦ ggf. REBOA (resuscitative endovascular balloon
occlusion of the aorta)
▪▪ endovascular occlusion of the aorta
▪▪ balloon inserted into the distal aorta through the
femoral artery (via a sheath)
▪▪ indication: pronounced bleeding pelvin, inguinal,
intra-abdominal
▪▪ insertion usually in the shock room under X-ray
examination
▪▪ A retrospective study (Nationwide Analysis of
REBOA in Civilian Trauma; Joseph et al, JAMA
Surg 2019), however, showed a mortality was
almost twice as high as in the control group, a
higher rate of acute kidney injury and a higher
rate of leg amputations.
-- fluid administration
-- tranexamic acid (1g in 10min as loading-dose [prec-
linically et best], then 1g in 8h)
• tension pneumothorax
-- frequency: in 13% cause of a trauma-related cardiac
arrest (Kleber et al, Resuscitation 2014)
-- genesis: A tension pneumothorax can be caused pri-
marily by the thoracic trauma, but also secondarily
by chest compressions (thoracic trauma 100 times
per minute!) .
-- symptoms: congested jugular veins (cave: may also
be absent in hypovolemia in a polytrauma patient),
cyanosis, shock, possibly skin emphysema (pal-
pable crackling), attenuated breathing sound (after
verification of correct tube position), hypersonorous
percussion sound, hyperbaric pressure alarm during
volume-controlled ventilation (e.g. in the emergency
ambulance)
-- therapy: The aim is to achieve thoracic decompres-
sion, possibly first by means of a relief puncture with
a large-volume indwelling venous cannula (only tem-
porarily to gain time; important: sufficient length [in
Monaldi position 45-50mm!], therefore there are also
special needles for the relief puncture), and then fi-
nally by applying a thoracic drainage (chest tube). If
it is possible to localise one side by auscultation and
percussion, the thoracic drainage is placed on this
side. If this is not possible, which is often the case
preclinically, a thoracic drainage should be placed
generously on both sides of the chest, especially if
there is only the slightest possibility of chest trauma.
The bilateral application of a chest drainage in the
case of a trauma-related cardiac arrest improves the
prognosis (Huber-Wagner et al, Resuscitation 2007)
and should be performed before the resuscitation is
terminated. A bilateral thoracostomy, i.e. you only
create the holes without inserting drainages, is also
sufficient
• pericardial tamponade
-- frequency: in 10% cause of a trauma-related cardiac
arrest (Kleber et al, Resuscitation 2014)
-- diagnosis: Without confirming the pericardial tam-
ponade with ultrasound, it is difficult to perform a
probatory pericardiocentesis preclinically. The pu-
rely clinical diagnosis of a pericardial tamponade is
extremely difficult preclinically: The Beck triad with
hypotension, tachycardia and quiet (muffled) heart
sounds is not very helpful, since polytrauma patients
usually are hypotonic and tachycardic and the heart
sounds are almost always quiet or almost impossible
to auscultate preclinically (e.g. due to street noise)
and in case of cardiac arrest there are no more heart
sounds at all. Here, portable miniaturized echo de-
vices (handheld devices; siehe page 229), which
are available on our emergency ambulance vehicle,
for example, are very helpful.
-- therapy: pericardiocentesis (pericardial puncture)
◦◦ Preclinical pericardiocentesis in a trauma-induced
cardiac tamponade is considered critically again
and again because it delays the necessary in-hos-
pital thoracotomy (Penetrating cardiac wounds:
Principles for surgical management; Gao et al,
World J Surg 2004). Since there is often already
coagulated blood in the pericardium, pericardio-
centesis is also often ineffective. Pericardiocente-
sis during resuscitation in the event of a traumatic
cardiac arrest is significantly less important than
thoracic decompression by means of a thoracic
drainage.
◦◦ Nevertheless, in my opinion you should immedia-
tely perform (at least try) pericardiocentesis if the
pericardial tamponade is confirmed by echocardi-
ography in a hemodynamically unstable patient:
It can be performed quickly on site and is only
minimally invasive in comparison to emergency
thoracotomy, which is maximally invasive. In most
cases it is also possible to draw at least some
blood, so that the circulation can be restored. The
first milliliters removed have the greatest relief ef-
fect! Ultimately, the situation is the same as in the
case of a traumatic myocardial perforation with a
hemopericardium as a complication of a pacema-
ker or AICD implantation: Here an immediate peri-
cardiocentesis is performed by default with usually
good success. If ROSC cannot be achieved, then
immediate emergency thoracotomy should be
considered (especially in cardiac arrest due to a
penetrating injury). According to the S3 guideline
for polytrauma 2016, pericardiocentesis is also re-
commended!
TCA: Most important is the detection
and immediate treatment of reversible
causes (especially bleeding, tension
pneumothorax and pericardial
tamponade)!
General Part 319

Fig. 514  Tourniquet (They should always be placed proxi-
mal to the extremity, a hand's breadth below the armpit on
the arm or below the groin on the leg.)
Fig. 515  pelvic binder
traumatic cardic arrest: generous
implantation of thoracic draina-
ges on both sides!
Thoracotomy (emergency)
• especially in-hospital, possibly even out-of-hospital
• especially recommended in penetrating (less in blunt)
chest injuries (classic: knife stab injury [cave: The stab
wound in the chest is usually relatively small and not
very spectacular, but can mainly take a deleterious
course due to a myocardial injury with consecutive pe-
ricardial tamponade!])
• clamshell thoracotomy
-- the most common emergency thoracotomy (espe-
cially perclininal [out-of-hospital]; however, no gene-
ral recommendation; a very invasive measure [ma-
ximally invasive])
-- preclinically (as an emergency physician) only in
case of a cardiac arrest (TCA [traumatic cardiac ar-
rest]; resuscitative thoracotomy) due to a penetra-
ting thoracic injury (classic: knife stab injury), if still
320 General Part
no ROSC occured despite both-sided minithoraco-
tomy and pericardial puncture: In traumatic cardiax
arrest, thoracostomy on both sides by means of a
minithoracotomy to relieve tension pneumothorax is
performed at first anyway. If no ROSC occurs, the
next step is (preferably after sonographic verification
of a pericardial effusion) the pericardial puncture. If
no ROSC occurs here either, then the clamshell tho-
racotomy should be considered preclinically under
the ongoing resuscitation.
-- Especially in a traumatic cardiac arrest, CPR has
only little benefit if the cause has not been remedied
("no-flow"-resuscitation).
-- procedure:
◦◦ first mini-thoracotomy in 5. ICR middle axillary line
(Bülau position) on both sides (note: The mino-
thoracotomies on both sides are usually already
present, since a thoracostomy has already been
performed on both sides. You can use these holes
now!)
◦◦ then deep skin incision (down to the rib level) with
the scalpel across the thorax
◦◦ Then the intercostal muscles are cut with scissors
both laterally and medially to the sternum.
◦◦ The the sternum ist severed. To do this, use sturdy
clothes scissors or thick bandage scissors (prefe-
rably a Gigli saw).
◦◦ then open up the chest (like a clamshell; this is
done by a helper standing at the head of the pa-
tient)
-- a bilateral anterolateral thoracotomy including ster-
notomy
-- required material: only scalpel and scissors (thick
bandage scissors), possibly a Gigli saw for the ster-
num
-- 4E-rule (for the requirements):
◦◦ Elapsed time (< 10min after cardiac arrest)
◦◦ Expertise (Tip: training course beforehand)
◦◦ Equipment
◦◦ Environment
-- therapy-options:
◦◦ relief of tension pneumpthorax (usually already
done beforehand by a bilateral thoracostomy any-
way)
◦◦ relief of pericardial tamponade
▪▪ the most important and crucial thing in emer-
gency thoracotomy
▪▪ wide opening of the pericardium with an inverted
T-cut with scalpel or scissors, clearing out the
tamponade
◦◦ internal (open) chest compressions (The heart
must be grasped in and not on the outside of the
pericardium. The pericardium must be adequate-
ly opened beforehand so that one can reach the
heart with the hands through the pericardium.
Then the heart is compressed from the tip bet-
ween the palms.
◦◦ care for injuries (e.g. compression / suture of the
thoracic internal artery, myocardial leasion [If a pe-
ricardial tamponade occurred after a penetrating
 injury, there is always an injury to the myocardium
that is responsible for the pericardial tamponade
which should be treated accordingly, e.g. with a
suture or even with compression by the finger until
you are in the target clinic.])
◦◦ aortic compression (very effective): The aorta is
simply pressed against the spine manually (by
hand) and thereby compressed. Thus the distal
circulation is abandoned and the proximal circu-
lation, in which the two most vital organs [heart
and brain] are located, is improved. The minimal
circulation should make the patient resuscible.
Cardiac concussion (commotio cordis)
• especially during sports (e.g. baseball, ice hockey, ka-
rate), traffic accident with chest trauma
• mostly male adolescents (average age: 14 years)
• complications:
-- A blow to the sternum (especially in the vulnerable
phase [ascending phase of the T wave, analogous
to the R to T phenomenon; but only accounts for 1%
of the entire heart cycle]) can trigger ventricular fib-
rillation.
-- injury to the pericardium → pericardial effusion, pos-
sibly pericardial tamponade
-- injury of the aorta → aortic dissection (25% of all fa-
tal traffic accidents are caused by traumatic aortic
dissection!)
-- injury of coronary arteries (esp. RIVA) → coronary
dissection, possibly myocardial infarction
-- injury fo the valves (especially aortic valve)
Fig. 516  26-year-old patient after thoracic trauma during
sports (baseball) with a coronary dissection of the RIVA
(see arrow) and consecutive myocardial infarction
Post-resuscitation phase
Definition
• During resuscitation damage is caused by ischemia,
after resuscitation damage is caused by reperfusion.
• post-cardiac-arrest-syndrome (PCAS)
-- reperfusion damage (release of free oxygen radicals
→ possibly administration of selenase as a radical
scavenger [Reisinger et al, Am J Emerg Med 2009];
no general recommendation)
-- sepsis-like syndrome → possibly routine broad-
spectrum antibiotic treatment (no general recom-
mendation); however, in the ANTHARTIC study (see
box) routine antibiotic prophylaxis in patients after
resuscitation who were cooled showed a lower rate
of ventilator-associated pneumonia (VAP)!
• If a supraglottic airway (e.g. laryngeal tube) was inser-
ted preclinically, the patient should be intubated endo-
tracheally (under controlled conditions) after success-
ful resuscitation in the emergency room of the clinic.
Hence a resuscitated patient can usually not be imme-
diately extubated, but must be ventilated for a longer
time.
• After a completed resuscitation, the ERC guidelines
2015 recommend a team-debriefing (e.g. in the in-
tensive care unit). If this is carried out regularly, the
chance of survival can be significantly improved during
subsequent resuscitations (Wolfe et al, Crit Care Med
2014).
The destination in-hospital after
successful out-of-hospital resuscitati-
on is not the intensive care unit, but
the emergency room!
Goals
• normoxemia (cave hyperoxemia → increased release
of free oxygen radicals → increase in brain damage):
Hyperoxemia after ROSC is harmful and increases
mortality (i.a. Kilganon et al, J Am Med Assoc 2010;
Bellomo et al, Crit Care 2011). Hyperoxemia is even
associated with higher mortality than hypoxemia (Kil-
gannon et al, JAMA 2010). Therefore, FiO2 should be
adjusted during ventilation so that SpO2 in the first
hour after resuscitation is 94-98% (and not 100%;
exceptions: carbon monoxide poisoning, anaemia).
However, in a retrospective study (Spindelböck et al,
Resuscitation 2013), in which preclinical BGA's were
analyzed, the group of hyperoxemia (paO2 > 300
mmHg; ROSC rate: 83%) showed a higher ROSC rate
than the group of hypoxemia (paO2 < 60 mmHg; ROSC
rate: only 19%) or normoxemia (paO2 60-300 mmHg;
ROSC rate: 51%).
• normocapnia (no hypokapnia; i.a. Roberts et al, Ann
Crit Care 2014)
• normoglycaemia (adjustment of blood glucose): target
< 180 mg/dl
General Part 321
• hemodynamic stabilization
• if necessary, thrombolysis (especially in acute pulmo-
nary embolism) or PCI (especially in acute myocardial
infarction)
• analgosedation (for at least 24h)
• treatment of seizures
• temperature management:
-- treatment of hyperpyrexia
-- hypothermia (most important!)
no post-ROSC hyperoxemia (is
harmful!)
ANTHARTIC study
Prevention of Early Ventilator-Associated Pneumonia after
Cardiac Arrest
François et al, N Engl J 2019
• multicenter randomized placebo-controlled trial
• 198 ventilated patients after successful (OHCA [out-of-
hospital cardiac arrest]) resuscitation with hypothermia
(TTM; 32-34°C)
-- with antibiotic prophylaxis (amoxicillin / clavulanic acid
1g / 0.2g i.v. 1-1-1 over 2 days)
-- without antibiotic prophylaxis
• results: antibiotic prophylaxis
-- primary endpoint (early [p.d. < 7 days] VAP [ven-
tilator-associated pneumonia] rate): significant reduc-
tion (from 34% to 19%)
-- secondary endpoints (i.a. mortality, late VAP, number
of ventilation-free days, length of ICU stay, antibiotic
resistances): no difference
Diagnostics after resuscitation
• 12-lead ECG
-- especially with the question of acute cardiac ische-
mia
-- is often forgotten in the context of hectic activity!
If the 12-lead ECG is only performed under hypo-
thermia, the Osborn wave (syn.: J-wave) is to be
considered as an important differential diagnosis to
ST elevation in STEMI: This is a camel hump-like
elevated ST segment, which is a classic feature of
hypothermia and is completely physiological!
• laboratory, BGA (In-hopsital a BGA should be taken,
especially for the question hyperkalaemia [→ possibly
lowering] and pH [→ possibly buffering with Nabic in
severe metabolic acidosis with pH <7.1])
• chest X-ray: especially to exclude rib fractures, sternal
fracture, pneumothorax, hematothorax
• sonography (FAST [focused assessment with sono-
graphy for trauma], SHOC [sonography in hypotension
and cardiac arrest])
-- thorax (pleura, lung; BLUE [bedside lung ultrasound
322 General Part
in emergency]):
◦◦ pleural effusion (possibly hematothorax)
◦◦ pulmonary edema (for sonographic verification of
pulmonary edema see page 393)
◦◦ pneumothorax (especially as a result of resuscita-
tion; for sonographic verification of pneumothorax
see page 1073)
-- abdomen: to exclude liver/spleen injury (free fluid)
-- heart (echocardiography): You look for signs of pul-
monary embolism (right ventricular load; then imme-
diately lysis), pericardial tamponade (then immedia-
tely pericardial puncture), wall motion abnormalities
(as a sign of myocardial infarction) and assess the
volume status. In addition, electromechanical dis-
sociation (EMD) can be immediately detected by
the lack of contractions, with the consequence that
chest compressions must be resumed immediately.
Shortly after intubation, esophageal intubation can
be ruled out (with the linear transducer). If neces-
sary, a pacemaker lead can be placed under echo-
cardiographic control on the bed side or, in the case
of massive pulmonary embolism, local lysis or local
embolus fragmentation can be performed with the
pulmonary catheter (block balloon with water instead
of air). The echo device should be placed at the bed-
side not only after, but already during each resusci-
tation in the emergency room or intensive care unit!
• computed tomography
-- CT-thorax (question: pulmonary embolism, aortic
dissection)
-- CCT (cranial CT)
◦◦ if the patient has fallen during cardiac arrest or if
there is a suspicion of a primary intracranial event
as the cause of the cardiac arrest (e.g. stroke,
SAH)
◦◦ generous indication (the collapse during resus-
citation also represents a trauma! additionally also
CT of the cervical spine)
-- possibly whole-body CT (WB-CT; trauma spiral):
The collapse during resuscitation already represents
a trauma. Furthermore, the resuscitation itself re-
presents a trauma: The patient suffers severe chest
trauma 100 times per minute! In many places, a
whole-body CT is therefore routinely performed after
every (successful) resuscitation. However, if 12-lead
ECG shows ST elevations in the sense of STEMI,
CT should be dispensed in my opinion, as this will
certainly delay the immediately necessary coronary
angiography. In addition, most of the relevant ques-
tions from CT can also be answered by sonography,
which is much faster.
• cardiac catheterization
• Basically, one should not make a diagnosis for the
cause of the cardiovascular arrest (and even initiate
appropriate therapy) without first performing a diagno-
sis. It is not uncommon to see that some diagnoses
are simply put together and made up (e.g. "probably
patient has shot a pulmonary embolism").

no diagnosis without diagnostic!
Fig. 517  Often a patient is tachycardic immediately after
resuscitation. This is completely normal and caused by the
effect of the administered adrenalin. As a rule, it is not ne-
cessary to do anything (such as administering a β blocker
or cardioversion), but to wait.
ultrasound (FAST) in every
successfully resuscitated patient
in the emergency room (like in
polytrauma)
Coronary angiography
• Most of all (successfully) resuscitated patients have
CHD (according to Nolan et al, Int Care Med 2014 in
66%). In 75% of the coronary angiography of resus-
citated patients a hemodynamically relevant CHD is
found (with in most cases unremarkable ECG), so that
officially a rapid invasive coronary diagnosis and pos-
sibly PTCA is generally recommended (among others
AHA-Guidelines for Cardiopulmonary Resuscitation
and Emergency Cardiovascular Care 2010, Part 9:
Post-Cardiac Arrest Care). However, there is a lack
of scientific evidence for this, there is no prospective
randomized trial available yet. The benefit of routine
coronary angiography after resuscitation has definitely
not yet been proven. Only in a French study (Geri et al,
Circ Cardiovasc Interv 2015; see box), which was not
randomized either (observational study only), the first
positive indications for invasive coronary diagnostics
with possibly PCI emerged. The recommendation is ul-
timately based on a single observational study (Spaul-
ding et al, N Engl J 1997; see box) and is, in my opini-
on, also relatively far from practice: 2/3 of all hospitals
at least here in Germany have no cardiac catheteriza-
tion lab at all and would have to transfer the recently
resuscitated patient. The inter-hospital transport alone,
where therapeutic hypothermia, among other things,
can be carried out only suboptimally if at all, is asso-
ciated with an increased risk for the patient. The de-
cisive factor after successful resuscitation concerning
the chance of survival of the patient is not the function
of the heart and thus the coronary angiography with
potential PCI, but the function of the brain and thus
therapeutic hypothermia! The main cause of death
after resuscitation is hypoxic encephalopathy and not
cardiogenic shock! Certainly, the majority of resuscita-
ted patients also has PAD (peripheral artery disease)
with hemodynamically relevant stenoses on the lower
limb: But also the function of the lower limb immedia-
tely after resuscitation is just as little relevant for the
survival of the patient as it would justify an immediate
angiography (of the peripheral arteries) with PTA!
• On the other hand, it must be remembered that the
most common cause of cardiac arrest is myocardial
infarction. If the patient has one, he should also be ca-
theterized.
• Coronary angiography after resuscitation should routi-
nely be performed after ventricular fibrillation (not after
asystole) and would strictly speaking only be necessa-
ry, if ST elevations or a complete LBBB in the ECG or
wall motion abnormalities in the echocardiography are
present. Nevertheless, we carry out coronary angio-
graphy very generously after a resuscitation, provided
there was no other clear cause for the cardiovascular
arrest. In the COACT study (see box), immediate car-
diac catheterization in patients after successful (out-of-
hospital) resuscitation in patients without ST elevations
did not show any advantages compared to postponed
cardiac catheterization. The benefit of coronary angio-
graphy after successful (out-of-hospital) resuscitation
in patients without ST elevations is currently being in-
vestigated in several studies (TOMAHAWK, DISCO,
ACCESS). According to the ESC guidelines for NSTE-
ACS 2020, after successful resuscitation, if the patient
is hemodynamically stable and there are no ST eleva-
tions, the cardiac catheter examination is not necessa-
ry immediately, but can only be carried out later.
• recommendations:
-- ESC guidelines (European Society of Cardiology):
immediate angiography with the aim of primary PCI
in patients with resuscitated cardiac arrest
◦◦ with signs of STEMI (but are only available in 50%;
incl. LBBB): class I recommendation
◦◦ without signs of a STEMI (but with a high degree
of suspicion of an myocardial infarction [e.g. angi-
na pectoris in advance, known CHD, ECG chan-
ges]): class IIa recommendation
-- ERC guidelines (European Resuscitation Council):
◦◦ with signs of STEMI (incl. LBBB): clear recom-
mendation for immediate coronary angiography
with PCI
◦◦ without signs of STEMI: no clear recommendation;
may be considered in high-risk patients or hemo-
dynamic instability after successful resuscitation
(then within 2 hours if possible)
• In addition to coronary angiography, ventriculography
maybe also performed, but it can just as well be repla-
ced by echocardiography. If the findings in coronary
angiography are inconspicuous, pulmonary angiogra-
phy is additionally performed in some places at the
cardiac catheterization table to rule out pulmonary
embolism. However, the CT-thorax is common for this.
• In principle, acute myocardial infarction in resuscitated
General Part 323
 patients is treated in the same way as in non-resus-
citated patients. Thus, an immediate coronary angio-
graphy with PTCA takes place in a patient with an ST
elevation myocardial infarction, regardless of whether
the patient has been resuscitated or not.
• As an emergency physician, it is best to be generous
with a resuscitated patient, especially if you have a
free choice, to go to a hospital with a cardiac cathe-
terization lab! In the meantime, so-called Cardiac Ar-
rest Centers have been established, in which patients
are treated after successful resuscitation in an inter-
disciplinary and multi-professional manner according
to a standardized procedure by CART (cardiac arrest
teams).
• Cardiac catheterization can also be performed safely
under hypothermia (i.a. Koreny et al, Resuscitation
2009; Koester et al, Clin Res Cardiol 2011). However,
hypothermia should be initiated before this happens.
The cardiac catheter examination must not delay the
onset of hypothermia! At the latest in the cardiac cathe-
terization laboratory, however, you should start cooling
(e.g. cooling using the CoolGard system via a venous
puncture in the groin).
• The most important thing after resuscitation is thera-
peutic hypothermia, not coronary angiography!
• In individual cases, a cardiac catheterization exami-
nation with PCI also during an ongoing resuscitation
(e.g. using a mechanical resuscitation alternative or
va-ECMO) should be considered.
Coronary angiography must not delay
the onset of therapeutic hypothermia
(but unfortunately it usually does)!
The decisive organ after resuscitation
is not the "pump" (heart), but the
"nut" (brain)!
PROCAT study
Immediate percutaneous coronary intervention is associ-
ated with better survival after out-of-hospital cardiac arrest:
insights from the PROCAT (Parisian Region Out of hospital
Cardiac ArresT) registry
Dumas et al, Circ Cardiovasc Interv 2010
• prospective observational study
• Coronary angiography in 435 successfully resuscitated
patients (not obviously non-cardiac cause of cardiac ar-
rest)
-- in 70% significant coronary lesion
◦◦ with ST elevation: in 96%
◦◦ without ST elevation: in 58%
• survival rate with coronary angiography and possibly
PCI: 40%
study
Immediate Percutaneous Coronary Intervention Is Asso-
ciated With Improved Short- and Long-Term Survival After
Out-of-Hospital Cardiac Arrest
Geri et al, Circ Cardiovasc Interv 2015
• prospective observational French study (not rando-
mized)
• 1723 patients with successfully resuscitated patients af-
ter non-traumatic cardiac arrest (OHCA [out-of-hospital
cardiac arrest]), who were admitted to a Paris hospital
between 2000-2012 (among others in 55% defibrillation,
71% hypothermia, 28% PCI)
• PCI → significantly higher survival rate (after 30d
[42% versus 26%], 3 years [37% versus 19%] and 10
years [32% versus 13%]; PCI ultimately doubled the
long-term survival rate!)

study

Immediate Coronary Angiography in Survivors of Out-of-

Hospital Cardiac Arrest
Spaulding et al, N Engl J 1997

• prospective observational study

• coronary angiography in 84 successfully resuscitated
patients (not obviously non-cardiac cause of cardiac ar-
rest)
-- in 71% significant stenoses (in 48% even occlusion of
a coronary vessel)
-- PCI in 43% attempted, in 33% successful
• ECG (ST segment changes) had only very poor predic-
tive power.

324 General Part


COACT study
Coronary Angiography after Cardiac Arrest without ST-
Segment Elevation
Lemkes et al, N Engl J 2019
• COACT: Coronary Angiography after Cardiac Arrest
• multicenter (19 centers in the Netherlands) open pros-
pective randomized trial
• 538 patients after successful (OHCA [out-of-hospital
cardiac arrest]) resuscitation in patients without ST ele-
vations with an initially shockable rhythm; coronary an-
giography:
-- immediately (within 2h [on average after 50min])
-- postponed (only after neurological recovery; on ave-
rage after 5 days; usually before discharging from ICU
to general ward)
• results:
-- primary endpoint (mortality after 90 days): no diffe-
rence
-- secondary endpoints (survival after 90 days with good
neurological outcome, myocardial damage, duration
of catecholamine therapy, time to reach target tempe-
rature of cooling, renewed VT / ventricular fibrillation,
acute kidney injury, duration of ventilation, neurologi-
cal status at discharge to general ward): no difference
• annotations:
-- PCI
◦◦ immediate coronary angiography: in every 3rd pati-
ent performed
◦◦ postponed coronary angiography: in every 4th pati-
ent performed
-- Coronary angiography was no longer performed in
35% of the patients randomized to the postponed
group.
-- exclusion criteria:
◦◦ ST elevation
◦◦ shock (e.g. cardiogenic shock)
◦◦ other apparently non-coronary causes of cardiac
arrest
If there is no STEMI (no ST elevation
in ECG after ROSC), an immediate
cardiac catheter examination is not
always necessary!
Hypothermia
Definition
• syn.: TTM (targeted temperature management [Accor-
ding to the ERC 2015 guidelines, this term should pre-
ferably be used.])
• Baron Dominique Jean Larrey (1766-1842; field surge-
on of Napoleon) observed that wounded soldiers who
were closer to fire had an increased mortality rate.
• mild hypothermia (32-34°C); annotationsto the target
temperature: In the FROST-I study (Lopez-de-Sa et al,
Intensive Care Med 2018; multi-center pilot study in
101 patients with OHCA), there was no difference in
outcome (survival with good neurological outcome, i.e.
mRS ≤ 3) between different target temperatures 32,
33 or 34°C.
• originally developed to reduce the metabolism of ma-
lignant tumours
• clear recommendation of ILCOR and ERC guideline
since 2003
• previously only practiced in 25% of intensive care units
in Germany (Wolfrum et al, Resuscitation 2007), now
much more common
• With an NNT (number needed to treat) of only 6,
hypothermia after resuscitation is one of the most ef-
fective measures in the whole of medicine!
• Also after hypothermia the prognosis factors are reli-
able! Only for NSE after hypothermia a different stan-
dard value applies (< 90 μg/l instead of < 33 μg/l).
Effects
• reduction of oxygen consumption (per degree by 10%)
• reduction of the formation of oxygen radicals
• neuroprotective (neurons of the CNS have an extre-
mely low tolerance for ischemia!)
• reduction of metabolic activity (only slight effect)
• anti-apoptotic
• anti-inflammatory
• anti-coagulant
Studies
• European: Hypothermia after cardiac arrest (HACA)
study group, N Engl J 2002 (see box)
• Australian: Bernard et al, N Engl J 2002 (see box)
General Part 325
• meta-analysis (Hypothermia for neuroprotection in
adults after cardiopulmonary resuscitation; Arrich et al,
Cochrane Database Syst Rev 2012): Hypothermia sig-
nificantly improves neurological outcome and reduces TTM study
mortality.
• TTM study (see box)
• THAPCA study (hypothermia in children; see page
293) Targeted Temperature Management (TTM) at 33°C versus
• HYPERION study (see box) 36°C after Cardiac Arrest
Nielsen et al, N Engl J 2013

• international multicenter (36 centers from Europe and

European study
HACA
Mild Therapeutic Hypothermia to Improve the Neurologic
Outcome after Cardiac Arrest
The HACA Study Group, N Engl J 2002
• multicenter randomized controlled trial
• HACA: Hypothermia after Cardiac Arrest
• 273 patients after cardiac arrest (initial rhythms: ventri-
cular fibrillation)
-- 136 patients: hypothermia (32-34ºC for 24h)
-- 137 patients: normothermia
• results: hypothermia
-- primary endpoint: good neurological outcome (p.d.
CPC [Cerebral Performance Category] 1-2) → signifi-
cantly more frequent
-- secondary endpoints:
◦◦ mortality after 6 months → significantly lower (41%
versus 55%)
◦◦ complication rate after 7 days: no difference
Hypothermia after resuscitation: after 6
months 15% more survivors!
Australian study
Australia) randomized controlled study
• 939 (the largest study on hypothermia to date) uncon-
scious patients after cardiac arrest with therapeutic hy-
pothermia:
-- target temperature: 33°C (473 patients)
-- target temperature: 36°C (466 patients)
• results:
-- no difference in mortality (survival rate after 6 months
in both arms: 51%)
-- no difference in neurological outcome
• annotations: Some experts question hypothermia after
cardiac arrest in general because of this study, which is
not necessarily correct:
-- Even 36°C is not normothermic, but hypothermic!
-- The results of this international study are not easily
transferable at least not to Germany: On the one
hand, 73% of the patients in this study had already
been resuscitated by bystanders (in Germany only
17%), and on the other hand the period from the oc-
currence of cardiac arrest to the onset of resuscitation
("no flow" time) was extremely short, with only one
minute on average. The shorter the "no-flow" time in
the end, the less important hypothermia becomes, of
course. Cerebral damage usually occurs after 2 mi-
nutes at the earliest. The majority of the patients here
had a "no flow" time of less than 1 minute: Actually, no
hypothermia is necessary at all here!
-- no protocol of analgosedation
-- no fixed cooling method (was left up to the respective
centre; partly without feedback systems)
-- It took very long (12 hours!) until the respective target
temperature was reached.
-- Patients with shock were excluded.

Treatment of Comatose Survivors of Out-of-Hospital Car-

diac Arrest with Induced Hypothermia
Bernard et al, N Engl J 2002

• multicenter randomized controlled trial

• 77 patients with OHCA and primary successful resus-
citation
-- hypothermia (33ºC within 2h for 12h)
-- normothermia
• primary endpoint: survival (hospital discharge) with good
neurological outcome
-- normothermia: 26%
-- hypothermia: 49%

326 General Part


HYPERION study
Targeted Temperature Management for Cardiac Arrest
with Nonshockable Rhythm
Lascarrou et al, N Engl J 2019
• multicenter (25 centers in France) randomized-cont-
rolled study (intervention study; open-label)
• 584 comatose patients after resuscitation after cardio-
vascular arrest (in 75% OHCA, in 25% IHCA) at a non-
shockable rhythms (asystole, pulseless electrical activity
[PEA]): for 24h
-- hypothermia (moderate; target temperature: 33°C)
-- normothermia (target temperature: 37°C)
• results: hypothermia
-- survival with godd (p.d. Cerebral Performance Ca-
tegory [CPC] 1-2 P.) neurological outcome (after 90d;
primary endpoint) → significantly increased (10.2%
versus 5.7%; absolutely by 4.5%, relatively by 80%)
-- mortality: no difference (survival rate after 3 months:
18%)
"Be hot - cool down" ((always cool
after successful resuscitation!) - as
soon as possible!
Indications
• In the ERC guidelines of 2005, hypothermia was only
recommended after resuscitation for ventricular fibrilla-
tion. In the ERC guidelines 2010 and 2015 it is recom-
mended after every successful resuscitation regard-
less of the initial rhythm (both in ventricular fibrillation
and asystole; i.a. Testori et al, BJM 2010: resuscitation
in asystole / EMD → significantly lower mortality and
better neurological outcome due to hypothermia; i.a.
HYPERION study 2019 [see box]).
• ERC guidelines 2010 + 2015: Unconscious adult pa-
tients with spontaneous circulation after prehospital
(accoring to guidelines; applies also to in-hospital) car-
diac arrest should be cooled for 24 hours regardless
of whether the initial rhythm was shockable or not (i.e.
hypothermia after both ventricular fibrillation and asys-
tole! After all, the brain does not really care what kind
of rhythm disturbance caused its hypoxia!).
• also recommended in cardiogenic shock (These pati-
ents were excluded in the two large hypothermia stu-
dies.) after successful resuscitation (i.a. Skulec, Acta
Anaesthesiol Scand 2008; Zobel et al, Crit Care Med
2012; COOL-Shock study [Schmidt-Schweda et al,
Resusc 2013]: even improved hemodynamics [cardiac
output ↑, CPO [cardiac power output] ↑])
• also recommended (ERC 2010 and 2015) for children
and asphyxial (mature) newborns (peripartum ische-
mic encephalopathy)
• not mandatory if the resuscitation time is short (< 5min)
The first large hypothermia study (HACA) was conducted
in patients with ventricular fibrillation, not asystole. Some
people then vehemently called for a study to be carried
out to determine whether hypothermia after resuscitation
is also useful in asystole, which in my opinion is abso-
lutely grotesque: Today, hypothermia can and must not
be withheld from any patient after resuscitation, so that
a study after resuscitation in asystole with randomiza-
tion with and without hypothermia would certainly not
be accepted by any ethical committee. According to the
Declaration of Helsinki, patients may not be included in
a study if it probably does them no good or even harms
them. The brain does not really care which underlying
rhythm disturbance (ventricular fibrillation or asystole)
caused its reduced perfusion. The fact that no study has
yet proven the benefit of hypothermia after resuscitation
in asystole does not at all justify refusal of performing hy-
pothermia in patients after resuscitation in asystole. This
is illustrated by a non-medical example: When jumping
out of an airplane, the jumper uses a parachute, although
it has never been proven in any study that the parachute
is useful for jumping out of an airplane, e.g. it reduces
the mortality of the jumper. Study fanatics would call for
a prospective-randomized double-blind study in which
one group ("verum group") there is a parachute in the
backpack of the jumper and the other group ("placebo
group") only a plastic bag in the backpack of the jumper.
This study has never existed and will never exist. And yet
the jumpers use the parachute when jumping out of the
plane, although there has never been a study to prove
the benefit. The use of a parachute is clearly recommen-
ded by the "International Society of Skydiving" (class IA
recommendation)!
Methods
• external cooling methods
• internal cooling methods
External cooling methods
• simple measures (e.g. undressing the patient, swit-
ching off the heating function of the intensive care bed)
• cold infusions:
-- 30 ml/kg of 4°C cold Ringer's solution (better than
NaCl 0.9% because of hypothermia-induced hypo-
kalemia) over 30min i.v. lower the body core tempe-
rature by 1.5°C (approx. 1500-2000ml).
-- Start already in the emergency room (easy and
fast available)!
-- The preclinical administration of cold saline solution
did not bring any advantages (studies: Bernard et al,
Circulation 2010; Kim et al, JAMA 2014 [see box]). It
is also explicitly not recommended (i.a. ESC-guide-
lines 2017: IIIB)
-- If cold infusions are admistered during (and not only
after; i.e. intraarrest) resuscitation, the CVP and thus
the RA pressure may increase with the result that
the coronary perfusion pressure (difference bet-
ween diastolic blood pressure and RA pressure) and
therefore the probability of a ROSC decreases.
• surface cooling with ice packs, cold and wet compres-
ses, cold mats (e.g. EMCOOLS pad [cooling pads pre-
General Part 327
 cooled to 9°C, which are then placed on the skin over a primarily locally (in the brain) and secondarily also sys-
large area; temperature reduction 3.0-3.5°C/h]) temically.
• cooling mattress and tent: Delta ThermR (KCI) • A flow rate of 40 l/min is set as standard. The tempe-
• water circulation blankets (blanket through which cold rature should be measured tympanically on a regular
water is passed, cooling by convection; e.g. Arctic Sun) basis. From a temperature below 34° C the flow is re-
• transsnasal evaporative cooling (i.a.RhinoChill) duced to 20 l/min.
• temperature reduction: 1.6°C/h
• costs:
-- device: 8600€
study -- per application (nasal catheter, 1 litre bottle of per-
fluorocarbon): approx. 1000€ (relatively expensive)
-- A special fee can be agreed with the health insu-
rance companies.
Effect of prehospital induction of mild hypothermia on sur-
• studies: After the pilot study (a feasibility study)
vival and neurological status among adults with cardiac
arrest PRINCE (see box) for cooling with RhinoChill already
Kim et al, JAMA 2014 during (and not only after; i.e. intraarrest) the resusci-
tation was very promising, the subsequent large mul-
• multicenter randomized controlled trial ticenter randomized controlled PRINCESS study (see
• 1359 successfully resuscitated patients after out-of-hos- box) was absolutely disappointing.
pital cardiac arrest
-- with preclinical administration of cold saline solution
(2 liters; 4°C)
-- without preclinical administration of cold saline solu-
tion
• results: preclinical administration of cold saline so-
lution
-- primary endpoints: no difference
◦◦ survival rate (hospital discharge)
◦◦ neurological status (hospital discharge)
-- secondary endpoints: i.a.
◦◦ frequent reoccurrence of pulselessness (rearrest)
◦◦ more frequent radiological signs of hyperhydration
(pulmonary edema) and poorer oxygenation (but
no longer duration of ventilation or higher rate of
re-intubation)

Fig. 518  Arctic Sun (C.R. Bard, Inc.) [37]

RhinoChill
• transnasal cooling system (non-invasive)
• formerly BeneChill company (Switzerland), now Brain- Fig. 519  RhinoChill incl. perfluorocarbon bottle (1 liter;
sufficient for approx. 30 min of cooling) and nasal cannula
Cool company (USA)
(The two tubes are inserted into the nostrils.)
• on the market since 2011
• battery operated (battery life: 4-6h)
• well suited especially preclinically (e.g. emergency
ambulance)
• Via a nasal catheter a fast evaporating cooling liquid
(perfluorocarbon) is sprayed into the nasal cavity (in-
duction of cooling). This then leads to hypothermia

328 General Part


PRINCE study
Intra-Arrest Transnasal Evaporative Cooling - a rand-
omized prehospital multicenter study
Castren et al, Circulation 2010
• PRINCE: Pre-ROSC Intra-Nasal Cooling Effectiveness
• pilot study (feasibility study)
• 200 patients with out-of-hospital cardiac arrest (OHCA)
-- with cooling during resuscitation (and not afterwards
[intra-arrest]; transnasal using RhinoChill)
-- without cooling during resuscitation (onset of cooling
only after ROSC)
• results: RhinoChill
-- no difference in mortality
-- no difference in ROSC
-- no difference in neurological outcome
-- Target temperature (34°C) was reached 3h earlier
than in the group where cooling was started only after
ROSC.
PRINCESS study
Effect of Trans-Nasal Evaporative Intra-arrest Cooling on
Functional Neurologic Outcome in Out-of-Hospital Cardiac
Arrest
Nordberg et al, JAMA 2019
• PRINCESS: Prehospital Resuscitation Intra Nasal Coo-
ling Effectiveness Survival Study
• multicenter prospective randomized controlled trial
• 677 patients with out-of-hospital cardiac arrest (OHCA);
in both groups after ROSC then systemic cooling in-
hospital)
-- with cooling during resuscitation (and not afterwards
[intra-arrest]; transnasal using RhinoChill)
-- without cooling during resuscitation
• results: RhinoChill
-- primary endpoint (survival with good neurological out-
come [CPC 1-2]) after 90 days: no difference (in the
subgroup onset of resuscitation < 10min + ventricular
fibrillation: significant reduction)
-- secondary endpoints:
◦◦ survival after 90 days: no difference
◦◦ sustained ROSC and reached hospital alive: no dif-
ference
◦◦ time to reach the target temperature of 34°C: signi-
ficantly reduced
Internal cooling methods
• Coolgard system (used in our hospital)
• veno-venous (hemofiltration, hemodialysis)
• intraperitoneal (Peritonealkühlung; sehr schnelles Er-
intraperitoneal (peritoneal cooling; very fast reaching
of the target temperature [within 15min])
• heart-lung machine (extracorporeal circulation)
Coolgard (Zoll)
• new designation: Thermogard
• definition: intravascular system for cooling or heating
• Indications:
-- cooling (e.g. after resuscitation; main indication)
-- warming (e.g. in case of hypothermia after drowning)
◦◦ From hypothermia < 30°C, external reheating
(e.g. with heating blankets) is contraindicated due
to the risk of afterdrop (external heating → peri-
pheral vasodilatation → The warm blood in the
body core mixes with the cold blood in the body
shell. → further drop of the body core temperature
→ ventricular fibrillation [like the classical "rescue
death"])! Here, internal heating is always obligato-
ry (e.g. by means of Coolgard system)!
◦◦ rewarming rate: initially 0.2 degrees/hour to 33°C,
then 0.5 degrees/hour
• principle (cooling): A mixture of cold saline solution and
a cooling liquid (propylene glycol) circulates in a closed
system to a special catheter (Icy-catheter), which is
placed into the inferior vena cava via the femoral vein.
The passing blood is cooled indirectly without blood
contact via cooling membranes of the catheter (bal-
loons [heat exchange balloons]).
• catheter:
-- for cooling: Icy catheter
◦◦ technical data: Length 38cm; 3 balloons, 3 infusi-
on lumina
◦◦ in total 5 lumina (one inflow lumen, one outflow
lumen and three free lumina [infusion lumina: Via
the three free lumina all drugs can be applied as
usual via a normal central venous catheter; thus
also usable as a CVC)
◦◦ maximum dwell time: 4 days
◦◦ only for femoral vein
◦◦ The subsequent rewarming, however, which takes
place passively, can also be carried out with the
Icy catheter, a change to the Cool-Line-catheter is
not necessary.
◦◦ new: Quattro-catheter (has 4 balloons and is
therefore even more effective; length 45cm [very
long, therefore not possible in very small patients;
chest X-ray or echocardiography is absolutely ne-
cessary after application to exclude an intracardi-
ac position; cave: pericardial tamponade due to
a perforation of the wall of the right atrium / ven-
tricle], 3 infusion lumina; maximum dwell time: 4
days; only for femoral vein
-- for warming: Cool-Line catheter
◦◦ technical data: length 22cm; 2 balloons, 3 infusion
lumina
◦◦ maximum dwell time: 7 days
◦◦ not only for femoral vein, but also for internal jugu-
lar or subclavian vein
• catheter placement:
-- puncture of the femoral vein (preferably sonogra-
General Part 329
 phically controlled), insertion of the guide wire (Sel-
dinger technique), dilator, insertion of the catheter,
suture
-- subsequent control by means of X-ray or echocar-
diography (catheter must not be intracardially po-
sitioned; applies especially to the Quattro-catheter,
which is relatively long)
• The catheters were coated with heparin for a long time
(contraindication: HIT II). However, by 2013 the cathe-
ters are heparin-free.
• The catheters are suitable for MRI.
• In a comparative study (Hoedemarkers et al, Crit Care
Med 2007) between external (cold packs, water cir-
culation blankets, cool infusions) and internal cooling
method by means of Coolgard, the target temperature
could be reached significantly faster with the Coolgard
system without "overshoot" (i.e. > 0.5°C below target Fig. 522  Coolgard [34]
temperature).

inflow lumen
outflow lumen

3 free lumina
(for infusions)

Fig. 523  Coolgard Icy catheter - It has a total of 5 lumina:

One inflow lumen, one outflow lumen and three free lumina,
which can be used in the same way as the lumina of a nor-
mal CVC for infusions. All medications can be administered
via this catheter, i.e. during the initial care with insertion of
accesses of a resuscitated patient (e.g. in the emergency
room) it is best to place the Coolgard Icy catheter imme-
diately, so that initially the installation of a normal central
venous catheter is not necessary.

Fig. 520  Coolgard

Fig. 524  Coolgard Icy catheter: Here the three balloons (ar-
rows) are illustrated. These are located in the inferior vena
cava and contain a mixture of cold saline solution and a
coolant: This is where cooling takes place.
Fig. 521  Coolgard Icy catheter: It is inserted in the femoral
vein using Seldinger technique.

330 General Part

Procedure
• onset of cooling:
-- as early as possible after ROSC: if possible already
out-of-hospital, at the latest in the emergency room
(before a possible coronary angiography!)
-- at least within 4 hours after cardiac arrest
-- Even a delayed start is still protective!
-- There are even studies (e.g. PRINCE, PRINCESS)
on the use of hypothermia already during (and not
only after; intraarrest) resuscitation (so-called pre-
ROSC hypothermia in addition to post-ROSC hypo-
thermia).
• velocity of cooling:
-- target temperature: 32-34°C (In the ERC guidelines
2015, 36°C is given as a further option.)
-- should be reached within 4h
• duration of cooling: 24h (ERC 2015; ERC 2010: 12-
24h), after prolonged (> 30min) resuscitation: 48h
• adjuvant measures (to suppress the body's own heat
production):
-- analgosedation (deep sedation!)
-- muscle relaxation (e.g. pancuronium every 2h
0.1mg/kg, e.g. 4mg every 2h), possibly Mg-sulfate
(esp. in hypomagnesaemia)
• site of temperature measurement: bladder, rectum,
tympanic (double measurement recommended)
• no interruption (if possible) for diagnostic or therapeu-
tic measures (e.g. transport to CT, coronary angiogra-
phie)
• heparin administration for thrombosis prophylaxis
-- i.v. not s.c., as hypothermia leads to a pro-
nounced centralization, so that heparin s.c. is only
insufficiently resorbed peripherally
-- unfractionated heparin (UFH) as a perfusor
-- without PTT control
-- dosage: heparin 400 IU/h (if platelets < 50000/μl →
only 200 IU/h)
• nutrition:
-- The energy requirement under hypothermia is redu-
ced by 30%.
-- Hypothermia is not a contraindication for enteral nu-
trition.
• rewarming:
-- passive
-- 0.25-0.5°C/hour (usually over 8-12 hours)
• The Icy catheter remains in the patient for a total of 72
hours in order to ensure normothermia via the Cool-
gard system in case of a fever.
Side effects
• shivering (DD seizure, myoclonia after resuscita-
tion)
• infections (especially pneumonia and sepsis [e.g. me-
ta-analysis Geurts et al, Crit Care Med 2014])
• coagulation disorders (platelets ↓, PTT ↑, coagula-
tion factor activity decreases by 10% per degree Celsi-
us), possibly bleeding
• leukocytes ↓
• hyperglycaemia (due to reduced insulin secretion;
possibly insulin perfusor)
• local cold damage (in case of external cooling)
• mydriasis (pupils wide and unresponsive to light
[cave: no sign of brain damage, but only an effect of
hypothermia])
• electrolyte disorders
-- potassium
◦◦ cooling: hypokalemia
◦◦ varming: hyperkalemia
-- calcium ↓, magnesium ↓, phosphate ↓
• hypovolemia (cold-induced diuresis!)
• blood pressure ↓ (cave esp. blood pressure drop in
case of pre-existing shock!)
• reduction of gastrointestinal motility (However, enteral
nutrition is still possible during hypothermia.)
• bradycardia (frequently!)
• ECG changes:
-- arrhythmias
-- PQ interval­ ↑, QT interval ↑, QRS width ↑­
-- Osborne wave (syn.: J wave; ST elevation with
raised J point, "hypothermic camel hump"; a side ef-
fect of hypothermia, no acute myocardial infarction!)
• Under hypothermia, less oxygen is consumed and less
carbon dioxide is produced, so ventilation should also
be adjusted accordingly to avoid hyperventilation. The
required tidal volumes are lower under hypothermia
than under normothermia. In addition, thoracic and
pulmonary compliance is reduced under hypothermia.
Do not confuse hypothermia-rela-
ted shivering with a seizure!
Contraindications
• severe trauma (e.g. resuscitation in case of poly-
trauma [TCA: traumatic cardiac arrest]), surgery (hy-
pothermia → bleeding risk ↑ )
• very unfavourable neurological prognosis
• (persistent) haemodynamic instability with MODS, e.g.
septic shock, cardiogenic shock (formerly considered
a contraindication; no longer; current recommenda-
tions: hypothermia is also possible in shock [e.g. car-
diogenic])
• severe manifest haemorrhage (However, if the
haemorrhage is interventionally / surgically treated
[e.g. Forrest Ia haemorrhage from a duodenal ulcer
that has been treatet interventionally with a OTS-Clip
or operatively by duodenotomy with ligature of the gas-
troduodenal artery], hypothermia may well be perfor-
med
• severe coagulation disorder (note: After lysis therapeu-
tic hypothermia is not contraindicated!)
• pregnancy: no contraindication
General Part 331

T ↓, pH ↓, Hb / Hct ↓ → bleeding ↑
lethal triad: hypothermia, acido-
sis, anaemia
Prognosis (after resuscitation)
• ROSC (return of spontaneous circulation) in 45%
• survival
-- according to rhythm:
◦◦ ventricular fibrillation: 10% (TROICA study: 20%)
◦◦ asystole:
▪▪ atraumatic: 5%
▪▪ traumatic: 1%
-- according to location:
◦◦ OHCA (out-of-hospital cardiac arrest): 10%
◦◦ IHCA (in-hospital cardiac arrest): 20%
-- according to time (onset of chest compression):
◦◦ 5 minutes: 50%
◦◦ 8 minutes: 25%
◦◦ 15 minutes: 8%
• significantly higher survival rate (45%) if cardiac arrest
occurs during sports (ARREST study 2012)
• 1-year survival rate (Germany):
-- 10% (without hypothermia)
-- with hypothermia (and bystander CPR) but already
50% today in Scandinavian countries (TTM study:
Nielsen et al, N Engl J 2013 [see page 326]): The
main reason for the low survival rate in especially
in Germany is the low proportion of bystander CPR
performed prior to the arrival of the rescue service
wie only 17%, which meanwhile increased fortuna-
tely to 42% due to the promotion and expansion. In
Scandinavian countries the survival rate is already
50% today! In the TTM study 50% survived in both
arms. In these countries the percentage of bystan-
der CPR is 73%. In Germany (survival rate after 6
months 10-20%, after 12 months 10%) these survi-
val rates can only be dreamed of at present!
• survival rate (hospital discharge): 13% (German Re-
suscitation Register 2018)
• Only 5% are discharged from the hospital with good
neurological outcome.
• main cause of death after (out-of-hospital) resusci-
tation: hypoxic encephalopathy
• In about 50% of the cases therapy is actively stopped
after resuscitation. A considerable proportion of these
(10%) unfortunately die (in the sense of a "self-fulfilling
prophecy") because the therapy was not escalated, re-
duced or even discontinued too early and hastily due
to a neurological prognosis that was wrongly assessed
as too poor (therefore as a tip: "take your time!" ["You
can still stop very easily and quickly!"]).
• assessment of prognosis only after 72h (not earlier!
There is no parameter in the first 72 hours that could
reliably predict a poor neurological prognosis! Last but
not least, this also gives you time to evaluate a possi-
ble organ donation!)
332 General Part
• After one year after survived cardiac arrest (successful
resuscitation) the quality of life of the patients is surpri-
singly good, contrary to widespread opinion (i.a. Smith
et al, Circulation 2015; in 84% no neurological deficit).
Most patients do not need support and can even return
to work.
• The prognosis after resuscitation is assessed clinically,
electrophysiologically, laboratory chemically and radio-
logically.
• Even after hypothermia the prognosis factors are
reliable! Only for NSE after hypothermia a different
standard value applies (< 90 μg/l instead of < 33 μg/l).
However, the prognosis should only be assessed 72
hours after normothermia has been reached (and not
72 hours after ROSC)!
• After a survived resuscitation, rehabilitation should be
carried out after the end of the intensive care stay.
• If a hereditary disease such as cardiomyopathy (es-
pecially hypertrophic cardiomyopathy, arrhythmogenic
right ventricular cardiomyopathy) or an ion channel
disease (e.g. Brugada syndrome, long QT syndrome)
is found to be the cause of the cardiac arrest, the fa-
mily members should be screened accordingly. Also,
especially in younger deceased patients, if the cause
of the cardiac arrest was not clear, an autopsy should
be generously sought: If a previously unknown heredi-
tary cause is found, this is of considerable importance
for the relatives (especially for the children) and their
sudden cardiac death at a young age can possibly
be avoided by appropriate clarification and measures
(e.g. prophylactic AICD implantation)
• To avoid in-hospital resuscitations, the current ERC
guidelines recommend the implementation of an
emergency team in the hospital (RRT: rapid respon-
sive team; not to be confused with the resuscitation
team, which only arrives after cardiovascular arrest).
This team is alerted if certain criteria are met. Most
cardiovascular arrests announce themselves and do
not come out of the blue!
current survival rate after resuscitati-
on in Germany: only 10%
possible survival rate today after
resuscitation (including bystander
CPR) and hypothermia: 50% (Scandi-
navia)!
 EuReCa TWO study

Survival after out-of-hospital cardiac arrest in Europe

Graesner et al, Resuscitation 2020

• multicenter prospective observational study

• 37054 patients with out-of-hospital cardiac arrest
(OHCA) in Europe, resuscitations performed in 25171
• Ergebnisse:
-- bystander CPR: in58%
-- ROSC: in 33%
-- survival rate (discharge from hospital alive): 8%
-- significantly higher survival rate when bystander CPR
was performed with ventilation (instead of chest-com-
pression-only; 14% versus 8%)

no premature therapy limitation or

reduction after resuscitation due to a
supposedly poor prognosis!

prognosis estimation after resuscitati-

on: only after 72h (not previously)!

Hypoxic encephalopathy

General Part 333

Definition • therapeutic hypothermia (TTM) performed
• syn.: • persistent myocloni in the further course
-- hypoxic ischemic encephalopathy (HIE) • EEG: severe general change with monomorphic basic
-- hypoxic brain damage activity of approx. 3/sec with frequent bilaterally syn-
chronous steep waves, no clear focus
• brain damage due to lack of oxygen
• neurological consultation: "A state well above apallic
-- global cerebral ischemia
cannot realistically be expected."
-- particularly vulnerable: hippocampus, cerebral cor-
tex, basal ganglia, cerebellum
• main cause of death after (esp. out-of-hospital) re-
suscitation
• ischemia tolerance of the brain (simplified):
-- 4 minutes → incipient neurological damage
-- 8 minutes → severe permanent neurological dama-
ge ("dependent on care")
-- 12 minutes → death
• mean time to arrival of the rescue service: 10 minutes
(deadline by law: 12 minutes [in Bavaria in Germany
according to the Bavarian law on emergency rescue
services BayRDG])!
• S1 guideline "Hypoxic-ischemic encephalopathy (HIE)
in adults" of the German Society for Neurology (DGN)
2018
• Most patients with a good neurological outcome wake
up within the first five days after resuscitation.
• An increasing brain edema in the context of hypo-
xic encephalopathy (e.g. after resuscitation) is no indi-
cation for measurement of intracranial pressure (ICP)
or for craniotomy (no benefit). A possible transfer to a
hospital with neurosurgery is therefore not necessary.
• Patients with hypoxic brain damage should be trans-
ferred to neurological rehabilitation at an early stage
if they have still a realistic prognosis. Before transfer,
samples should be taken again, e.g. zu exclude multi- Fig. 525  40-year-old patient with hypoxic brain damage (af-
ter resuscitation after myocardial infarction)
resistant bacteria. Furthermore, the patient is equip-
ped with the following devices before the transfer (of-
ten disrespectfully referred to as "reha piercing); note: Prognostic factors (unfavorable prog-
All 3 interventions are also possible under DAPT [dual nosis)
anti-platelet therapy, e.g. ASA + clopidogrel].): • clinical (The clinical-neurological examination should
-- tracheal cannula (not mandatory) best be done without sedation and muscle relaxation
-- PEG if possible!)
-- suprapubic catheter (SPC; puncture fistula for urina- • electrophysiological
ry bladder drainage) • laboratory chemical
• If the prognosis is infaust, especially in younger pa- • radiological
tients brain death diagnostic (see page 1370) should
be carried out and a possible organ donation should
be evaluated.
There are only parameters for a poor
prognosis, no parameters for a good
prognosis!
The main cause of death after
resuscitation is hypoxic encephalopa-
thy and not cardiogenic shock! for evaluation of prognosis always
assess several factors (multimodal
approach)!
Case
• 40 years old man
• suddenly collapsed, resuscitation in ventricular fibrilla- Clinical prognostic factors
tion (ROSC after 15 minutes) • absent light reaction of the pupils on both sides (es-
• acute myocardial infarction (ST elevations in II, III, aVF pecially on day 3) → with very high probability severe
[see ECG]); PCI + stent implantation RCA performed) hypoxic encephalopathy (poor outcome)!

334 General Part

 -- the most important clinical factor!
-- However, at admission the light reaction is falsely Myocloni are not a sure indicator of a
positive in 30% (Okada et al, Resusc 2012). poor outcome!
• absence of brainstem reflexes
-- corneal reflex (absence of the corneal reflex on both
sides → with high probability severe hypoxic ence- Electrophysiological prognostic parame-
phalopathy [but less reliable for a poor outcome than ters
the absence of light reaction of the pupils])
• EEG (electroencephalogram) - The following criteria
-- oculocephalic reflex (findings) are a strong indicator of a poor outcome:
-- cough reflex -- low-voltage EEG (p.d. amplitude of the voltage < 10
• absence of response to pain stimuli in the first 3 days μV), especially burst-suppression-EEG (p.d. ampli-
(after hypothermia: in the first 7 days; overall, however, tude of the voltage < 10 μV > 50% of the duration of
relatively unreliable [can definitely not predict a poor recording), maybe even flatline-EEG; note: An EEG
outcome; i.a. Dragancea et al, Resuscitation 2015]) is usually not available in a (especially internal) in-
• myocloni tensive care unit. The criteria "burst-suppression-
• seizure EEG" and "flatline-EEG" can also be derived using
-- in 25% after resuscitation the BIS system (BIS: bispectral index; see page
-- A status epipepticus is a strong indicator of a poor 177), which is relatively widespread. A small study
outcome! (Leary et al, Resuscitation 2010) showed that a BIS
> 45 within 24 hours after resuscitation was associ-
ated with a good neurological outcome (specificity
Absent bilateral pupil and corneal 86%, sensitivity 63%). However, there is little evi-
reflexes after > 72h have a very dence for BIS to predict the outcome after resusci-
high predictive value (95%) for a tation, so that it was understandably not included in
poor outcome! the S1 guideline.
-- continuous periodic discharges with suppressed
background activity (< 10 μV)
Myocloni
-- α-coma
• Lance-Adams myocloni
-- status epilepticus
• post-axonal early myoclonic jerks (day 1)
• median-nerve-SSEP
• occurring in 25% of all patients with hypoxic encepha-
-- bilateral loss of the N20 wave (electrical amplitude
lopathy
across the contralateral cortex 20ms after stimulati-
• DD seizure on of the median nerve at the wrist)
• only poorly responsive to antiepileptic drugs -- The derivation should be performed at several points
• in 91% poor outcome (Seder et al, Crit Care Med along the median nerve.
2015), however (also according to the S1 guideline -- interpretation:
2018) definitely not a sure indicator of a poor outcome
◦◦ absence of the medianus-SSEP on both sides af-
(Myoclonus are often automatically equated with a
ter 72h → almost 100% poor outcome (very high
poor outcome, which is not correct!)
sensitivity) [very reliable])
• therapy
◦◦ SSEP-amplitude after 72h > 2.5 μV → with very
-- clonazepam (Rivotril; drug of choice high probability no severe hypoxic encephalopa-
-- piracetam (Nootrop) thy (good outcome!)
◦◦ 1 amp. = 60ml = 12g; dosage: 3-12g twice daily in
a short infusion over 30 min
◦◦ dose reduction in renal failure (creatinine 2-3 mg/
dl → 50% of the dose; creatinine 3-8 mg/dl → 25%
of the dose)
◦◦ contraindications: intracranial haemorrhage, end-
stage renal failure (creatinine > 8 mg/dl; but nor-
mal dose in case of hemodialysis)
-- propofol
-- antiepileptic drugs (often not helpful):
◦◦ valproic acid (Orfiril)
◦◦ levetiracetam (Keppra, Desitin)
• quoad vitam no influence (but often extremely stress-
ful, especially for caregivers and relatives)

General Part 335


Fig. 526  electroencephalogram (EEG) in the intensive care
unit
Laboratory chemical prognostic parame-
ters
• types
-- NSE (neuron-specific enolase)
◦◦ after 72h > 33 μg/l (after hypothermia: > 90 μg/l) →
strong indicator for a poor outcome!
◦◦ the best studied biomarker
◦◦ high specificity, but low sensitivity (unreliable)
◦◦ NSE < 17 μg/l after 72h → with very high proba-
bility no severe hypoxic encephalopathy (good
outcome!)
◦◦ DD: NSE elevation also in
▪▪ hemolysis (should always be excluded; hemoly-
sis parameters: LDH ↑, indirect bilirubin ↑, hap-
toglobin ↓, hemoglobinuria; hemolysis, espe-
cially often under ECMO or if the blood sample
is transported not vibration-free)
▪▪ after seizure
▪▪ NSE-producing tumours (here NSE usually >
1000 μg/l; especially small cell lung cancer [tu-
mour marker], neuroendocrine tumours)
-- protein S100 B at day 2-3 > 0.56 μg/l
◦◦ release from astroglia cells after cerebral hypoxia
◦◦ shorter T1/2 than NSE
◦◦ DD: Protein S100 increase also in the context of
bacterial infections
◦◦ not recommended
• evaluation: The laboratory chemical prognosis para-
meters are, however, relatively unreliable overall. At
least you should never use them alone for assess-
ment, but always choose a multimodal approach. In
the S1 guideline "Hypoxic-ischemic encephalopathy",
the determination of the NSE is clearly recommended.
Radiological prognostic parameters
• A CCT is often performed, but is usually not very hel-
pful so that it was not recommended for estimating the
prognosis for a long time. Meanwhile after the imple-
mentation of newer signs, cerebral imaging (CT, MRI)
is clearly recommended in the guidelines (including
the S1 guideline "Hypoxic-ischemic encephalopathy"
336 General Part
of the German Society of Neurology 2018)
• newer signs:
-- LOB-sign (loss of boundery):
◦◦ loss of grey-white matter differentiation
◦◦ A grey to white matter ratio (GWR: grey-white-
ratio) < 1.2 indicates an extremely poor outcome
(almost 100% mortality; Metter et al, Resuscitation
2011).
◦◦ S1 guideline "Hypoxic-ischemic encephalopathy":
GWR < 1 → strong indicator for a poor neuro-
logical outcome
-- sulcal effacement-sign
◦◦ detection of fluid in the sulci
◦◦ specificity of 100% and sensitivity of 32% for a
poor neurological outcome (Inamasu, Resuscita-
tion 2010)
• possibly MRI (higher sensitivity and specificity than CT,
but more complex and not available in most hospitals)
• Be careful with a premature diagnosis of brain ede-
ma in CCT in children / adolescents: Here physiologi-
cally, the lateral ventricles are often relatively narrow,
so that as a non-radiologist, especially if you are only
used to CCT images of older patients, you are often
over-hasty to make a diagnosis of brain edema. CCT
in children / adolescents should always be evaluated
by a specialist (radiologist, neurosurgeon) before ma-
king a diagnosis of brain edema!
• A proven cerebral edema cannot predict the course
of the disease sufficiently. Despite a brain edema de-
tected by CCT, only 22% had a poor outcome in one
study (Fugate et al, Ann Neurol 2010), i.e. brain edema
alone should not be a reason for limiting or reducing
therapy! Particularly after an asphyxia-induced cardi-
ac arrest, brain edema is often only transiently present
and is rarely accompanied by a relevant increase in in-
tracranial pressure (Sakabe et al, Intensive Care Med
1987; Morimoto et al, Crit Care Med 1993).
• An indication for CCT after resuscitation would be, for
example, the suspicion of a subarachnoid hemorrhage
as the cause of the resuscitation, the suspicion of an
intracranial bleeding after lysis therapy during resus-
citation or a drop on the head as part of the collap-
se (especially with oral anticoagulants in medication).
Brain edema in CCT after resuscitati-
on alone is no reason for therapy
limitation or even therapy reduction!
Fig. 527  CCT: sever hypoxic brain damage (i.a. loss of
grey-white matter differentiation, swelling in the area of ​​the
pons with herniation)

Fig. 529  CCT: sever hypoxic brain damage

Fig. 528  CCT: sever hypoxic brain damage (i.a. complete

loss of grey-white matter differentiation, almost complete
compression of the lateral ventricles)

General Part 337

Special Part
Cardiology

ACUTE CORONARY
SYNDROME
Classification
According to a proposal by the European Society of Car-
diology (ESC) and the American College of Cardiology
(ACC), acute coronary syndrome has been divided into
the following 3 groups since 2000:
• STEMI (ST-elevation myocardial infarction): with ST-
elevations (exact: persistent, i.e. > 20min)
• NSTEMI (Non-ST-elevation myocardial infarction): wit-
hout (persistent) ST-elevation, but positive troponin
• unstable angina pectoris: by definition troponin nega-
tive (twice); definition unstable angina pectoris: first
event (de novo angina), symptoms at rest, increase in
duration, intensity or frequency
To simplify matters, the division can also be made into:
• STE-ACS (acute coronary syndrome with ST elevation
myocardial infarction)
• NSTE-ACS (acute coronary syndrome without ST ele-
vation myocardial infarction)
The earlier division into Q-wave and non-Q-wave infarcts
is obsolete, since Q-waves only develop after about 12h
and can occur in both STEMI and NSTEMI.
As a counterpart to acute coronary syndrome, there is
now also the term chronic coronary syndrome (i.a. ESC
Guidelines for the diagnosis and management of chronic
coronary syndromes 2019) instead of the term stable co-
ronary heart disease (CHD).
Fig. 530  Pathophysiology of acute myocardial infarction:
Plaque rupture and consecutive thrombotic occlusion of
the coronary vessel occur.
342 Cardiology
Epidemiology
CHD (coronary heart disease) is the most frequent fa-
tal disease in industrialized nations like Germany before
malignancies (No.2) and stroke (No.3) and is respon-
sible for 13% of all deaths. Approximately 300 infarcts
/ 100,000 inhabitants occur per year with about 140000
deaths annually. Myocardial infarctions occur more fre-
quently in the 5th-6th decade of life. Myocardial infarction
is the most frequent cause of cardiovascular arrest and
thus the most frequent reason for resuscitation. The pro-
bability of suffering a myocardial infarction in the course
of life (lifetime prevalence) is 30% for men and 15% for
women. At an age below 75 years, men predominate, at
an age above 75 years, women are at higher risk (each
in a ratio of 2:1). The mortality rate of myocardial infarc-
tion is still 16% despite all the progress made. If the eva-
luation of death certificates with a suspected myocardial
infarction is included in the statistics, the mortality rate
is even 50%. The main mortality is pre-hospital. More
women (52%) die of heart attacks than men (48%). The
mortality rate in women is almost twice as high as in men
("Eva infarction"), partly due to the frequently atypical cli-
nic and the associated delayed diagnosis. Early mortality
in NSTEMI is ten times lower than in STEMI, but the cu-
mulative mortality after one and two years is just as high
as in STEMI. After four years, the mortality in NSTEMI is
even twice as high as in STEMI (mainly due to the higher
age and comorbidities). In an observation study (Yeh et
al, N Engl J 2010) on 46086 North American patients,
both the myocardial infarction rate and myocardial infarc-
tion mortality decreased by 24% during the observation
period 1999-2008. The incidences were 70/100,000 for
STEMI and 132/100,000 for NSTEMI. ACS is the second
most frequent emergency medical intervention with a
fraction of approximately 20% (after the seizure). 30% of
all patients presenting with thoracic pain in the emergen-
cy room have acute coronary syndrome.
The average pre-hospital time in Germany is 225 min
(GOAL register) and has even increased over the last 10
years (1995: 160 min) despite all efforts to educate pati-
ents. The main loss of time lies in the extended time bet-
ween the onset of symptoms and the patient's emergen-
cy call. 40% of all infarctions occur in the early morning
hours (12 PM-6 o'clock AM; due to the sympathicoadren-
ergic activation). In 30% an acute myocardial infarction
occurs in previously asymptomatic patients (in the sense
of a first manifestation of CHD). Unfortunately in Germa-
ny it is still the case that despite all the discussion about
thrombolysis and PTCA, 40% of STEMI patients do not
receive any reperfusion therapy at all. According to data
from the German Heart Attack Register 2013, however,
the proportion has decreased to 10%
Epidemiology:
STEMI (1/3) ↓
NSTEMI (2/3) ↑
 2015)
• for STE-ACS: ESC Guidelines for the management of
acute myocardial infarction in patients presenting with
study ST-segment elevation 2017

Symptoms
German nationwide data on current trends an manage- • severe retrosternal and left-sided chest pain ("excru-
ment of acute myocardial infarction: discrepancies bet- ciating pain"): If acute chest pain occurs, the risk of suf-
ween trials and real-life
fering cardiac arrest within the next hour is 33% (Muller
Freisinger et al, Eur Heart J 2014
et al, Circulation 2006)! Only 10% of all patients with
• statistical evaluation of InEK data (DRG-based) on myo- chest pain have an acute myocardial infarction (Mo-
cardial infarction in Germany in 2005, 2007 and 2009 ckel et al, Eur J Emerg Med 2013).
• myocardial infarction: 1.3% of all hospital admissions • characteristics:
• changes: -- oppressive, burning (not sharp ["Sharp does not
-- STEMI ↓ (38%) count!"]), chest tightness
-- NSTEMI ↑ (62%) -- not triggerable by:
• average age: ◦◦ compression from outside (A thoracic pain trigge-
-- STEMI: 66 years red by external pressure has a very high negative
-- NSTEMI: 71 years predictive value for a myocardial infarction, i.e. it
• PCI: makes a myocardial infarction very unlikely to be
-- STEMI: in 66.6% the cause [Grani et al, BMJ Open 2015]. If a pati-
-- NSTEMI: in 36.6% ent has severe chest pain with external pressure
• hospital mortality: 11% [e.g. when attaching the echo transducer], then
-- STEMI: 12.1% one should also search for a plasmacytoma ge-
-- NSTEMI: 9.9% nerously [u.a. protein electrophoresis, immunfixa-
tion].)
◦◦ change of position (independent of position)
◦◦ respiration (independent of breath)
study • radiation of the pain into the neck, left shoulder / arm,
back, lower jaw (e.g. admission by dentist), upper ab-
domen (especially in inferior wall infarction)
• approx. 30min persistent, no longer relievable by nit-
roglycerin
Impact of call-to-balloon time on 30-day mortality in con-
temporary practice • dyspnea as angina equivalent (especially in proximal
Varcoe et al, Heart 2016 RIVA and left main stenosis)
• clamminess
• retrospective cohort study (BCIS registry [British Cardio-
• nausea, vomiting
vascular Intervention Society])
• 16907 patients with STEMI • fear of death
• call-to-balloon time (CTB) • paleness
-- average: 121min • prodromal angina pectoris in 60%
-- The longer call-to-balloon time (CTB) was, the higher
the 30d mortality was. Myocardial infarction without pain (30%) in the sense of
◦◦ CTB < 90min: mortality 3.5% a silent ischemia may occur:
◦◦ CTB 90-150min: mortality 4.8% • diabetes mellitus
◦◦ CTB > 150min: mortality 9.4% -- caused by autonomic neuropathy
-- The story that patients with diabetes mellitus often
do not have angina pectoris during myocardial in-
farctionk may more be a myth than a fact: In the
CHARITEM study 2014 it was shown that diabetics
Fig. 531  Especially in younger patients who suffered from have angina pectoris in myocardial infarction just
myocardial infarction, familial hypercholesterolemia should as frequently as non-diabetics. Conversely, silent
also be sought. It is the most common genetic disease at ischemia is just as common in non-diabetics as in
all with a prevalence of 1: 250. The typical xanthelasma can diabetics. It has also been shown in earlier PTCA
be seen here. studies that the time from inflation of the balloon to
the development of angina pectoris in diabetics is no
longer than in non-diabetics.
Guidelines • analgosedated (e.g. ventilated) patients in intensive
• for NSTE-ACS: ESC Guidelines for themanagement of care units
acute coronary syndromes in patients presenting wit- • essential (primary) arterial hypertension
hout persistent ST-segment elevation 2020 (previous • old people

Cardiology 343
• status post heart transplantation (denervation of the
heart)

Fig. 532  Herpes zoster ("shingles"; different examples)

as a cause of chest pain: The typical vesicles arranged in
groups can be seen (in the second picture most of them
already encrusted). There are two lesions along a derma-
tome on the back. Most frequently, a thoracic dermatome
is affected. Since the skin changes are often on the back,
the patient often does not notice them either. To recognize
this, the patient must be undressed! It is an endogenous
reinfection by varicella. The therapy of choice is the admi-
nistration of aciclovir 5 x 800mg p.o. daily for 7 days and
not the acute PCI!

Types
According to the new universal definition of infarction
(Thygesen et al, Circ 2012), five different subtypes of
myocardial infarction (see infobox) are distinguished pa-
thophysiologically. The subtype most relevant for intensi-
ve care medicine and by far the most frequently occur-
ring is subtype II, i.e. non-obstructive cardiac ischemia:
There is no thrombus occluding a coronary vessel, so
that no coronary angiography is necessary here! Cardiac
ischaemia without obstruction of the coronary arteries
is also subsumed under the term MINCA (myocardial
infarction with normal coronary arteries; syn.: MINOCA
[myocardial infarction with non-obstructive coronary ar-
teries]).

344 Cardiology

Diagnostics
• electrocardiography (ECG)
• cardiac enzymes
• echocardiography
ECG
Infarct signs
A 12-lead ECG should be performed within 10 minutes
after the first medical contact (FMC). The typical sign of a
STEMI is the ST elevation with monophasic deformation
of the QRS complex ("cat hump") in at least two conti-
guous leads (chest leads > 0.2 mV, limb leads > 0.1 mV).
The updated ESC guidelines require even more detailed
criteria for the STEMI (see infobox).
Reciprocal ST depressions occur accordingly in the reco-
procal leads. The diagnosis of infarction is more difficult
with bundle branch blocks: Whereas with the right bundle
branch block (RBBB) only the leads V1-V3 are usually
not usable, with left bundle branch block (LBBB) the ST
segment is usually not usable in all leads. A Q in I and
aVL as well as a poor R wave progression up to a loss of
the R-waves over the anterior wall (usually already suba-
cute infarct) can be indicative of an anterior wall infarct in
LBBB. A newly developed LBBB (if pre-ECG is present or
can be determined) is diagnostically usable and is typical
for a large anterior wall infarct (proximal LAD occlusion).
Patients can also be asked whether they are familiar with
a LBBB. Many patients actually know that. If it not be
clarified quickly whether the LBBB is known or not, echo-
cardiographically a complete akinesia of the anterior wall
is groundbreaking. The Sgarbossa criteria (see infobox;
according to Sgarbossa et al, N Engl J 1996) are helpful
in identifying STEMI in patients with LBBB. In the case of
myocardial infarction and LBBB in particular, cardiac ca-
theterization with PCI should be performed immediately
if one of the following criteria is met:
• clinical: hemodynamic instability (e.g. acute left heart
failure, cardiogenic shock
• electrocardiographic:
-- Sgarbossa ≥ 3P.
-- ST/S ratio > 25%
• echocardiographic: anterior wall akinesia (Myocardial
infarction with LBBB is predominantly caused by an
occlusion of the LAD. If there is no anterior wall aki-
nesia in a patient with ACS and LBBB, it is not a STE-
MI equivalent, i.e. you don't have to perform a cardiac
catheterization immediately and you can wait for the
cardiac enzymes.)
A newly occurring right bundle branch block (RBBB), ho-
wever, is not considered a clear sign of infarction. Herre
especially pulmonary embolism should be considered
as an important differential diagnosis. In RBBB only the
leads V1-V3 cannot be used, the rest however can be
used! According to the ESC guidelines for STEMI 2017,
the right bundle branch block was somewhat upgraded
as an infarction criterion: Cardiac catheterization should
be performed if persistent ischemic symptoms occur.
Even in patients with an implanted pacemaker, who typi-
cally have a LBBB due to right ventricular stimulation, the
ST segment is generally not usable. The Scarbossa crite-
ria can also be helpful here. A widespread misconception
is that in pacemaker-free ECG (without stimulation), the
ST-segment would be usable: Even in pacemaker-free
ECG, ST-sections frequently appear due to the "cardiac
memory", which are completely physiological and have
nothing at all to do with ischemia!
Furthermore, the indirect signs of infarction must be ta-
ken into account:
• new bundle branch block (mostly LBBB)
• loss of the R-waves in (subacute) anterior wall infarc-
tion
• AV-blockings (especially in inferior wall and septum
infarction)
Cardiology 345
 In a left main coronary artery (LMCA) ischemia (e.g. acu-
te LMCA occlusion; note: The LMCA is the proximal part
of the left coronary artery before division into LAD and
RCX.) the ECG often shows an ST elevation in aVR (the
“forgotten lead”; p.d. > as in V1) and pronounced ST de-
pressions with deep T in V3-V5

It is also important to know the Wellens' sign (see info-

box).

Fig. 533  acute anterior myocardial infarction

Fig. 535  ST elevations in aVR in conjunction with pronoun-

ced ST depressions in V4-V6 are a typical finding of acute
left main occlusion.

Fig. 534  acute inferior myocardial infarction (different ex-

amples)

In the case of a proven inferior myocardial infarction, it

is also essential to also derive the right ventricular leads
(V1R-V6R [placed inversely to the left chest leads; see
page 384], especially V4R), in order to detect an addi-
tional right heart infarction, which is present in 30% of
cases of inferior myocardial infarction, which has consi-
derable therapeutic consequences.
Fig. 536  The descending ST segment depressions with
preterminally negative T in V1-V3 are completely normal in
a complete right bundle branch block as here and not be
seen as a sign of ischemia.

346 Cardiology
 > 5mm

Fig. 539  But also an excessive (ST elevation > 5mm) dis-
cordance is pathological (Sgarbossa C).

15 mm
5 mm

5 mm
15 mm

Fig. 540  However, the Smith criterion is better than the

Sgarbossa C criterion for assessing an excessive discor-
dance: An ST/S ratio (relation of the ST segment alteration
to the S wave; here 5/15 = 33%) of over 25% is pathological
and indicates the presence of a STEMI.

Fig. 541  cardiac memory: In patients with cardiac pacema-

kers, ST changes and T negativities are often found in the
stimulation-free interval: These have nothing to do with is-
Fig. 537  In the case of a left bundle branch block, there is chemia and are completely normal here!
normally a discordance between the beginning (= baseline
ST segments) and the end (= T waves) of the chamber com-
plex.

Fig. 538  Pathological is a concordance (left: ST elevation

[Sgarbossa A], right: ST depression [Sgarbossa B]).

Cardiology 347
Fig. 542  Wellens sign type B (different examples)

Fig. 544  de Winter sign: ST depressions (in V5 and V6) and

excessive symmetrical T waves can be seen in the chest
leads. The ascending part of the T wave begins below the
isoelectric line (best recognizable in V5). Furthermore,
in the limb leads an ST elevation in aVR > 0.5mm can be
seen. In patients with angina pectoris, the de Winter sign
is a STEMI equivalent, i.e. coronary angiography with PCI
must be carried out immediately! In doubt echocardiogra-
phy should be performed quickly, in which one would see
an akinesia of the anterior wall.

Fig. 543  de Winter sign: ST depressions and high peak T

wave precordial

348 Cardiology
 DD ST elevations
part I

Fig. 545  de Winter sign: An ST elevation in aVR can be

seen in the limb leads. Furthermore, the chest wall leads
show ST depressions in V3-V6 as well as excessive sym-
metrical T waves, the ascending limb of which lies clearly
below the isoelectric line.

Fig. 546  While the ST segment in LBBB is usually not usab-

le in all leads, in RBBB (like here) this is only the case in
the leads V1-V3. ST segment changes in all other leads can
be interpreted in the same way as without RBBB. Here, for DD ST elevations
example, there are clear ST elevations in V4-V5 (also V3) in part II
the sense of a STEMI of the anterior wall.

The ST elevation in acute myocardial infarction is typical-

ly monophasic beginning from the R wave with a convex
course. Again and again it is stated (sometimes with a
smile) that an ST elevation infarction can be easily re-
cognized in the 12-lead ECG and cannot be overlooked.
However, it is often not so simple and trivial in everyday
clinical practice! The classic clear infarction-typical ST
elevation is not always available. Furthermore, one has
to consider that with the diagnosis "STEMI" in the emer-
gency department the whole machinery (cardiac catheter
team) gets started. Important differential diagnoses for
myocardial infarction, all of which are associated with ST
elevations, are summarized in the infobox (DD ST ele-
vations)

You should also be careful with women with breast im-

plants (e.g. silicone): Here, due to the implant ("electrical
jammer"), often T negatives and ST depressions in V1-
V4 can be seen without ischemia (i.a. Bun et al, EURO-
SPACE 2017).

After cardiac catheter examination with intervention a 12-

lead ECG should immediately be performed after arrival
at the ICU / IMC, so that you have a baseline ECG in the
case the patient gets chest pain again.

Cardiology 349
 2
1

3 4

Fig. 547  ST elevations: 1: myocardial infarction, 2. pericar-

ditis, 3. left bundle branch block, 4. vagotonia, 5. aneurysm

Fig. 548  vagotonia

Infarction: localization

myocardial infarction
localization

350 Cardiology
Infarction: vessels

myocardial infarction
vessels

LCA (main stem)

LCX

RCA
LAD

The LCX occlusion is sometimes not visible in the ECG.

But you can recognize it in the echocardiography by po-
stero-lateral akinesia. A strictly posterior infarction ("true
posterior infarct"; LCX occlusion), which occurs frequent-
ly in the inferior infarct, is only visible in V7-V9. Typical
are inverse ST depressions in V2 and V3 (simply turn
around ECG!), which should be reminiscent of a poste-
rior infarction. Fig. 549  In the chest wall leads one can see inverse ST de-
pressions in V1-V3. If you turn the EKG around and look
at it from behind (e.g. through a bright window), you can
see ST elevations (arrows). Now the chest leads V7-V9 are
additionallyderived, in which ST elevations can be seen in
the sense of a STEMI. This was caused bay an LCX occlusi-
on, in which the ST elevations are typically not seen in the
(conventionally derived) 12-lead ECG.

Cardiology 351
Infarction: stages

myocardial infarction
stages

Fig. 552  intermediate stage (inferior MI): ): still detectable

ST elevation, but already T-negativation in II, III, avF

Fig. 553  ECG in a patient with obesity permagna: The Q

wave here in III is completely normal and has nothing to do
with a Pardee Q after a previous myocardial infarction. The
morphology of the Q wave typically changes. This Q wave
is constitutional (obesity).

Cardiac enzymes
Fig. 550  early stage: high, tent-shaped T wave; important • troponin
differential diagnosis in emergency medicine: hyperkale-
mia!)
• CK, CK-MB
• myoglobin
• innovations:
-- copeptin
◦◦ precursor of vasopressin (the C-terminal part of
the vasopressin prohormone)
◦◦ syn.: C-terminal proAVP
◦◦ a "stress marker"
◦◦ non-cardiospecific (in contrast to troponin)
◦◦ studiey:
▪▪ Reichlin et al, JACC 2009: copeptin < 14 pmol/l
→ in 99.8% no myocardial infarction
▪▪ BIC-8 study (Möckel et al, Eur Heart 2014): ACS
+ troponin and copeptin (< 10 pmol/l) negative
Fig. 551  early stage: high, tent-shaped T wave above the → no acute cardiac ischemia, discharge from
anterior wall in a myocardial infarction with proximal LAD emergency department possible
occlusion ◦◦ ESC guidelines NSTE-ACS 2020: not recommen-
ded
-- H-FABP (heart-fatty acid-binding protein)
◦◦ early marker (2-3h)
◦◦ compared to troponin higher sensitivity, but lower
specificity
◦◦ ESC guidelines NSTE-ACS 2020: not recommen-
ded

352 Cardiology
 -- echocardiography: evidence of a wall movement dis-
order ( There is no infarction without wall move-
In STEMI, never wait until the cardiac ment disorder!)
enzymes are available!
• Fourth universal definition of myocardial infarction,
Thygesen et al, Eur Heart J 2018:
-- Here especially the concept of myocardial damage
Troponin
is put in the foreground. This is always the case if
the troponin value is above the 99th percentile. The
myocardial damage is acute when there is a dyna-
mic (rise or fall > 20%) of troponin. If this is not the
case, myocardial damage is chronic.
-- Sectional imaging (MRI, CT) was also included as
an option for defining myocardial infarction.
• Once the PCI has been performed, you no longer need
to determine troponin. The determination of the CK is
• very high specificity then sufficient for the further course.
• only positive after approx. 4 hours
• types: Just as little as you do a "kidney
-- troponin T (tropomyosin binding) catheter" for every kidney damage or
-- troponin I (inhibitory) a "brain catheter" for every brain
-- troponin C (calcium binding) damage, you always have to perform
• innovations: a heart catheter for every heart
-- high-sensitive troponin T (see infobox) damage (positive troponin)!
-- ultra-sensitive troponin I (i.a. Reichlin et al, N Engl
2009)
• maximum after 20h
• up to 2 weeks positive (Therefore, one should better
determine the CK to exclude a reinfarct!)
• renal insufficiency
-- troponin T: increased
-- troponin I: not increased (even in renal insufficiency)
• An increased troponin is in principle always the result
of myocardial damage (destruction of cardiomyocytes;
ischemia marker). Troponin is a quantitative marker
for myocardial damage. However, this does not ne-
cessarily have to be caused by obstruction of a co-
ronary vessel, which would result in coronary angio-
graphy with PCI. For example, acute bleeding anemia
with hypovolemic shock or severe carbon monoxide
poisoning leads to ischemia of all organs in the body.
The ischemia of the heart can be measured using the
troponin as a cardiac ischemia marker. If you would
have a laboratory chemical marker ("Brainitin" [note:
fictitious]) for cerebral ischemia, this would also be
increased. Then you will certainly not catheterize the
brain vessels ("brain catheter") with the question of
whether a thrombus is inside! Also with kidney failure
with evidence of renal ischemia (already possible to-
day with new biomarkers [e.g. NGAL]) nobody comes
up with the idea of performing
​​ a renal artery catheter
(renovasography).
• Myocardial infarction is not present in every elevated
troponin. According to the revised definition (Third uni-
versal definition of myocardial infarction; Thygesen et
al, Eur Heart J 2012) a myocardial infarction is only
present if, in addition to elevated heart enzymes, one
of the following criteria is met:
-- symptoms (angina pectoris
-- ECG: changes (ST segment changes, newly diag-
nosed LBBB)

Cardiology 353

hs-troponin increased > 5 times ULN
→ to 90% myocardial infarction type I;
for rule-out 0h/1h algorithm sufficient
(i.e. you can leave patient in the
emergency department)!
354 Cardiology
HISTORIC study
Cardiac Troponin to Guide the Use of Noninvasive Testing
in Patients Ruled Out for Myocardial Infarction
Mills et al, Circulation 2019
• multicenter (10 centers in Scotland) cluster randomized
controlled study
• 32,837 patients who presented to the emergency room
with chest pain (of any duration); here a new ("ultra-
fast") rule-out algorithm (early rule out) was compared
with a standard algorithm (controls of troponin after 6h
and 12h); new algorithm: high-sensitive troponin
-- < 5 ng/l (A very low value was deliberately chosen
here): to 99,6% no infarction (rule-out) → discharge
from emergency department ( after only one tro-
ponin determination without further control [0h/0h al-
gorithm]!)
-- between 5 ng/l and the 99th percentile (i.e. in men 26
ng/l and in women 16 ng/l): → redetermination after
3h
◦◦ increase by more than 3 ng/l → admission to hos-
pital
◦◦ no increase by more than 3 ng/l (rule-out) → di-
scharge from emergency department
-- above the 99th percentile: p.d. infarction
• resultrs: early-rule-out algorithm compared with stan-
dard algorithm
-- shorter stay in hopsital (by 3,3 hours)
-- safety endpoint (myocardial infraction or death after
discharge [after 30 days and 1 year]): no difference
CK, CK-MB
• CK (creatine kinase) and its cardiac muscle-specific
subtype CK-MB (MB: muscle brain; typical in infarc-
tion: 6-10% of CK)
• 4 isoenzymes:
-- CK-MM (skeletal muscle type [m: muscle])
-- CK-BB (brain type [b: brain])
-- CK-MB (myocardial muscle type): CK-MB typically
accounts for 6-10% of total CK in myocardial infarc-
tion. A CK-MB portion of < 6% speaks for a release
from the skeletal muscles, a CK-MB portion of > 20%
is found in disorders caused by the isoenzymes CK-
BB or in the presence of macro-CK.
-- CK-MiMi (mitochondrial type)
• macro-CK:
-- type 1: immune complex of CK-BB and IgG; occur-
rence: 1% (especially older patients); no disease
value
-- type 2: combination of several CK-MiMi molecules;
occurrence: especially in malignancies
• i.a. incorrectly high CK in hemolysis
• indications:
-- infarct size (The level of the CK correlates well with
the size of the infarction. CK values > 1000 U/l are
indicative for a large infarction.)
-- re-infarction
Myoglobin
• It becomes positive immediately and is therefore well
suited in the emergency department (in contrast to tro-
ponin, where mostly a control determination is neces-
sary) to exclude acute cardiac ischemia immediately.
• The big disadvantage, however, is that it is very unspe-
cific, so it is not generally recommended.
Troponin
Myo-
globin
CK
Fig. 554  Temporal course (kinetics) of cardiac enzymes:
Troponin only becomes positive after 4 hours, myoglobin
immediately: If myoglobin is negative, cardiac ischemia
is (almost) excluded. Troponin remains positive for a long
time, CK, on the other hand, decreases rapidly and is there-
fore much better suited for the diagnosis of re-infarction
than troponin.
Echocardiography
A transthoracic echocardiography should be performed
routinely in acute coronary syndrome (preferably in the
emergency department). On the one hand one should
get a rough overview of the global systolic function
(pump function) of the heart. On the other hand, one
should look for wall movement abnormalities: If there
are no wall movement abnormalities, 95% of the patients
have no acute cardiac ischemia (high negative predictive
value). A prerequisite, however, is that an earlier infarc-
tion ("acinetic scar") can be ruled out. Furthermore, pos-
sible infarct complications should be investigated. With a
STEMI, however, coronary angiography with PCI should
be carried out immediately without any delay caused by
echocardiography.
Therapy
• general Measures
• coagulation therapy
• recanalization therapy
General measures
• non-pharmacological
• pharmacological
Non-pharmacological measures
• i.v. access (peripheral; in myocardial infarction, if pos-
sible with planned thrombolysis, no CVC or invasive
blood pressure measurement)
• invasive blood pressure measurement usually not ne-
cessary (if it is performed, then not on the right arm
[radial artery] or right groin [femoral artery], since this
is the approach for the coronary angiography)
• possibly admission on a Chest Pain Unit (CPU)
• oxygen administration
-- Hyperoxemia is harmful (i.a. Wijesinghe et al, Heart
2009; Cabello et al, Cochrane Database 2010; AVO-
ID study 2014 [see box]), as it can lead to increased
release of oxygen radicals and thus to an expansion
of the infarct size.
-- only in hypoxemia (SpO2 < 90%), dyspnea or pul-
monary congestion
-- Also in the ESC Guidelines 2017 oxygen adminis-
tration is explicitly discouraged as long as SpO2 >
90% (IIIB).
-- in the case of a myocardial infarction with cardioge-
nic shock, however, target SpO2 > 95%
• bed rest
• monitoring for a total of 48 hours (i.a. also depen-
ding on the ejection fraction and the infarction size:
Monitoring can usually be discontinued when the CK
has dropped to < 500 U/l.)
• stool regulation (opiates → constipation; therefore ad-
minister lactulose if necessary)
• About 10% of all myocardial infarction patients have
anemia. The transfusion of RCC (e.g. in the case of
anemia caused by bleeding due to anticoagulation
and antiaggregation) is recommended only from Hb
< 7 g/dl (ESC guidelines 2015 IIb recommendation).
A restrictive transfusion regime also applies in acute
coronary syndrome (especially myocardial infarction)!
Unfortunately, there is only little evidence on this topic.
In the REALITY study (Steg et al, ACC 2020) on the
one hand, the liberal versus the restrictive transfusion
regime showed no advantages at all with regard to the
primary endpoint (death, reinfarction, stroke or emer-
gency revascularization), but on the other hand it even
led to more infections and acute lung failure!
Cardiology 355
 AVOID study
A randomized controlled trial of oxygen therapy in acute
myocardial infarction
Stub et al, AHA 2014
• prospective multicenter randomized controlled study
• AVOID: air versus oxygen in myocardial infarction
• 490 patients with STEMI and normoxemia
-- with oxygen administration
-- without oxygen administration
• result: oxygen administration
-- significantly increased myocardial infarction size
-- higher degree of myocardial damage (troponin I, car-
dio-MRI
DETO2X-AMI study
Oxygen Therapy in Suspected Acute Myocardial Infarction
Hofmann et al, N Engl J 2017
• registry-based randomized clinical study (Sweden)
• DETO2X-AMI: Determination of the Role of Oxygen in
Suspected Acute Myocardial Infarction
• 6229 patients with suspected myocardial infarction and
SpO2 > 90%
-- with oxygen administration
-- without oxygen administration
• result: oxygen administration
-- primary endpoint (mortality after 1 year): no difference
-- secondary endpoint (i.a. troponin, re-hospitalization):
no difference; also in the follow-up study no difference
in all-cause mortality, cardiovascular death or hospita-
lization due to heart failure (Jernberg et al, Circulation
2018)
356 Cardiology
NZOTACS study
The New Zealand Oxygen in Acute Coronary Syndromes
trial
Stewart et al, ESC 2019
• registry-based randomized clinical study (New Zealand)
• NZOTACS: New Zealand Oxygen Therapy in Acute Co-
ronary Syndrome
• 40872 patients with acute coronary syndrome
-- high-oxygen group (always oxygen administration in-
dependet of SpO2)
-- low-oxygen group (oxygen administration only if
SpO2< 90%)
• redults: no difference in mortality after 30d (primary
endpoint)
no routinely oxygen administration in
acute coronary syndrome!
Pharmacological measures
• analgesia (Pain increases sympathetic tone and myo-
cardial oxygen consumption and can thus enlarge the
infarct size!)
-- opiates
◦◦ morphine (drug of choice): 5mg i.v., then fractiona-
ted until patient is pain-free
◦◦ fentanyl 0.05–0.1 mg
-- previously 10mg metoclopramide for prophylaxis of
opioid-induced nausea
-- Opiates (side effect: gastrointestinal atony) can de-
lay the intestinal absorption of orally administered
ADP receptor antagonists. In the IMPRESSION
study (Kubica et al, Eur Heart J 2016), for example,
morphine administration reduced the plasma con-
centration of ticagrelor by 36%.
-- The ESC guidelines downgraded morphine from I to
IIa recommendation.
-- In a retrospective data analysis of the CIRCUS study
(Bonin et al, JAMA 2018), the administration of mor-
phine in patients with STEMI was shown to be safe
(i.a. no increased rate of cardiovascular events).
-- no NSAID (NSAID should also be stopped because
they lead to excess mortality!)
• sedation
-- Midazolam, Lorazepam
-- usually not necessary because the sedative effect of
morphine is usually sufficient
• congestion → diuretics (e.g. furosemide 40 mg i.v.)
• ventricular tachycardia → amiodarone
• Early start with ACE inhibitors or angiotensin receptor
blockers (only if an ACE inhibitor intolerance is present
[e.g. irritable cough], 10 times more expensive; then
 preferrably valsartan)
-- There are traditionally two positions here:
◦◦ liberal: for all patients after myocardial infarction,
provided there are no contraindications (significant
reduction in mortality [GISSI-3-/, ISIS-4 study]) to
prevent „remodeling“ (conversion of the damaged
myocytes into connective tissue cells)
◦◦ restrictive: only with reduced ejection fraction, ar-
terial hypertension or diabetes mellitus (i.a. also
so recommended in the ESC guidelines)
-- examples:
◦◦ captopril 3 x 6.25 mg p.o., then slowly increase
◦◦ ramipril 1.25 mg p.o., then slowly increase
-- If you consider (e.g. with severe heart failure) to
switch to an ARNI (angiotensin receptor neprilysin
inhibitor; e.g.. Entresto [sabucitril + valsartan]), you
should start right away with an angiotensin recep-
tor blocker (preferably valsartan). The ACE inhibitor
must be discontinued at least 36 hours in advance,
otherwise the risk of angioedema is significantly in-
creased. This is not necessary with an angiotensin
receptor blocker: Here you can start with an ARNI
immediately after discontinuation.
• aldosterone antagonist (mineralocorticoid receptor an-
tagonist [MRA]): indicated in case of a reduced ejec-
tion fraction (EF <40%) after myocardial infarction from
day 3 (note: possible up to creatinine of 2.5 mg/dl /
GFR 30 ml/min or potassium 5.0 mmol/l)
-- spironolactone (Aldactone [RALES study]; however,
no benefit in myocardial infarction without heart fai-
lure [ALBATROSS study 2015]); dosage: 1 x 25mg
p.o.
-- eplerenone (Inspra [EPHESUS study]; possibly also
after STEMI without heart failure within 24h [REMIN-
DER study 2013: significant reduction of the com-
bined primary endpoint, but not yet approved for it]);
dosage: initially 1 x 25mg, then increase to 2 x 25mg
p.o.
-- finerinone (not yet approved)
• statins (CSE inhibitors [CSE: cholesterol synthesis en-
zyme])
-- goal: plaque stabilization (studies: MIRACL, LIPID)
-- most effective: atorvastatin, rosuvastatin
-- high dose (e.g. atorvastatin 40mg)
-- as early as possible; i.a. PROVE-IT study (Cannon
et al, N Engl J 2004): Here an early and intensive
lipid reduction led to a significant reduction in the pri-
mary combined endpoint (death, myocardial infarc-
tion, stroke).
-- most important side effect: rhabdomyolysis
◦◦ important DD for the increase in CK after infarction
◦◦ especially with ticagrelor because ticagrelor incre-
ases the plasma concentration of statins
◦◦ This can be distinguished with CK-MB, which is
increased in infarction, but not in rhabdomyolysis.
-- Lipide levels should be determined early in the first
days after infarction (as quickly as possible). Patients
no longer have to be fasted for the determination of
lipids as propagated for a long time. Furthermore,
the determination does not necessarily have to take
place in the morning (consensus paper [European
Heart Journal 2016] of the European Atherosclerosis
Society [EAS] and the European Federation of Cli-
nical Chemistry and Laboratory Medicine [EFLM]).
-- target LDL after 4 weeks: < 55 mg/dl (ESC / EAS
Guidelines for the Management of Dyslipidaemias
2019; previous recommendation: < 70 mg/dl); if with
a statin alone despite increasing the dose (note:
Doubling the statin dose only lowers the LDL by 6
mg/dl.) the target LDL cannot be reached (in 58%
of cases), there are the following options (in order):
◦◦ additionally ezetimibe (Ezetrol; 1 x 10mg)
▪▪ inhibition of cholesterol absorption
▪▪ additional LDL reduction by 20%
▪▪ IMPROVE-IT study (Cannon et al, N Engl J
2015)
▪▪ combination preparations: Inegy = simvastatin +
ezetimibe; Atozet = atorvastatin + ezetimibe
◦◦ possibly PCSK9 inhibitor (Proprotein Convertase
Subtilisin Kexin; monoclonal IgG antibodies; the-
reby an LDL on average of 30 mg is achieved!
class I recommendation in the ESC / EAS guide-
lines, however relatively expensive [approx. 600€
per month], in Germany, therefore, the Federal
Joint Committee GBA limits the ordinance)
▪▪ evolocumab (Repatha; a monoclonal IgG1 an-
tibody): 140mg every 2 weeks s.c. (FOURIER
study [Sabatine et al, N Engl J 2017])
▪▪ alirocumab (Praluent; a monoclonal IgG2 an-
tibody): 75mg bzw. 150mg every 2 weeks s.c.
(ODYSSEY-Outcomes study [Steg et al, ACC
2018]; already from the market due to a lost pa-
tent dispute)
• diabetics:Oral antidiabetic drugs (especially metfor-
min) should be paused temporarily (if necessary Ac-
trapid s.c.) and especially in severe cases requiring
intensive care, a pre-existing insulin therapy should be
converted to an insulin perfusor.
• Hypokalemia should be avoided: It leads to hyperpola-
risation at the cell membrane and thus to an increased
occurrence of arrhythmia, especially of the vulnerable
myocardium. But hyperkalemia also increases morta-
lity (Grodzinsky et al, Am J Med 2016). The target po-
tassium after infarction is 4-5 mmol/l.
• β-blocker
• nitrates (glyceroltrinitrate [nitroglycerin])
• possibly colchicine
-- In the COLCOT study (Tardif et al, N Engl J 2019)
colchicine (0.5 mg once a day; started within 30 days
after the infarction) showed a significant reduction
in ischemic events (primary combined endpoint of
death from cardiovascular cause, resuscitation af-
ter cardiac arrest, myocardial infarction, stroke and
angina pectoris with the need for revascularization).
-- not yet a general recommendation
• no evidence:
-- glucose-insulin-potassium therapy
◦◦ syn.: Rackley regime, euglycemic clamp, HIET
(high-dose insulin euglycemic therapy)
◦◦ The administration of insulin is supposed to incre-
Cardiology 357
 ase the glycolysis in the myocardial cells, so that
the heart muscle cell has more energy available
and the contractility increases. Glucose was only
given to avoid hypoglycaemia. Insulin therapy of-
ten leads to hypokalemia, which is substituted with
potassium.
◦◦ not recommended (CREATE-ECLA study [Cobb et
al, JAMA 2005]; IMMEDIATE study [Selker et al,
JAMA 2012])
-- calcium antagonists (calcium channel blockers)
◦◦ dihydropyridines (e.g. nifedipine): contraindicated
in ACS (up to 4 weeks after) due to reflex tachy-
cardia with consecutively reduced coronary perfu-
sion (i.a. coronary steal phenomenon)
◦◦ non-dihydropyridines (e.g. diltiazem, verapamil):
contraindicated in systolic heart failure (HFREF)
due to the negative inotropic effect
-- magnesium
-- ciclosporin (CIRCUS study [Cung et al, N Engl J
2015]: no reduction in reperfusion damage after a
myocardial infarction)
Glyceroltrinitrate (nitroglycerin)
Dosage
• spray (1 puff = 0.4 mg)
• capsule (0.8 mg)
• perfusor: 1 ampoule = 50mg nitroglycerin = 50ml → 1
mg/ml, infusion rate 1-6 ml/h
Contraindications
• severe aortic valve stenosis (The application of nit-
rate leads to a reduction of the preload, which is essen-
tial to overcome the stenosis. The application of nitrate
to aortic stenosis can lead to a complete circulatory
collapse. Angina pectoris is a classic symptom of the
triad of aortic stenosis, along with syncope and stress
dyspnea. Before administering a nitro spray for angina
pectoris, auscultation of the heart (A missing systolic
murmur excludes severe aortic valve stenosis! A seve-
re aortic valve stenosis can almost always be auscul-
tated [exception: severe reduced ejection fraction]!) is
therefore obligatory and is unfortunately almost always
forgotten (especially preclinical)!
• HOCM (hypertrophic obstructive cardiomyopathy)
• intake of phosphodiesterase-5 inhibitors (due to the in-
creased risk of a pronounced decrease in blood pres-
sure):
-- sildenafil (Viagra, Revatio; in the last 24h)
-- vardenafil (Levitra; in the last 24h)
-- tadalafil (Adcirca; in the last 48h)
• SBP < 90 mmHg
• right ventricular myocardial infarction
-- at every 3rd inferior wall myocardial infarction!
-- Certainly, the right ventricular ECG leads will not al-
ways be applied preclinically before every nitro ad-
ministration. If you do not see an inferior MI in the
12-lead ECG, the patient usually does not have a
right ventricular MI, since this almost exclusively oc-
curs together with an inferior MI and almost never in
isolation.
358 Cardiology
Before nitro administration always
heart auscultation to exclude severe
aortic valve stenosis!
Indications
Nitrates should only be administered at:
• hypertensive crisis
• pulmonary edema (reduction of preload by nitrates)
• angina pectoris (not indicated if there are no symp-
toms!)
Assessment
• The nitrate test frequently carried out in clinical practi-
ce is of little significance: On the one hand, no impro-
vement occurs in 50% although an ACS is present,
on the other hand, an improvement occurs in 50%
although there is no ACS at all (e.g. in esophageal
motility disorders; e.g. pulmonary embolism [Nitro also
lowers the pulmonary artery pressure.]). A nitrate test,
i.e. the use of nitrate for differential diagnosis, is defini-
tely not recommended (i.a. ERC guidelines 2015, ESC
guidelines 2017).
• In STEMI, nitrates have no effect (ISIS-IV study: no ad-
vantage in terms of mortality, heart failure, cardiogenic
shock and post-infarction angina). .
β-blocker
Dosage
• representatives:
-- metoprolol (Beloc): 1 amp. = 5ml = 5mg; 2-3mg i.v.
repetitively
-- esmolol (Brevibloc, Esmocard): 1 amp. = 10ml =
100mg; 40-50mg (exactly: 0.5 mg/kg) i.v.
• according to target heart rate (60-70/min)
Assessment
• effect: reduction of myocardial oxygen consumption by
lowering the heart rate, blood pressure and contractili-
ty (i.a. meta-analysis Freemantle et al, BMJ 1999)
• studies:
-- Hjalmarson et al, Am J Cardiol 1997: significant re-
duction of mortality by 20%
-- COMMIT/CCS-2 study (Chen et al, Lancet 2005): no
reduction of mortality
◦◦ reduced risk of ventricular fibrillation and reinfarc-
tion
◦◦ increased risk of cardiogenic shock
-- METCOCARD-CNIC study (Ibanez et al, Circ 2013):
The administration of metoprolol i.v. prior to PCI in
patients with STEMI led to a reduced infarct size
(measured by MRI).
-- EARLY-BAMI study (Roolvink et al, J Am Coll Cardiol
2016): The administration of metoprolol i.v. prior to
PCI in patients with STEMI did not lead to a reduced
infarct size (measured by MRI).
-- BEAT-AMI study (Er et al, JACC Cardiovasc In-
terv 2016): Patients with STEMI showed a signifi-
cantly lower troponin increase in the group of early
 β-blockade (immediately after PCI esmolol as conti-
nuous infusion over 24h) than in the placebo group.
-- The permanent p.o.-taking of a β-blocker after a
myocardial infarction leads to a significant reduction
in mortality in the long-term course (Andersson et al,
J Am Coll Cardiol 2014; OBTAIN study [Goldberger
et al, J Am Coll Cardiol 2015]).
• recommendations (ESC-/ ERC guidelines):
-- no routine indication for early i.v. administration
preclinical or in emergency (only in hypertensive cri-
sis or TAA)
-- p.o. administration when stable (if possible within 24
hours [Bugiardini et al, Am J Cardiol 2016]): for all
patients after myocardial infarction, provided there
are no contraindications (e.g. higher grade AV block,
severe bradycardia, right ventricular MI, acute left
heart failure [With regard to heart failure therapy,
one starts first with a mineralocorticoid receptor ant-
agonist such as e.g. spironolactone and an ACE in-
hibitor or AT-II antagonist and only at the end with a
β-blocker.], hemodynamic instability [e.g. cardioge-
nic shock], bronchial asthma) (ESC guidelines 2017:
class IIA recommendation; if EF < 40% even class IA
recommendation!)
Coagulation therapy
• anticoagulation
• antiaggregation
Anticoagulation
• heparin
• fondaparinux (Arixtra)
• bivalirudin (Angiox)
no change in anticoagulation
(increased bleeding rate [SYNERGY
study])
Heparin
• unfractionated heparin (UFH)
• low molecular weight heparin (LMWH)
in patients with cumarines / novel
oral anticoagulants (dabigatran,
rivaroxaban, apixaban, edoxa-
ban): no heparin!
Unfractionated heparin (UFH)
• indirect factor II inhibitor (factor II: thrombin)
• 60 E/kg bw (weight-adapted dosage! max. 5000 E) as
bolus i.v., then 1000 E/h
• target PTT 60-80 sec
• 24h after intervention (PCI; note: After a complication-
free PCI and stent implantation, the patient usually no
longer needs full anticoagulation at ICU / IMC.)
Low molecular weight heparin (LMWH)
• dosage enoxaparin:
-- < 75 years: 0.5 mg/kg as bolus i.v., then 1 mg/kg
1-0-1 s.c.
-- > 75 years: no bolus, only 1 mg/kg 1-0-1 s.c.
-- creatinine clearance < 30 ml/min: 1 mg/kg only 1 x
daily s.c.
• monitoring with impaired renal function → Anti-factor
Xa unit
-- determination 4h after the s.c. administration of the
LMWH
-- target level: 0.6-1.0 mU/l
• studies:
-- ExTRACT-TIMI 25 study: enoxaparin versus UFH in
patients with STEMI → significant reduction in mor-
tality
-- ATOLL study (see box)
• If STEMI is followed by fibrinolytic therapy, the additi-
onally necessary anticoagulation should be performed
with enoxaparin (initial bolus i.v., then s.c.) instead of
unfractionated heparin.
• ESC guidelines:
-- 2012: enoxaparin recommended before UFH
-- 2015: enoxaparin equivalent to UFH recommended
(IB) when fondaparinux is not available
• advantages over unfractionated heparin:
-- no coagulation controls (PTT) necessary
-- safe bioavailability
-- (almost) never HIT II
ATOLL study
Intravenous enoxaparin or unfractionated heparin in pri-
mary percutaneous coronary intervention for ST-elevation
myocardial infarction
Montalescot et al, Lancet 2011
• multicenter randomized open-label study
• 910 patients with STEMI
-- Enoxaparin 0,5 mg/kg i.v.
-- UFH i.v.
• result: combined primary endpoint (death, infarct compli-
cations, major bleeding) →no difference
Fondaparinux (Arixtra)
• pentasaccharide
• Factor Xa inhibitor (Factor X: thrombokinase)
• dosage: initially 2.5mg i.v., then 2.5mg s.c./d (not
7.5mg!)
Cardiology 359
• approved for ACS without ST elevation
• Immediately after administration of fondaparinux co-
ronary angiography is no longer possible, as throm-
bosis at the heart catheter is frequent (therefore not
in STE-ACS, since coronary angiography is immedi-
ately indicated here); If coronary angiography should
performed, therefore administration of unfractionated
heparin (85 IU/ kg bw) is obligatory before coronary
angiography.
• ESC guidelines:
-- for NSTE-ACS (i.e. without ST elevations; ESC gui-
delines 2015): IB (Here fondaparinux is highly re-
commended as it has the best benefit-risk profile.
The recommendation applies regardless of the the-
rapeutic strategy, i.e. whether PCI is performed or
not. Only if fondaparinux is not available enoxaparin
or UFH should be given.)
-- for STE-ACS (i.e. with ST elevations; ESC guideli-
nes 2017): IIIB (Here fondaparinux is explicitly not
recommended for the primary PCI.)
• contraindicated if creatinine clearance < 20 ml/min
OASIS-5 study
Comparison of Fondaparinux and Enoxaparin in Acute Co-
ronary Syndromes
Yusuf et al, N Engl J 2006
• multicenter randomized controlled study
• 20078 patients ACS
-- fondaparinux initially 2.5mg i.v., then 2.5mg s.c./d
-- enoxaparin 2 x 1mg/kg/d
• results: fondaparinux
-- no difference in rate of ischemic events (death, myo-
cardial infarction, refractory anemia)
-- halving the bleeding rate
-- significantly reduced mortality (after 30 days)
Bivalirudin (Angiox)
• definition:
-- direct factor II inhibitor (factor II: thrombin)
-- hirudin analogue
• indication:
-- anticoagulation during PCI (as an alternative to he-
parin + GpIIb/IIIa blocker)
-- mainly as bail-out therapy in angiographic evidence
of high thrombus load, slow flow / no flow phenome-
non or thrombotic complications
-- The ESC-guidelines 2012 preferred bivalirudin (es-
pecially as bailout therapy) to the combination of
GpIIb/IIIa-receptor antagonists and UFH (class IB
recommendation), but no longer the ESC guidelines
since 2014.
• dosage:
-- initialy bolus of 0.75 mg/kg, then infusion with 1.75
mg/kg/h (for the duration of PCI)
360 Cardiology
-- renal insufficiency:
◦◦ GFR 30-50 ml/min: bolus unchanged, but then 1.4
mg/kg/h
◦◦ GFR 15-30 ml/min: no bolus, infusion with 1 mg/
kg/h
◦◦ GFR < 15 ml/min: no bolus, infusion with 0.25 mg/
kg/h
• studies:
-- REPLACE-2 (Lincoff et al, JAMA 2003): In patients
with ACS and PCI, bivalirudin versus UFH + GpIIb/
IIIa-receptor antagonists was not inferior in the com-
bined endpoint (death, myocardial infarction, urgent
revascularization), but showed significantly less
bleeding.
-- ACUITY (Stone et al, N Engl J 2006): In patients with
moderate or high risk ACS, bivalirudin versus UFH
+ GpIIb/IIIa-receptor antagonists was not inferior in
the combined endpoint (death, myocardial infarction,
unplanned revascularization), but showed signifi-
cantly less bleeding.
-- HORIZONS-AMI (Stone et al, N Engl J 2008): In pa-
tients with STEMI, bivalirudin versus UFH + GpIIb/
IIIa-receptor antagonists showed a significant reduc-
tion in bleeding rate and mortality.
-- EuroMAX (Steg et al, N Engl J 2013): (The preclini-
cal administration of bivalirudine versus UFH + GpII/
bIIIa antagonists showed a reduction in bleeding
rate in patients with STEMI.
-- BRIGHT (Han et al, JAMA 2015): Bivalirudine is
superior to both heparin (UFH) monotherapy and
combination therapy UFH + GpIIb/IIIa-receptor an-
tagonist (tirofiban) in PCI of patients with myocar-
dial infarction (both STEMI and NSTEMI). A signifi-
cant reduction of the primary combined endpoint of
death, reinfarction, ischemia-related revascularizati-
on, stroke and bleeding could be demonstrated.
-- HEAT-PPCI (Shahzad et al, Lancet 2014): under
UFH significantly less MACE (major cardiac adver-
se events [death, myocardial infarction, stroke]) than
under bivalirudine, no difference in bleeding rate
-- MATRIX (Valgimigli et al, N Engl J 2015): no advan-
tage regarding the occurrence of MACE (major ad-
verse cardiac events [death, myocardial infarction,
stroke]) for bivalirudin compared to UFH
• assessment (compared to heparin [UFH]):
-- advantages
◦◦ shorter T½ (only 25min) → better controllability
◦◦ less bleeding
◦◦ no monitoring of coagulation necessary
◦◦ also applicable in case of HIT (Bivalirudin is a hi-
rudin analogue.)
-- disadvantage: expensive
• recommendation (ESC guideline 2017): for anticoagu-
lation as part of the PCI in patients with HIT
Antiaggregation
• ASA
• ADP-receptor antagonists
• GpIIb/IIIa-receptor antagonists
• voraxapar (Zontivity)
-- a thrombin receptor antagonist (PAR-1)
-- approved in the US since 2014 for acute coronary
syndrome in combination with ASA and an ADP-re-
ceptor antagonist (triple platelet inhibition)
-- studies:
◦◦ TRACER (Tricoci et al, N Engl J 2012: significant
reduction of myocardial infarction relapses only in
post-hoc analysis)
◦◦ TRA-2P-TIMI-50 (Morrow et al, N Engl J 2012):
significant reduction of ischemic events)
-- dosage: 40mg as loading-dose, then 2.5mg per day
p.o.
-- prerequisite: no bleeding or stroke history
-- no general recommendation
ASA
• inhibition of cyclooxygenase 1 → thromboxan ↓
• ASA alone already reduces acute mortality in STEMI
by 25% (extremely effective, just as effective as throm-
bolysis alone, in combination with thrombolysis even
by 50% (i.a. Bertrand et al, Eur Heart J 2002)
• indicated for all types of ACS
• dosage: 1 amp. 500mg Aspisol i.v. (note: 250mg as ef-
fective as 500mg [ACUTE study Zeymer et al, Thromb
Haemostasis 2017]), then 100mg p.o./d
• llifelong long-term therapy
• If the patient already has ASA in the premedication,
the loading dose should still be given again neverthel-
ess (reasons: possible incompliance with the intake,
relative ASA intolerance, low side effects of the admi-
nistration of the dose of 500 mg).
• no discontinuation before CABG surgery (note: As a
matter of principle, ASA should not be discontinued
even before non-cardial surgery in CHD patients!)
• contraindicated in ASA allergy (syn.: M. Widal)
-- Samter's triad: ASA allergy, bronchial asthma, nasal
polyps
-- a pseudoallergy (not IgE mediated)
-- options here:
◦◦ alt: clopidogrel + VKA (Vitamin K antagonist; target
INR 2,0-2,5)
◦◦ new: ADP-receptor antagonist + NOAC (according
to the recent studies (see page 367; PIONEER
AF-PCI [for rivaroxaban], RE-DUAL PCI [for da-
bigatran], AUGUSTUS [for apixaban], ENTRUST
AF-PCI [for Edoxaban])
ADP-receptor antagonists
• syn.: P2Y12 antagonists
• representatives
-- thienopyridines:
◦◦ ticlopidine (Ticlid; withdrawn from market)
◦◦ clopidogrel (Plavix)
◦◦ prasugrel (Efient)
-- cyclopentyltriazolopyrimidines:
◦◦ ticagrelor (Brilique)
◦◦ cangrelor (Kengrexal)
Clopidogrel (Plavix)
• ADP-receptor antagonist (irreversible inhibition)
• loading-dose (ESC 2014)
-- NSTEMI:
◦◦ conservative procedure → 300 mg
◦◦ interventional procedure (planned acute PCI) →
600 mg (8 tablets a 75mg; meanwhile there are
tablets with 300mg)
-- STEMI:
◦◦ < 75 years: 300 mg
◦◦ > 75 years: 75mg
• then daily 75mg (CURRENT study [Mehta et al, AHJ
2008]: in the first week twice a day → significantly
reduced combined primary endpoint [cardiovascular
death, heart attack, stroke])
• studies
-- Clopidogrel in addition to ASA reduces the rate of
cardiovascular events in ACS (Yusuf et al, N Engl
J 2001).
-- Clarity-TIMI study (Sabatine et al, N Engl J 2005):
In 3491 patients with STEMI who received ASA and
were lysed, the additional administration of clopidog-
rel instead of placebo resulted in a higher number of
vessels with TIMI 3 flow.
• 600mg better than 300mg (also the PCI under 600mg
clopidogrel is safe [ISAR-React study])
• If the patient already has clopidogrel in the preme-
dication, the loading dose should still be given again
nevertheless.
• myocardial infarction → clopidogrel for 12 months
• discontinuation 5 days before planned CABG surgery
• Clopidogrel is a prodrug that is only converted into the
active form in the liver by the enzyme CYP 2C19
• non-responder:
-- 30% of the Caucasians have a polymorphism in the
gene of the liver enzyme CYP2C19, so that no con-
version of the prodrug clopidogrel to the active form
can take place!
-- To detect non-responders, platelet function must be
measured. There are several methods for this pur-
pose:
◦◦ light transmission aggregometry (LTA; optical ag-
gregation measurement; Born's method)
◦◦ impedance aggregometry (Multiplate)
◦◦ platelet function analysis (PFA-100; measurement
of closure time)
• stents: DAPT (dual antiplatelet therapy) between ASA
100mg +
-- bare-metal stents (BMS; uncoated): clopidogrel
75mg for 4 weeks
-- drug-eluting stents (DES; coated): clopidogrel 75mg
for 6 months (note: after an infarction always 12
months [no matter if BMS or DES])
• in acute coronary syndrome today no longer standard
(better plasugrel or ticagrelor; clopidogrel only if there
are contraindications for prasugrel and ticagrelor [but
then with measurement of the platelet function]), in
elective PCI with stable coronary artery disease how-
ever still standard (the only tested and approved ADP-
Cardiology 361
 receptor antagonist!)
• For PTCA and stent with stable CHD, i.e. outside of
acute coronary syndrome, clopidogrel remains the first
choice ADP antagonist, also for patients with ACS who
need oral anticoagulation.
• studies:
kein Clopidogrel mehr im ACS: 30%
sind Non-Responder (cave Stent-
thrombose)!
Combination with proton pump inhibitors
(PPI)
• attenuation of effect (PPI → inhibition of the liver en-
zyme CYP 2C19 → conversion of prodrug clopidogrel
into the active form ↓)
• studies:
-- Ho et al, JAMA 2009: 8205 patients with clopidogrel
after ACS
◦◦ without PPI
◦◦ with PPI (omeprazole) → significantly more fre-
quent cardiovascular events with PCI / CABG, re-
hospitalization and death
-- According to the retrospective cohort study of Levy
(Annuals of Internal Medicine 2010) no increased
rate of cardiovascular events with significantly less
gastrointestinal bleeding was shown. Bhatt (N Engl J
Med 2010) also demonstrated in 3761 patients with
CHD and dual platelet aggregation with ASA and
clopidogrel that proton pump inhibitors (omeprazole)
led to a significantly lower rate of upper gastrointes-
tinal bleeding and ulcers and no increased rate of
cardiovascular events such as cardiovascular death,
myocardial infarction, revascularization or stroke..
• simplest solution: splitting (PPI in the morning, clo-
pidogrel in the evening)
Prasugrel (Efient)
• ADP-receptor antagonist (irreversible inhibition)
• faster and stronger effect on platelet aggregation than
clopidogrel
• smaller range of fluctuation and earlier maximum of
effect than with clopidogrel
• since 2009 approved for ACS (STEMI, NSTEMI, un-
stable angina pectoris) with PCI
• especially patients with diabetes mellitus and STEMI
• dosage: saturation with 60mg, then 10mg p.o. once a
day
• contraindication: TIA / stroke in anamnesis (as in sub-
group analysis of TRITON-TIMI 38 significantly increa-
sed bleeding rate)
• dose reduction (also saturation with 60mg, but then
only 5mg maintenance dose)
-- age > 75 years
-- weight < 60 kg
• no non-responders described (to date)
• no interaction with PPI described
• discontinuation 7 days prior to planned CABG surgery
• ESC guidelines 2014: IB (clopidogrel only IC; in diabe-
tes even IA)
362 Cardiology
• tip: grinded administration (crushed tablets) → even
faster onset of action (CRUSH study [Rollini et al, J
Amer Coll Cardiol 2016]; in the COMPARE-CRUSH
study (Vlachojannis et al, Circulation 2020), however,
no advantage [no improved coronary flow])
-- TRITON-TIMI 38s study (approval study; see box)
-- TRILOGY-ACS study (Roe et al, N Engl J 2012): no
advantage for prasugrel compared to clopidogrel in
patients with conservatively treated ACS (i.e. without
invasive examination / PCI)
-- TRANSLATE-ACS study (Wang et al, TCT 2014): no
advantage for prasugrel compared to clopidogrel in
patients with ACS (but only observational study)
-- ISAR-SHOCK registry (Orban et al, Thromb Hae-
most 2014): lower mortality in infarction-related car-
diogenic shock with prasugrel compared to clopido-
grel
TRITON-TIMI 38 study
Prasugrel compared with clopidogrel in patients undergo-
ing percutaneous coronary intervention for ST-elevation
myocardial infarction
Montalescot et al, Lancet 2009
• multicenter randomized controlled study
• 3534 patients with STEMI + PCI
-- clopidogrel (loading dose 300 mg, maintenance dose
75 mg)
-- prasugrel (loading dose 60 mg, maintenance dose 10
mg)
• results: prasugrel
-- significantly reduced combined primary endpoint
(death, myocardial infarction, stroke); especially in
diabetics
-- all-cause mortality: no difference
-- bleeding rate: no difference
study
Prasugrel versus Clopidogrel in Patients with ACS
Wiviott et al, N Engl J 2007
• multicenter randomized controlled study
• 13608 patients with planned coronary intervention in
ACS
-- clopidogrel
-- prasugrel
• results: prasugrel
-- significantly reduced combined primary endpoint
(death, myocardial infarction, stroke)
-- halving stent thrombosis
-- significantly more bleeding
Ticagrelor (Brilique) -- dyspnea as a typical side effect
• ADP-receptor antagonist (P2Y12-receptor inhibitor; re- ◦◦ in the approval study (PLATO) in 13.8%
versible inhibition) ◦◦ especially in patients with obstructive lung disea-
• a cyclopentyltriazolopyrimidine (not thienopyridine ses (bronchial asthma, COPD)
• short T½ (only 7h) ◦◦ due to the structural similarity to adenosine, which
-- advantage: rapidly operable causes bronchoconstriction
-- disadvantage: administration necessary twice a day ◦◦ usually only mild and spontaneously regressive
(note: If, for example, a loading dose is given in the (after a few weeks), so that usually no discontinu-
morning as part of a PCI with stent implantation, 1 x ation of ticagrelor is necessary (A switch to clopi-
90 mg must be given again on the same day in the dogrel should only be made in the case of persis-
afternoon or in the evening due to the short half-life.) tent severe dyspnea, for which there is no other
• no hepatic metabolism (no biotransformation in vivo; explanation.)
ticagrelor is not a prodrug unlike clopidogrel and pra- -- increase in creatinine (usually only to a small extent;
sugrel) if GFR < 30 ml/min, however, acute kidney injury is
• since 2010 approved for ACS (STEMI, NSTEMI, un- twice as common as with clopidogrel [approval study
stable angina pectoris) regardless of whether a PCI PLATO])
occurred or not (conservative) -- increase in urea
• in combination with ASA -- increased rate of ventricular pauses > 5 seconds
• dosage: loading dose 180mg (2 tablets), then 90mg (asymptomatic)
1-0-1 p.o. (for 1 year) • In costrat to the other ADP receptor antagonists, ti-
• also grinded administration via gastric tube possible cagrelor cannot be antagonized by DDAVP (minirin);
(e.g. in infarction-related cardiogenic shock when pati- currently only possible by adding platelet concentra-
ent is ventilated [MOJITO study, Parodi et al, Eur Heart tes; antidote under development (monoclonal antibody
J 2014]) PB2452 in Phase-I study [Bhatt et al, N Engl J 2019])
• meanwhile also available as orodispersible tablets
• discontinuation 5 days before planned CABG surgery
• ATLANTIC study (Montalescot et al, ESC 2014): Prec- PLATO study
linical administration of ticagrelor to STEMI showed no
benefit in terms of primary endpoint regression of ST
elevation or TIMI III flow.
• interactions: Ticagrelor versus Clopidogrel in Patients with Acute Coro-
-- macrolides (especially clarithromycin): contrain- nary Syndromes
dicated, as they lead to a massive increase in the Wallentin et al, N Engl J 2009
plasma concentration of ticagrelor and thus to an in-
creased risk of bleeding • multicenter randomized controlled study
• 18624 patients with ACS
-- statins: increased risk of rhadomyolysis since
-- clopidogrel
ticagrelor increases the plasma concentration of
statins (therefore maximum dosage: 40mg [e.g. for -- ticagrelor (loading dose 180mg, then 90mg twice
daily)
simvastatin, atorvastatin])
• results: ticagrelor
-- digitalis: Ticagrelor leads to increased digitalis -- significantly reduced primary endpoint (death, myo-
levels. cardial infarction, stroke)
-- dabigatran: Ticagrelor increases dabigatran levels -- significantly reduced mortality
by 25% (no interaction with the other NOAC [rivaro-
xaban, apixaban, edoxaban]).
-- verapamil: increased risk of bleeding
-- cyclosporin: increased risk of bleeding
-- false negative HIPA test (heparin-induced platelet
activation) in HIT diagnostics
• contraindications:
-- active bleeding
-- status post intracranial hemorrhage
-- moderate to severe hepatic insufficiency (i.e. Child B
and C; contraindicated according to product informa-
tion, because not examined here)
-- simultaneous intake of CYP3A4 inhibitors (espe-
cially macrolides [especially clarithromycin], ketoco-
nazole, phenytoin, carbamazepine, phenobarbital,
ritonavir, atazanavir)
• side effects: especially

Cardiology 363
 ry endpoint)
-- CHAMPION-PLATFORM study (Bhatt et al, N Engl J
2009: cangrelor versus placebo during PCI followed
PRAGUE-18 study by clopidogrel → no reduction in primary end-
point [study was prematurely discontinued])
-- CHAMPION-PHOENIX study (see box)
• suitable especially for intubated patients in whom oral
Randomized comparison of ticagrelor versus prasugrel in administration is difficult (cangrelor: intravenous) and
ST elevation myocardial infarction
for patients in whom CABG surgery is planned (only
Widimsky et al, Circulation 2016
very short T½)
• prospective randomized study ("head to head" compa- • ESC guidelines 2017: cangrelor as an option (now in-
rison) cluded for the first time; IIb), if the patient has not recei-
• 1230 patients with STEMI: ved an ADP-receptor antagonist yet at the time of the
-- prasugrel PCI or if oral intake is not possible
-- ticagrelor
• reslut: no difference in the combined primary endpoint
(death, re-infarction, revascularization, stroke, transfusi- CHAMPION-PHOENIX
on, prolonged hospital stay
study

Clinical Trial Comparing Cangrelor to Clopidogrel Standard

ISAR-REACT-5 study of Care Therapy in Subjects Who Require Percutaneous
Coronary Intervention
Harrington et al, N Engl J 2013

Ticagrelor or Prasugrel in Patients with Acute Coronary • prospective randomized study

Syndromes
Schüpke et al, N Engl J 2019
• multicenter randomized study (open-label)
• 4018 patients with acute coronary syndrome (STEMI
[45,6%], NSTEMI [44,1%], unstabile angina pectoris
[10,3%]) and planned PCI (preloading only in case of
STEMI)
-- prasugrel
-- ticagrelor
• results:
-- primary combined endpoint (death, myocardial in-
farction, stroke [after 1 year]): significantly lower with
prasugrel (6.9%) than with ticagrelor (9.3%)
-- bleeding (secondary endpoint): no difference
Principles
• substance: In acute coronary syndrome only prasugrel
ACS: prasugrel better than ticagrelor
(i.a. ESC guidelines 2020 possibly due
to the almost unmanageable number
of interactions of ticagrelor)!
• pre-loading: A loading-dose before the coronary an-
Cangrelor (Kengrexal)
• ADP-receptor antagonist (P2Y12-receptor antagonist;
reversible inhibition)
• i.v.-administration (30 μg/kg as bolus, then 4 μg/kg/min
for 2-4h; no dose reduction necessary in renal insuf-
ficiency)
• very short T½ (only 3-5min) → normalization of platelet
function after 1h
• studies:
-- CHAMPION-PCI study (Phase III study; Harrington
et al, N Engl J 2009: cangrelor versus clopidogrel in
patients with ACS + PCI → no reduction in prima-
• 10942 patients with PCI (56.1% stable angina pectoris;
25.7% NSTEMI; 18.2% STEMI)
-- cangrelor (i.v.)
-- clopidogrel (p.o.)
• results: cangrelor
-- primary endpoint (death, myocardial infarction, ische-
mia-related revascularization after 30d, stent throm-
bosis): significant reduction
-- secondary endpoints: i.a.
◦◦ stent thrombosis: significant reduction
◦◦ rate periprocedural myocardial infarction: signifi-
cant reduction
◦◦ bleeding (GUSTO criteria): no difference
or ticagrelor should be used today, as both substances
have proven to be superior to clopidogrel. Clopidog-
rel is ineffective in 30% of all patients due to polymor-
phism.
giography should not be used for NSTE-ACS (non-ST
segment elevation): The ACCOAST study (see box)
showed no efficiency on the one hand and an increa-
sed bleeding rate on the other. The substances should
only be given in the cardiac catheterization lab once
the coronary anatomy has been determined and the
indication for PCI has been established. Otherwise,
many patients receive these substances unnecessari-
ly (e.g. because no PCI is necessary or CABG surgery
is planned), which only increases their risk of bleeding.
Furthermore, the substances show a rapid onset of ac-
tion anyway. With STEMI, however, the loading-dose
should be applied immediately.

364 Cardiology
• procedure in case of thrombocytopenia: In case of
thrombocytopenia (e.g. frequently occurring under
ECMO) the risk of bleeding is massively increased
under dual platelet inhibition. If the patient requires
dual platelet inhibition (e.g. PTCA + stent in myocar-
dial infarction with cardiogenic shock under ECMO),
the ADP-receptor antagonist is omitted from a platelet
count < 50000/μl and only ASA is given.
• duration of dual antiplatelet therapy (DAPT): After a
myocardial infarction, DAPT is recommended for 12
months (IA recommendation) regardless of whether
BMS or DES was used. It is imperative that the pati-
ent is advised of the absolute need to take DAPT ta-
blets when discharged (cave stent thrombosis)! This
should also be documented accordingly in the patient
file. However, the ESC Guidelines 2015 allow a cer-
tain amount of upward and downward leeway. For
example, the duration of DAPT can be shortened to
3-6 months in the case of a high risk of bleeding or
urgent surgery (IIb recommendation). According to the
ESC guidelines for NSTE-ACS 2020, the DAPT can
be shortened to 3 months (IIA recommendation) Simi-
larly, in patients with a high risk of ischemia and low
risk of bleeding, the duration of DAPT can be extended
beyond 12 months (IIa recommendation). To estimate
the risk of bleeding the HAS-BLED score (see page
8; goal < 3P.) or the PRECISE-DAPT score (goal
< 25P.; 5 parameters: hemoglobin, leukocytes, age,
creatinine clearance, previous bleeding; onlinec cal-
culator: www.precisedaptscore.com) can be used. In
the PEGASUS-TIMI-54 study (Sabatine et al, N Engl
J 2015), prolonged (> 12 months) administration of ti-
cagrelor (for both 2 x 90mg and only 2 x 60mg) after
a myocardial infarction led to a significant reduction in
the primary combined endpoint (cardiovascular death,
myocardial infarction, stroke) with increased bleeding
at the same time. Ticagrelor has been officially appro-
ved for prolonged therapy since 2016. In the studies
ISAR-SAFE (Schulz-Schüpke et al, EHJ 2015) and
OPTIDUAL (Helft et al, ESC 2015), however, no ad-
vantage could be shown for the prolonged DAPT, so
that the data are contradictory. In the SMART-DATE
study (Hahn et al, Lancet 2018), a DAPT of only 6
instead of 12 months in patients with ACS and im-
plantation of a DES was not inferior with regard to the
primary endpoint (combined endpoint from all-cause
mortality, myocardial infarction and stroke within 18
months ). In the TICO study (see box), patients after
PCI + stent implantation in ACS even had a net benefit
(hemorrhagic and ischemic events taken together), if
the DAPT was discintinued after 3 months (then only
monotherapy with ticagrelor).
ACCOAST study
A Comparison of Prasugrel at the Time of Percutaneous
Coronary Intervention or as Pre-treatment At the Time of
Diagnosis in Patients with Non-ST-Elevation Myocardial
Infarction
Montalescot et al, N Engl J 2013
• prospective randomized study
• 4033 patients with NSTEMI; prasugrel
-- with loading (30mg before coronary angiography, if
PCI: again 30mg in the cath lab)
-- without loading (60mg only in the cath lab, if the indi-
cation for PCI was determined)
• premature termination of study: with loading
-- no reduction of the primary endpoint (cardiovascular
arrest, infarct, stroke, emergency revascularization)
-- significantly more bleeding
TICO study
Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin
on Major Bleeding and Cardiovascular Events in Patients
With Acute Coronary Syndrome
Kim et al, JAMA 2020
• multicenter prospective randomized controlled study
• 3,056 patients with ACS and PCI + stent implantation;
for 3 months DAPT (ASA + ticagrelor), for the next 9
months:
-- without ASA (monotherapy with ticagrelor)
-- with ASA (still DAPT)
• result: only DAPT for 3 months (then monotherapy with
ticagrelor)
-- primary combined endpoint of severe bleeding on
the one hand and ischemic cardiovascular or cereb-
rovascular events (death, myocardial infarction, stent
thrombosis, stroke, target vessel revascularization
[TVR]) on the other handafter 12 months: significant
reduction
-- secondary points: i.a.
◦◦ severe bleeding: significantly reduced
◦◦ stent thrombosis: no difference
ACS: only prasugrel or ticagrelor (no
longer clopidogrel)
keine loading-dose mehr beim no more
loading-dose at NSTE-ACS before
cardiac catheterization (only to be
administered in cath lab if indication for
PCI is given)
Cardiology 365
 thrombocytopenia < 50000/μl →
discontinue ADP-receptor
antagonist (ASA only)
Triple-Therapie
If there was also an indication for oral anticoagulation
(e.g. atrial fibrillation [10% of all patients with PCI], me-
chanical valve) in patients after PCI and stent implan-
tation, triple therapy consisting of ASA, clopidogrel and
VKA (vitamin K antagonist) was performed for a long
time, which significantly increased the bleeding rate. Ac-
cording to the results of the WOEST and ISAR-TRIPLE
studie (see box), this is no longer absolutely necessary!
10% of all patients with PCI +
stent implantation have atrial
fibrillation and thus an indication
for oral anticoagulation!
WOEST study
What is the Optimal antiplatElet and anticoagulant therapy
in patients with oral anticoagulation and coronary StenTing
Dewilde et al, Am Heart J 2009
• multicenter randomized controlled study
• 573 patients with oral anticoagulation with warfarin
(mainly atrial fibrillation, mechanical valve replacement)
+ stent implantation (therapy duration: DES 12 months,
BMS 1 month)
-- warfarin + clopidogrel + ASA (triple therapy)
-- warfarin + clopidogrel
• results: warfarin + clopidogrel (i.e. without ASA)
-- no increased rate of thromboembolic events (espe-
cially stent thromboses, myocardial infarction, stroke)
-- halving of the bleeding rate
-- significant reduction of mortality
366 Cardiology
ISAR-TRIPLE study
A Prospective Randomized Trial of Six Weeks Versus Six
Month of Clopidogrel in Patients Treated with Concomitant
Aspirin and Oral Anticoagulation Therapy Following Coro-
nary
Sarafoff et al, J Am Coll Cardiol 2015
• multicenter randomized controlled study
• 614 patients with oral anticoagulation (mainly due to at-
rial fibrillation) and DES implantation
• triple therapy (ASA, clopidogrel, warfarin)
-- for 6 months
-- for 6 weeks (Clopidogrel was discontinued after 6
weeks.)
• results:
-- primary endpoint (combined: death, myocardial in-
farction, stent thrombosis, stroke, severe bleeding):
no difference
-- secondary endpoints: i.a.
◦◦ ischemic events (cardiac death, myocardial infarc-
tion, stent thrombosis, ischemic stroke): no diffe-
rence
◦◦ severe bleeding: no difference
no more general triple therapy! omit
ASA (or clopidogrel)!
Whether a triple therapy should actually be carried out
and, above all, for how long, depends essentially on
three factors:
• stroke risk (CHA2DS2-VASc score)
• bleeding risk (HAS-BLED score)
• clinical situation in which stenting occurred (in stable
coronary artery disease or in acute coronary syndro-
me)
Very helpful here is the ESC recommendation "Manage-
ment of antithrombotic therapy in atrial fibrillation pati-
ents presenting with acute coronary syndrome and / or
undergoing percutaneous coronary or valve interven-
tions" (Lip et al, Eur Heart J 2014). The ESC Guidelines
2015 for NSTE-ACS recommend a procedure depending
on the bleeding risk, which can be estimated with the
HAS-BLED score (see page (see page 8):
• low bleeding risk (HAS-BLED 0-2 P.): triple therapy for
6 month, then oral anticoagulation + ASA or clopidogrel
for a total of 12 months, then only oral anticoagulation
• high bleeding risk (HAS-BLED ≥ 3P.): triple therapy for
1 month, then oral anticoagulation + ASA or clopidogrel
for a total of 12 months, then only oral anticoagulation
Oral anticoagulation can be performed with warfarin (tar-
get INR 2.0-2.5 [exception: mechanical mitral valve, here
target INR 2.5-3.0]) or with novel oral anticoagulants
(NOAC). If NOAC is chosen for triple therapy, the lowest
dose should always be used (dabigatran 2 x 110mg, ri-
varoxaban 1 x 15mg, apixaban 2 x 2,5mg, edoxaban 1 RE-DUAL PCI
x 30mg). Clopidogrel should be preferred as an ADP-re-
ceptor antagonist, because there is the most experience
study
for this.Meanwhile, there are already data on safety and
effectiveness for prasugrel and ticagrelor. Several stu-
dies (PIONEER AF-PCI [for rivaroxaban], RE-DUAL PCI Dual Antithrombotic Therapy with Dabigatran after PCI in
[for dabigatran], AUGUSTUS [for apixaban], ENTRUST Atrial Fibrillation
AF-PCI [for edoxaban]; see infobox) could clearly show Cannon et al, N Engl J 2017
that the classic triple therapy consisting of a vitamin K
antagonist, ASA and ADP-receptor antagonist is clear- • multicenter randomized study
ly inferior to the dual therapy consisting of a NOAK and • 2725 patients with atrial fibrillation and PCI + stent im-
ADP-receptor antagonist: The dual therapy was equally plantation
effective with a significantly lower bleeding rate, so that -- triple therapy: VKA (vitamin K antagonist) + ASA +
ADP-receptor antagonist (clopidogrel or ticagrelor)
the classic triple therapy (especially over a long period)
-- dual therapy: dabigatran (2 x 110mg) + ADP-receptor
should only be carried out today in justified exceptional
antagonist (clopidogrel or ticagrelor)
cases (e.g. renal insufficiency, mechanical valve). In eve-
• results: dual therapy
ryday clinical practice, triple therapy is usually carried out
-- significantly lower bleeding rate
for 14 days, as the vulnerable phase with the increased
-- no increased rate of thromboembolic events
risk of stent thrombosis is then overcome.

The ESC Guidelines 2020 for the NSTE-ACS recom-

mend the following procedure:
• triple therapy only for the duration of the hospital stay
AUGUSTUS
(max. 1 week) study
• then NOAC + ADP-receptor antagonist (preferably clo-
pidogrel) for 12 months (in case of a high risk of blee-
ding) only 6 months) Antithrombotic Therapy after Acute Coronary Syndrome or
• then after 12 months only NOAC PCI in Atrial Fibrillation
Lopes al, N Engl J 2019

• multicenter randomized study

PIONEER AF-PCI
study
Prevention of Bleeding in Patients with Atrial Fibrillation
Undergoing PCI
Gibson et al, N Engl J 2016
• multicenter randomized study
• 2124 patients with atrial fibrillation and PCI + stent im-
plantation (50% ACS, 50% stable angina pectoris); note:
ADP-receptor antagonists: clopidogrel (94%), prasugrel
(2%) or ticagrelor (4%); 3 groups:
-- VKA (vitamin K antagonist) + ASA + ADP-receptor an-
tagonist (group I)
-- rivaroxaban
◦◦ high dose (1 x 15mg) + ADP-receptor antagonist
(group II)
◦◦ low dose (2 x 2.5mg) + ASA + ADP-receptor anta-
gonist (group III)
• results:
-- significant clinical bleeding (safety endpoint) → si-
gnificant reduction with rivaroxaban (41% in group II,
37% in group III [relative risk reduction])
-- cardiovascular death, myocardial infarction, stent
thrombosis, stroke: no difference
• 4614 patients with atrial fibrillation and acute coronary
syndrome or PCI + stent implantation; for everybody
ADP-receptor antagonist (93% clopidogrel, 6% ticagre-
lor, 1% prasugrel); for 6 months; 2 arms (2 x 2 factorial
design):
-- anticoagulation:
◦◦ VKA (vitamin K antagonist)
◦◦ apixaban (2 x 5mg; 2 x 2.5mg if 2 og the 3 crite-
ria are met: creatinine > 1.5 mg/dl, age > 80 years,
weight < 60kg)
-- antiaggregation:
◦◦ with ASA (triple therapy)
◦◦ without ASA (dual therapy)
• results:
-- primary endpoint (major bleeding or clinically relevant
non-major bleeding): significant reduction both in the
apixaban group (10.5% versus 14.7%) and in the
group without ASA (9% versus 16%); lowest among
apixaban without ASA (7.3%), highest among VKA
with ASA (18.7%)
-- secondary endpoints:
◦◦ mortality and re-hospitalization → significant re-
duction with apixaban (no difference with or without
ASA)
◦◦ ischemic events (stroke, myocardial infarction,
stent thrombosis, emergency revascularization) →
no difference
-- overall, with dual therapy with apixaban and ADP-
receptor antagonist (mostly clopidogrel), less blee-
ding and less hospitalization without an increased rate
of ischemic events

Cardiology 367

ENTRUST AF-PCI
study
Edoxaban-based versus vitamin K antagonist-based anti-
thrombotic regimen after successful coronary stenting in
patients with atrial fibrillation
Vranckx et al, Lancet 2019
• multicenter randomized non-inferiority study
• 1506 patients with atrial fibrillation and PCI + stent im-
plantation (either with acute coronary syndrome or stab-
le angina pectoris):
-- dual therapy: edoxaban 1 x 60mg (1 x 30mg, if GFR
15-50 ml/min, weight ≤ 60kg or P-glycoprotein inhibi-
tor) + ADP-receptor antagonist
-- triple therapy: VKA (vitamin K antagonist) + ADP-re-
ceptor antagonist + ASA
• results:
-- primary endpoint (major bleeding or clinically relevant
non-major bleeding) → dual therapy was not inferior
(note: However, no superiority could be shown.)
-- secondary endpoint (ischemic events [stroke, myo-
cardial infarction, stent thrombosis, emergency revas-
cularization]) → no difference
meta-analysis
Safety and efficacy of dual versus triple antithrombotic the-
rapy in patients with atrial fibrillation following percutane-
ous coronary intervention
Golwala et al, Eur Heart J 2018
• 5317 patients with atrial fibrillation and PCI + stent im-
plantation
-- triple therapy
-- duale therapy
• results: duale therapy
-- significantly lower bleeding rate (by 47%)
-- MACE (major cardiac adverse events): no difference
-- no difference in mortality
classic triple therapy only in justified
exceptional cases!
The sole anticoagulation (i.e. without additional ASA) in
atrial fibrillation is sufficient for additional CHD if:
• with stent:
-- stable CHD
◦◦ BMS > 1 month
◦◦ DES > 6 month
-- ACS: > 1 year (regardless whether BMS or DES)
• without stent: at once
368 Cardiology
CHD with stent & atrial fibrillation: after
one year only OAC (no platelet
inhibitor necessary anymore)!
If one chooses NOAC for oral anticoagulation, it should
be noted that after one year the low dose is then increa-
sed back to the normal dose.
GpIIb/IIIa-receptor antagonists
• representatives:
-- irreversible inhibition: abciximab (ReoPro)
-- reversible inhibition:
◦◦ tirofiban (Aggrastat)
◦◦ eptifibatide (Integrilin)
• application:
-- upstream (already prior to cardiac catheterization
lab in the emergency department; meta-analysis
[Montalescor et al, JAMA 2004]: little advantage for
upstream)
-- downstream (only in the cardiac catheterization lab
after insertion of the arterial sheath)
-- recommendation (ERC): only in the cardiac cathe-
terization lab (downstream; i.a. On-TIME-2- studiy
2010, i.a. meta-analysis de Luca et al, Am J Cardiol
2011: Upstream application led to an increased blee-
ding rate.)
• side effects
-- bleeding
-- thrombopenia (does not apply to eptifibatide)
• assessment:
-- generally only useful if PCI is also performed (excep-
tion: diabetics); if conservative approach:
◦◦ not abciximab due to an increased mortality (GUS-
TO IV-ACS study [Somoons et al, Lancet 2001])
◦◦ tirofiban: only in diabetics (significant reduction of
30-day mortality even with conservative approach
[Boersma et al, Lancet 2002])
-- The combination of GpIIb/IIIa-receptor antagonist
with thrombolysis does not lead to a reduction in
mortality, but to increased bleeding (GUSTO V study
[Topol et al, Lancet 2001]).
-- In the previous ESC guidelines, GpIIb/IIIa-receptor
antagonists had a relative high priority (NSTEMI:
class I; STEMI: class IIA for abciximab, class IIB for
tirofiban, class IIC for eptifibatid).
-- In the meantime, however, they have been devalued
significantly: In the current ESC guidelines, GpIIb/
IIIa-receptor antagonists are only recommended as
bail-out therapy in angiographic evidence of high
thrombus load, slow flow / no flow phenomenon or
thrombotic complications. Otherwise, routine use is
no longer recommended. If GpIIb/IIIa-receptor anta-
gonists are used, they should always be combined
with heparin (usually UFH). The ESC guideline 2012
preferred bivalirudin as a bail-out therapy over the
combination of GpIIb/IIIa-receptor antagonists and
UFH (class IB recommendation), but the ESC guide-
lines do not do this any longer since 2014.
 -- fibrinolysis
-- intracranial hemorrhage < 30d ago
-- active bleeding (gastrointestinal)
• additional ASA, ADP antagonists and heparin
• immediate and short effect (5h after end of infusion
normal platelet function again, after 4h surgery is pos-
sible)
• antagonizable only by hemodialysis

Eptifibatide (Integrilin)
• GPIIb/IIIa-receptor blocker
Abciximab (ReoPro) • dosage: bolus 180 μg/kg i.v. (double bolus; at 10min
intervals), then 2 μg/kg/min over 18h (max. 96h)
• antibody against GPIIb/IIIa-receptor
• dose reduction in renal insufficiency:
• 1 bottle = 5ml = 10mg
-- creatinine clearance 50-30 ml/min: only a bolus of
• dosage: 0.25 mg/kg as bolus i.v., then 0.125 μg/kg/min
180 μg/kg (no double bolus), then 1 μg/kg/min
(up to a maximum of 10 μg/min) over 12h
-- creatinine clearance < 30 ml/min or hemodialysis:
• Intracoronary (i.c.) administration has no advantages
contraindicated
compared to i.v. administration (i.a. AIDA STEMI study
[Desch et al, J Am Coll Cardiol 2013]). • concomitant UFH (not LMWH)
• additional ASA, ADP-receptor antagonists and heparin • Studien: PURSUIT, ESPRIT, EARLY-ACS (increased
bleeding rate without anti-ischemic benefits)
• costs: approx. 1000 € (tirofiban: 350 €)
• indications:
• RAPPORT study (Brener et al, Circ 1998): additional
administration during acute PCI → significant reduc- -- unstable angina pectoris
tion of death, reinfarction and necessary revasculari- -- NSTEMI
zations -- perioperative bridging therapy (see page 378)
• GpIIb/IIIa-receptor antagonist of choice in infarct-rela- • contraindications:
ted cardiogenic shock -- oral anticoagulation with warfarin and INR > 2 or no-
• possibly allergic reaction against the antibody fragment vel oral anticoagulants
• If platelets are transfused after administration of abci- -- thrombocytopenia < 100000/μl
ximab in the form of platelet concentrates, these are -- stroke < 30d
not inactivated (in contrast to tirofiban and eptifibatide) -- suspected gastrointestinal bleeding
-- major surgery / trauma < 6 weeks
Tirofiban (Aggrastat)
-- creatinine clearance < 30 ml/min or hemodialysis
• GPIIb/IIIa-receptor blocker
-- fibrinolysis
• indications:
-- pregnancy
-- "troponin positive unstable AP" (according to manu-
• antagonizable only by haemodialysis
facturer; i.e. NSTEMI), especially in high risk pati-
ents (e.g. known CHD)
-- unstable angina pectoris in diabetics (even if tropo- coagulation therapy in ACS:
nin negative) ASA 500mg i.v.
-- after complex PCI Heparin 5000E i.v. (not if VKA /
-- perioperative bridging therapy (see page 378) NOAK)
• risk reduction in diabetics also with conservative ap- prasugrel / ticagrelor p.o.
proach - STEMI: preloading
• approval studies: PRISM-/ RESTORE study - NSTEMI: no preloading (only if
• dosage: coronary angiogram is present)
-- initially 0.4 μg/kg/min as loading dose over 30min,
then 0.1 μg/kg/min as maintaince dose
-- simplified bolus therapy: 10 μg/kg/min, then 0.1 μg/
kg/min
-- ESC guidelines 2012: 25 μg/kg over 3min, then 0.15
μg/kg/min over 18h
• accumulation in renal insufficiency (from GFR < 30 ml/
min: ½ dose)
• over a total of 2 days (cost: 350 €)
• contraindications:
-- oral anticoagulation with warfarin and INR > 2 or no-
vel oral anticoagulants

Cardiology 369
 Definition
• reopening of the infarct vessel with fibrinolytics
• 9 large studies: significant reduction of mortality in
STEMI by 18% (versus placebo)
• informed consent if possible (before benzo-/ opiate ad-
ministration), but signature is not obligatory (approved
emergency treatment)
• door-to-needle-time: 15min (ESC guidelines 2017:
only 10min!)
• TIMI classification (thrombolysis in myocardial infarc-
tion): see infobox
• reperfusion rate: 80 % (TIMI-3 flow)
• Thrombolysis may still be performed at STEMI (e.g. in
Germany), it is not yet prohibited by law!
• In addition to thrombolysis, anticoagulation must be
performed: Here enoxaparin (initial bolus i.v., then
s.c.) should be preferred to unfractionated heparin. In
addition to thrombolysis, antiplatelet therapy (i.e. ASA
+ ADP-receptor antagonist [only clopidogrel, loading-
dose only 300mg]) must also be performed. In the
TREAT study (Berwanger et al, ACC 2018), however,
ticagrelor was not inferior to clopidogrel (no increased
bleeding rate). Thrombolysis replaces neither antico-
agulation nor antiaggregation!

RECANALIZATION THERAPY

Recanalization therapy for STE-ACS

• types:
-- pharmacological: lysis (in Germany for example only
in 5% )
-- interventional: acute PCI (in Germany for example
in 95%; today fisrt choice [high density of cardiac
catheterization labs in Germany])
-- operative: surgical myocardial revascularization
(CABG [coronary artery bypass graft] surgery; in in-
dividual cases)
• timing: In principle, recanalization therapy is indica- Indication
ted only within 12h after onset of symptoms. In unc- • STEMI with symptom onset < 12h, if time delay to acu-
lear cases, especially with persistent complaints or ST te PCI is > 120min and there are no contraindications
elevations, recanalization therapy is still useful 12-48 (ESC guidelines: IA recommendation!)
hours after the onset of symptoms. However, in pati- • Acute PCI, however, is the first choice for STEMI to-
ents who appear more than 48 hours after the onset day. Due to the high density of cardiac catheterization
of symptoms, a non-invasive ischemia diagnostic (e.g. labs especially here in Germany, thrombolysis is only
ergometry, stress echocardiography) should first be rarely necessary. It can still be indicated in rural areas
performed. or in bad weather conditions (e.g. onset of winter), if
the time delay until PCI is more than 2 hours.
Lysis (thrombolysis, fibrinolytic thera-
py) Contraindications
see infobox

Lysis is the most frequently used

recanalization therapy for STEMI
worldwide!

370 Cardiology
 prednisolone, H1 and H2 blocker) (cave: streptokinase
allergy)
• T1/2 30min
• abandoned nowadays

Urokinase (Actosolv)
• 3 Mio IU as bolus i.v.
• no allergic reactions like streptokinase
• T1/2 16min
• abandoned nowadays (for lysis in myocardial infarc-
tion lysis therapy; not appoved for this either)

Anistreplase (Eminase)
• an APSAC (Anisoyl-Plasminogen-Streptokinase-Acti-
vator)
• 30U (1 amp.) over 5min i.v. (beforhand 40mg dexame-
thasone)
• T1/2 100min
• abandoned nowadays

Actilyse (Alteplase, rt-PA)

• front-loaded scheme (according to Neuhaus): 100mg
in 90min
• Actilyse 15mg (= 15ml) as bolus i.v., then 0.75 mg/kg
(up to 50mg) in 30min, then 0.5 mg/kg (up to 35mg)
in 60min
• first heparin (UFH) 60 IU/kg (max. 4000 IU) as bolus,
then accompanying 12 IU/kg/h (max. 1000 IU; target
PTT: 50-70 sec)
• T1/2 15min

Rapilysin (Reteplase, r-PA)

• 2 boluses of 10 U (= 10mg) each at interval of 30min
• after 2nd bolus heparin (UFH) 1000 IU/h
• T1/2 18min

Tenecteplase (Metalyse, TNK-tPA)

In approx. 10-15% a contraindication • single shot 0.5 mg/kg = 100 U/kg
for thrombolysis is present! Resuscita- • weight-dependent dosage (ESC 2017: at age > 75 ye-
tion is not a contraindication (possibly ars only half dose):
even an indication) for thrombolysis! -- < 60kg: 6000U = 30mg = 6ml
-- 60-70kg: 7000U = 35mg = 7ml
-- 70-80kg: 8000U = 40mg = 8ml
Fibrinolytics -- 80-90kg: 9000U = 45mg = 9ml
• first generation: unspecific (not fibrin-specific; no lon- -- > 90kg: 10000U = 50mg = 10ml
ger relevant today) • full heparinization immediately
-- streptokinase • T1/2 18min
-- urokinase
-- anistreplase Complications
• second generation: specific (fibrin-specific) • epistaxis and bleeding in the mouth area: mostly harm-
-- actilyse (Alteplase, rt-PA) less
-- rapilysin (Reteplase, r-PA) • with heavy bleeding:
-- tenecteplase (Metalyse, TNK-tPA) -- stop thrombolysis
-- protamin
Streptokinase (Kabikinase, Streptase)
◦◦ for heparin antagonization
• 1.5 Mio IU in 60min, then (only after 12h) 25000 IE
◦◦ 1 amp. = 5ml, 1ml = 1000 IU = 10 mg
heparin (UFH) over 24h without bolus
◦◦ simple dosage: 1000 IU of protamin antagonize
• often quick + fibrinogen ↓↓, PTT ↑ → ignore!
1000 IU of heparin (equimolar).
• always prescribe antiallergic medication ("cocktail":
◦◦ also possible with low-molecular weight heparins

Cardiology 371
 (but only 60% antagonizable), e.g. enoxaparin:
within the first 8h after administration 100 IU of
protamin per mg enoxaparin, 8-12h: 50 IU prota-
min per mg enoxaparin, > 12h: protamin no longer
indicated
◦◦ side effects:
▪▪ allergic reaction (especially with known fish pro-
tein allergy, since protamine is obtained from
salmon)
▪▪ blood pressure ↓↓ (therefore only slowly as a
short infusion)
▪▪ pulmonary vasoconstriction, PAP ↑
▪▪ hypercoagulability
-- volume, FFP
-- fibrinogen
-- if necessary antifibrinolytics (see page 1172)
◦◦ aprotinin (Trasylol)
◦◦ tranexamic acid (Cyclokapron, Standard)

Success criteria (reperfusion criteria)

• decrease in chest pain (most important)
• decrease in ST elevation by more than 50% in 3h (ST-
segment resolution)
• reperfusion arrhythmias (e.g. idioventricular rhythm
[see inobox])
• wash-out effect of enzymes:
-- CK maximum after 4h is indicative of successful
thrombolysis; if maximum only after 16h: unsuccess-
ful
-- myoglobin (high sensitivity): maximum after 3h, rate
of increase 150 ng/ml/h
failed thrombolysis: in 20% → rescue
PCI
The question of whether a cardiac catheterization must
also be performed after every successful thrombolysis
is always a controversial one: On the one hand, routi-
ne invasive examination after successful thrombolysis
significantly reduced the rate of re-occlusions and re-
infarctions. On the other hand, no mortality benefit has
yet been demonstrated in a single study (i.a. GRACIA-1
study: no mortality benefit; Beck et al, Am Heart J 2005:
no mortality benefit; CAPITAL AMI study, JACC 2005:
no mortality benefit, ASSENT 4 study, Lancet 2004: in-
creased mortality for facilitated PCI [premature disconti-
nuation of study], OAT/TOSCA-2 study [Dravik et al, Circ
2006]: no benefit). If a cardiac catheterization is chosen
after successful thrombolysis, it should be performed
early (< 24h) in any case (significantly lower combined
endpoint of death and re-infarction [e.g. GRACIA 1 study,
Lancet 2004]). The current ESC guidelines explicitly re-
commend that cardiac catheterization should be perfor-
med within 24 hours (but not < 3 hours [due to increased
bleeding rate; ESC 2017: not < 2h]) even after successful
thrombolysis.

Even after successful thromboly-

sis, coronary angiography should
be performed within 2-24h!

372 Cardiology
Types
• prehospital lysis
-- Prehospital thrombolysis is better than intrahospital
thrombolysis (meta-analysis Morrison et al, JAMA
2000) mainly due to time gain (average time gain:
60min) and leads to a relative reduction of mortality
by 17% compared to intrahospital thrombolysis.
-- PREMIR register (prehospital myocardial infarction
register in Germany): The time delay to PCI in Ger-
many is an average of 76 minutes.
-- recommendations:
◦◦ ESC guidelines for STEMI: lysis if symptoms <
12h and time delay to PCI > 2h (in the previous
ESC guidelines: 1h)
◦◦ ERC guidelines 2015: STEMI + transport time
> 30min → lysis (prehospital)!
• intrahospital lysis
Lysis in resuscitation
• 70% of all cardiovascular arrests are caused by throm-
botic vascular occlusion (acute myocardial infarction,
pulmonary embolism).
• ILCOR 2005: lysis in CPR
-- in suspected pulmonary embolism
-- in initial failure
• ERC 2010 and 2015:
-- in suspected pulmonary embolism recommended
only (not even more than ultima ratio in suspected
myocardial infarction)
-- Actilyse 50mg
• TROICA study (see page 306): no benefit
Facilitated PCI
This is PCI after pre-treatment with thrombolysis. In the
BRAVE 1 study, STEMI patients treated with reteplase
and abciximab prior to PCI showed no mortality benefit.
In the ASSENT-4-PCI study, patients with STEMI who
were treated with tenecteplase prior to PCI even showed
an increased mortality (excess mortality!), so that the
concept of facilitated PCI no longer has any significance
today.
STREAM study
Fibrinolysis or Primary PCI in ST-Segment Elevation Myo-
cardial Infarction
Armstrong et al, N Engl J 2013
• prospective randomized study
• 1892 patients with STEMI within 3h after onset of sym-
ptoms, in whom acute PTCA was not possible within 1h
(mainly because hospital had no cardiac catheterization
lab), but then after transfer after 6-24h
-- with previous lysis (tenecteplase)
-- without previous lysis
• results: with previous lysis
-- primary endpoint (death, shock, cardiac decompen-
sation, reinfarction within 30d): no difference (note: no
difference even after 1 year)
-- secondary endpoints: i.a.
◦◦ stroke: significantly increased
◦◦ intracranial hemorrhage: significantly increased
DANAMI-2 study
A Comparison of Coronary Angioplasty with Fibrinolytic
Therapy in Acute Myocardial Infarction
Andersen et al, N Engl J 2003
• multicenter randomized controlled study
• 1129 patients with STEMI in hospitals without cardiac
catheterization laboratory (CCL)
-- transfer to center with acute PCI
-- lysis on site
• results: transfer for acute PCI
-- significant reduction in combined endpoint (death,
reinfarction rate, stroke; main cause: fewer reinfarc-
tions)
-- benefit up to a time loss due to tranfer of 2h
-- no difference in mortality
Hospitals without a cardiac catheterization laboratory
(CCL) should transfer a patient with STEMI to an appro-
priate center with the possibility of PCI if the time lost is
< 120min. The DI-DO (door-in to door-out-time; in the
hospital without CCL) should be < 30min, otherwise lysis
on site should be performed. The transfer must be done
with an emergency physican and not with the intensive
care transport (takes far too long).
Cardiology 373
Acute PCI (PTCA) -- studies:
◦◦ TAPAS study (Svilaas et al, N Engl J 2008): signi-
ficantly improved myocardial perfusion
◦◦ TASTE study (Frobert et al, N Engl J 2013): no
mortality advantage (not even after one year [Lan-
gerquist et al, N Engl J 2014])
◦◦ TOTAL study (Jolly et al, N Engl J 2015): no morta-
lity advantage (even increased stroke rate)
• Infarct vessels are often vasospastic, so that the vessel
size is often underestimated and much too small stents
are implanted. Therefore, intracoronary nitro should al-
ways be applied before the angiographic sequence in
which the stent size is ultimately determined.

Definition
• reopening of the occluded vessel with PCI (percutane-
ous coronary intervention; syn.: PTCA [percutaneous
transluminal coronary angioplasty])
• In STEMI, the cardiac catheterization must be perfor-
med immediately. The emergency physician should go
directly to the CCL (no detour via the intensive care
unit or emergency room and any monitoring there; only
loss of time). The result of the heart enzymes must not
be waited for.
• goals (time):
-- door-to-balloon-time
◦◦ with announcement < 30min
◦◦ without announcement < 60min
◦◦ note: average time at STEMI until revasculari-
zation by PCI: 150 min (Rosenkranz et al, Clin Res
Cardiol 2007)
-- contact-to-balloon-time (time from the first medical
contact [FMC; e.g. emergency staff] to PCI): < 90min
• access (arterial):
-- current ESC guidelines (STEMI): especially radial
instead of femoral access recommended (since less
bleeding [i.a. RIVAL study 2011, RIFLE-STEACS Fig. 555  Acute PCI with stent [7]
study 2012, STEMI-RADIAL study 2014, MATRIX
study 2015])
-- Ultimately, however, the interventionalist should
choose the access with which he has the most ex-
perience, regardless of any guideline recommenda-
tions.
• Primary stent implantation is preferable to balloon an-
gioplasty alone.
• thrombus aspiration:
-- However, thrombus aspiration should first be perfor-
med at STEMI according to ESC guidelines 2014, if
possible, in order to avoid distal embolization with
consecutive decreased myocardial perfusion at ca- Fig. 556  Acute PCI (pressure syringe)
pillary level. However, the current studies were com-
pletely negative, so that thrombus aspiration should
only be performed in selected cases and no longer
routinely. Accordingly, thrombus aspiration is no lon-
ger routinely recommended in the 2017 ESC guide-
lines (IIIA recommendation).

374 Cardiology
 sudden deterioration after PCI +
stent implantation: pericardial
tamponade, acute stent thrombo-
sis, coronary dissection with
aortic dissection, retroperitoneal
hematoma (with femoral access)

Preventive PCI
Standard in STEMI, is the PCI only of the infarct arte-
ry ("culprit lesion", "guilty" artery), i.e. of the arterywhich
is responsible for ischemia. The question is whether
an additional stenosis, which is currently not the cause
of ischemia, should also be treated as a precaution
(concept of preventive PCI; syn.: multivessel PCI). The
PRAMI study (see box) showed a reduction in the event
rate by almost two thirds by preventive PCI. The DANA-
Fig. 557  Coronary angiography: RCX occlusion in acute la- MI3-PRIMULTI and the CvLPRIT study (see box) also
teral wall infarction revealed similar results. According to the previous ESC
guidelines, multivessel PCI was only recommended in
Indications
infarct-related cardiogenic shock. Following the positive
• acute PCI results of these studies, multivessel PCI for myocardial
-- STEMI (immediate; incl. probably new LBBB), NS- infarction was upgraded somewhat from III to IIb in the
TEMI (as a rule within 72 h) 2017 ESC guidelines. However, in patients with infarct-
-- after lysis related cardiogenic shock, the CULPRIT-SHOCK study
◦◦ after unsuccessful lysis (in 20%; "rescue PCI"): 2017 (see page 402) even showed an increased morta-
immediately lity for multi-vessel PCI!
◦◦ after successful lysis: within 24h (but not < 2h);
note: Even after successful lysis coronary angio-
graphy is recommended within 2-24h
-- in case of contraindications against lysis (10-15% PRAMI study
present)
• elective PCI (in case of proof of ischemia)
-- renewed angina pectoris (post infarct angina)
-- ventricular tachycardia (on the monitor or in long Randomized Trial of Preventive Angioplasty in Myocardial
term ECG) Infarction
-- inducible ischemia (stress ECG, stress echocardio- Wald et al, N Engl J 2013
graphy)
• multicenter prospective randomized study
-- ejection fraction < 40%
• 465 patients with STEMI and multi-vessel CHD and PCI
of the infarct artery
Types -- without PCI of the stenosed non-infarct artery, i.e.
• according to indication single-vessel PCI
-- primary PCI -- with PCI of the stenosed non-infarct artery, i.e. multi-
vessel PCI (preventive PCI)
-- secondary PCI
• result: preventive PCI
◦◦ facilitated PCI (after successful lysis)
-- combined primary endpoint (cardiac death, myo-
◦◦ rescue PCI (after unsuccessful lysis) cardial infarction, refractory angina pectoris): signifi-
• according to urgency cant reduction (by 64%!)
-- emergency (acute PCI) -- even premature discontinuation of study
-- elective -- note: The reduction of the refractory angina pectoris
• according to objective was mainly responsible for the significance, which is
only a relatively "soft" endpoint.
-- therapeutic
-- preventive

Cardiology 375
 DANAMI3-PRIMULTI
study
The third DANish study of optimal Acute treatment of pa-
tients with ST-segment elevation Myocardial Infarction
Engstrom et al, Lancet 2015
• randomized controlled study
• 627 patients with STEMI and PCI of the infarct artery
-- without PCI of the stenosed non-infarct artery, i.e.
single-vessel PCI
-- with PCI of the stenosed non-infarct artery, i.e. multi-
vessel PCI (preventive PCI)
• results: preventive PCI
-- primary endpoint (combined of death, non-fatal myo-
cardial infarction, revascularization necessary due to
ischemia [exception: infarct lesion]): significant reduc-
tion (by 44%!)
-- secondary endpoints:
◦◦ mortality: no difference
◦◦ incidence of myocardial infarction: no difference
CvLPRIT study
Complete versus Lesion only PRimary-PCI Trial
Gershlick et al, JACC 2015
• open randomized British study
• 296 patients with STEMI and PCI of the infarct artery
-- without PCI of the stenosed non-infarct artery, i.e.
single-vessel PCI
-- with PCI of the stenosed non-infarct artery, i.e. multi-
vessel PCI (preventive PCI)
• results: preventive PCI
-- significantly longer treatment time (55min vs. 41min),
more contrast medium application (250ml vs. 190ml),
but no increased rate of stroke, bleeding complica-
tions or contrast induced renal failure
-- significantly less clinical complications
-- significantly less severe cardiovascular compli-
cations (MACE: major adverse cardiac events; 10%
versus 21.2%)
-- significantly lower risk for combined endpoint
death, heart attack or heart failure (5% versus 13%)
376 Cardiology
COMPARE-ACUTE study
Fractional Flow Reserve-Guided Multivessel Angioplasty
in Myocardial Infarction
Smits et al, N Engl J 2017
• 885 patients with STEMI and PCI of the infarct artery
-- without PCI of the stenosed non-infarct artery, i.e.
single-vessel PCI
-- with PCI of the stenosed non-infarct artery (including
FFR measurement [FFR: fractional flow reserve]), i.e.
multivessel PCI (preventive PCI)
• results: preventive PCI
-- primary endpoint (combined from death, non-fatal
myocardial infarction, revascularization, cerebrovas-
cular events within 12 months): significant reduction
-- secondary endpoints:
◦◦ mortality: no difference
◦◦ incidence of myocardial infarction: no difference
meta-analysis
Complete vs culprit-only revascularization for patients with
multivessel disease undergoing primary percutaneous
coronary intervention for ST-segment elevation myocardial
infarction: A systematic review and meta-analysis
Bainey et al, Am Heart J 2014
• 46324 patients (26 studies) with STEMI and PCI
-- 83% single-vessel PCI (infarct artery only)
-- 17% multivessel PCI (preventive PCI)
• result: multivessel PCI
-- no difference in hospital mortality
-- significantly reduced long-term mortality

COMPLETE study
Complete Revascularization with Multivessel PCI for Myo-
cardial Infarction
Mehta et al, N Engl J 2019
• multicenter randomized controlled study
• 4041 (largest study to date on this topic) patients with
STEMI and multivessel disease and PCI of the infarct
artery ("culprit leson")
-- without PCI of the stenosed non-infarct artery / arte-
ries
-- with PCI of the stenosed non-infarct artery / arteries,
i.e. multivessel PCI (preventive PCI, complete revas-
cularization)
• result: preventive PCI → significant reduction in pri-
mary combined endpoint (cardiovascular mortality and
myocardial infarction)
• note: The revascularization was not completely carried
out in the first cardiac catheterization. In fact, mostly only
the intervention of the infarct artery took place here ("cul-
prit leson"). The complete revascularization was perfor-
med only in a second cardiac catheterization, which took
place before discharge from hospital.
Stents
• BMS (bare metall stents)
• DES (drug eluting stents)
DES (drug eluting stents)
• representatives: see infobox
• objective: intima proliferation ↓ → restenose rate ↓
• An increased rate of infarction was initially reported
(BASKET-LATE study [Pfisterer et al, JACC 2006], La-
gerquist et al, N Engl J 2007 [Swedish SCAARS regis-
ter], what, however, was not confirmed in the course.
A meta-analysis (Kastrati et al, N Engl J 2007) showed
no increased mortality.
• indication:
-- especially complex stenoses (small vessels, long
stenoses, in-stent stenosis)
-- STEMI: In a cohort study (Mauri et al, N Engl J 2008
[see box]) patients with acute myocardial infarction
(STEMI / NSTEMI) showed significantly lower mor-
tality for DES compared to BMS. However, a large
meta-analysis (Brarr et al, JACC 2009) of 26521 pa-
tients could not confirm this.
• recommendations:
-- In the current ESC guidelines on STEMI, the use
of DES instead of BMS is recommended!
-- In the ESC/EACTS Guidelines on myocardial reva-
scularization 2018 for all PCI (regardless of whether
acute coronary syndrome or stable angina pectoris)
generally only DES are recommended and no more
BMS at all.
• post-treatment (dual antiplatelet therapy [DAPT]) with
ASA and ADP-receptor antagonists (clopidogrel, pra-
sugrel or ticagrelor) for 6 months with stable CHD (12
months after infarction regardless of whether BMS or
DES was used)
• After implantation of a DES, DAPT consisting of ASA
and an ADP-receptor antagonist (clopidogrel, prasug-
rel or ticagrelor) must be continued for 12 months (for
ACS; for stable CHD 6 months) due to the increased
risk of stent thrombosis (highest risk in the first month
after stent implantation). Elective surgery should not
be performed during this period. If, however, the ope-
ration cannot be delayed for such a long time (e.g.
unclear tumor of the lower abdomen, especially ma-
lignoma), clopidogrel (not ASA!) can be discontinued
and perioperative bridging therapy (see infobox) with
a short-acting GpIIb/IIIa-receptor antagonist (tirofiban,
eptifibatide) can be performed, what we, however, ra-
rely do in everyday clinical practice. Bridging therapy
is only possible with GpIIb/IIIa-receptor antagonists
(especially tirofiban, eptifibatide), but not with heparin!
The same applies to the newer ADP-receptor antago-
nists. If DES of the 3rd generation (e.g. Xience PRO /
Prime / V [Abbott Vascular], Coroflex ISAR NEO bzw.
Blue NEO [Braun], Promus Element [Boston Scientific]
were used, what is standard today, the ADP-receptor
antagonist can be paused after only three months.
• New are now resorbable stents (BVS: bioresorbable
vascular scaffholds; dual platelet inhibition required for
6 months [without infarct]; vasomotion of the coronary
vessels thus possible again), but which have come un-
der criticism due to an increased stent thrombosis rate
with consecutive increased mortality and have now al-
most completely disappeared from the market:
-- Absorb (Abbott)
◦◦ framework: lactic acid (then degenerates to H20
and CO2)
◦◦ coating: everolimus
◦◦ studies:
▪▪ ADSORB II study (Serruys et al, Lancet 2014):
non-inferiority to DES (after 1 year; however in-
ferior after 3 years [with respect to late decrease
of vascular lumen])
▪▪ ABSORB STEMI TROFO II study (Serruys et al,
ESC 2015): non-inferiority to DES in STEMI
-- Desolve (Elixir)
◦◦ framework: lactic acid (then degenerates to H20
and CO2)
◦◦ coating: myolimus
-- Dreams (Biotronik)
◦◦ framework: magnesium
◦◦ coating: paclitaxel
Cardiology 377
 study

Drug-Eluting or Bare-Metal Stents for Acute Myocardial

Infarction
Mauri et al, N Engl J 2008

• population-based cohort study

• 7217 patients with acute myocardial infarction and PCI
-- BMS (bare metal stents)
-- DES (drug eluting stents)
• result: DES → significantly lower mortality (after 2
years; both STEMI and NSTEMI)

meta-analysis

Use of Drug-Eluting Stents in Acute Myocardial Infarction

Brar et al, JACC 2009

• meta-analysis (18 studies)

• - 26521 patients with STEMI
-- BMS
-- DES
• results: no difference (mortality, stent thrombosis,
myocardial infarction, TVR [target vessel revascularisa-
tion])

DAPT study

Twelve oder 30 months of dual antiplatelet therapy after

drug-eluting stents
Mauri et al, N Engl J 2014

• multicenter randomized controlled study

• 9961 patients with PCI + DES implantation
• dual antiplatelet therapy (DAPT):
-- for 12 months
-- for 30 months
• results: dual antiplatelet therapy for 30 months
-- significantly fewer stent thromboses
-- significantly reduced combined endpoint of death,
myocardial infarction and stroke
-- significantly more bleeding
-- significantly increased mortality (reason: significantly
more cancers in the 30-month group even before ran-
domization)

Fig. 558  different stents [7]

378 Cardiology
Timing
For a long time the dogma that a late PCI (> 12h after
the onset of symptoms) was no longer meaningful was
valid. However, the BRAVE-2 study was able to show
that PCI up to 48 hours can significantly reduce the size
of the infarction. However, PCI is no longer efficient after
three days.
Advantages of PCI over lysis
• higher TIMI-3 flow rate (reopening of the infarct vessel;
PCI 90-95%, lysis only 80%)
• also feasible with contraindications for lysis
• lower ICH (intracranial hemorrhage) rate (fibrinolysis
2%, PCI 1%)
• lower reinfarction rate
• possibility of early risk stratification (e.g. main stem
stenosis, 3-vessel CHD → indication for CABG)
• lower mortality (Lysis reduces mortality in STEMI by
18%, PTCA by 37%, i.e. by twice!)
• PCI is also better than the lysis regardless of the time
(PCAT-2 [large meta-analysis]: Boersma et al, Eur
Heart J 2006)
Excursus: Stable CHD (chronic coronary
syndrome)
The daily practice especially in Germany of very frequent
PCI with stable CHD (about 300000/year, more than all
other EU countries combined!) should be critically exami-
ned: In a meta-analysis in 2006, Yusuf was able to show
that PCI has no survival advantage at all with stable CHD
and even showed a trend towards higher infarct rates
and mortality. PCI in patients with stable angina pectoris
is a purely symptomatic measure that reduces pain ("ex-
pensive painkiller"). So far, there is not a single prospec-
tive randomized controlled study that has shown that PCI
reduces the risk of myocardial infarction or mortality in
stable CHD. This is not surprising, since plaque ruptu-
re with myocardial infarction usually does not occur at
the stenosed site. PCI does not cure unstable plaques.
One does not die of stenosis ("benign" form of CHD),
but of thrombosis. Accordingly, in the COURAGE Study
(Boden et al, N Engl J 2007), patients with stable CHD
showed no reduction in mortality or infarct rates due to
PCI compared to (optimal) drug therapy alone. A follow-
up analysis of the COURAGE data (Spertus et al, Circ
Cardiovasc 2013) also showed that only 16% of patients
undergoing conservative therapy required PCI within
one year. Even a follow-up period of 15 years showed
no difference in mortality (Sedlis et al, N Engl J 2015). In
a meta-analysis (Initial coronary stent implantation with
medical therapy versus medical therapy alone for stable
coronary artery disease; Stergiopoulos et al, Arch Intern
Med 2012), PCI did not lead to a reduction in mortality,
myocardial infarction rates or a reduction in the rate of
unplanned revascularization in stable angina pectoris
compared to purely conservative therapy. There was not
even a reduction in angina pectoris symptoms. A further
meta-analysis (see box) showed that this was not even
the case if an inducible ischemia was detected in stable
angina pectoris. In a meta-analysis (Windecker al, BMJ
2014) only PCI with DES of the newer generation (e.g.
everolimus) could show a mortality advantage. Due to
the well-known fact that performing an invasive measure
alone can have significant placebo effects, the ORBITA
study was carried out (see box): Even here, the real in-
tervention showed no advantages compared to the sham
intervention. The prognostic relevance to hard endpoints
of PCI in stable CHD was examined in the ISCHEMIA
study (see box), the largest study ever on this topic: The-
re is no prognostic benefit here either (only a symptoma-
tic benefit).
You live with stenoses and die of
thromboses!
Prognostically relevant are only proximal LAD and left
main stem stenosis and three-vessel-disease (exactly:
only if ejection fraction < 40%): Here, however, surgical
and not interventional myocardial revascularization (i.e.
PCI) is explicitly recommended (e.g. SYNTHAX study).
In the EXCEL study (Stone et al, N Engl J 2016), PCI in
left main stem stenosis (non-complex) was not inferior
to surgery (primary combined endpoint: death, stroke,
myocardial infarction). The 5-year data were discussed
vigorously and effectively in the media between invasive
cardiologists and cardiac surgeons.
Pressure wire measurement (FFR: fractional flow reser-
ve) is very important for stable CHD today (i.a. ESC-Gui-
delines on Chronic Coronary Syndromes 2019). Here, in
the cath lab, a pressure wire is used to measure whether
the stenosis that is seen in the coronary angiography is
significant or not. PCI is only performed if it is significant
(i.e. FFR ≤ 0.80). The FAME studies formed the basis for
the recommendation:
• FAME I (Tonino et al, N Engl J 2009): Here, PCI with
versus without a previous FFR measurement in pati-
ents with multi-vessel CAD showed a significant re-
duction in the primary combined endpoint (death, non-
fatal myocardial infarction, renewed revascularization
within one year).
• FAME II (de Bruyne et al, N Engl J 2012): If a ste-
nosis was found in coronary angiography, FFR was
measured. With an FFR ≤ 0.80, randomization was
carried out in PCI plus best pharmacological therapy
versus only best pharmacological therapy alone. With
an FFR> 0.80 there was no PCI, only best pharmaco-
logical therapy. The primary combined endpoint consi-
sted of death, myocardial infarction and urgent revas-
cularization. The study was discontinued prematurely
because the FFR group showed a reduction in the
primary combined endpoint early. This was due to a
significantly reduced rate of urgent revascularizations.
Cardiology 379
 meta-analysis
Percutaneous Coronary Intervention Outcomes in Patients
With Stable Obstructive Coronary Artery Disease and Myo-
cardial Ischemia - A Collaborative Meta-analysis of Con-
temporary Randomized Clinical Trials
Stergiopoulos et al, JAMA Intern Med 2013
• 4063 patients with stable angina pectoris with proven (!)
inducible ischemia (stress test, imaging, fractional flow
reserve [FFR])
-- PCI + stent implantation
-- conservative
• results: PCI + stent implantation
-- no reduction in mortality
-- no reduction in myocardial infarction rate
-- no reduction in unplanned revascularization
-- no reduction in angina pectoris symptoms (not even
that!)
ORBITA study
Percutaneous coronary intervention in stable angina: a
double-blind, randomized controlled trial
Al-Lamee et al, Lancet 2017
• multicenter randomized controlled study
• 200 patients with stable CHD (severe single-vessel CHD
[stenosis > 70%; incl. FFR measurement]) and optimal
pharmagological therapy (before ober 6 weeks); cardiac
catheterization:
-- with real intervention (PCI + stent implantation)
-- without real intervention (only shame intervention)
• result: PCI + stent implantation
-- no improvement in resilience
-- no reduction in angina pectoris symptoms
380 Cardiology
ISCHEMIA study
International Study of Comparative Health Effectiveness
With Medical and Invasive Approaches
Hochman et al, AHA 2019
• multicenter international prospective randomized study
• ISCHEMIA: International Study of Comparative Health
Effectiveness With Medical and Invasive Approaches
• 5179 patients (the largest study to date on this topic)
with stable angina pectoris and proven (at least modera-
te) ischemia in non-invasive tests (i.a. ergometry, stress
echocardiography, myocardial scintigraphy, MRI); opti-
mal pharmagological therapy
-- with PCI + stent implantation (or CABG)
-- without PCI + stent implantation (or CABG)
• results: with PCI + stent implantation (or CABG)
-- primary combined endpoint (cardiovascular death,
myocardial infarction, resuscitation in cardiac arrest,
hospitalization for unstable angina or heart failure): no
difference (after 3.3 years)
-- secondary endpoints
◦◦ all-cause mortality: no difference
◦◦ angina pectoris symptoms (Seattle Angina Questo-
naire): significant reduction
◦◦ quality of life: significant improvement
• exclusion criteria:
-- EF < 35%
-- renal insufficiency with a GFR < 30 ml/min
-- left main stenosis (in CT angiography)
-- status post PCI + stent implantation or CABG in the
last 12 months
-- NYHA III / IV
meta-analysis
Routine Revascularization versus Initial Medical Therapy
for Stable Ischemic Heart Disease: A Systematic Review
and Meta-Analysis of Randomized Trials
Bangalore et al, Circulation 2020
• 14877 patients (14 RCT) with stable angina pectoris
-- with PCI + stent implantation (or CABG)
-- without PCI + stent implantation (or CABG)
• results: with PCI + stent implantation (or CABG)
-- primary endpoint: mortality → no reduction
-- secondary endpoints: i.a.
◦◦ significantly less frequent angina pectoris (both sta-
ble and unstable)
◦◦ significantly less spontaneous, but more periproce-
dural myocardial infarctions
◦◦ no difference in the occurrence of heart failure
Recanalization therapy for NSTE- Here, three invasive strategies for NSTEMI were inve-
stigated: immediate, early (12-48h [on average after
ACS 18h]) and elective (only in persistant angina pecoris or
proven ischemia). There was no difference either in
the primary endpoint (infarct size according to CK-MB)
or the secondary endpoints (death, recurrence, rehabi-
litation within 6 months).
• meta-analysis (Zheng et al, Lancet 2017): An early-
invasive (< 24h) versus late-invasive (> 24h) strategy
showed no overall reduction in mortality in patients
with NSTE-ACS. This was only the case in high-risk
patients (i.a. GRACE score > 140P., increased tropo-
nin, diabetes mellitus).
• VERDICT study (Kofoed et al, Circulation 2018 [see
box])

VERDICT study

Studies
• RITA-3 study (Fox et al, Lancet 2002): Here, the strate-
gies routinely invasive versus selectively invasive (i.e. Early Versus Standard Care Invasive Examination and
only for proven ischemia or persistent angina pectoris, Treatment of Patients with Non-ST-Segment Elevation
otherwise conservative) were compared in patients Acute Coronary Syndrome
Kofoed et al, Circulation 2018
with NSTE-ACS. The routine invasive procedure ulti-
mately showed only symptomatic (less angina pecto- • multicenter prospectiv randomized study
ris), but no prognostic benefit (no reduction in mortality • 2147 patients with NSTE-ACS
or the rate of myocardial infarction).
-- early-invasive (< 12h [on average after 4.7h])
• ICTUS study (de Winter et al, N Engl J 2005): Here, -- late-invasive (48-72h [on average after 61.6h])
1200 patients with NSTEMI (NSTE-ACS + increased • result (early-invasive):
troponin) were randomized into an early invasive and • primary combined endpoint (death, myocardial infarc-
a selectively invasive (e.g. only for persistent angina tion, hospitalization for heart failure or refractory myo-
pectoris) group. There was no significant difference cardial ischemia) → no reduvtion (exception: high risk
in the primary combined endpoint (death, myocardial [GRACE score > 140P.])
infarction, rehospitalizations). Myocardial infarction
(transmural) was even significantly more common in
the early invasive group (15% versus 10%). The 5-year Scores
data of the ICTUS study (Damman et al, JACC 2010) The urgency for invasive examination (cardiac catheteri-
showed no difference in myocardial infarction rate and zation) in acute coronary syndrome without ST elevation
no difference in mortality. (NSTE-ACS) can be estimated with different scores:
• FRISC II study (Lagerqvist et al, Lancet 2006): Here, • GRACE score (GRACE: global registry of acute coro-
the strategies early invasive and selectively invasive nary events; according to Mehta et al, N Engl J 2009;
were compared. The early invasive approach showed most used; see infobox)
a significant reduction of the combined primary end- • PURSUIT score
point of death and myocardial infarction.
• TIMI-Risk score
• TIMACS study (Mehta et al, N Engl J 2009): In patients
• CRUSADE score (to estimate the periinterventional
with NSTE-ACS, early-invasive (< 24h) versus late-
bleeding risk in NSTE-ACS; according to Subherwal et
invasive (> 36h) strategy showed no overall reduction
al, Circulation 2009; see infobox)
in the primary combined endpoint (death, myocardial
infarction, stroke). This was only the case in the sub-
group of high-risk patients (i.a. GRACE score > 140P.,
increased troponin, diabetes mellitus).
• FIR study (a meta-analysis [from RITA-3, ICTUS and
FRISC-II]; Fox et al, ACC 2010): Here, the strategies
routinely invasive versus selectively invasive (i.e. only
for proven ischemia or persistent angina pectoris,
otherwise conservative) were compared in patients
with NSTE-ACS. The routinely invasive strategy sho-
wed a significant reduction in cardiovascular death and
myocardial infarction.
• LIPSIA-NSTEMI study (Thiele et al, Eur Heart J 2011):

Cardiology 381
 Timing (according to ESC)
• very high risk → immediately invasive (< 2h)
-- hemodynamic instability (i.a. cardiogenic shock)
-- mechanical complications of myocardial infarction
-- electrical instability (VT, ventricular fibrillation)
-- pronounced ST-depressions (> 0.2mV), intermittent
ST-elevations
-- persistent / recurrent angina pectoris

382 Cardiology
• high risk → early invasive (< 24h)
-- rise or fall (speaks for dynamics and decline of myo-
cytes) of troponin (compatible with an infarction
-- ECG changes (ST-depressions, T-negations)
-- GRACE score: > 140 P.
• intermediate risk → invasive (< 72h)
-- diabetes mellitus
-- renal insufficiency (GFR < 60 ml/min)
-- reduced ejection fraction (EF < 40%)
-- status post CABG
-- status post PCI / stent in the last 6 months
-- early post-infarct angina
-- GRACE score: 109-140 P.
• low risk (if none of the criteria mentioned is met; GRA-
CE score < 109 P.) → electively invasive or not invasi-
ve at all (First of all, non-invasive ischemia diagnosis
[exercise ECG, stress echocardiography] is indicated
here.)
Surgical myocardial revascularizati-
on (CABG)
• immediate
-- haemodynamically unstable
-- infarct complications (mechanical)
-- left main stenosis
• day 1-3: stable (with extracorporeal circulatory sup-
port)
• > 7 days: stable (without extracorporeal circulatory
support)
Unfortunately, there are no randomized controlled stu-
dies on this topic. Usually, the interventional correction
(especially in STEMI) of the causing stenosis / occlusi-
on ("culprit-lesion", infarct artery) takes place primarily
during the cardiac catheterization examination. If this is
not possible for interventionally, surgery should be per-
formed immediately. The ESC / EACTS Guidelines on
myocardial revascularisation recommend a procedure
analogous to the stable CHD in the case of multi-vessel
coronary artery disease, i.e. interventional myocardial
revascularisation in the case of 1- to 2-vessel coronary
artery disease, and surgical myocardial revascularisati-
on in the case of 3-vessel coronary artery disease, left
main stenosis or proximal LAD stenosis. If the patients
are stable, surgery within 48-72h is sufficient. The sur-
gical mortality (CABG) in acute myocardial infarction is
5-10% (previously 30%) and therefore twice as high as
in elective surgery. ASA should be continued periopera-
tively, ADP-receptor antagonists should be discontinued
(clopidogrel and ticagrelor 5 days, prasugrel 7 days) if
the patient is stable.
Right ventricular myocardial infarction
(RVMI)
Definition
• infarction of the right ventricle
• mostly proximal RCA occlusion
• occurrence:
-- 30% in inferior myocardial infarction, 15% in antero-
septal infarction
-- Isolated right ventricular myocardial infarction is rare
(only in 3%).
-- 5% of all patients with infarct-related cardiogenic
shock have an right ventricular myocardial infarction.
The right ventricular leads (at least
V4R) should be derived in every
inferior wall infarction → therapeutic
consequence!!
Symptoms
• bradycardia
• signs of right heart failure: i.a.
-- congested jugular veins
-- Kussmaul's sign (inspiratory increase of jugular vein
pulse)
• cardinal symptom: blood pressure decrease in inferior
myocardial infarction (cardiogenic shock) without pul-
monary congestion (hypotension in inferior myocardial
infarction without congestion)!
acute MI (esp. inferior myocardial
infarction) with bradycardia, hypotensi-
on, congested jugular veins and
missing pulmonary congestion →
RVMI!
important DD:
- RVMI: bradycard
- pulmonary embolism: tachycard
Diagnosis
• ECG:
-- almost always associated with an inferior wall MI, i.e.
ST-elevations in II, III, aVF
-- ST-elevation in III > II (high sensitivity for a RVMI)
-- ST-elevation in V1 and ST-depression in V2 (high
specifity for a RVMI)
-- ST-elevations in the right ventricular leads (espe-
cially V4R)
-- With modern EKG devices, the right ventricular
leads and also V7-V9 (for the posterior infarction)
are generated automatically from the normal 12-lead
ECG so that the electrodes do not need to be glued
on additionally in the special positions.
• echocardiography:
-- right ventricular dilatation and hypo- or akinesia
-- in contrast to pulmonary embolism
◦◦ no increased PAP
◦◦ inferior wall movement disorders (hypo-/ akinesia;
RVMI almost always combined with inferior wall
MI!)
Cardiology 383
• cardiac catheterization:
-- coronary angiography: mostly proximal RCA occlu-
sion
-- hemodynamics:
◦◦ RV pressure curve:
▪▪ RVEDP > LVEDP
▪▪ possibly dip-plateau phenomenon
◦◦ RA pressure curve:
▪▪ high a-wave, deep y-descent (due to compli-
ance disorder of the right ventricle)
▪▪ configuration: with atrial infarction M-shaped
(poor prognosis), without atrial infarction W-
shaped (favourable prognosis)
Fig. 559  ECG: right ventricular leads (simply mirror-inver-
ted to left ventricular chest leads)
Therapy
• fluid administration (to increase preload)
-- Patients with RVMI profitieren (especially in cardio-
genic shock) benefit enormously from fluid adminis-
tration. The right ventricle itself is almost complete-
ly independent of the preload (volume), there is no
Frank Starling mechanism like on the left ventricle.
The right ventricle is largely dependent on the af-
terload (pressure). In RVMI the right ventricle only
insufficiently pumps the blood towards the left heart,
i.e. the left ventricular preload is too low. This can
be increased by fluid administration with a consecu-
tively increase of the cardiac output.
-- target CVP > 20 mmHg (orientation at the CVP only
optional; for the estimation of the preload see page
225)
• recanalization:
-- Lysis is much more effective in RV infarction than in
LV infarction (Zehender et al, 1993).
-- PCI nevertheless better than lysis
• no preload-lowering drugs
-- nitrates (decrease in preload due to dilatation of ve-
nous capacity vessels)
-- diuretics
-- morphine (also lowers preload) [by dilatation of ve-
nous capacity vessels])
• no β-blockers (since typically on day 2/3 [infarct
edema] higher grade AV-blocks)
• cardiogenic shock → fluid administration + dobutamine
384 Cardiology
• if ventilation is required: set as low a PEEP as pos-
sible (A too high PEEP lowers both the left and right
ventricular preload and increases the right ventricular
afterload!)
Infarct complications
If a patient is suddenly worse after a recent myocardial in-
farction with interventional revascularisation, acute stent
thrombosis and infarct complications should be considered.
If a MI patient suddenly deteriora-
tes, do not immediately perform a
"suspeced re-infarction" and
cardiac catheterization, but rather
think of possible MI complicati-
ons and auscultate!
Ventricular fibrillation
• most frequent cause of death in myocardial infarction
• note: The most frequent cardiac arrhythmia, however,
in the context of an acute coronary syndrome is not
ventricular, but atrial fibrillation.
• types:
-- primary ventricular fibrillation: < 24h (i.e. before re-
vascularization)
-- secondary ventricular fibrillation: >24h (i.e. after re-
vascularization; worse prognosis)
• therapy: defibrillation
• If ventricular fibrillation occurs after PCI with stent
implantation, acute stent thrombosis (mortality 50%)
must be considered and the patient generously cathe-
terized again.
• procedure if it occurs after 48 hours (and acute stent
thrombosis excluded):
-- amiodarone saturation (SCD-Heft study: not more
effective than placebo, in NYHA III even excess mor-
tality)
-- ICD implantation (at the earliest after 4 weeks; pos-
sibly bridging with wearable defibrillator vest [e.g.
LifeVest])
Fig. 560  ventricular fibrillation
Fig. 561  R on T phenomenon: If a stroke (such as extra-
systole [premature ventricular contraction] or pacemaker
stimulus) falls into the vulnerable phase (= ascending leg of
the T wave), ventricular fibrillation can be triggered.
Acute left heart failure (pulmonary
edema)
Definition
• frequency:
-- lysis era: in 40% in myocardial infarction (perma-
nent heart failure after myocardial infarction: in 42%)
[Spencer et al, J Am Coll Cardiol 1999])
-- PCI era: in 8% in myocardial infarction (permanent
heart failure after myocardial infarction: in 5% [HO-
RIZONS-AMI study: Kelly et al, Am Heart J 2011])
• more common in women (by 34%) than in men (analy-
sis of the ISACS-TC register [Cenko et al, JACC 2019])
• loss of > 20% of the functional myocardium
• no cardiac catheterization in pulmonary edema or as
long as the patient cannot lie flat (if necessary peri-
interventionell NIV or intubate beforehand)
• note on the term "acute left heart failure": This refers to
myocardial pump failure as a result of a myocardial in-
farction. Otherwise, the term refers only to a syndrome
that can be caused by numerous different causes (e.g.
valve vitium, arrhythmia, etc.), all of which are treated
differently.
• mortality:
-- hospital mortality: 15%
-- 1-year mortality: 30%
Classifications
Symptoms
• respiratory distress:
-- dyspnea (note: The symptom of dyspnea [and not
chest pain] is the symptom with the highest morta-
lity!)
-- orthopnea (respiratory distress when lying flat)
-- bendopnea
◦◦ respiratory distress when bending forward (i.a.
Drazner et al, JACC Heart Fail 2014)
◦◦ This increases the LVEDP and consecutively also
the pressure in the left atrium and thus also the
wedge pressure, so that there is a backflow into
the lung and thus respiratory distress.
• angina pectoris: Even without myocardial infarction,
patients with decompensated heart failure can develop
angina pectoris. This is because the increased LVEDP
(left ventricular enddiastolic pressure) compresses the
capillaries so that coronary perfusion decreases.
• foamy, possibly bloody tinged sputum, possibly white
foamy secretions from the tube (pulmonary edema)
• cyanosis, grey facial colour
• sinus tachycardia
Diagnostics
• clinical examination
-- congestion of jugular veins: In the case of a high up-
per body the jugular veins should no longer be visi-
ble when the upper body is positioned at 45° (spe-
cificity 94%).
-- hepatojugular reflux (persistent visible filling of the
jugular veins under pressure on the liver)
-- Gaertner's sign (no more emptying of the veins of
the back of the hand when lifting the forearm above
atrial height)
-- auscultation:
◦◦ lung:
▪▪ rattling noises basally on both sides (note: The
mucus rattling in pneumonia can sound decep-
tively similar, so that one should also think of this
cause in patients without leg edema and with fe-
ver!)
▪▪ expiratory spasticity (asthma cardiale [interstitial
pulmonary edema])
◦◦ heart: 3rd heart tone ( specificity 99%: If one
hears a 3rd heart tone, in 99% the dyspnea of the
patient is due to heart failure!), possibly gallop
rhythm (in sinus tachycardia)
Cardiology 385
• chest X-ray
-- signs of congestion: cranialized pulmonary vascular
drawing, widened pulmonary veins in the hilus regi-
on, Kerley B lines, pleural effusion
-- An inconspicuous chest X-ray (e.g. no signs of con-
gestion), however, does not exclude cardiac decom-
pensation. Although the specificity for pulmonary ve-
nous congestion is high at 96%, sensitivity is low at
54% (Collins et al, AEM Journal 2016). Especially in
patients with COPD there are often no signs of con-
gestion in chest X-rays due to peripheral vascular
reattachment
• laboratory: i.a.
-- increased natriuretic peptides
◦◦ BNP > 100 pg/ml or NT-pro-BNP > 300 pg/ml
◦◦ Determination, however, is not mandatory (but
ESC 2016: IA recommendation)
◦◦ annotations:
▪▪ An increased BNP or NT-pro-BNP alone is not
an indication for forced diuretic therapy! It is also
increased in the case of recompensated heart
failure. The patient must also be decompensa-
ted clinically (especially dyspnea, leg edema),
sonographically or in X-ray.
▪▪ A normal BNP or NT-pro-BNP largely excludes
cardiac decompensation.
▪▪ BNP or NT-pro-BNP, however, incorrectly low in
patients with obesity (The higher the BMI, the
lower the BNP or NT-pro-BNP. Natriuretic pep-
tides increase insulin resistance and increase
lipolysis so that their synthesis in obesity is re-
duced. Furthermore, obesity leads to an overex-
pression of clearing receptors of natriuretic pep-
tides, so that their renal clearance is increased.
According to the ESC guidelines 2019 [Practical
guidance on the use of natriuretic peptide con-
centrations] the upper limit should be reduced
by 50%.)
▪▪ BNP under ARNI (angiotensin receptor neprily-
sine inhibitor; valsartan + sacubitrile) not usable
(only NT-proBNP!)
-- frequently (in 50%) increased troponin (frequently
even massively increased; also without infarction!)
-- increased LFTs (transaminases, bilirubin) and low
quick (increased INR) due to congestion (pitfall: In
addition to increased LFTs, patients often also have
right-sided upper abdominal pain due to liver capsu-
le tension. Furthermore, the gallbladder wall is usu-
ally also thickened sonographically, so that there is
no false indication for cholecystectomy, which with
cardiac decompensation also has a significantly in-
creased perioperative mortality!)
• pleurasonography (syn.: thoracic ultrasound [TUS])
-- evidence of pleural effusion (mostly right-sided ["The
right side belongs to the heart!"])
-- evidence of pulmonary edema:
◦◦ The detection of pulmonary edema is also possi-
ble by pleural sonography in experienced hands.
◦◦ Sonography has a significantly higher sensitivity
than X-ray with regard to the detection of pulmo-
386 Cardiology
nary edema (i.a. Wooten et al, J Ul­trasound Med
2019: sensitivity of sonography 96%, whereas
sensitivity of X-ray only 65%).
◦◦ assessment: with regard to pulmonary edema
▪▪ sensitivity: 97%
▪▪ specifity: 95%
◦◦ linear transducer, sounding of intercostal; thorax
sonography works with artifacts: These are desi-
red here, so that all improvement modes (e.g. THE
[tissue harmonic imaging]) that suppress artifacts
should be switched off on the ultrasound device.
◦◦ B-lines ("comet tail" artefacts, "flashlight" pheno-
menon, "spotlight")
▪▪ vertical lines (indicate liquid; in contrast to the
A-lines, which run horizontally [reverberations]
and indicate air [A: air; increased A-lines e.g.
with exacerbated COPD or bronchial asthma];
memo: There are no A and B lines side by side
simultaneously.)
▪▪ ≥ 3 B-lines per intercostal space ; note: The
number given is only to be seen as relative and
depends among other things on the device used
and its setting. Therefore as a tip: Before sound-
ing the patient, you should briefly sound yourself
ventrally on the thorax (It is best to briefly turn
away from the patient so that he does not see
you.). So you have a good comparison!
▪▪ on both sides and homogeneously distributed
▪▪ note: Dorsal and basal B-lines are also possible
in healthy individuals.
◦◦ good correlation of pleural sonography with
▪▪ extravascular lung water (Agricola et al, Chest
2005; Zhao et al, BMC Pulmonary Medicine
2015; Picano et al, Eur Heart J 2016; Anile et
al, Crit Ultrasound J 2017; ELWICARE [currently
ongoing study])
▪▪ wedge pressure: Above a wedge pressure of
18mmHg B-lines occur (Lichtenstein et al, BLUE
protocol, Springer 2016).
• echocardiography (i.a.. extended inferior vena cava
with insufficient respiratory modulation)
• advanced hemodynamic monitoring (if present):
-- increased extravascular lung water index (ELWI)
-- pulmonary vascular permeability index (PVPI) < 3
-- increased LVEDP (wedge pressure; pulmonary ca-
theter)
Fig. 562  congested jugular veins

difficult

Fig. 564  Pleural sonography (thoracic ultrasound): The ar-

rows point to the B-line: This is a downward reverberation
("comet tail"). ≥ 3 B-lines per intercostal space on both si-
des indicate pulmonary edema.

bed shot
Fig. 563  chest X-ray: decompensated heart failure (various
examples)

Cardiology 387

Fig. 565  This is what pulmonary edema looks like in the
chest CT. CT is certainly not the first choice diagnostic tool
for the detection of pulmonary edema. However, if a chest
CT is performed in unclear dyspnea (e.g. to exclude pul-
monary embolism), pulmonary edema is often misinterpre-
ted as bilateral pneumonic infiltrates. This is because we
are mostly familiar with pulmonary edema from chest X-ray
and not from chest CT.
Therapy
• upper body elevation
• oxygen administration (but only if SpO2 < 90% or paO2
< 60mmHg
• diuretics
-- only loop diuretics (e.g. furosemide 40-80mg i.v. [on-
set of action: 5min; maximum of action: 30min; dura-
tion of action: 2h]; cave: cave: hypokalemia-induced
tachycardia)
-- note: Often a high level of creatinine is accompanied
by anxiety to dehydrate the patient and often a com-
pletely nonsensical combination of diuretics and vo-
lume is used to avoid aggravating renal failure. Pati-
ents are in section 3 of the Frank-Starling curve due
to volume overload (see page 204). Furthermore,
the curve is shifted down here. Volume withdrawal
can increase the stroke volume and thus the cardiac
output! Here, too, the aim is to reduce the volume by
volume withdrawal. This leads to an increase in car-
diac output and a consecutive increase in renal per-
fusion, so that creatinine falls off and does not rise.
• nitrates (glycerol trinitrate, syn.: nitroglycerin)
-- effect: peripheral vasodilatation
◦◦ low dose (< 5 mg/h): especially venous → reduc-
tion of the preload (main effect [nitrates mainly af-
fect the venous vessels.])
◦◦ high dose (> 5 mg/h): mainly arterial → reduction
of the afterload
-- significantly more effective than diuretics
-- in addition to loop diuretics recommended in acute
heart failure if SBP > 90mmHg
-- application: as spray or as perfusor (better; 1
mg/1ml;, infusion rate 1-6 ml/h)
• morphine (i.a. preload reduction [by dilation of venous
capacity vessels]):
-- especially in agitated and tachypnoeic patients
-- otherwise rather restrictive, since the ADHERE stu-
388 Cardiology
dy (see box) showed negative effects (note: Morphi-
ne is also negative inotropic!)
• possibly bloodless bloodletting (rotating tourniquets):
This is an old, but also very simple measure. A blood
pressure cuff is placed proximally on all 4 extremities
and 3 of them are inflated so that the venous back-
flow to the heart is prevented. One limb is decongested
every 10 minutes and the limb that has not yet been
congested is congested. Ultimately, no benefit could
be shown in the studies, so that this method is consi-
dered obsolete.
• pleural effusion: pleural puncture if necessary (Cardiac
pleural effusions do not always have to be punctured
immediately. These can usually be easily eliminated or
at least reduced by forced diuretic therapy. Therapeu-
tic pleural puncture should only be performed immedi-
ately if there is a large pleural effusion and pronounced
dyspnea, especially if the patient is also anuric.)
• An existing β-blocker therapy should be continued as
long as the patient is still haemodynamically stable.
In a meta-analysis (Prins et al, JACC Heart Failure
2015), discontinuation of the β-blocker led to increased
mortality in patients with acute heart failure.
• if necessary inotropics
-- dobutamine
-- levosimendan (officially approved since 2014 in Ger-
many under the trade name Simdax for the treat-
ment of acute decompensated heart failure; see
page 404)
• if necessary ventilation (especially NIV with a very high
priority) with high PEEP
DOSE study
Diuretic Strategies in Patients with Acute Decompensated
Heart Failure
Felker et al, N Engl J 2011
• prospective randomized study
• 308 patients: loop diuretics (furosemide) in acute de-
compensated heart failure
-- high (2.5 x daily dose) / low (1 x daily dose) dose
-- boluswise / continuous
• result: no difference (symptoms, increase in creatinine)
• note: The study was ultimately too small to answer this
clinically important question.
 REALITY-AHF study ADHERE study

Time-to-furosemide treatment and mortality in patients Morphine and outcomes in acute decompensated heart
hospitalized with acute heart failure failure; an ADHERE analysis
Matsue et al, JACC 2017 Peacock et al, Emerg Med J 2008

• REALITY-AHF: Registry Focused on Very Early Presen- • ADHERE: Acute Decompensated Heart Failure National
tation and Treatment in Emergency Department of Acute Registry
Heart Failure • retrospective analysis
• multicenter prospective observational study (cohort stu- • 147,362 patients with acute decompensated heart fai-
dy) lure
• 1,291 patients with acute heart failure; time of furosemi- -- 20,782 patients (14%): with morphine
de administration („door-to-furosemid“-time): -- 126,580 patients (86%): without morphine
-- < 60min (early treatment) • results: morphine
-- > 60min (late treatment) -- increased mortality
• result: < 60min (early treatment) → significantly lower -- significantly more frequent pulmonary congestion (in
mortality (The earlier the loop diuretic was applied, the chest X-ray)
lower the mortality [note: a relatively banal result].)
-- more frequent requiring intensive care and ventilation
-- higher consumption of inotropics
-- longer hospital stay

ALARM-HF study acute left heart failure: generous

nitroglycerin-perfusor (as long as
SBP > 90mmHg)

Short-term survival by treatment among patients hospital-

ized with acute heart failure: the global ALARM-HF registry
using propensity scoring methods Cardiogenic shock
Mebazaa et al, Intensive Care Med 2011 see next chapter (page 392)
• retrospective cohort study
• 4953 patients with acute decompensated heart failure
Ventricular septal rupture (VSR)
• results:
-- diuretics + vasodilators (e.g. NO, sodium nitroprus- Definition
side [SNP]) vs. diuretics alone → significantly lower • syn.: infarction VSD
mortality (7.6% vs. 14.2%) • occurring mainly in anterior wall MI (LAD occlusion)
-- positive inotropic substances or vasopressors → sig-
• typically on day 2-3
nificantly increased mortality (risk increase by factor
2.43) • tear in the muscular part of the septum
• sudden deterioration ("suspected reinfarction")
• frequency:
-- 2% of all MI patients
-- 6% of all patients with infarct-related cardiogenic
shock (SHOCK register)
• mortality: 70%
• special form: Gerbode shunt (connection between the
left ventricle and the right atrium [LV-RA fistula]; see
also page 75)

Types
• anterior VSR
-- in anterior wall MI
-- more frequent (75%)
-- only isolated septal affection
-- better prognosis
• posterior VSR

Cardiology 389
 -- in inferior wall MI
-- less frequent (25%)
-- in addition to the septum also mostly affection of the
free wall and the support apparatus of the mitral val-
ve
-- worse prognosis

Diagnosis
• clinical examination
-- palpation: parasternal bruit
-- auscultation: new systolic murmur over Erb's point
(classical loud noise; amplification by catecholami-
nes)
• echocardiography (TTE, TEE):
-- detection of the substance defect in the ventricular Fig. 567  chest CT: defect in the ventricular septum in VSR
septum (in the TTE mainly from substernal, but also
from parasternal)
-- conspicuously hyperkinetic (p.d. EF > 70%; due to
the volume load) and possibly also dilated (LVEDD >
58mm) left ventricle
-- detection of the left-to-right shunt in the color duplex
• chest X-ray: central pulmonary edema (hyperperfusion
[„plethora pulmonalis“])
• CT thorax if necessary
• levocardiography (syn .: ventriculography)
• pulmonary catheter:
-- conspicuously high mixed venous oxygen saturation
(= saturation in the pulmonary artery; > 80%)
-- leap in step oximetry test (e.g. SO2 in the right atri-
um 71%, in the pulmonary artery 93%)

A VSR cannot be missed in the

auscultation!

Fig. 568  Levocardiography (pigtail catheter in the left ven-

tricle): The contrast medium transition from the left to the
right ventricle (arrow) is visible.

Fig. 566  Echocardiography: VSR with defect in the ven-
tricular septum and detection of left-to-right shunt in the
color duplex
Therapy
• surgical closure (patch plastic)
• There is disagreement about the timing: On the one
hand it is stated that the patient should be stabilized
for two weeks if possible (e.g. by va-ECMO or IABP),
since the patch sutures do not hold in the newly infarc-
ted myocardium. On the other hand it is argued that
with a longer waiting time the patient often deteriorates
haemodynamically further and further, so that he is fi-
nally no longer operable at all.
• possibly interventional occlusion (e.g. Amplatzer Mu-
scular VSD Occluder; only in individual cases [e.g. as
a bridging measure to surgery]; no standard therapy)
• reduction of the afterload (to reduce the left-to-right
shunt; e.g. with sodium nitroprusside [SNP]) and of the
preload (with diuretics)
• no noradrenaline, since shunt becomes larger (due to
an increase of the afterload)
• in case of shock (especially if refractory to therapy):
possibly discontinue therapy

390 Cardiology
Myocardial rupture • papillary muscles (PM):
-- posteromedial PM
Definition ◦◦ supply via RCA
• often impressive as sudden cardiac death ◦◦ occurrence in inferior wall myocardial infarction
• The rupture of the myocardium results in bleeding into ◦◦ more frequently infarcted
the pericardial sac (haematopericardium) with conse- -- anterolateral PM
cutive pericardial tamponade. ◦◦ supply via LAD
• severe ("tearing") pain ◦◦ occurrence in anterior wall myocardial infarction
• typically on day 3-5 ◦◦ less frequently infarcted
• echocardiography:
-- pericardial effusion, onion-skin-shaped mass in the Diagnosis
pericardial space (clot) • auscultation:
-- substance defect in the myocardium -- new systolic murmur via the apex of the heart (often
• prognosis: infaust (mortality: 98%) very quiet; may even be absent due to the high pres-
• extremely rare sure in the left atrium!)
-- most frequent cause of a newly occurring systolic
Risk factors murmur
• older women • sudden pulmonary edema that does not improve with
diuretics
• arterial hypertension
• echocardiography (TTE, if necessary TEE):
• anterior wall myocardial infarction
-- flail leaflet, prolapsing into the left atrium
• first event of myocardial infarction
-- severe mitral valve regurgitation
Therapy • pulmonary catheter: excessive v-wave (as a sign of se-
vere mitral valve regurgitation)
• immediate surgery
• BP reduction with sodium nitroprusside until surgery Therapy
• pericardial puncture senseless
• intubation, ventilation with high PEEP (> 10 mmHg)
• afterload reduction:
Pericardial tamponade -- diuretics
• causes (especially in the context of an acute coronary -- sodium nitroprusside (SNP)
syndrome):
-- glycerol trinitrate (NO)
-- myocardial rupture
• indication for IABP
-- acute aortic dissection
• Mitral valve regurgitation due to a flail leaflet is always
-- coronary perforation through the guide wire in the
an indication for surgery (regardless of the severity of
acute PCI
mitral valve regurgitation)!
◦◦ especially in distal vessel sections (often no con-
• immediate surgery
trast agent paravasate recognizable during the
-- mitral valve reconstruction (incl. anuloplasty ring)
examination)
-- possibly in the same session surgical revasculariza-
◦◦ on average after 4h (not immediately!)
tion of the inferior wall
• otherwise with regard to pericardial tamponade (among
-- surgical mortality: 39%
others pericardial puncture) see page 98

Acute mitral valve regurgitation Aneurysm, intracavitary thrombi

Definition Definition
• most common mechanical complication of myocardial
• acute mitral valve regurgitation as a result of:
infarction
-- a tear of the papillary muscle (usually lethal) or par-
• aneurysm in 15% of all patients with a anterior wall
tial tear of the tendinous chords in the context of a
myocardial infarction
myocardial infarction
• mainly apically localized (anterior wall aneurysm)
-- an akinesia in the infarction area with a consecu-
tively insufficient papillary muscle • Thrombi occur almost exclusively in large anterior wall
myocardial infarctions with dyskinesia when the pati-
• 1% of all patients with myocardial infarction (especially
ent reaches the clinic subacutely and is not immedia-
in the case of a inferior wall myocardial infarction)
tely fully anticoagulated. The risk of arterial embolisms
• In acute mitral valve regurgitation, the left atrium is
is relatively low, only 1% of all cardiac thrombi become
usually not enlarge and therefore the pressure in the
symptomatic due to embolisms.
left atrium relatively high.
• on average already 22h after onset of myocardial in-
farction

Cardiology 391
Diagnosis
• ECG: persistent ST-elevation, R-loss over the anterior
wall
• echocardiography:
-- dyskinesia (p.d. systolic outward movement of the
affected wall segment [here: apex])
-- maybe detection of a thrombus (if necessary, use of
left heart contrast medium [e.g. SonoVue] for better
visualization)
Fig. 569  several 12-lead ECGs in process: The first ECG
was performed at the time of admission to the emergency
department and shows ST elevations over the anterior wall,
so that a cardiac catheter examination was carried out im-
mediately. This showed a proximal LAD occlusion that was
supplied with PCTand a stent. In the subsequent second
ECG shortly after being admitted to the ICU, there were no
more ST elevations. Furthermore, there was already an al-
most complete loss of the R-waves over the anterior wall.
The third ECG which was routinely derived at the following
day showed ST elevations (in V2 und V3), which lead to pa-
nic. But it was only an anterior wall aneurysm. Typical for
this is the ST elevation with loss of the R-waves. The ante-
rior wall aneurysm could easily be verified immediately by
echocardiography.
392 Cardiology
Therapy
• if a thrombus is detected heparin (full anticoagulation),
then oral anticoagulation for 6 months (no fibrinolytic
therapy with proven thrombus in the left ventricle: Here
the risk that the thrombus decays and parts of it now
embolize [especially into the brain] is too high!)
• ventricular restoration in interval if necessary with pro-
nounced heart failure symptoms
-- surgical: ventricular restoration surgery according to
Dor
◦◦ aneurysmectomy
◦◦ studies:
▪▪ SAVER study (Athanasuleas et al, J Am Coll
Cardiol 2001): relatively low surgical mortality,
relatively high benefit
▪▪ STICH study (Jones et al, N Engl J 2009): no
benefit
-- interventional (catheter-assisted insertion of a pa-
rachute system into the left ventricle via a sheath in
the femoral artery, so that the acinetic useless apex
of the heart is switched off [left ventricular partitio-
ning] and thus the entire LV volume is reduced [e.g.
PARACHUTE studies])
• note: no indication (as no benefit) for a prophylactic
oral anticoagulation (with VKA / NOAK) in the case of
highly reduced EF (e.g. ischemic / dilated cardiomyo-
pathy) + sinus rhythm:
-- WASH study (Cleland et al, Am Heart J 2004)
-- WATCH study (Massier et al, Circulation 2009)
-- WARCEF study (Homma et al, N Engl J 2012)
-- COMMANDER-HF study (Zannad et al, N Engl J
2018 [rivaroxaban for ischemic cardiomyopathy and
sinus rhythm: no benefit])
Fig. 570  Echocardiography: apical four-chamber view with
thrombus in the left ventricle
DD Pseudoaneurysm
A very important differential diagnosis to a true aneurysm
with enormous therapeutic consequences is the pseudo-
aneurysm: This is a myocardial rupture of the free wall
into the pericardial space covered only by a pericardial
adhesion. Echocardiographically, a narrow neck (< 40%
of the maximum aneurysm diameter), a sharper angle
and a more abrupt change in contour are typically seen
in contrast to the real aneurysm. This differential diagno-
sis is important because a pseudoaneurysm is not an in-
dication for anticoagulation (like the real aneurysm [with
thrombus]), but an indication for (urgent) surgery. The
differential diagnosis must be performed echocardiogra-
phically. A left heart contrast medium (e.g. SonoVue) can
also be used for better visualization
Fig. 571  pseudoaneurysma With a real aneurysm (left),
both the myocardium (red) and the pericardium (black) are
bulging
Fig. 572  With a real aneurysm (left), both the myocardi-
um (red) and the pericardium (black; exactly: visceral part
of the pericardium [syn.: epicardium]) are bulging, with a
pseudoaneurysm (right) only the pericardium. Here there
is a rupture of the myocardium which is only covered by
the pericardium (exactly: parietal part). In the pseudoaneu-
rysm the neck is much narrower and the angle much more
pointed.
Bradycardias
• frequent and almost only inferior wall myocardial in-
farction
• often AV blocks
• usually harmless
• if necessary atropine or dobutamine
• spontaneous remission frequently in the first 3 days
• if necessary temporary pacemaker, but very rarely a
permanent pacemaker is necessary (One should wait
at least 10 days with the implantation of a permanent
pacemaker! Most patients recover and then do not
need a permanent pacemaker. But especially in an
interdisciplinary intensive care unit, where one often
feels a certain pressure from the surgical departments
to provide free beds, this is unfortunately often not
done and often too early unnecessary a permanent
pacemaker is implanted.)
Wait at least 10 days with the
implantation of a permanent pacema-
ker in AV block III after a inferior wall
MI! Most patients recover and do not
need one!
inferior wall MI anterior wall MI
occurence often rare
necessity of implan-
tation of a permanent
pacemaker rare often
Pericarditis
Types
• early pericarditis (< 7 days after myocardial infarction:
perikarditis epistenocardiaca (15% of the MI patients;
typically chest pain again 1-3 days after the infarction)
• late pericarditis (> 7 days after myocardial infarction):
Dressler's syndrome (also occurring after cardiac sur-
gery [postcardiotomy syndrome])
Diagnosos
• anamnesis: pericardial chest pain (increase with inspi-
ration, no stopping with respiratory pause [in contrast
to pleural chest pain]), possibly fever
• clinical examination (auscultation): possibly pericardial
rubbing
• ECG: ST-elevations (pericarditis-typical)
• laboratory:
-- cardiac enzymes negative (exception: perimyocar-
ditis)
-- possibly increased inflammation values (leukocytes,
CRP)
-- possibly antimyocardial antibodies (Dressler's syn-
drome)
• echocardiography: possibly small pericardial effusion
(also pleural effusion)
Cardiology 393

Fig. 573  Pericarditis epistenocardiaca: Patient who had a
NSTEMI 2 days ago and underwent a PCI + stent implanta-
tion of RCX; now post-infarction-angina with ST-elevations:
However, one does not see infarct-typical, but pericarditis-
typical elevations. Furthermore, there is no elevation in the
area of the former infarct vessel (RCX). Echocardiography
showed a small pericardial effusion. The CK controls were
inconspicuous.
Therapy
• ASA
-- means of choice (ESC guidelines STEMI 2017)
-- highly dosed: 500-1000mg 3-4 x daily over 1-2
weeks, the dose reduction by 250-500mg every 1-2
weeks
• NSAID (contraindicated however in heart failure and
renal failure with GFR < 30 ml/min)
-- ibuprofen (i.a. coronary perfusion↑), dosage: 4 x
400-800mg
-- diclofenac 3 x 50mg (POPE study [Meurin et al, Ann
Int Med 2010]: no benefit in postcardiotomy syndro-
me)
• steroids
-- prednisolone 0.5-1.0 mg/kg for 3 days, then tapering
within 2 weeks
-- of minor importance (thinning of the infarct zone →
risk of rupture), ESC guidelines STEMI 2017: not re-
commended; therefore only in case of contraindica-
tions for ASA and NSAID
• colchicine (see page 97): always as a combination
partner; studies on colchicine in postcardiotomy syn-
drome:
-- COPPS-2 study (Imazio et al, JAMA 2014): Prophyl-
actic administration of colchicine after cardiac surge-
ry reduced the incidence of postcardiotomy syndro-
me after three months from 29% to 19%.
-- POPE-2 study (Meurin et al, Eur Heart J 2014): Col-
chicine was of no benefit in pericardial effusions after
cardiac surgery.
• switching from full anticoagulation to low-dose (risk of
bleeding into the pericardium with consecutive tampo-
nade), ASA can be continued
-- wall movement disorders: Acinetic areas such as af-
ter a myocardial infarction predispose to thrombus
formation.
-- cardiac wall aneurysm (mostly of the anterior wall)
• On the one hand, a stroke can occur as a complica-
tion of a myocardial infarction (possibly TEE for the
question of cardiac source of embolism), on the other
hand, 30% of all stroke patients have an elevated tro-
ponin T without a myocardial infarction. Neurogenic
ECG changes also frequently occur in stroke patients:
QT-interval prolongation (38%), ST-segment changes
(22%) and T-negativations (15%).
Tako-Tsubo Cardiomyopathy
Definition
• synonyma:
-- stress cardiomyopathy
-- broken heart syndrome
• first description by Dote 1991 (J Cardiology)
• transient regional systolic dysfunction
-- almost exclusively apical (but also mid- ventricular or
basal possible)
-- concerns especially the left ventricle (but also possi-
ble right ventricular or biventricular)
• ballooning of the apex of the left ventricle ("apical bal-
looning")
• The ventricle looks similar to an octopus trap (Japane-
se: "tako-tsubo").
• in 25% associated with left ventricular obstruction of
the outflow tract (Stähli et al, Eur Heart J 2011)
• in 12% cardiogenic shock
Fig. 574  In Tako-Tsubo cardiomyopathy, the left ventricle
is dilated and ballooned and looks similar to an octopus
trap (courtesy of Mr Dr. Olivier Hejl, chief physician of the
clinic for Internal Medicine, St. Franziskus hospital Eitorf
[Germany]).

Stroke
Etiology
• 1% of all patients with myocardial infarction suffer a
stroke. • catecholamines (cardiotoxicity! especially due to ex-
cessive stimulation of the β-receptors [Therefore, tako
• intracardial thrombus formation:
tsubo cardiomyopathy is much less common with nor-
-- atrial fibrillation (especially in the left atrial appenda- adrenaline than with dobutamine or adrenaline.])
ge [LAA])

394 Cardiology
 -- endogenous be associated with apical akinesia, is the large ante-
◦◦ stress-induced rior wall myocardial infarction with proximal LAD oc-
◦◦ neurogenic in stroke / SAH (sympathetic hypersti- clusion. This must be excluded at all costs, because
mulation with catecholamine release) a large anterior wall MI is not reversible in contrast
◦◦ pheochromocytoma to a Tako-Tsubo cardiomyopathy! This is always an
exclusion diagnosis! Note: A large anterior wall MI is
-- exogenous (e.g. intensive care unit)
usually accompanied by maximum CK levels > 1000
• triggers: i.a. IU/l. Maximum CK values < 300 U/l speak strongly
-- deaths of relatives against a myocardial infarction and for a Tako-Tsubo
-- traffic accident cardiomyopathy, whereby one should also not wait
-- fear of surgery so long, until a CK > 1000 U/l has developed with
-- visit to the dentist (e.g. injection of local anaesthetics myocardial infarction.
[important DD for anaphylactic shock!]) -- coincidence of CHD and Tako-Tsubo cardiomyopa-
-- asthma attack, exacerbated COPD thy: 15%
-- but also strong positive (and not just negative) emo- • cardiac MRI if necessary
tions („happy heart“ syndrome [Ghadri et al, Eur
Heart J 2016])

Epidemiology
• almost exclusively women affected (a gender-specific
disease! note: In Japan, however, men are more fre-
quently affected.)
• especially older women (postmenopausal)
• 2.6% of all acute coronary syndromes
• most frequent cause of MINCA (myocardial infarction
with normal coronary arteries; syn.: MINOCA [myocar-
dial infarction with non-obstructive coronary arteries])

Diagnosis
• anamnesis (older women; typical angina pectoris;
stress event in the previous history)
• ECG
-- ST-elevations (not always attributable to a coronary
vessel)
-- T-negativations (isosceles; ubiquitous); often similar
to the Wellens type B sign (see page 347) in proxi-
mal LAD stenosis
-- frequently QT-interval ↑, possibly torsade de pointes
• laboratory
-- positive cardiac enzymes (i.a. troponin ↑), pro-BNP
↑ (pro-BNP is usually much higher in relation to tro-
ponin.)
-- biomarkers (constellation of microRNAs) for DD
STEMI / Tako-Tsubo cardiomyopathy (A signature of
circulating microRNAs differentiates takotsubo cardi-
omyopathy from acute myocardial infarction; Jagus-
zewski et al, Eur Heart J 2013; no clinical routine yet) Fig. 575  ECG in Tako-Tsubo cardiomyopathy (various ex-
• echocardiography amples): The typical deep isosceles T-negativations with
-- significantly reduced pump function (ejection frac- a preserved R-progression (just like Wellens type B sign)
above the anterior wall are visible. Furthermore, the QT in-
tion)
terval is prolonged.
-- apical ballooning with akinesia
• - cardiac catheterization
-- typically completely inconspicuous coronary arteries
-- in levocardiography apical ballooning with akinesia
and significantly reduced ejection fraction
-- Although one is relatively sure that a Tako-Tsubo
cardiomyopathy is present, one should always ge-
nerously perform a cardiac catheterization: The
most important differential diagnosis, which can also

Cardiology 395
 et al, Front Psychol 2017)
• long-term outcome as in patients with acute coronary
syndrome (Ghadri et al, J Am Coll Cardiol 2018)
• risk of recurrence: 10% (in 4 years)
• increased risk of cancer
-- cancer incidence twice as high as in the normal po-
pulation
-- cancer in every 6th patient with Tako-Tsubo cardio-
myopathy (J Am Heart Assoc 2019)

Fig. 576  Levocardiography (pigtail in the left ventricle): The

balloon-like bulge of the left ventricle can be seen.

Tako-Tsubo cardiomyopathy:
always exclusion diagnosis
(especially exclusion of proximal
LAD occlusion with anterior wall
MI)!

Therapy
• therapy option: β-blockers (protection against the
further cardiotoxic effect of catecholamines)
• cardiogenic shock: catecholamines contraindicated
(because they trigger the disease!); options:
-- pharmacological: phosphodiesterase-3 inhibitors,
levosimendan
-- non-pharmacological: IABP, Impella, va-ECMO,
VAD (ventricular assist device)

cardiogenic shock in Tako-Tsubo

cardiomyopathy: catecholamines
contraindicated!

Prognosis
• after 4-5 weeks typically complete restitutio ad inte-
grum again (almost always reversible)
• mortality: 3%
• risk factors for complications (Santoro et al, JAMA Car-
diology 2019; from these the GEIST score [see info-
box] was also developed for estimation of prognosis)
with poorer prognosis:
-- male gender
-- reduced ejection fraction
-- involvement of the right ventricle
-- neurological disorders
• poorer prognosis for physical (especially men) instead
of psychical (especially women) triggers (Konstatinos

396 Cardiology
 study

Clinical features and outcomes of Takotsubo (stress) car-

diomyopathy
Templin et al, N Engl J 2015

• retrospective cohort study (analysis of the international

Tako-Tsubo registry
• 1750 patients with Tako-Tsubo cardiomyopathy
• results:
-- w:m = 9:1
-- mean age: 68 years
-- trigger:
◦◦ psychical (28%; especially in women)
◦◦ physical (28%; especially in men)
-- in 58% presence of a neurological or psychiatric di-
sease
-- symptoms:
◦◦ angina pectoris (76%)
◦◦ dyspnea (47%)
◦◦ synkope (8%)
-- distribution:
◦◦ apical: 82%
◦◦ mid- ventricular 15%
◦◦ basal: 2%
◦◦ focal: 1%
-- median EF: 41%
-- increased troponin levels: in 87% (CK not significantly
increased)
-- cardiogenic shock: in 12.4%
-- mortality (hospital): 3.7%

Cardiology 397

CARDIOGENIC SHOCK
Definition
• SBP < 90 mmHg > 30min or catecholamine depen-
dence (the most important diagnostic parameter)
• cardiac index (CI) < 1,8 l/min/m2
• LVEDP (wedge pressure) > 20 mmHg (pulmonary ar-
tery catheter [PAC])
Epidemiology
• main cause of hospital mortality in myocardial infarc-
tion (i.e. after hospital admission [prior to hospital ad-
mission: ventricular fibrillation])
• loss of more than 40% of the functional myocardium
• median age: 68 years
• occurrence: in 6% with myocardial infarction
-- STEMI (especially anterior wall MI): 8.6% (NRMI re-
gister [Babaev et al, JAMA 2005])
-- NSTEMI: 4.9% (Goldberg et al, Am Heart J 2001)
• 75% of patients with cardiogenic shock due to myocar-
dial infarction develop it within the first 24 hours after
onset of symptoms (50% even within the first 8 hours).
• median duration
-- from symptom onset to cardiogenic shock: 6.2h
-- from hospital admission to cardiogenic shock: 5h
• incidence ↓, i.a. AMI-PLUS register 2008: cardiogenic
shock in acute coronary syndrome:
-- 1997: 12.9%
-- 2006: 5.5%
• for a long time considered the shock form with the
highest mortality (now it is septic shock with a mortality
of 50%; mortality of cardiogenic shock: 45%)
Predictors
• older patients
• women
• diabetics
• 3-vessel CHD
• CABG surgery in the medical history
398 Cardiology
Etiology
• acute myocardial infarction (No.1; 80%) → infarct-rela-
ted cardiogenic shock
-- 2/3 STEMI
-- 1/3 NSTEMI
• infarct complications
-- ventricular septal rupture (infarction VSD)
-- myocardial rupture
-- papillary muscle rupture with acute mitral valve re-
gurgitation
• acute pulmonary embolism
• acute aortic dissection
• inflammatory (myocarditis [especially giant cell myo-
carditis], endocarditis)
• acute thrombosis of a mechanical heart valve
-- most frequent cause: inadequate anticoagulation
(The risk is usually completely underestimated.)
-- diagnosis:
◦◦ echocardiography (TTE, TEE)
◦◦ assessment of whether the double leaflets (Doub-
le leaflet prostheses are the most frequently used
mechanical valves today.) open properly
-- therapy: lysis (ESC / EACTS guideline 2017: Altepla-
se 10mg as bolus, then 90mg over 90min), if neces-
sary emergency surgery
• pericardial tamponade (most frequent cause: malig-
nancy!)
• vitia (heart valve diseases): especially
-- acute mitral valve regurgitation
◦◦ Due to the short duration, the left atrium had no
time to dilate, so that the pressure in the left atrium
increases massively. Both backward failure with
pulmonary edema and forward failure with cardi-
ogenic imminate.
◦◦ causes:
▪▪ acute endocarditis
▪▪ papillary muscle rupture due to myocardial in-
farction
▪▪ chord rupture in mitral valve prolapse
▪▪ trauma
-- acute aortic valve regurgitation
◦◦ Due to the short duration, the left ventricle had
no time to dilate, so that the pressure in the left
ventricle (LVEDP) increases massively. The pres-
sure between the LVEDP and the diastolic blood
pressure are equalized. The LVEDP is significantly
higher than the wedge pressure (PCWP).
◦◦ mortality without surgery 75%, with surgery 25%
(therefore immediate surgery necessary)
◦◦ causes:
▪▪ aortic dissection (type Stanford A)
▪▪ acute endocarditis
▪▪ trauma
▪▪ post-interventional after TAVI
-- severe aortic valve stenosis, decompensated by
tachyarrhythmia ("If aortic stenosis becomes tachy-
cardic, one can only pray!"); note: A very good and
in terms of hemodynamics very effective option for
 a severe aortic stenosis with cardiogenic shock is Etiology
the balloon valvulopasty (fisrt part of a TAVI). The • unclear (autoimmunological component)
second part of the TAVI (implantation of the biopros-
• prolactin
thesis) is then only carried out in the further course,
since cardiogenic shock often leads to sepsis in -- increased levels in PPCM
which one does not want to implant foreign material -- cardiotoxic (damage to the endothelium and the mi-
into the body. crocirculation of the myocardium)
-- frequency management in vitia: -- possibly bromocriptine as prolactin inhibitor
◦◦ in valve stenoses always strive for bradycardia
◦◦ in valve regurgitations always strive for tachycar- Risk factors
dia (The lower the heart rate, the higher the regur- • preeclampsia
gitation volume.) • arterial hypertension
• arrhythmias • tocolytics
• β-Blocker intoxication • nicotine abuse
• peripartum cardiomyopathy • twin pregnancy
• postcardiotomy syndrome • teenage pregnancies and older mothers
• pheochromocytoma crisis (Due to the massively incre-
ased afterload, there is an increase in wall tension and Symptoms
consecutively often a massive decrease in the ejection • sudden onset
fraction and stroke volume.)
• cough (DD pneumonia)
• Tako-Tsubo cardiomyopathy (in 12% cardiogenic
• dyspnea (DD pulmonary embolism), orthopnea, tac-
shock)
hypnoea
• end-stage cardiomyopathy
• congested jugular veins (examination at 45° upper
body elevation)
Peripartum cardiomyopathy (PPCM) • leg edema

Complications
• acute left heart failure, pulmonary edema, cardiogenic
shock
• cardiac arrhythmias
• thrombus formation, embolisms (central [e.g. stroke] or
peripheral)

Definition
• occurrence during last trimester up to 6 weeks post-
partum in the mother
• image of dilated cardiomyopathy (DCM)
• incidence 1:2500 births
• most frequent cause of cardiac death in the mother in
pregnancy and postpartum (most frequent cause of
death at all: pulmonary embolism)
Guideline
ESC guideline 2016 (Current management of patients
with severe acute peripartum cardiomyopathy: practical
guidance from the Heart Failure Association of the Euro-
pean Society of Cardiology Study Group on peripartum
cardiomyopathy)
Diagnostics
• anamnesis, physical examination
• ECG
• laboratory (especially proBNP, prolactin)
• chest X-ray (especially postpartum, but is also allowed
in pregnancy [especially in late pregnancy])
• Echokardiographie: image of dilated cardiomyopathy
(DCM): i.a.
-- EF (ejection fraction; p.d. < 45%) ↓
-- LVEDD (left ventricular end-diastolic diameter) ↑
(note: In pregnancy, physiologically, there is only a
[slight] increase in the size of the right heart.
-- The left heart must not enlarge, i.e. there is no phy-
siological pregnancy-related increase in LVEDD!)
Therapy
• initiate delivery (from 34th WOP)
• heart failure therapy (During pregnancy ACE inhibi-
tors or ARBs are contraindicated due to teratogenic
effects.)
• acute left heart failure:
-- loop diuretics i.v., possibly nitro-perfusor (if SBP >
110 mmHg)
-- respiratory insufficiency → ventilation (especially
NIV)

Cardiology 399
 -- therapy-refractory cardiogenic shock → mechanical Guidelines
circulatory support (e.g. Impella, va-ECMO)
• no breastfeeding (prolaktin ↑) • international: ESC guidelines for the diagnosis and
treatment of acute and chronic heart failure 2016
• prolactin inhibitor:
• national: S3 for infarct-related cardiogenic shock 2019
-- bromocriptine (2 x 2.5mg daily for 2 weeks, then
- Diagnosis, Monitoring and Therapy
2.5mg daily for 6 weeks); note:
◦◦ However, short-term therapy with bromocriptine
2.5 mg daily for just one week proved to be equi- Diagnostics
valent to long-term therapy (Hilfiker-Kleiner et al,
Eur Heart J 2017). • EcG
◦◦ in extremely severe cases initially even 2 x 5mg to • chest X-ray (signs of congestion)
2 x 10mg possible (Here prolactin should be deter- • laboratory (e.g. cardiac enzymes, pro-BNP, lactate [the
mined every day: It should be suppressed.) most important laboratory shock parameter!])
-- quinagolide • echocardiography
• status post resuscitation in ventricular arrhythmia/ ven- -- TTE
tricular fibrillation → ICD implantation (shocks → no -- TEE
infantile damage [Natale et al, Cirulation 1997]); alter-
native: defibrillator vest (e.g. LifeVest) during pregnan-
cy and ICD implantation only postpartum

Prognosis
• mortality: 15%
• only in 30% restitutio ad integrum
• no re-pregnancy any more (contraindicated; especially
if the ejection fraction is still reduced)

Symptoms
• arterial hypotension or requiring catecholamines (low-
output [LCOS: low cardiac output syndrome]), 1/4
of cases without hypotension (so-called normotensive
= "cryptogenic" shock)
• tachycardia (heart rate > 100/min)
• agitation, confusion, disturbance of consciousness
• skin:
-- pale, cool, clammy (always touch hands and feet:
are cold and wet!)
-- mottled
-- prolonged recapillarization time (> 2s)
• dyspnea, orthopnea
• cyanosis
• congested jugular veins Monitoring
• oliguria (< 0.5 ml/kg/h)
• 3rd heart tone, possibly gallop rhythm • basic monitoring
• basal crackles on both sides, possibly expiratory spas- -- SpO2
ticity (asthma cardiale) -- ECG
-- invasive blood pressure measurement
-- Diurese
Differential diagnoses (frequent) • advanced (hemodynamic) monitoring
• hypovolemia -- echocardiography
• overdose of nitrates (It is not uncommon for a patient ◦◦ TTE
with a known CHD and, for example, a myocardial ◦◦ TEE
infarction that has already taken place, to apply too -- cardiac power output (CPO)
many nitro puffs to himself when he again gets angina -- cardiac output measurement
pectoris symptoms.) ◦◦ pulmonary artery catheter (PAC)
• vasovagal reaction (A myocardial infarction is very ◦◦ PiCCO:
painful!)
▪▪ pulse contour analysis not possible with IABP
and problematic with very low-output [CI < 1,3

400 Cardiology
 l/min/m2])
▪▪ The PAPIKAS study (see box) in patients with
cardiogenic shock (incl. hypothermia / IABP)
showed a good correlation between the hemo-
dynamic parameters measured with PiCCO and
those measured with the pulmonary catheter
(e.g. cardiac index, systemic-vascular resis-
tance) .
cardiogenic shock (especially if
persistent) → advanced hemodynamic
monitoring (e.g. PAC / PiCCO!)
obligatory!
PAPIKAS study
A comparative clinical trial of pulmonary catheter versus
PiCCO device during therapy of patients with acute heart
failure and cardiogenic shock
Schwab et al, Crit Care 2011
• 11 patients (77 measurements) with cardiogenic shock
• comparison PAC / PiCCO
• good correlation of hemodynamic parameters (CI, SV,
SVR; also under hypothermia / IABP)
• cardiac index
-- wedge pressure (PAC): no correlation
-- GEDI (PiCCO): gute good correlation
Echocardiography
• to clarify the cause
• beim infarktbedingten kardiogenen Schock deutliche
Verminderung der EF (SHOCK-Trial: mostly, however,
only to a moderate to higher degree and not to a ma-
ximum degree [average EF 30%], as in the case of
infarction, akinesia of the infarction area occurs, but
frequently compensatory hyperkinesia of the opposite
wall segments takes place)
• infarct complications
• TTE, maybe TEE
Cardiac power output (CPO)
• CPO = MAP x CI x 0.0022
-- MAP: mean arterial pressure
-- CI: cardiac index (CI = CO / BSA)
• energy available to maintain perfusion of vital organs
• unit: Watt
• CPI (cardiac power index) = CPO / BSA
• norm:
-- CPO > 0,6 W
-- CPI > 0.5-0.7 W/m2
• parameter:
-- for the hemodynamic monitoring in cardiogenic
shock
-- for prognosis (prognosis parameter)
◦◦ the only validated hemodynamic prognostic para-
meter in cardiogenic shock
◦◦ The lower the CPO, the higher the mortality in car-
diogenic shock (Fincke et al, Eur Heart J 2004;
Torgersen et al, Crit Care 2009).
◦◦ CPO 0.53 Watt → mortality 66%
Therapy
• recanalization
• pharmacological therapy
• assist devices (mechanical circulatory support)
• supportive therapy
Recanalization
• types:
-- pharmacological: lysis ( in 50% unsuccessful in
cardiogenic shock)
-- interventional: acute PCI
◦◦ better than fibrinolysis (also) in cardiogenic shock
(SHOCK trial)
◦◦ if possible within 2h
◦◦ also up to 36h (12h limit no longer applies! regard-
less of the time of the infarction)
◦◦ 80% of all patients with an infarct-related cardio-
genic shock have a multivessel CHD. In contrast
to myocardial infarction without cardiogenic shock,
in myocardial infarction with cardiogenic shock not
only the intervention of the infarct artery ("culprit
leasion", "guilty" artery) was recommended accor-
ding to the ESC guidelines, but also the interven-
tion of all simultaneously present higher-grade (>
90%) stenoses (multivessel PCI, preventive PCI)
empfohlen. However, the recommendation was
largely based on register data only. The CULPRIT-
SHOCK study 2017 (see box) even showed an
increased mortality due to the multivessel PCI in
infarct-related cardiogenic shock, so that the gui-
deline recommendation has changed accordingly.
◦◦ approach: preferably radial rather than femoral
(Valgimigli et al, Lancet 2015: significantly redu-
ced combined endpoint from mortality, myocardial
infarction or stroke)
◦◦ GpIIb/IIIa-receptor antagonists
▪▪ possibly abciximab advantageous in cardioge-
nic shock (Heer et al, Heart 2006)
Cardiology 401
 ▪▪ only in the cardiac catheterization lab after
sheath installation
▪▪ but also only recommended (as in the case of
myocardial infarction without cardiogenic shock)
as bail-out therapy for angiographic detection of
a high thrombus load, "slow flow" / "no flow" phe-
nomenon or thrombotic complications (therefore
rarely indicated)
-- possibly surgically: operative myocardial revascula-
rization (CABG)
• Early revascularization is the only validated (SMASH
study [Urban et al, Eur Heart J 1999], SHOCK study
[siehe box], FITT-STEMI study [siehe box]) for infarct-
related cardiogenic shock!

SHOCK study

Early Revascularization in Acute Myocardial Infarction Fig. 577  filiform left main stem stenosis: PCI and primary
Complicated by Cardiogenic Shock stent implantation (DES) were performed. Subsequently, a
Hochman et al, N Engl J 2001 regular TIMI grade 3 flow was observed.

• SHOCK: should we emergently revascularize occluded

coronaries for cardiogenic shock
• multicenter (63 centers) randomized controlled study
• 302 patients with infarct-related cardiogenic shock
-- 152 patients: early (within 6h) revascularization (55%
PCI, 38% CABG)
-- 150 patients: initial pahramcological stabilization, in-
cluding lysis (63%), IABP (86%); late revasculariza-
tion in 25%
• results: early revascularization
-- primary endpoint: mortality after 1 month → no signi-
ficant difference
-- secondary endpoints:
◦◦ mortality at 6 months → significant difference
(50.3% versus 63.1%)
◦◦ Mortalität nach 12 Monaten → signifikanter Unter- CULPRIT-SHOCK study
schied 53.3% versus 76.7%)
-- From early revascularization only patients < 75 years
had significant benefit (> 75 years: no difference PCI/
CABG versus lysis + conservative therapy).
PCI Strategies in Patients with Acute Myocardial Infarction
and Cardiogenic Shock
Thiele et al, N Engl J 2017

• European multicenter randomized controlled study

FITT-STEMI study
Impact of treatment delay on mortality in ST-segment el-
evation myocardial infarction (STEMI) patients presenting
with and without haemodynamic instability
Scholz et al, Eur Heart J 2018
• retrospective analysis
• 12675 patients with STEMI and acute PCI
• The shorter the contact-to-balloon time, the lower the
mortality (especially in cardiogenic shock: reduction in
mortality by 50% if contact-to-balloon time < 90min)
• mortality (cardiogenic shock): 42%
• 706 patients with infarct-related cardiogenic shock (the
largest study to date on cardiogenic shock) with multi-
vessel CHD and PCI of the infarct artery („cuprit lesion“)
-- without PCI of the stenosed non-infarct arteries, i.e.
single-vessel PCI
-- with PCI of the stenosed non-infarct arteries, i.e. mul-
tivessel PCI (preventive PCI)
• results: multivessel PCI
-- primary endpoint (death or RRT-dependent kidney fai-
lure within 30d: significantly more frequent (espe-
cially increased overall mortality [absolutely by 8%]);
note: even after 1 year (Thiele et al, N Engl J 2018)
-- secondary endpoints (i.a. hemodynamic stabilisation,
dosing of catecholamines, cardiac biomarkers [CK,
troponin], stroke, bleeding): no difference

402 Cardiology
Pharmacological therapy
• inotropics
-- dobutamine
-- adrenaline (epinephrine; not recommended!)
-- levosimendan
-- PDE inhibitors
• vasopressors (vasoconstrictors)
-- noradrenaline (norepinephrine)
-- vasopressin
-- dopamine (obsolete; i.a. SOAP-II study 2010: in the
subgroup cardiogenic shock even excess mortality
by dopamine!)
• vasodilators
-- sodium nitriprusside (NPS)
-- nitrats (in addition to loop diuretics recommended
[ESC IC recommendation] in acute heart failure if
SBP > 90mmHg [rarely therefore in cardiogenic
shock]; one should, however, be less oriented to
blood pressure than to cardiac output and systemic-
vascular resistance [SVR]: If the SVR is too high in
cardiogenic shock, the afterload must be reduced
despite systolic blood pressure < 90mmHg [e.g. with
a nitro-perfusor] to increase cardiac output again!)
• new substances
first dobutamine (maximum 50 mg/h
or up to heart rate of 120/min
not sufficient → additional noradre-
nalin
not sufficient → additional levosi-
mendan
mostly combination of dobutamine and
noradrenaline (standard)
Dobutamine (Dobutrex)
• means of choice in cardiogenic shock
• ESC guidelines: grade IIA recommendation
• agonist to β1/2-receptors
• positive inotropic, non vasoconstrictive (even little va-
sodilatory effect)
• dosage
-- perfusor: 5 mg/ml, infusion rate 1-10 ml/h (upper li-
mit only optional, from > 10 ml/h but often no further
therapeutic benefit due to tachycardia)
-- from heart rate > 120/min no dose increase any
more, then additionally
◦◦ noradrenaline
◦◦ ivabradine (Procoralan; a If-channel inhibitor [f:
funny]; only with sinus rhythm; off-label)
• If the patient has previously been treated with
β-blockers (e.g. as home medication with known
CHD), higher doses are necessary
• occasionally tachyphylaxis (reduction of effect by down
regulation of the receptors) after 48 hours
meta-analysis
Dobutamine for patients with severe heart failure: a sys-
tematic review and meta-analysis of randomized controlled
trials
Tacon et al, Intensive Care Med 2011
• meta-analysis (14 randomized controlled trials)
• 673 patients with acute heart failure
-- dobutamine
-- placebo (standard treatment)
• result: dobutamine → no significant reduction in mor-
tality (even tendently increased mortality, but not statis-
tically significant)
Adrenaline
• In some places adrenaline is given instead of dobuta-
mine in cardiogenic shock. This is to be rejected, since
adrenalin increases beside the inotropic effect (ago-
nist at the β-receptors) also the afterload by periphe-
ral vasoconstriction (agonist at the α-receptors) which
is counterproductive in cardiogenic shock, where the
SVR mostly is increased. Dobutamine does not have
this disadvantage. The addition of a vasodilator (e.g.
nitroglycerin) is also not recommended.
• Pathophysiologically, adrenaline (instead of the com-
bination of dobutamine and noradrenaline) would only
be useful in patients with cardiogenic shock who have
reduced SVR (approx. 20% of patients; e.g. additional
SIRS). However, compared to the combination of do-
butamine and noradrenaline, this leads to significantly
Cardiology 403
 more side effects such as increased cardiac arrhythmi-
as, lactate increase and reduced splanchnic perfusion
(Levy et al, Crit Care Med 2011; see box).
• In a meta-analysis (Leopold et al, Int Care Med 2018
[see box]), adrenaline even showed an increased mor-
tality compared to other inotropic agents / noradrenali-
ne (mortality 2.5 times higher)!
• Usually no dobutamine is available preclinically (as an
emergency physician) at the emergency ambulance.
From a pathophysiological point of view it would make
sense here to give adrenaline rather than noradrena-
line!
• In the OptimaCC study (see box; so far the only ran-
domly controlled study), adrenaline was even inferior
to noradrenaline!
study
Comparison of norepinephrine-dobutamine to epinephrine
for hemodynamics, lactate metabolism, and organ function
variables in cardiogenic shock. A prospective, randomized
pilot study
Levy et al, Crit Care Med 2011
• open randomized controlled pilot study
• 30 patients with cardiogenic shock
-- dobutamine + noradrenaline
-- adrenaline
• results: adrenaline
-- same efficiency in increasing blood pressure and car-
diac output
-- significantly more cardiac arrhythmias
-- augmented lactate increase
-- reduced splanchnic perfusion
CardShock study
Current real-life use of vasopressors and inotropes in car-
diogenic shock - adrenaline use is associated with excess
organ injury and mortality
Tarvasmäki et al, Crit Care 2016
• prospective observational study
• 219 patients with cardiogenic shock
• comparison of different inotropics (dobutamine, levosi-
mendan, adrenaline) and vasopressors (noradrenaline,
adrenaline)
• results:
-- mortality (after 90 days): 41%
-- increased mortality with adrenaline (multivariate
analysis)
-- increased increase in cardiac and renal biomarkers
with adrenaline
404 Cardiology
meta-analysis
Epinephrine and short-term survival in cardiogenic shock
Leopold et al, Int Care Med 2018
• 2583 patients with cardiogenic shock
-- adrenaline
-- other inotropics (dobutamine, levosimendan) or vaso-
pressors (noradrenaline)
• result: adrenaline → increased mortality (after 4
weeks; 3-fold)
OptimaCC study
Epinephrine Versus Norepinephrine for Cardiogenic Shock
After Acute Myocardial Infarction
Levy et al, J Am Coll Cardiol 2018
• multicenter prospective randomized controlled study
• 57 patients with infarct-related cardiogenic shock
-- noradrenaline
-- adrenaline
• results: adrenaline
-- same efficiency in increasing blood pressure and car-
diac output
-- more frequent therapy-refractory cardiogenic
shock (hence premature termination of studiy)
-- higher heart rate, increased pressure-frequency pro-
duct (i.e. increased oxygen consumption)
-- augmented lactate increase
no adrenalin in cardiogenic shock
(increased mortality!), not even in
combination with nitroglycerin (not
recommended!)
Levosimendan (Simdax)
Definition
• "calcium sensitizer": stabilization of the calcium-indu-
ced conformational change of troponin C → extension
of the duration of actin-myosin transverse bridges →
positive inotropic
• vasodilatory (via ATP-dependent potassium channels;
"inodilator"; afterload ↓), antiischemic
• also positive lusitropic effect
-- promotion of relaxation (by reducing calcium over-
load)
-- like PDE-3 inhibitors
-- therefore also a good option for severe diastolic dys-
 function
• decrease of pulmonary arterial pressure (PAP) and
pulmonary vascular resistance (PVR), therefore also a
good option for acute right heart failure
• low to no arrhythmia tendency
• no increase in myocardial oxygen consumption
• no tachyphylaxis
• good alternative to dobutamine
• ESC prefers use of levosimendan over dobutamine in
acute worsening of heart failure.
• Levosimendan was not approved in Germany for a
long time (but e.g. in Austria) and was therefore often
produced by the pharmacy of the hospital itself or or-
dered from the international pharmacy. Since 2014, it
has also been officially approved in Germany under
the trade name Simdax for the treatment of acute de-
compensated heart failure (Orion Pharma GmbH)
• therapy refractory cardiogenic shock: levosimendan si-
gnificantly better than PDE inhibitors (Fuhrmann et al,
Crit Care Med 2008)
• price for 1 ampoule, which is usually sufficient: 745€
Dosage
• 1 amp. = 5ml = 12.5mg (1ml = 2.5mg) in 250ml G5%
(via infusomat) over 24h
• 12-24 μg/kg over 10min as loading-dose (in decom-
pensated heart failure; no bolus in cardiogenic shock),
then 0.05-0.2 μg/kg/min (according to MAP; standard:
0.1 μg/kg/min)
• renal insufficiency: Up to a GFR of 30 ml/min no dose
reduction is necessary, from a GFR < 30 ml/min levosi-
mendan is officially contraindicated, whereby it is also
often given with a GFR < 30 ml/min, since one stands
anyway with one's back to the wall.
• max. for 24h or up to a total dose of 12.5 mg (conside-
rable accumulation; active metabolite OR-1896 [T½ =
80h]) → long-lasting effect)
Fig. 578  Levosimendan (Simdax): 1 amp. = 5ml = 12.5mg
(storage in the refrigerator)
Indications
• infarct-related cardiogenic shock and lack of improve-
ment under dobutamine (therapy refractory; ESC gui-
delines: grade IIB recommendation) or in patients who
had β-blockers in the previous medication
• β blocker intoxication (to increase inotropy; other me-
chanism of action; β-receptors blocked here)
• cardiogenic shock in Tako-Tsubo cardiomyopathy (Ca-
techolamines are contraindicated here!)
• also an option for acute right heart failure, as levosi-
mendan lowers the PA pressure and pulmonary vascu-
lar resistance (also recommended in the ESC guideli-
ne on acute right heart failure 2016)
Studies
• RUSSLAN study (Moiseyev et al, Eur Heart J 2002):
lower mortality with levosimdan versus placebo
• CASINO study (Zairis et al, J Am Coll Cardiol 2004):
levosimendan significantly better than dobutamine
• LIDO study (Follath et al, Lancet 2002): In patients with
severe heart failure, levosimendan showed an advan-
tage over dobutamine in terms of cardiac output incre-
ase and survival rate..
• SURVIVE study (Mebazaa et al, JAMA 2007): In this
large study (1327 patients), the benefit for levosimen-
dan could not be confirmed (although lower pro-BNP
levels, but overall no reduction in all-cause mortality).
• Especially for the indication of perioperative circulatory
support in the context of a cardiac thoracic surgery (es-
pecially CABG) with reduced ejection fraction the stu-
dies LICORN (Cholley et al, JAMA 2017), CHEETAH
(Landoni et al, N Engl J 2017) und LEVO-CTS (Mehta
et al, N Engl J 2017) showed no benefit.
meta-analysis
Levosimendan for the treatment of acute severe heart fail-
ure: A meta-analysis of randomized controlled trials
Delaney et al, International Journal of Cardiology 2010
• meta-analysis (19 studies)
• 3650 patients with acute severe heart failure
-- dobutamine
-- levosimendan
• results: levosimendan
-- significant improvement in hemodynamics
-- significant reduction in mortality
Cardiology 405
 -- 1 mg/kg/min for 10min
-- then 1.25-7.5 μg/kg/min according to MAP

meta-analysis Side effects

• ventricular arrhythmias
• decrease of blood pressure (due to vasodilation)
• nausea, vomiting
Levosimendan Treatment for Heart Failure: A Systematic • pericarditis
Review and Meta-Analysis
Gong et al, J Cardiothorac Vasc Anesth 2015 • increased formation of intrapulmonary shunts → wor-
sening of oxygenation
• meta-analysis (25 studies) • liver dysfunction (transaminases ↑)
• 5349 patients with acute severe heart failure • thrombocytopenia
-- dobutamine
-- levosimendan Assessment
-- placebo • patients with
• results: levosimendan → significant reduction in -- dilated cardiomyopathy → benefit well
mortality -- ischemic cardiomyopathy → benefit poorly
• OPTIME-CHF study (Cuffe et al, JAMA 2002): in-
PDE inhibitors creased mortality with milrinone excess (significantly
worse than placebo [especially due to malignant car-
Definition diac arrhythmia])
• inhibitors of the phosphodiesterase (PDE) 3 → inhibiti- • increased mortality in infarct-related cardiogenic shock
on of degradation of cAMP (Felker et al, JACC 2013)
• positive inotropic, vasodilatory („inodilator“) • only in combination with dobutamine (not as monothe-
rapy; good e.g. in patients pre-treated with β-blockers)
• long T½ (2h), therefore less controllable than catechol-
amines (T½ only 2-3min)
dobutamine PDE-3 inhi- levosimen-
• indication: catecholamine tolerance (other mechanism
bitors dan
of action → effect also with down regulation of the re-
ceptors under catecholamine therapy or in patients cAMP ↑ ↑ -
pre-treated with β-blockers) myocardial
• also positive lusitropic effect (like levosimendan; pro- O2 consump-
motion of relaxation), therefore also a good option for tion ↑ yes no no
severe diastolic dysfunction antago-
nism with
β-blocker yes no nein
tachyphylaxis yes no no

Vasopressin (Pitressin)
• a (pure) vasoconstrictor
• 1 amp. = 20 IE
• advantage: effect even in an acidic environment (cate-
cholamines are nearly no longer active from pH < 7.0.)
• possible alternative to noradrenalin in decreased SVR
(e.g. with pronounced acidosis)
• pulmonary vascular resistance (PVR) ↓, pulmonary
arterial pressure (PAP) ↓ (therefore a good option for
acute right heart failure)
• studies:
Representatives -- Jolly et al, Am J Cardiol 2005: In this small study (36
• amrinone (Wincoram) patients with cardiogenic shock), vasopressin show-
ed a significantly greater increase in blood pressure
-- 30 μg/kg/min for 2h
than norepinephrine. Only vasopressin (and not nor-
-- then 5-10 μg/kg/min according to MAP adrenaline) increased the CPO (prognostic parame-
-- from the market (reason: severe thrombocytopenia) ter!).
• milrinone (Corotrop) -- Russell et al, N Engl J 2008: vasopressin versus nor-
-- 30 μg/kg/min for 10min adrenaline → no difference
-- then 0.375-0.75 μg/kg/min according to MAP -- VANCS study (Hajjar et al, Anaesthesiology 2017
• enoximone (Perfan) [a prospective randomized controlled monocentric
study]): In the postoperative vasoplegic syndrome

406 Cardiology
 in cardiac thoracic surgery vasopressin was better
than noradrenaline (significant reduction in primary
combined endpoint mortality or severe complica-
tions [stroke, invasive ventilation > 48h, deep wound
infection of the sternum, re-operation, acute kidney
failure] after 30 days).
-- In a retrospective analysis (Hootman et al, Circulati-
on 2018), vasopressin (alone or in addition to other
vasopressors / inotropics) showed an increased
mortality in cardiogenic shock!
Sodium nitroprusside (SNP; Nipruss)
• a vasodilator (effect especially arterial)
• NO-releasing substance
• very short duration of action
• dosage
-- perfusor: 1 amp. (= 60mg) + 3ml NaCl 0.9% + 47ml
G5%
-- infusion rate: 1-21 ml/h; start with 1 ml/h, then titrate
dose up to the desired effect; 0.15-0.60 μg/kg/min =
0.6-2.4 mg/h
• always apply only diluted with glucose 5% (never pu-
rely)
• light protection (e.g. aluminum foil)
• indication: cardiogenic shock and SVR > 1000 dyn
x cm x sec5 despite reduction of noradrenaline (note:
Another indication for sodium nitroprusside is the the-
rapy refractory hypertensive crisis.)
• Sodium nitroprusside (like NO) increases the intracra-
nial pressure (ICP) and is therefore contraindicated in
patients with increased intracranial pressure.
• cyanide poisoning
-- SNP releases not only NO, but also cyanide (danger
of cyanide poisoning), which is converted by rhoda-
nide synthetase to 100x less toxic rhodanide (thio-
cyanate).
-- From a dosage of 0.15 mg/min the additional admi-
nistration of sodium thiosulphate 10% 50-100 mg/kg
(at 0.5 ml/h from d4, at 1 ml/h from d2, at 2 ml/h
immediately!) is recommended. According to recent
findings, the additional administration of sodium thio-
sulphate can be abandoned, however, the recom-
mendation continues to be included in the official
drug information 2017 (especially with impaired kid-
ney function or administration longer than24h [Here,
the thiocyanate level should also be determined and
should be < 0.1 mg/ml]).
-- sodium thiosulphate 10% (There is an ampoule with
10ml and bottles with 100ml and 500ml. The perfu-
sor is pulled up purely and should be connected via
a separate venous access. The ratio [with regard to
the weight] of NPN to sodium thiosulfate should be
1:10):
◦◦ SNP perfusor 1-10 ml/h → sodium thiosulphate
perfusor 1 ml/h
◦◦ SNP perfusor 11-20 ml/h → sodium thiosulphate
perfusor 2 ml/h
◦◦ SNP perfusor 21-30 ml/h → sodium thiosulphate
perfusor 3 ml/h
◦◦ SNP perfusor 31-40 ml/h → sodium thiosulphate
perfusor 4 ml/h
• maximum dose: 1.5 mg/kg
• The preparation of Nipruss was recalled 2013 by the
company UCB Pharma GmbH and further selling was
stopped. Since 15.04.2017 it has been distributed by
Mitsubishi Tanabe Pharma and is available again.
• in 10% necessary for cardiogenic shock
• alternatives:
-- ACE inhibitor (cautiously)
-- nitrate (nitro perfusor)
Fig. 579  Sodium Nitroprusside (SNP; Nipruss): 1 dry pow-
der vial of 60 mg
Methylene blue
• effect: inhibition of monoaminooxidase (MAO: enzyme
which breaks down catecholamines)
• tetramethylthionone chloride
• indication:
-- classically postoperative vasoplegic syndrome (ca-
techolamine refractory hypotension) in cardiac sur-
gery: massively reduced systemic vascular resis-
tance (SVR) despite high doses of norepinephrine
-- as a therapy attempt (no general recommendation)
-- alternative: vasopressin or vasopressin analogues
(e.g. terlipressin)
-- We administer methylene blue in cases where sys-
temic vascular resistance (SVR) remains very low
despite norepinephrine perfusor at a very high dose.
• dosage: 1.5-2 mg/kg for 20-30min
• side effects:
-- blue discoloration of urine, tear secretion, saliva,
skin → repeated administration hardly reasonable
-- hemolysis (especially in glucose-6-phosphate dehy-
drogenase deficiency)
-- increase in pulmonary arterial pressure (PAP ↑) and
pulmonary vascular resistance (PVR ↑)
-- After administration of methylene blue a false low
saturation is measured in pulse oximetry.
New substances
Cardiology 407
 symptoms or mortality)
-- ROSE-AHF study (Chen et al, JAMA 2013; see box):
nesiritide in acute heart failure and renal insufficien-
New substances cy: no improvement in renal function
overview

ASCEND-HF study

Acute Study of Clinical Effectiveness of Nesiritide in De-

compensated Heart Failure
O´Connor et al, N Engl J 2011

• multicenter randomized controlled study

• 7414 patients with acute decompensated heart failure
and standard therapy
-- Nesiritide
-- placebo
• results (nesiritide):
-- primary endpoints:
◦◦ dyspnea: no difference
◦◦ rehospitalization due to heart failure or death of any
cause: no difference
-- secondary endpoints: i.a.
◦◦ mortality: no difference
L-NAME (Tilarginin) ◦◦ renal function: no difference
• pathophysiology: infarction → systemic inflammation
→ expression of NO synthase­↑ → NO ↑­ → vasodi-
latation
• L-NAME (L-N-mono-methyl-arginine), syn.: tilarginine ROSE-AHF study
(a NO-synthase inhibitor)
• studies:
-- LINCS study (Cotter er al, Eur Heart J 2003; a small
pilot study): L-NAME significantly reduced 30-day Low-Dose Dopamine or Low-Dose Nesiritide in Acute
mortality in 30 patients who remained in cardiogenic Heart Failure With Renal Dysfunction: The ROSE Acute
shock despite revascularization, IABP and catechol- Heart Failure Randomized Trial
amine therapy (dobutamine and norepinephrine). Chen et al, JAMA 2013
-- TRIUMPH study (Kielstein et al, JAMA 2007):
• multicenter randomized controlled study
◦◦ tilarginine 1 mg/kg as bolus, then 1 mg/kg kg/h for • 360 patients with acute heart failure and impaired renal
a total of 5h in patients with infarct-related cardio- function (GFR 15-60 ml/min); 2 arms:
genic shock -- nesiritide versus placebo
◦◦ premature discontinuation (after 398 patients) -- dopamine versus placebo
because no reduction of mortality could be seen • results: Neither Nesiritide nor dopamine showed a
reduction in primary endpoints (cumulative urine volume
Nesiritide after 72h; cystatin C.
• a recombinant human BNP
• effects: Ularitide
-- vasodilatory (afterload ↓)
• a recombinant natriuretic peptide
-- diuretic
• modification of urodilatin (a natriuretic hormone secre-
• dosage: bolus 2 μg/kg, then 0.01 μg/kg/min ted in the distal tubule of the kidney)
• approval for treatment of acute heart failure in the USA • dosage: 15 ng/kg/min over 48h
(not in Europe)
• studies:
-- VMAC study (JAMA 2002): small pilot study (impro-
vement of dyspnoea and reduction of wedge pres-
sure)
-- ASCEND-HF study (O´Connor et al, N Engl J 2011;
see box): ineffective (no significant difference in

408 Cardiology
 TRUE-AHF study RELAX-AHF study

Effect of Ularitide on Cardiovascular Mortality in Acute Serelaxin, recombinant human relaxin-2, for treatment of
Heart Failure acute heart failure (RELAX-AHF): a randomized, placebo-
Packer et al, New Engl J 2017 controlled trial.
Teerlink et al, Lancet 2013
• prospective randomized study
• 2157 patients with acute decompensated heart failure • phase III study
and standard therapy • RELAX-AHF: Relaxin in acute Heart Failure
-- ularitide 15 ng/kg/min over 48h • 1161 patients with acute heart failure with standard the-
-- placebo rapy
• result (ularitide): no reduction in cardiovascular mor- -- serelaxin 30 μg/kg per day over 48h
tality -- placebo
• results:
-- significantly diminished dyspnea (primary endpoint
Serelaxin -- significantly lower cardiovascular mortality after 180d
• a recombinant human Relaxin-2 (But this was only the safety parameter, not the prima-
ry endpoint of the study.)
• Relaxin-2:
• annotations:
-- a vasoactive peptide
-- Unfortunately, only patients with systolic blood pres-
-- i.a. a pregnancy hormone sure > 125mmHg were included in the study. The
-- It is produced in the placenta, endometrium, corpus question is whether for these patients such an expen-
luteum, mammary gland and in the prostate. sive drug is really meaningful and necessary. Actually,
we would need a new drug therapy option for patients
• dosage: 30 μg/kg per day over 48h
with circulatory instability (especially for cardiogenic
• especially in acute diastolic heart failure shock).
• studies: -- no sufficient sample size regarding mortality; there-
-- RELAX-AHF study (see box): turned out positive fore RELAX-AHF-2 study with planned 6500 patients
-- RELAX-AHF-2 study (see box): turned out negative with primary endpoint reduction in cardiovascular
mortality and worsening in initially stabilized patients
• not yet and will not be approved (consultant exclusion with acute heart failure; unfortunately, patients with an
EMA 2014 negative vote) SBP < 125mmHg are also excluded here

RELAX-AHF-2 study

Effects of Serelaxin in Patients with Acute Heart Failure

Metra et al, N Engl J 2019

• multicenter, double-blind, placebo-controlled, rando-

mized study
• 6545 patients with acute heart failure with standard the-
rapy (esp. furosemide i.v.)
-- serelaxin 30 μg/kg per day over 48h
-- placebo
• results (press release from Novartis already in March
2017):
-- co-primary endpoints (cardiovascular death on day
180, worsening heart failure on day 5 [e.g. requiring
ventilation, renal replacement therapy]): no difference
-- secondary endpoints (i.a. all-cause mortality, hospita-
lization due to heart failure, length of hospital stay):
no difference

Cardiology 409
CABG (coronary artery bypass graft)
• high perioperative mortality
• nevertheless surgical myocardial revascularization re-
commended even in cardiogenic shock (since survival
advantage [SHOCK trial: White et al, Circulation 2005])
• Usually no CABG surgery is performed during shock.
• Usually cardiothoracic surgery in the context of a car-
diogenic shock is only performed in the presence of
mechanical infarct complications such as ventricular
septal rupture (infarct VSD) or acute mitral valve re-
gurgitation due to papillary muscle rupture.
Assist devices (mechanical circulatory
support)
• IABP
• minimally invasive heart pumps
-- turbine pumps (percutaneous, axial)
◦◦ Impella
◦◦ HeartMate PHP
◦◦ iVAC2L (PulseCath)
◦◦ Cardiobridge
-- Rotaflox
-- Tandem Heart
• extracorporeal support systems (va-ECMO, extracor-
poreal life support [ECLS], mechanical circulatory sup-
port [MCS]; see espacially page 645)
-- examples: Lifebridge, Cardiohelp, i-cor
-- (still) no prospective randomized study (similar situ-
ation as for a long time with IABP); currently ongoing
studies on va-ECMO in cardiogenic shock: EURO-
SHOCK, ECLS-SHOCK
• ventricular assist devices (VAD; "artificial heart")
Intraaortic balloon pump (IABP)
Definition
• proceed: intraaortic balloon counterpulsation
• first used by the Kantrowitz brothers in 1968 in patients
in cardiogenic shock (JAMA 1968)
• balloon catheter, which is inserted over the femoral ar-
tery into the descending aorta
• balloon:
-- made of polyurethane
-- different volumes (up to 30-50ml; depending on pa-
tient size)
• position: descending aorta
410 Cardiology
-- proximal end: 2cm distal to the branching of the left
subclavian artery
-- distal end: proximal to the renal arteries
• principle:
-- inflation of the balloon during diastole with about
40ml of helium gas → increase in diastolic blood
pressure (diastolic augmentation) → pressure in
the coronary arteries ­↑ → coronary perfusion (takes
place in diastole) ↑
-- in the systole collapse of the balloon (deflation) and
suction effect → afterload ↓ (main effect! The po-
tential improvement of coronary perfusion is only a
side effect and is only relevant if a complete reva-
scularization was not successful in the previously
performed cardiac catheterization. Otherwise, IABP
has no added benefit in terms of improving coronary
perfusion [Kern et al, Am Heart J 1999].)
• IABP increases not only the coronary, but also the
cerebral perfusion, since the diastolic inflation of the
balloon also increases the pressure in the extracrani-
al arteries (brachiocephalic trunk, left common carotid
artery).
• placement of IABP via the femoral artery after (ipsila-
teral; mostly) or during (contralateral) acute PCI under
fluoroscopy
• trigger:
-- ECG (most frequent trigger; R-wave; also possible
in atrial fibrillation)
-- blood pressure
-- pacemaker
• increase in MAP and cardiac output without increase in
myocardial oxygen consumption
• The increase in cardiac output caused by IABP is usu-
ally only small (0.4-0.6 l/min).
• mostly well tolerated
• also safe and effective in fibrinolysis
• with systolic BP < 60-70 mmHg mostly no longer ef-
fective
• full heparinization necessary (systemic heparin perfu-
sor depending on ACT [target: 150-180s])
• no discontuation > 30min
Fig. 580  IABP [23]

Fig. 581  The balloon is inflated in the diastole: This in-
creases the pressure in the ascending aorta and conse-
cutively in the coronaries, so that the coronary perfusion,
which takes place in the diastole, is intensified (augmenta-
tion) [23].
Fig. 582  In systole, the balloon contracts (deflation): This
exerts a suction effect and the afterload decreases (main
effect of IABP!) [23].
Fig. 583  scheme of the IABP [23]
Indications
• infarct-related cardiogenic shock (significant re-
duction of mortality [from 60% to 30%]); in the earlier
guidelines still a class I indication (in the meantime no
more recommended and degraded to III)
• myocardial infarction with mechanical complications
(ventricular septal rupture [infarct VSD], papillary mu-
scle rupture with acute mitral valve regurgitation)
• optionally also with severe decompensated aortic val-
ve stenosis for hemodynamic stabilization (Aksoy et al,
Heart 2010)
Contraindications
• acute aortic dissection (danger of progression of diss-
ection)
• aortic aneurysm (thoracic: Here the balloon cannot
seal the dilated aorta.)
• severe aortic valve regurgitation (increase in regurgi-
tation volume due to increased pressure in the aorta
during diastole)
• severe PAD
Complications
• vascular injury (22%)
• haemorrhage (13%)
• leg ischaemia (14%; therefore regular clinical leg con-
trol incl. palpation of pulse and measurement of occlu-
sion pressure via doppler is obligatory!)
Control
• The balloon should inflate at the beginning of the dias-
tole and deflate at the end of the diastole:
-- inflation: at the beginning of the diastole
-- deflation: at the end of the diastole
• diastole
-- ECG: end of T-wave until R-spike
-- arterial pressure curv
◦◦ dicrotic point (syn.: dicrotic notch): closure of the
aortic valve (beginning of diastole)
◦◦ anacrotic point (syn.: anacrotic notch): opening of
the aortic valve (end of diastole)
• In the devices of the newer generation, automatic pul-
se curve recognition allows self-adjustment of the sys-
tem, so that problems of too early / too late inflation or
deflation only occur very rarely.
Cardiology 411
Fig. 584  ECG: The diastole goes from the end of the T-wave
to the R-spike.

dicrotic
point Fig. 588  inflation too late (only after the dicrotic notch):
The balloon is inflated far too late, so that the IABP is not
fully effective here (reduced coronary perfusion).
anacrotic
point

Fig. 585  arterial blood pressure curve: The diastole goes

from the dicrotic (closure of the aortic valve) to the anacro-
tic point (opening of the aortic valve).

Fig. 589  deflation too early (before the anacrotic point);

result: suboptimal coronary perfusion (The suction pheno-
menon may even cause a flow reversal in the carotid artery
and the coronary arteries and thus even a deterioration of
the coronary perfusion!)

Fig. 586  ideal case: inflation at the dicrotic point and de-
flation at the anacrotic point (The augmentation phase, i.e.
the time during which the balloon is inflated, is marked in
yellow.)

Fig. 590  deflation too late (only after the anacrotic point):
The balloon is deflated far too late, so that the IABP is not
fully effective here (reduced afterload reduction); increase
in myocardial oxygen consumption

Fig. 587  inflation too early (prior to the dicrotic point): The
balloon is inflated although the aortic valve is not closed
yet. Result: gegurgitation via the aortic valve (aortic valve
regurgitation), increase in LVEDP and myocardial oxygen
consumption
Assessment
• For a long time, a class I recommendation (AHA [Ame-
rican Heart Association]: IA, ESC [European Society of
Cardiology] IC) was surprisingly valid in the guidelines
for IABP in cardiogenic shock, although there were no

412 Cardiology
 prospective randomized trials at all. The evaluation of
the benchmark register (Cohen et al, Eur Heart J 2003),
which showed that mortality was lower in US hospitals,
which traditionally had a high IABP frequency, than in IABP-SHOCK study I
non-US hospitals, where the IABP frequency was lo-
wer, had a decisive influence on this recommendation.
This study was further refined by Datascope, one of
the leading IABP manufacturers at the time. Intra-aortic balloon counterpulsation in patients with acute
• There were only register data (studies: GUSTO, KO- myocardial infarction complicated by cardiogenic shock:
VACK, SHOCK, NRMI; TACTICS): The prospective, randomized IABP SHOCK Trial for at-
tenuation of multiorgan dysfunction syndrome
-- Patients after lysis in cardiogenic shock benefit more
Prondzinsky et al, Crit Care Med 2010
from IABP.
-- Patients after PCI in cardiogenic shock benefit less • 45 patients with infarct-related cardiogenic shock and
from IABP. PCI
• Following the negative IABP Shock-II study (see box), -- without IABP
IABP was downgraded to a IIB recommendation in the -- with IABP
ESC guidelines in 2013 and to a III recommendation • primary endpoint: morbidity (APACHE II score) → no
in the ESC guidelines in 2016. Routine use of IABP difference
in cardiogenic shock is no longer recommended. It
should be noted, however, that there is no evidence
in the sense of a prospective randomized study for va-
ECMO in cardiogenic shock either, which is currently
increasingly used!
IABP-SHOCK study II
• However, still a good indication for IABP are mechani-
cal infarction complications such as ventricular septal
rupture (infarct VSD) or a papillary muscle rupture with
acute mitral valve regurgitation as a bridging measure Intraaortic Balloon Support for Myocardial Infarction with
Cardiogenic Shock
(e.g. for transport) up to surgical treatment. In the cur-
Thiele et al, N Eng J 2012
rent ESC guidelines, a IIa recommendation also ap-
plies here. Due to the rarity of these mechanical infarct • multicenter (42 centers) prospective randomized cont-
complications, there have been and will be no pros- rolled study
pective randomized studies on this topic. • 598 patients with infarct-related cardiogenic shock and
• Furthermore IABP continues to be used in cardiac PCI
thoracic surgery (especially in postcardiotomy syndro- -- without IABP (300 patients)
me). There is even a separate S3 guideline "Use of -- with IABP (298 patients)
intra-aortic balloon counterpulsation in cardiac surge- • results:
ry" 2015 of the German Society for Thoracic and Car- -- primary endpoint (mortality [30 days]): no diffe-
diovascular Surgery (DGTHG). rence (IABP group 39.7%; control group: 41.3%)
-- note: also no difference in mortality after 6 and 12
months (Lancet 2013) and after 6 years (Circulation
2018)
meta-analysis -- secondary endpoints (blood pressure, dosage and
duration of catecholamine therapy, lactate, duration of
intensive care, renal function): no difference
-- no increased rate of complications in the IABP group
compared to the control group (major bleeding, peri-
A systematic review and meta-analysis of intra-aortic bal- pheral ischemia, sepsis, stroke)
loon pump therapy in ST-elevation myocardial infarction:
should we change the guidelines?
Sjauw et al, European Heart Journal 2009
IABP: time to say goodbye!
• 10529 patients with STEMI and cardiogenic shock
• results
-- lysis + IABP: reduced mortality
-- PCI + IABP: increased mortality (excess mortality!)
Impella
Definition
• company: Abiomed
• turbine pump in left ventricle (microaxial rotary pump;
sucks blood in the left ventricle and ejects it into the
ascending aorta)
• working principle of the Archimedes' screw from an-

Cardiology 413
 cient Egypt for irrigating the fields or of an ship's pro-
peller
• length of stay: max. 7 days
• full heparinization necessary as well as continuous
flushing with glucose-heparin solution to prevent blood
from entering the motor and cooling the drive unit
• The Impella leads to a reduction in the afterload (see
also working diagram of the left ventricle on page
413) and relieves the left ventricle, which is supposed
to recover. The LVEDP (left ventricular end-diastolic
pressure) decreases
• increased hemolysis (hence regular checks of hemo-
globin, LDH, indirect bilirubin, haptoglobin)
• It is placed interventionally (via a sheath [introducer
sheath for Impella CP: 14F] in the femoral artery, via
guidewire; non-surgical) under X-ray fluoroscopy usu-
ally in the cath lab. Finally, a switch is made to a reposi-
tion sheath (13F). The correct position is checked with
the echocardiography (TTE; also during the course in
the intensive care unit). The catheter inlet should be
in the left ventricle (i.e. proximal the aortic valve), the
catheter outlet in the ascending aorta (i.e. distal the
aortic valve).
• The turbine pump generates a laminar (no pulsatile)
flow. The more severely the pump function is restric-
ted, the more work the pump takes over and the less
pulsatile and more laminar the blood flow becomes.
You cannot hear the jet auscultatory with the stetho-
scope.
• battery (e.g. for transport): 1 hour run time

Seizes (versionen)
Fig. 591  Impella: The arrow points to the turbine driven
• Impella 2.5 (maximum flow rate: 2.5 l/min; access: screw.
12F; percutaneously implantable)
• Impella CP (maximum flow rate: 4.0 l/min; access:
pigtail
14F; percutaneously implantable)
• Impella 5.0 (maximum flow rate: 5.0 l/min; access:
22F; not percutaneously implantable [only via surgical pressure inlet
vascular access]) measure-
ment outlet
Indications
• cardiogenic shock
-- acute myocardial infarction
-- myocarditis
• post-HTX (after heart transplantation) motor
• high-risk interventions (e.g. main stem PCI, mapping Fig. 592  Impella: The inlet should be in the left ventricle.
and ablation of ventricular tachycardia) Here the blood is sucked in by the turbine pump. The out-
let should be in the ascending aorta just above the aortic
valve. Here the blood is then ejected again. The motor is
located directly above the outlet, followed by the the ope-
ning for the pressure measurement (at thisconventional
pressure measuring bag with NaCl 0.9%), which generates
the placement signal.

414 Cardiology
Fig. 593  reposition sheath: Via this he catheter can be
pulled back and forth over a sterile protective cover after
opening the Tuohy valve, thus correcting the position of the
Impella.

Fig. 595  Impella 5.0

Fig. 594  Impella 2.5 Contraindications

• aortic valve vitium:
-- aortic valve stenosis with valve opening area <
1.5cm2 (moderate)
-- aortic valve regurgitation (from moderate; the cathe-
ter in the aortic valve itself induces a mild aortic val-
ve regurgitation)
• hypertrophic obstructive cardiomyopathy
• mechanische Aortenklappenprothesemechanical aor-
tic valve prosthesis
• ascending aorta aneurysm
• ventricular septal defect (e.g. after infarction)
• thrombus in left ventricle
• PAD (severe)

Control
• performance levels (p):
-- p1-p8 (maximum)
-- The goal is the maximum setting to relieve the ven-
tricle as much as possible.

Cardiology 415
 -- p2: neutral run rate (effectively no more support here corrected) reduce the performance level by 1-2 levels)
[only compensates the mechanically induced aortic -- causes:
valve regurgitation by the catheter; therefore never ◦◦ ventricular filling too low (preload too low; Impella
set lower than p2]) depends on preload) → fluid administration
• position control ◦◦ incorrect position → repositioning (under echocar-
-- by curves on the monitor: diographic control)
◦◦ placement signal (above; red; unit: mmHg): It indi- ◦◦ right ventricle failure
cates the position of the outlet. This should be in -- consequences:
the aorta. The signal should be configured pulsati- ◦◦ The Impella flow is less than expected.There is
le and aortic (i.e. diastolic pressure present). If it is an average expected flow rate for the respective
configured ventricularly (i.e. no diastolic pressure Impella version for each performance level, which
present), the pump has slipped too far into the left can be found in the corresponding tables of the
ventricle and must be withdrawn. company.
◦◦ motor current curve (below; green; unit: mA): This ◦◦ only insufficient circulatory support
should be pulsatile. The pulsatility comes from the
◦◦ hemolysis
fact that the current consumption in the systole is
higher than in the diastole. If it is flat, the pump • heparin perfusor (UFH) according to target-ACT 160-
does not work and there is no support because 180s or target-PTT 50-70s (if HIT II: argatroban syste-
it has no pressure gradient to overcome. This is mically [but not locally in the purge solution; here then
because both the inlet and outlet are in the same only glucose without heparin])
area: either both in the ventricle (ventricular place-
ment signal → The pump must be withdrawn.) or
both in the aorta (aortic placement signal → The
pump must be pushed forward.). Since a flat curve
means that the pump is not working and therefo-
re there is no mechanical circulation support, the
pharmacological circulation support (catecholami-
nes) must always be increased.
-- by echocardiography
◦◦ B-mode:
▪▪ The inlet should be in the left ventricle 3.5 cm Fig. 596  curves on the display of the control console moni-
in front of the aortic valve (exactly: aortic valve tor: above (red) the placement signal, below (green) the mo-
annulus). tor current curve. The placement signal is configured cor-
▪▪ The tip of the pump should be in the area of ​​the rectly to be pulsatile and aortic, i.e. the diastolic pressure is
apex of the heart. It should lie free here, d.h. significantly greater than zero. The position of the pump is
correct. The motor current curve is also normally pulsatile.
without contact to the wall. The mitral leaflets
(especially the anterior mitral leaflet) should not
be disturbed in their movement.
◦◦ colour Doppler: Aliasing (mosaic pattern; due to
the blood being ejected through the outlet) should
only be recognized after the aortic valve, not in or
in front of the aortic valve.
-- by chest X-ray
• purge: flushing of the motor
-- To prevent blood from entering the motor and coo-
ling it, it is purge with an infusion solution containing
glucose (to increase viscosity; mostly G5%) and he-
Fig. 597  The motor current curve (green) is flat, i.e. both
parin (usually 10 IU UFH per ml).
openings (inlet and outlet) are in the same area. The place-
-- purge flow: 3-30 ml/h (standard: 15 ml/h) ment signal (red) is configured aortally, i.e. both openings
-- purge pressure: 300-1100 mmHg are in the aorta. The pump has slipped out of the left ven-
◦◦ purge pressure too high: tricle (most common cause: Valve was not screwed shut.)
and must be pushed forward. Procedure: reduction of per-
▪▪ leak formance to p2, increase in catecholamines, then repositio-
▪▪ too high glucose concentration in the purge so- ning under echocardiographic control
lution
◦◦ purge pressure to low:
▪▪ kink
▪▪ too low glucose concentration in the purge so-
lution
• suction alarm (possibly oscillations in the motor current
curve) → always first (until the cause is clarified and

416 Cardiology
Fig. 598  The motor current curve (green) is flat, i.e. both
openings (inlet and outlet) are in the same area. The place-
ment signal (red) is configured ventricularly (diastolic blood
pressure to zero), i.e. both openings are in the left ventric-
le. The pump has slipped too far into the left ventricle and Fig. 600  Echocardiography (TTE): The correct position of
must be withdrawn. Procedure: reduction of performance the Impella is shown. The tip of the catheter (see arrow)
to p2, increase in catecholamines, then repositioning under points towards the apex of the left ventricle, but it is still
echocardiographic control free in the ventricle without contact to the wall.

Fig. 599  The motor current curve (green) is normally pulsa-

tile, but the placement signal (red) is flat. This is because
the ejection fraction of the left ventricle is severely redu-
ced. The lower the ejection fraction, the lower the pulsatility
Most of the work here is done by the pump, which is also
correct because the left ventricle should be relieved . Fig. 601  Echokardiographie (TTE): The distance between
the inlet (exactly: tear drop) and the aortic valve (exactly:
aortic valve annulus) should be 3.5 cm.

motor
outlet

tear
drop
inlet

Fig. 602  Chest X-ray of a patient with Impella

Cardiology 417
Annotations
• resuscitation:
-- set to level p2 during the chest concession
-- defibrillation / cardioversion: possible
• PiCCO:
-- pulse contour analysis: not usable because the tur-
bine pump generates a laminar and not a pulsatile
flow (The better the ejection fraction of the patient,
the more pulsatile the curve and the better the pulse
contour analysis can be used. In the case of a highly
reduced ejection fraction, the main work is carried
out by the pump: Here you have an almost exclusi-
vely laminar flow, so that the pulse contour analysis
cannot be used at all.)
-- thermodilution:
◦◦ cardiac output (CO), stroke volume (SV) and sys-
temic vascular resistance (SVR): usable (A stu-
dy [Sasko et al, Clin Res Cardiol 2018) showed
a good correlation between the measured values​​
with the pulmonary artery catheter and the PiCCO
system with these parameters under Impella.])
◦◦ volume parametere (ITBV, GEDV, EVLW): not
usable
• prone positioning: also possible under Impella
• weaning (from Impella):
-- The first goal is to completely discontinue the cate-
cholamines. Once this has been done, the perfor-
mance level is quickly (within one day) reduced from
p8 up to p2.
-- removal: cut the threads of the sheath, open the
Tuohy valve, withdraw the catheter to the reposition
sheath (cave: The sheath is smaller than the cathe-
ter [e.g. with Impella CP catheter 14F, sheath only
13F], i.e. the catheter has to be pulled out together
with the sheath), pull the white plug beforehand (so
that the Impella pump is completely off and the blood
does not splash around in the room), then manually
press the puncture site
• ECMella: In therapy-refractory cardiogenic shock va-
ECMO is often used. The retrograde flow in the aorta,
however, leads to an increase in afterload here. Im-
pella reduces the afterload, so that va-ECMO is often
combined with an Impella here. The blood is pumped
out of the left ventricle by the impella, thus relieving it
(venting, LV-unloading). In a retrospective study (Pap-
palardo et al, Eur J Heart Fail 2017), the combination
of va-ECMO and Impella (ECMella) significantly redu-
ced hospital mortality in therapy-refractory cardiogenic
shock from 80% to 47%.
• Meanwhile there is already an Impella system for right
heart support (Impella RP). Here the turbine pump,
which is located in the inferior vena cava, sucks in the
blood and ejects it into the pulmonary artery. The sys-
tem is implanted percutaneously via the femoral vein.
(access: 22F). A combination of the Impella for the left
and right heart is also possible (Bipella).
Assessment
• studies:
-- ISAR-SHOCK study (Seyfahrt et al, J Am Coll Cardi-
ol 2008): Impella showed no survival advantage over
418 Cardiology
IABP in patients with therapy refractory cardiogenic
shock.
-- PROTECT II study (O´Neill et al, Circulation 2012):
Impella was compared with IABP in high-risk inter-
ventions. Although Impella showed advantages in
haemodynamics, there was no difference in the pri-
mary endpoint (30-day MACE [major adverse cardi-
ac events]).
-- IMPRESS-in-Severe-Shock study (Ouweneel et al,
JACC 2017): Impella showed no survival advantage
over IABP in patients with therapy refractory cardio-
genic shock.
-- Schrage et a, Circulation 2018: In this retrospective
registry study, compared to IABP (collective of the
IABP-SHOCK-II study), the Impella showed no sur-
vival advantage with increased complications (espe-
cially bleeding).
-- Dhruva et al, JAMA 2020: In this retrospective cohort
study, the Impella even showed a worse outcome
(higher hospital mortality and higher bleeding rate)
compared to the IABP.
-- DANSHOCK study (Danish Cardiogenic Shock Tri-
al): currently ongoing study on Impella in patients
with therapy refractory infarct-related cardiogenic
shock (especially in Germany: DanGer [DANS-
HOCK Germany])
• A complete circulatory support (e.g. cardiac arrest as
part of a resuscitation) is not possible with Impella, a
minimum ejection fraction is a prerequisite.
HeartMate PHP
• company: St. Jude Medical
• PHP: percutaneous heart pump
• similar to Impella a turbine pump in the left ventricle
• interventional (via a sheath in the femoral artery, via
guidewire; non-surgical) placement under x-ray fluoro-
scopy
• approval study: SHIELD (fulfilled safety endpoints in
high-risk PCI)
• diameter: at insertion (arterial access) 13F, in ventricle
24F
• maximum flow rate (CO): 4-5 l/min
• CE approval since 2015 in Europe for high-risk PCI
and patients with cardiogenic shock
Cardiobridge
• company: Zeiss
• percutaneously via the femoral artery into the distal
aortic arch (at the level of the diaphragm) inserted pro-
peller, which continuously pumps the blood distally into
the aorta
• reduction of afterload
• seizes: 10F, 14F
Tandem Heart
• company: CardiacAssist Inc
• extracorporeal centrifugal pump that draws blood from
the left atrium (21F) and pumps it retrogradely into the
femoral artery (15-17F) (The blood is drawn from the
 left atrium and pumped into the femoral artery.)
• placement: percutaneous puncture of the femoral vein,
then transseptal puncture (controll by X-ray fluorosco-
py and TEE) necessary; especially in an emergency
often not so easy; furthermore increased risk of dislo-
cation of the transseptally placed cannula)
• maximum flow rate: 4 l/min
• maximum dwell time: 14 days
• target-ACT: 200s
• meanwhile also a system for right heart support (The
blood is pumped from the right atrium into the pulmo-
nary artery.)
• assessment:
-- improved hemodynamics compared to IABP, but no
mortality advantage (Westbay et al, Nat Rev Cardiol Fig. 603  Lifebridge
2012)
Cardiohelp
-- only rarely used today
• company: Maquet
Lifebridge • mobile heart lung machine (i.a. centrifugal pump, oxy-
genator)
• company: Zoll
• maximum flow rate: 4-6 l/min (almost complete CO re-
• mobile heart lung machine (i.a. centrifugal pump, oxy-
placement!)
genator)
• 2 sheaths (implantation without cardio technician)
• maximum flow rate: 4-6 l/min (almost complete CO re-
placement!) -- femoral artery (15-17F)
• 2 sheaths (implantation without cardio technician) -- femoral vein (18-23F)
-- femoral artery (15-17F) • transportable (weight 10kg)
-- femoral vein (18-23F) • maximum dwell time: 30 days
• transportable (weight 18kg) • target-ACT: 150-200s
• target-ACT: > 480s (very high; cave bleedings) • operation of the system optionally also possible with
heparin-free components (e.g. with HIT II)
• maximum dwell time: only 6h

Cardiology 419

Fig. 604  Cardiohelp [23]
Fig. 605  i-cor (Xenios company): transportable va-ECMO
system. The support is pulsatile here. Triggering is per-
formed by ECG (also possible with atrial fibrillation). The
maximum flow (analogous to IABP) is generated in the dia-
stole, so that the coronary perfusion is improved. The i-cor
system is a combination of IABP and ECMO.
Support devices
according to ejection fraction
420 Cardiology
Efficacy
flow rates (CO)
LVEDP
LVEDV
Fig. 606  Various working diagrams of the left ventricle
(syn.: pressure-volume relationships; for basic principles
see page 192) are shown. The area under the curve cor-
responds to the stroke work (syn.: pressure-volume work).
The higher the stroke work, the higher the afterload and
therefore the total oxygen turnover. It can be seen that the
stroke work under Impella (black) is significantly lower
than without mechanical support (red). With ECMO (blue;
veno-arterial: e.g. Lifebridge, Cardiohelp) the stroke work
is even increased (due to the retrograde flow in the aorta)!
The afterload for the left ventricle is reduced by Impella and
increased by va-ECMO. For this reason, va-ECMO is often
used in combination with the Impella (va-ECMO + Impella
= ECmella).
va-ECMO increases the left ventricu-
lar afterload, which is disadvantage-
ous in cardiogenic shock!

meta-analysis
Percutaneous short-term active mechanical support de-
vices in cardiogenic shock: a systematic review and col-
laborative meta-analysis of randomized trials
Thiele et al, European Heart Journal 2017
• 149 patients with cardiogenic shock
-- with the use of devices for mechanical circulatory sup-
port (Impella, Tandem-Heart, va-ECMO)
-- without the use of these devices (controll group)
• result: devices
-- improvement in hemodynamics (MAP ↑, PCWP ↓,
lactate ↓)
-- no reduction in mortality
mechanical circulatory support: no
randomized-controlled studies (still
purely experimental!) ESC: also only
IIB recommendation
Ventricular Assist-Devices (VAD)
Definition
• ventricular mechanical support system
• implantation cardiothoracic surgical mostly via a com-
bination of partial hemisternotomy (in the upper region)
and an anterolateral mini thoracotomy
• Due to the declining number of heart transplants, more
and more VADs are being implanted. Goldstand, how-
ever, is the heart transplant, which should always be
evaluated before the implantation of a VAD.
Types
These can be differentiated according to various aspects:
• according to the location:
-- intracorporeal (electric pumps; laminar flow; e.g. In-
cor)
-- extracorporeal (pneumatic pumps; pulsatile flow;
e.g. Biomedicus, Excor)
• according to the flow:
-- pulsatile (earlier)
-- non-pulsatile (syn.: laminar [continuous]; today)
• according to the number of ventricles supported:
-- univentricular (80%):
◦◦ for the left ventricle: LVAD (left ventricular assist
device)
◦◦ for the right ventricle: RVAD (right ventricular as-
sist device)
▪▪ An inlet cannula is inserted (analogously to the
LVAD) into the right ventricle (alternatively into
the right atrium in the superior vena cava). This
leads to a pump, which then directs the blood
into the pulmonary artery via an outlet cannula
▪▪ examples: PVAD (Paracorporeal Ventricular As-
sist Device; Thoratec), CentriMag (Levitronix)
▪▪ very rare
-- biventricular (20%): BiVAD (biventricular assist de-
vice)
◦◦ necessary if the right ventricular function is no lon-
ger maintained (in case of combined left and right
heart failure)
◦◦ most frequent system: EXCOR (Berlin Heart com-
pany)
◦◦ here mostly pulsatile flow
• according to the extent:
-- partial (heart support)
-- complete (heart replacement: artificial heart [TAH:
total artificial heart; only CE certified system: Cardio-
West] as the ultima ratio for biventricular failure)
• according to the type of function of the pump:
-- electric (in univentricular systems [e.g. LVAD]; lami-
nar flow; standard today)
-- pneumatic (in biventricular systems [BIVAD]; pulsati-
le flow; only rarely today)
• according to the time:
-- short-term systems
-- long-term systems
LVAD (left ventricular assist device)
• standard today (the most commonly used assist
device)
• Here, the apex of the left ventricle is opened using a
combination of partial hemisternotomy (in the upper
area) and anterolateral mini-thoracotomy and a can-
nula (inlet cannula; inflow) is sutured in. The blood is
then passed out of the heart to a pump (CF pump [CF:
continuous flow]) and then led back through a cannula
into the ascending aorta (outlet cannula; outflow). The
pump works electrically.
• The pump is connected to the control unit (controller)
via a power cable (driveline), which is tunneled under
the skin (to avoid infection), usually to the right of the
navel, from the heart through the pericardium to the
exit point. This in turn is connected to a power source
(either rechargeable batteries or power adapter).
• prerequisite: preserved right ventricular function (nor-
mal TAPSE; only the left and not the right heart is sup-
ported)
• flow:
-- flow type: laminar (non-pulsatile)
-- flow rate: up to 10 litres/min
• most common systems:
-- 2nd generation (axial pumps)
◦◦ Heart Mate II (Abbott company [formerly St. Jude
Medical, formerly Thoratec]; the most commonly
implanted assist device worldwide)
◦◦ Heart Assist 5 (Reliant Heart company)
◦◦ INCOR (Berlin Heart company)
-- 3rd generation (centrifugal pumps)
◦◦ Heart Mate 3 (rotational speed: 6000-15000 rpm
[rpm: revolutions per minute]; here the rotor of
Cardiology 421
 the pump is made to levitate by magnetic forces,
which reduces the damage to the blood flowing
through the pump; MOMENTUM-3- study [Mehra
et al, N Engl J 2019]: significantly longer survival
with Heart Mate 3 than with Heart Mate II)
◦◦ HVAD (HeartWare Ventricular Assist Device;
HeartWare company; rotational speed: 1800-4000
rpm)
• very good short and long-term results (longest descri-
bed running time: 11 years)

Fig. 608  left ventricular assist device (LVAD): HeartMate II

of Abbott company [44]

Fig. 607  left ventricular assist device (LVAD): HVAD of

HeartWare company

Fig. 609  left ventricular assist device (LVAD): HeartMate

III of Abbott company [44] - The controller (control unit) is
connected on the one hand to the Driveline (power cable to
the pump) and on the other hand to the power supply (here
two batteries).

422 Cardiology
 exit point of the power
cable

"driveline"
(power cable; under the
controller
abdominal skin)

Fig. 610  patient with an LVAD system (here HeartMate II)

Goals
• "bridge"
-- "bridge to recovery" (BTR): The system is left until
the pump function has recovered (e.g. after a myo-
cardial infarction or a myocarditis). Then it will be
explanted again. Overall, however, this is rarely the
case (10%).
-- "bridge to transplantation" (BTT; most common indi-
cation): The system is left until the patient is trans-
planted (note: The number of heart transplants in
Germany reached a historic low in 2013.).
-- "bridge to decision" (BTD): The system is left until
a decision has been made on the further procedure
(e.g. therapy limitation after prolonged resuscitati-
on). in case of therapy refractory
• "destination therapy" (DT): Due to a lack of prospects cardiogenic shock (e.g. myocardi-
for or contraindications to transplantation, the system tis in a young patient): early
is the only treatment option (2-year survival rate of contact to cardiothoracic surgical
patients with LVAD: 80% [Kormos et al, J Heart Lung centre for evaluation of a VAD!
Transplant 2019])
Complications (emergencies)
• pericardial tamponade (immediately postoperatively):
If cardiovascular arrest occurs within the first 10 days
after VAD implantation, re-sternotomy should be per-
formed (after confirmation of the diagnosis in the echo-
cardiography) immediately if this does not respond to
defibrillation, as this is usually caused by a bleeding
into the pericardial sac. A low fluid accumulation in the
pericardium may well be.
• bleeding
-- often caused by anticoagulation (oral anticoagulati-
on with VKA [vitamin K antangonist]), also frequently
acquired von Willebrand syndrome (The von Wil-
lebrand factor is destroyed by the excessive shear
stress)
-- frequent emergency: unquenchable epistaxis
-- The main fear is intracranial bleeding!
• infections (especially in the area of the outlet of the
power cable ["driveline"], pocket) , maybe sepsis (fre-
quent cause of death!)
• pump thrombosis
-- causes: especially insufficient anticoagulation, loss
of fluid with hemoconcentration (e.g. diarrhea)
-- signs:

Cardiology 423
 ◦◦ increase in haemolysis parameters (important es-
pecially LDH)
◦◦ increase in power consumption (due to increased
friction) of the pump ("power spikes")
-- consequences: pump failure, embolism (e.g. stroke)
-- prophylaxis:
◦◦ obligatory: oral anticoagulation with VKA with a tar-
get INR of 2.5-3.5 or perfusor with unfractionated
heparin (target PTT 50-70s [e.g. perioperatively or
in case of severe bleeding])
◦◦ optional: additionally inhibition of platelet aggrega-
tion (mostly ASA or clopidogrel; recommended by
most cardiac centers)
-- therapie: lysis (with alteplase)
• pump stop (most common cause: power supply inter-
ruption): Here one has to differentiate whether the pa-
tient has only a heart support or a heart replacement
system. An LVAD is only a heart support system, so
that when the pump stops, the patient is not yet dead.
• He still has a (if only very poorly) pumping ventricle,
so that acute left heart failure gradually develops. It is
different with a patient with an artificial heart (TAH: total
artificial heart): This is a heart replacement system so
that when the pumps stops, the patients has a cardiac
arrest immediately.
• embolism (especially stroke)
• loss of power supply; causes:
-- empty battery (therapy: immediate change to a full
battery or connection to the power adapter for the
mains power supply)
-- disconnection (e.g. cable from controller [therapy:
reconnect])
-- defects on the "driveline" (e.g. cable break as part of
a trauma, cutting the cable with suicidal intent)
-- water damage (e.g. finding the patient in the pool)
• right heart failure (after LVAD implantation)
-- frequency: in 20%
-- cause: caused on the one hand by septal deviation
in the context of volume relief of the left ventricle, on
the other hand by increased right ventricular preload
-- Therefore one should regularly determine the right
ventricular function (TAPSE, TASV) in the echocar-
diography.
• aortic valve regurgitation (very unfavorable because it
leads to recirculation and thus to a decrease in the ef-
fectiveness of the system)
• psychiatric complications (especially suicidality): The
fact that the whole life depends on a single machine is
extremely stressful.
Main complications in an LVAD
patient: stroke (due to intracranial
hemorrhage or embolic cerebral
infarction) and driveline infection
with sepsis!
Management
• monitoring: LVAD systems today have a non-pulsatile,
i.e. laminar flow. Therefore, you cannot palpate the
424 Cardiology
pulse of the patient. This must not be misinterpreted
as cardiac arrest. Furthermore, blood pressure cannot
be measured preclinically (non-invasive; NIBP) be-
cause one cannot hear Korotkoff tones or derive them
oscillometrically. However, an invasive blood pressure
measurement is possible, especially the measurement
of the mean arterial pressure (MAP) as a parameter for
the perfusion can be derived easily and is also crucial.
Frequently, no saturation can be derived from pulse
oximetry: This measures the difference between the
minimum absorption in the systole and the maximum
absorption in the diastole. With a non-pulsatile flow,
however, there is no longer a systole and diastole. A
good (especially easy to use preclinical) parameter for
hemodynamics is the recapillarization time.
• ECG:
-- The ECG (e.g. monitor) can be used as usual in a
patient with LVAD. Only in patients with a total arti-
ficial heart (TAH) an ECG cannot be derived: Here
there is always an asystole shown.
-- Due to the influence cannula in the left ventricle in
LVAD, excitation regression disorders and block pic-
tures are often seen in the 12-lead ECG, which is
completely normal. Here the comparison with previ-
ous ECGs is crucial.
-- A common cause of cardiac arrhythmia is suction
of the pump on the wall as a result of hypovolemia,
which can easily be remedied by fluid administration.
• If you are unsure whether the system is still working
or not, you only need to put on the stethoscope and
auscultate: You can hear an extremely loud machine
noise when the pump is running.
• procedure in system failure (pump stop): First you
should check the connection points (between "driveli-
ne" and controller and between power supply and con-
troller) and re-connect if necessary. Then you should
change the batteries or connect the controller to the
power supply. If the system still does not work, you
should connect the replacement controller that every
patient has. If the pump has been down for a longer
time, thrombi may have formed in the heart (i.a. due to
the retrograde flow from the ascending aorta to the left
ventricle), which can then embolize when the system is
restarted. However, with a system failure of up to three
minutes, this is not a problem.
• As an emergency physician, you must never refuse an
indicated transport to the hospital with supposed excu-
ses ("lack of instruction in the corresponding medical
device law", e.g. in Germany based on §23 part.1 StVO
[securing the load]). Immediate transport is necessary
to avert acute dangers to the life and limb of the pati-
ent, so that no liability has to be assumed (in Germany
§ 34 StGB; §228 BGB). You take all the equipment in-
cluding batteries, charging station, replacement cont-
roller, VAD logbook (documentation by patient himself
["diary"]), VKA ID card and announce the patient be-
forehand by telephone to the appropriate target clinic
(heart center). Both ground-based transport and air re-
scue (with the rescue helicopter) are possible.
• In general, you should always consult the clinic (heart
center) that has implanted the LVAD system generous-
ly in the event of (especially VAD-associated) emer-
 gencies or ambiguities. In the patient's emergency ID
card, the contact person is indicated with a telephone
number (usually also on the back of the controller). The
corresponding companies can also usually be reached
by telephone continuously via a 24-hour hotline.
• In principle, reprogramming of the device should only
be carried out by or in consultation with an experienced
user (e.g. cardio technician) and under echocardiogra-
phic control.
• A CT in a patient with an LVAD is possible, but not an
MRI.
• In the case of overridden oral anticoagulation (INR >
5) with VKA and a relevant bleeding at the same time,
antagonization can be performed: It is advised against
the administration of vitamin K (Konakion) , as this can
lead to an excessive effect with consecutive pump
thrombosis and embolism. You should rather give FFP
carefully here.
• If you have a patient with an LVAD in the intensive care
unit, you should always connect him to the fixed power
supply and not to the batteries.
• Strict hygiene (i.a. sterile gloves, sterile gowns, octe-
nisept) should be observed when changing dressings
in the area where the power cord exits ("driveline";
cave infections!). Driveline infections with consecutive
sepsis are a common cause of death in LVAD patients!
• The pump system depends on the preload and after-
load:
-- preload: If the preload is reduced (e.g. hypovole-
mia), the left ventricle is no longer sufficiently filled
and the pump is sucked into the ventricular wall. The
display then shows significant (by more than 50 rpm
[revolutions per minute]) fluctuations of the rotational
speed. This also often leads to cardiac arrhythmias.
The therapy here consists in fluid administration to
increase the preload. A right heart failure (e.g. pul-
monary embolism, right heart infarction) or a peri-
cardial tamponade can also lead to a reduced filling
of the left ventricle with a decrease in the left ventri-
cular preload.
-- afterlod: MAP should not be higher than 80 mmHg,
otherwise the afterload is too high. With increased
afterload the pump speed decreases and the aortic
valve regurgitation (increased retrograde flow) incre-
ases in the echocardiography. The goal is a MAP
between 60-80 mmHg. Hypertension should be tre-
ated accordingly.
• LVAD are only support systems and not replacement
systems, i.e. pumping function of the left ventricle is
still present (albeit limited) in every LVAD patient. In
the event of a complete failure of the system, the own
pump function takes over the work alone. In an emer-
gency, an attempt can be made to increase the inotro-
py with dobutamine.
• resuscitation:
-- A patient with an LVAD is basically resuscitated in
the same way as a patient without an LVAD.
-- Although the risk of injury as part of a chest com-
pression is increased (injury to the apex of the left
ventricle through the inflow cannula or the ascending
aorta through the outflow cannula), chest compres-
sion is possible and should also be carried out whe-
never necessary.
-- However preclinically, one should not start prematu-
rely with chest compression only because of a mis-
sing pulse. Due to the non-pulsatile (laminar) flow,
no pulse is palpable.
-- Only in patients with a total artificial heart (TAH) no
chest compression is possible, since there is no own
heart at all. Defibrillation, cardioversion or the admi-
nistration of inotropics (such as dobutamine) is also
not possible here. Here you have to resuscitate the
device (i.e. get it going again) and not the patient!
-- possibly implantation of a va-ECMO
-- Cardioversion or defibrillation is also possible at any
time in patients with an LVAD because the system is
electrically shielded. Some patients are additionally
equipped with an AICD anyway. For defibrillation, it is
also not necessary to disconnect the controller from
the power supply. If ventricular fibrillation occurs in a
patient with LVAD, this does not primarily disturb the
left ventricle, since this is supported. Due to ventricu-
lar fibrillation, however, the right ventricle no longer
works at all, so that no more blood can be pumped
to the left side and the left ventricle can no longer be
filled, and the pump can ultimately no longer eject
blood from the left ventricle into the ascending aor-
ta. Patients usually tolerate ventricular fibrillation for
several minutes. A clearly reduced flow ("low flow"
alarm) appears on the display. For defibrillation, the
patients often need a little analgosedation because
they are usually still awake.
LVAD patient: no pulse palpabe (no
hasty chest compressions); auscultati-
on (loud machine noise!)
Pump parameters
• rotational speed (the most important parameter)
-- specification in rpm (revolutions per minute) or in U/
min
-- ranges:
◦◦ HVAD (HeartWare Ventricular Assist Device; a
centrifugal pump): 1800-4000 rpm
◦◦ Heart Mate II/III (an axial pump): 6000-15000 rpm
-- It should be constant. Fluctuations of the rotational
speed (> 50 rpm) are mostly caused by suction of
the pump on the ventricular wall as a result of a re-
duced left ventricular preload and thus filling of the
left ventricle (e.g. as a result of hypovolemia) or by
right heart failure.
-- A decrease in rotational speed is usually the result
of an increased afterload (hypertension; MAP > 80
mmHg). Arterial hypertension should be treated.
-- The rotational speed should only be reprogrammed
under echocardiographic control. In the echocar-
diohraphy, care must be taken to ensure that the
septum is in the middle, the aortic valve opens in-
termittently and the mitral valve regurgitation is only
mild.
Cardiology 425
• flow
-- syn.: cardiac output (however only a from rotational
speed, power and viscosity [entered hematocrit] cal-
culated and no real cardiac output)
-- specification in l/min
-- norm: > 2.5 l/min
• PI (pulsatility index)
-- specification: no unit (dimensionless)
-- depending on:
◦◦ contractility (The higher the contractility, the higher
the PI.)
◦◦ rotational speed (The
​​ higher the rotational speed,
the lower the PI.)
-- norm: 3-4
◦◦ The higher the PI, the less work is taken over by
the pump (less relief). The work is done more by
the own heart (because of good contractility).
◦◦ The lower the PI, the more work is taken over by
the pump (higher relief). The work is done less by
the own heart (because of poor contractility).
• performance Fig. 611  Various pump parameters are shown on the dis-
-- syn.: power consumption play of the control unit (controller; here HeartMate II). There
-- specification in Watt is no key (or key combination) with which you can switch
off the pump, so you don't have to be afraid here. Further-
-- The higher the rotational speed, the higher the per- more, you cannot change any settings with the controller
formance. (only possible with the monitor device). In the event of mal-
-- An increase in performance indicates pump throm- functions, the controller gives different acoustic and visual
bosis. The power consumption is increased here alarms of different urgency levels (i.a. red: high urgency
due to the friction. level). A corresponding alarm information sheet should al-
ways be close to the patient.
• charging status

Fig. 612  Changes to the setting can only be made with

the monitor device. In principle, this should only be done
in consultation with the cardio technician and only under
echocardiographic control. If you have a patient with an
LVAD in your intensive care unit, you should connect him
to this monitor. This will be delivered immediately after con-
tacting the company by phone. The monitor is inserted bet-
ween the controller and the power supply module.

426 Cardiology

Fig. 613  There is no battery in the controller itself (only
an emergency battery with a running time of 15 minutes).
Therefore, the controller must always be connected to a
power supply: either as here to a battery (14V lithium; note:
The patient is always connected to two batteries as stan-
dard for safety reasons.) or to a power supply. A battery
lasts 12 hours.
Fig. 614  charging station for the batteries: It takes 4 hours
to charge a battery.
Fig. 615  power supply unit (fixed station power supply mo-
dule) for permanent power supply (mains current)
Echocardiography
• Left ventricle size: In case of a malfunction of the pump
(e.g. as a result of thrombosis), the left ventricle gets
dilated (often until ballooning).
• position of the cannula: It should be at a sufficient di-
stance from the septum so that it does not suck up.
• aortic valve: It is usually always closed and does not
open due to the fusion of the sails, which are almost no
longer required due to the non-pulsatile flow. The pre-
sence of aortic valve regurgitation is very unfavorable
("poison" for the LVAD), since this causes the blood
that is ejected into the aorta via the outlet cannula to
flow back into the left ventricle (recirculation), so that
a circulation forms in the heart, that makes the LVAD
ineffective. It occurs on average after three years. In
severe cases, the aortic valve must even be closed
surgically (operation according to Park).
• position of the interventricular septum: It should be in
the middle.
-- If the cannula sucks, the septum is shifted to the left
-- A malfunction of the pump (e.g. as a result of throm-
bosis) leads to a dilation of the left ventricle so that
the septum is shifted to the right.
• assessment of the right ventricle: The function of the left
ventricle is relatively insignificant in an LVAD patient,
since it is supported anyway. The function of the right
ventricle ("Achilles' heel" of the LVAD) is much more
important and prognostically relevant, which should
be assessed accordingly (TAPSE, TASV). If there is
a relevant right ventricular dysfunction, upgrading to a
biventricular system (BiVAD) must be discussed.
• assessment of the flow in the inlet and outlet cannula
in the B-mode (presence of thrombi) and by using color
Doppler and cw Doppler:
-- The inlet cannula (in the left ventricle) is usually
easy to recognize, the outlet cannula (in the aorta)
is mostly difficult to recognize (tip: scan from supra-
sternal).
-- In the HVAD system, the inlet cannula can someti-
mes not be seen due to the typical "waterfall" type
artifact of the centrifugal pump.
-- A velocity > 2 m/s speaks for an obstruction (usually
caused by thrombosis).
Fig. 616  Echocardiography: The inlet cannula can be seen
in the apex of the left ventricle.
Supportive therapy
• fluid administration
-- in cardiogenic shock only very cautious (only with
reduced preload, which is rather rare)
◦◦ earlier recommendation: target CVP 10-12 mmHg
and target LVEDP [wedge pressure] < 18 mmHg
◦◦ today, however, no longer orientation towards fil-
Cardiology 427
 ling pressures; better orientation towards the func-
tional parameters SVV and PPV as well as the
volume parameters GEDV and ITBV
◦◦ if necessary, perform "fluid challenge"
▪▪ volume responsiveness test, i.e. whether the
preload is reduced and the cardiac output can
be increased by adding volume
▪▪ crystalloid150-350ml (4 ml/kg) binnen 15min
◦◦ for the estimation of the preload or volume respon-
siveness see page 225
-- exclusion of pulmonary congestion
-- exception: right ventricular myocardial infarction
(RVMI: Here, patients in cardiogenic shock benefit
from fluid administration.)
• no β-blockers (i.a. van Diepen et al, Crit Care Med
2014) and nitrates (only in case of high SVR) or ACE
inhibitors in cardiogenic shock (discontinue!)
• RCC administration: also only from Hb < 7 g/dl (SI unit:
4.3 mmol/l; target Hb 7-9 g/dl, not > 10 g/dl!)
• loop diuretics (continuous administration via perfusor),
if necessary additional thiazide or xipamide (("sequen-
tial nephron blockade" to break through diuretic resis-
tance); note: If acute kidney failure is also present, hig-
her doses of loop diuretics are required.
-- furosemide 10 mg/ml → up to max. 2 ml/h
-- torasemide 10 mh/ml → up to max. 1 ml/h
• therapy refractory oliguria (cardiorenal syndrome)
[classification: see infobox])
-- acute kidney failure: in 55% in cardiogenic shock
-- early renal replacement therapy (RRT):
◦◦ CVVH or only SCUF (slow continuous ultrafiltrati-
on, i.e. only drainage, no detoxification)
◦◦ The patients in cardiogenic shock are due to
volume overload in section 3 of the Frank-Starling
curve (see page 204). Volume withdrawal can
increase the stroke volume and thus the cardiac
output!! However, a negative fluid balance is often
an impossibility, especially in non-internally mana-
ged intensive care units. Furthermore, the Frank
Starling curve is shifted down here.
◦◦ studies: i.a.
▪▪ UNLOAD study (Constanzo et al, J Card Fail
2010): significantly fewer rehospitalizations
▪▪ Patarroyo et al, J Am Coll Cardiol 2012: signifi-
cant improvement in haemodynamics
▪▪ CARRESS-HF study (Bart et al, N Engl J 2012):
no benefit
-- strongest independent prognostic parameter (Ma-
renzi et al, Crit Care Med 2010)
• intubation and ventilation
-- Cardiogenic shock is (in case of acute respiratory
failure) an absolute indication for invasive ventilation
(no NIV in cardiogenic shock [contraindication!).
-- high PEEP (>10 mbar; reduces preload); excep-
tion: right ventricular myocardial infarction (use the
lowest possible PEEP here!)
-- protective ventilation
-- sedation depth: RASS -2/-3 (deep sedation in
shock!)
428 Cardiology
• hypothermia: Cardiogenic shock without prior resusci-
tation is not an indication for hypothermia (i.a. SHOCK-
COOL study [Fuernau et al, Circulation 2019]: no im-
provement in hemodynamics [no increase in CPO]).
However, if a patient is in cardiogenic shock after re-
suscitation, hypothermia is not contraindicated and is
explicitly recommended in cardiogenic shock after suc-
cessful resuscitation (i.a. Skulec, Acta Anaesthesiol
Scand 2008; Zobel et al, Crit Care Med 2012; COOL-
SHOCK study [Schmidt-Schweda et al, Resusc 2013]:
even improved hemodynamics [cardiac index ↑, CPO
↑]). Cardiogenic shock after successful resuscitation is
not a contraindication for hypothermia.
• 20% of all patients with cardiogenic shock develop
SIRS (possibly sepsis) via cytokine release with the
result that systemic-vascular resistance decreases
and a vasoconstrictor (norepinephrine) is necessary.
Therefore, an advanced haemodynamic monitoring is
always necessary for detection and therapy control.
• therapy of shock liver (ischemic / hypoxic hepatitis):
Cardiogenic shock is the most frequent cause of shock
liver (mortality of shock liver: 50%; see page 869)!
18% of all patients with cardiogenic shock and 7% of
all patients after (out-of-hospital) cardiac arrest deve-
lop a shock liver (Jung et al, Clin Res Cardiol 2016).
• As soon as the patient does not require catecholami-
nes any more (after infarct-telated cardiogenic shock
and with a further impaired pump function [ejection
fraction < 35%]), an appropriate heart failure therapy
(see infobox) should be started.
catecholamine-refractory cardiogenic
shock in inferior wall MI → think of
right ventricular MI (especially in the
absence of pulmonary congestion) →
fluid administration!
The most important (and the only
validated) measure in cardiogenic
shock is early revascularization by
acute PCI!
 • if lactate (parameter of tissue perfusion) > 4 mmol/l:
infaust prognosis
• If cardiogenic shock is survived, however, the long-
term prognosis is very good.

mortality of cardiogenic shock:

45%

The main cause of death in

cardiogenic shock is not cardiac,
but extracardiac (septic multior-
gan failure)!

study

Thirty-Year Trends (1975 to 2005) in the Magnitude, Mana-

gement and Hospital Death Rates Associated With Cardio-
genic Shock in Patients With Acute Myocardial Infarction
Goldberg et al, Circulation 2009

• 13663 patients with infarct-related cardiogenic shock

from 1975-2005
• incidence (of cardiogenic shock in myocardial infarction)
↓ (1975: 7.3%; 2005: 4.1%)
• mortality ↓ (1975: 73.7%; 2005: 42%)

Prognosis
• Cardiogenic shock used to be the shock form with the
highest mortality. In the Worcester Heart Attack study
(Goldberg et al, Am Heart J 2001), a mortality rate of
72% was reported. However, the mortality of cardio-
genic shock has fortunately clearly decreased to 42%
in the last 30 years thanks to the progress made in
interventional cardiology (Babaev et al, JAMA 2005).
Today, the shock with the highest mortality is the septic
shock with a mortality rate of 50%. .
• mortality
-- without recanalization: 75%
-- with recanalization
◦◦ with lysis: 50%
◦◦ with PCI: 30%
• strongest independent predictor: occurrence of acute
kidney failure (in 55%; Marenzi et al, Crit Care Med
2010)
• main cause of death: multiorgan failure (not cardi-
ac!)

Cardiology 429
 Classification
CARDIAC ARRHYTHMIAS • tachycardic cardiac arrhythmias (tachycardia: heart
rate > 100/min)
• bradycardic cardiac arrhythmias (bradycardia: heart
rate < 60/min)

Cardiac arrhythmias represent our daily bread not only in

internal intensive care units but also in all intensive care
units. The incidence of (persistent) cardiac arrhythmia in
intensive care units is 12% (Annane et al, Resp Crit Care
Med 2008). Of these, 47% are atrial fibrillation (the most
common cardiac arrhythmia in intensive care), 13% are
atrial flutter and 13% are higher grade AV blockages. Pa-
tients with sepsis develop atrial fibrillation as an expres-
sion of septic cardiomyopathy in 30% of cases, which
worsens the prognosis.

tachycardic cardiac
arrhythmias
• narrow QRS complex tachycardia (NCT: narrow com-
plex tachycardia)
• wide QRS complex tachycardia (WCT: wide complex
tachycardia)

Tachycardia

OMG tachycardia ("oh my god"):

wide complex tachycardia (WCT)
NOMG tachycardia ("not oh my
god"): narrow complex tachycar-
dia (NCT)

430 Cardiology

NARROW COMPLEX TACHY-
CARDIA (NCT)
Irregular narrow complex tachycar-
dia
• almost always atrial fibrillation
• rarely atrial flutter with inconstant conduction
Atrial fibrillation
Definition
• most common cardiac arrhythmia
• a supraventricular tachycardia characterized by disor-
ganized electrical atrial activity (micro-reentry) without
effective atrial contraction
• incidence ↑ with increasing age (in the 6th decade: 5%,
in the 7th decade: 10%)
• twice as high mortality compared to the normal popu-
lation
• ESC Guidelines for the diagnosis and management
of atrial fibrillation developed in collaboration with the
European Association of Cardio-Thoracic Surgery
(EACTS) 2020
FROG-ICU study
New-onset atrial fibrillation in critically ill patients and its
association with mortality
Arrigo et al, Inter J Cardiol 2018
• prospective multicenter cohort study (observational stu-
dy)
• 1841 intensive care patients who were either ventilated
for > 24 hours or treated with inotropics
• results:
-- in 19% atrial fibrillation
-- significantly increased mortality in newl-onset atrial
fibrillation (47%) compared to patients with recur-
rent atrial fibrillation (34%) or without atrial fibrillation
(23%)
-- new-onset atrial fibrillation as an independent risk fac-
tor for hospital mortality
Classification
• according to duration (However, anticoagulation is re-
commended regardless of the type of atrial fibrillation!):
-- paroxysmal (spontaneous termination within 7 days)
-- persistent (cardiovertable [pharmacological / electri-
cal])
-- permanent (no longer cardiovertable; accepted by
physician and patient)
• according to symptoms: EHRA classifikation (EHRA:
European Heart Rhythm Association)
-- I: no complaints (asymptomatic)
-- II: moderate complaints (normal daily activity not yet
restricted)
-- III: severe complaints (normal daily activity already
restricted)
-- IV: massive complaints (normal daily activity no lon-
ger possible)
Fig. 617  Tachyarrhythmia absoluta
Therapie (Tachyarrhythmia absoluta)
• checking and, if necessary, balancing serum electroly-
tes (especially potassium 4.5-5.5 mmol/l, magnesium
> 1 mmol/l
• digoxin (e.g. Novodigal, Lanicor)
-- 2-3 amp. Lanicor (a 0.25mg) i.v.
-- prior measurement (if possible) of potassium, calci-
um, creatinine and, if necessary, digitalis levels (if
digitalis in previous medication)
-- dosage more by clinic (less by level [Digitalis levels
play a role more in toxicology.])
-- digitoxin unsuitable due to slow onset of action
-- contraindications: i.a.
◦◦ acute myocardial infarction (Here the Na-K-
ATP-ase is already inhibited by the ischemia, so
that the digitalis toxicity is increased.)
◦◦ WPW syndrome
◦◦ malignant hyperthermia (Glycosides increase the
intracellular calcium concentration and thus rein-
force malignant hyperthermia.)
◦◦ electrolyte disorder
▪▪ hypokalemia
▪▪ hypercalcemia
▪▪ hypomagnesemia
◦◦ HOCM (hypertrophic obstructive cardiomyopathy;
Digitalis leads due to its inotropic effect to an incre-
ase in intracavitary pressure gradient
-- In a post-hoc analysis (Increased mortality
among patients taking digoxin - analysis from the
AFFIRM study; Whitbeck et al, Eur Heart J 2012) of
the AFFIRM study, total mortality increased by 41%,
cardiovascular deaths by 35% and arrhythmia-rela-
ted deaths by 61% with the use of digoxin! However,
a post-hoc analysis of the AFFIRM study carried out
with another method in the following year could not
Cardiology 431
 confirm this. Also in the retrospective cohort study
TREAT-AF (Turakhia et al, J Am Coll Cardiol 2014),
the group treated with digitalis showed (after corre-
sponding adjustment of the comparison groups) an
increased mortality. The same result was found in a
meta-analysis (Vamos et al, Eur Heart J 2015). Ano-
ther meta-analysis (Ziff et al, BMI 2015) showed no
increase in mortality. The meta-analysis by Korecha
et al (BMJ 2015), which included all studies on digi-
talis since 1960, also showed no increase in morta-
lity. Prospective studies on this topic were (finally)
started (DIGIT-HF, RATE-AF).
• verapamil (Isoptin) 2.5-5mg (max. 20mg) slowly i.v.
-- substance with the strongest frequency regula-
tion
-- never in combination with β-Blocker or in patients
who have β-blockers in the previous medication (due
to the danger of higher degree AV-blocks)
-- not in patients with systolic heart failure (HFREF
[heart failure with reduced ejection fraction]) due to
the negative inotropic effect
• β-blocker
-- long-acting: metoprolol (Beloc) i.v. (slowly 1-3mg re-
petitively up to max. 15mg)
-- short-acting: esmolol (Brevibloc, Esmocard) 40-
50mg (exactly: 0.5 mg/kg; over 1min) i.v.
-- ultra short-acting: landiolol (Rapibloc):
◦◦ T1/2 only 3-4 min, duration of action 15min
◦◦ since 2017 on the market
◦◦ highest β1 selectivity
◦◦ only low (around 10%) drop in blood pressure
◦◦ dosage (bottle with powder with 300mg or 600mg;
concentrate 1ml/10mg): initially 100 μg/kg over
1min, then continuously 10-40 μg/kg/min
• amiodarone (Cordarex): 150-300mg i.v. or as short in-
fusion (in 250ml G5%)
• R-wave triggered synchronized cardioversion in short
anesthesia (e.g. 0.05mg fentanyl + 50-100mg propo-
fol)
• tachyarrhythmia absoluta in hyperthyroidism →
drug of choice: propranolol (Dociton) 1-2mg i.v
• In (especially stressed) intensive care patients it is
often very helpful to lower the increased sympathetic
tone by administering a benzodiazepine.
Tachyarrhythmia is not the result of a
lack of volume (a micro-reentry)!
Volume administration is therefore
not a therapy for tachyarrhythmia!
Rhythm versus frequency control
• Frequency control (target heart rate permanently <
110/min) is just as good as rhythm control (AFFIRM
study [see box], RACE study). In patients with heart
failure, the rhythm control by electrical cardioversion
showed no benefit in mortality (AF-CHF study [see
box]), but the atrial fibrillation ablation showed an be-
nefit in mortality (CASTLE-AF study [Marrouche et al,
432 Cardiology
N Engl J 2018]).
• PIAF study (Hohnloser et al, Lancet 2000): better resi-
lience of patients in sinus rhythm
• spontaneous conversion rate: 17%
AFFIRM study
Comparison of Rate Control and Rhythm Control in Pa-
tients with Atrial Fibrillation
The Atrial Fibrillation Follow-up Investigation of Rhythm
Management (AFFIRM) Investigators, N Engl J 2002
• multicentre randomized controlled study
• 4060 patients with atrial fibrillation
-- rhythm control (amiodarone, sotalol)
-- frequency control (β-blocker, diltiazem, verapamil)
• results
-- no difference (even tendentially increased in rhythm
control group!)
-- more hospitalizations and adverse events in rhythm
control group
AF-CHF study
Rhythm Control versus Rate Control for Atrial Fibrillation
and Heart Failure
Roy et al, N Engl J 2008
• prospective multicenter randomized study
• 1376 patients with atrial fibrillation and heart failure
(NYHA III/IV, EF < 35%)
-- rhythm control (electrical cardioversion)
-- frequency control
• results: frequency control
-- no mortality benefit
-- increased hospital admissions
Cardioversion
• pharmacological (rarely indicated; e.g. in pacemaker
patients [cave, however, in patients who are complete-
ly pacemaker-dependent: Both flecainide, propafeno-
ne and amiodarone lead to an increase of the myocar-
dial threshold, so that an exit block can occur and the
patient then becomes completely asystolic. If a medi-
cal cardioversion is performed here, the programming
device should always be already connected in order to
increase the output, i.e. above all the pulse amplitude,
in case of an exit block.])
• electrical
Pharmacological cardioversion
• flecainide (50mg i.v.; cave: Here a conversion of atrial
fibrillation into atrial flutter [so-called class IC atrial flut-
 ter] with a 1: 1 conduction to the chamber is possible!),
propafenone (both only with normal ejection fraction
due to the negative intotropic effect)
• amiodarone
-- advantage: also possible with reduced ejection frac-
tion
-- disadvantages:
◦◦ relatively slow onset of action
◦◦ low cardioversion rate (only 23% [PIAF study];
amiodarone is a bad cardioversion agent!)
• Vernakalant
Propafenone (Rytmonorma)
• 4 tablets a 150mg at once p.o. (i.v.-administration [2
mg/kg] without benefit)
• early administration (within 3h)
• side effects:
-- nausea, vomiting
-- headache, dizziness, visual disturbance, paresthe-
sia
-- QRS widening
-- bronchial obstruction (cave in COPD / bronchial
asthma)
• contraindication:
-- heart failure (echocardiography previously obligato-
ry to exclude a decreased ejection fraction!)
-- note: in case of structural heart disease (e.g. CHD)
permitted (for cardioversion; not for relapse prophy-
laxis)
• success rate: 70% (electrical: 90%), success mostly
after 4h
Vernakalant (Brinavess)
• ARDA (atrial-repolarisation delaying agent)
• atrial selective (in contrast to all other antiarrhythmics
almost only acts on the atrium)
• a multichannel blocker
• since 2010 approved for i.v. cardioversion of atrial fib-
rillation (< 7d, after cardiac surgery < 3d)
• studies:
-- ACT I-III (significantly higher cardioversion rate than
placebo [ACT I: 51% versus 4%, ACT III: 51,2% ver-
sus 3,6%])
-- AVRO (significantly higher cardioversion rate than
amiodarone)
• dosage: 3 mg/kg i.v. over 10min (if 15min after the end
of further atrial fibrillation → 2 mg/kg)
• success rate: 52% (AVRO study; also no miracle drug!)
• median time to conversion to sinus rhythm: 10min
• monitoring after administration subsequently for 5h
• contraindications:
-- heart failure NYHA III/IV; EF < 35%
-- acute coronary syndrome or status post acute coro-
nary syndrome in the last 30d
-- aortic valve stenosis (higher grade)
-- SBP < 100 mmHg
-- QT interval prolongation
-- within 4h after administration of an antiarrhythmic
class I/III
• side effect: i.a. metallic taste in the mouth, sneezing,
nausea
• price: 1 amp. (500mg) 395 €
Electrical cardioversion
• informed consent (for elective cardioversion):
-- risk of anaesthesia
-- ventricular fibrillation
-- thromboembolism (e.g. stroke)
-- myalgias (e.g. muscle ache)
-- burns
• possibly discontinuation of digitalis (increased risk of
higher-grade AV blocks and ventricular arrhythmias) in
elective cardioversion
• TEE:
-- if duration of atrial fibrillation not certain < 48h:
prior TEE sufficient to exclude intracardiac thrombus
(replaces 3-4 weeks of anticoagulation [ACUTE stu-
dy, ACE study])
-- recommended in the current ESC guidelines also for
duration < 48h
-- best TEE and electrical cardiobversion in one sessi-
on (only one short anaesthesia; not spread over two
sessions with one short anaesthesia each)
-- In case of emergency (e.g. haemodynamically
already unstable patient due to TAA) no TEE is ne-
cessary before!
-- also necessary before pharmacological (and not just
electrical) cardioversion (e.g. before administration
of amiodarone [In an emergency, however, just like
with the electrical cardioversion, no TEE is neces-
sary]); the administration of a class I or III (e.g.
amiodarone) anti-arrhythmic represents an attempt
at cardioversion, but not the administration of a class
II (β-blocker) or class IV (calcium antagonist) anti-
arrhythmic or of digitalis
-- Often, spontaneous echo contrast ("smoke", streaks,
vortex) is found in the TEE in patients with atrial fi-
brillation in the left atrium. This is due to an increa-
sed erythrocyte aggregation (“money roll formation”)
and is caused by the disturbed atrial contractility.
The spontaneous echo contrast accordingly shows
no regression under anticoagulation, since the anti-
coagulation does not improve the contractility in the
left atrium. The sole detection of spontaneous echo
contrast (even in pronounced form) without detec-
tion of a thrombus is therefore not a contraindication
to cardioversion.
-- If a thrombus appears in the TEE (e.g. in the left
atrial appendage), oral anticoagulation should be
performed for 3 weeks and then a TEE should be
performed again: If there is still a thrombus, no cardi-
oversion is performed, only frequency control.
-- Non-elevated D-dimers almost rule out a thrombus
in the LAA! Sensitivity:
◦◦ according to Habara et al, Eur Heart J 2006: 97%
◦◦ according to Almorad et al, BMJ Heart 2020: even
100% (if D-dimers in ng/ml < 10 x age of the pati-
ent in years)
Cardiology 433
• compensation of electrolyte disorders (e.g. target po-
tassium > 4 mmol/l, magnesium > 1 mmol/l)
• short anaesthesia:
-- analgesic (note: It is not uncommon to see that elec-
trical cardioversion is carried out only with a seda-
tive [hypnotic; e.g. propofol] without an analgesic.
You shouldn't do that! An electrical cardioversion is
extremely painful. Propofol is only sedative and not
analgesic, i.e. the patients definitely feel the pain,
tehy just can't say it!):
◦◦ fentanyl 0.03-0.10 mg or
◦◦ alfentanil (Rapifen)
▪▪ 1 amp. = 1mg
▪▪ dosage: 10-30 μg/kg (e.g. 70kg patient: 1mg)
▪▪ frequent side effect: thoracic rigidity (tip: before
1/2 vial, then hypnotic, then again 1/2 vial)
-- hypnotic (sedative; e.g. etomidat 5-10mg or propofol
50-100mg)
• possibly short bag mask ventilation (usually not neces-
sary); note: If it is an emergency and the patient is not
fasting, he must first be intubated ("crush" intubation,
rapid sequence induction).
• using paddles or adhesive electrodes
• The a.p. cardioversion ("sandwich" technique; e.g.
with adhesive electrodes) has a higher success rate
than the conventional (sternal-apical) cardioversion
(applies only for monophasic, not for biphasic).
• Biphasic cardioversion is clearly superior to monopha-
sic cardioversion.
• energy dose: Joule (J)
-- atrial flutter: usually only low energy necessary (start
with 30-50 J [biphasic]; children: 0.5 J/kg)
-- atrial fibrillation: usually higher energy necessary
(100 J, 200 J, 360 J); abortion if 2 x 360 J was un-
successful; in this case we administer 150 mg ami-
odarone i.v. during the short anesthetis and perform
another cardioversion attempt with 360 J after 5 mi-
nutes
-- ventricular tachycardia: initially 200 J, then 360 J
• R-wave triggered ("SYNC"-button has to be pressed
again after each shock!), in order not to stimulate the
vulnerable phase (first half of the T wave, i.e. the as-
cending part; R on T phenomenon; but only makes up
1% of the entire cardiac cycle) and to trigger ventricu-
lar fibrillation
• If the patient is an AICD carrier, an internal cardioversi-
on can also be performed.
• no longer indicated if: i.a.
-- size of left atrium > 55mm (only relative; one attempt
is justified)
-- duration of atrial fibrillation > 1 year
-- missing symptoms (cardioversion only if atrial fibril-
lation is symptomatic!)
• As soon as the patient is awake, he should be exami-
ned roughly neurologically with regard to an embolic
cerebral infarction as a complication of cardioversion
(movement of all 4 extremities, drooping corner of the
mouth, eyelid closure on both sides and frowning).
• After a successful cardioversion, the aim should be
to maintain the sinus rhythm. Means of choice for the
434 Cardiology
maintainance of sinus rhythm are β-blocker. Digita-
lis should be discontinued with sinus rhythm, because
it increases the risk of rebounding in atrial fibrillation!
• Frequently, however, in intensive care patients car-
dioversion does not lead to (lasting) success in atrial
fibrillation, as the patients often have catecholamine
perfusors and the endogenous sympathetic tonus (tip:
benzodiazepine!) is often even increased.
• If the electrical cardioversion was unsuccessful, the
patient can be saturated with amiodarone and then the
electrical cardioversion repeated. Saturation:
-- If amiodarone is given intravenously over a longer
period (> 24 hours), it should be administered cen-
tral-venously via a CVC, as it irritates the veins.
-- perfusor: 5 amp. a 150mg a 3ml + 35ml G5%, 15mg/
ml (alternatively also as an infusion in 250ml G5%
[here no CVC absolutely necessary])
-- saturation dosage: 6g
◦◦ daily 1000mg over 6 days or
◦◦ daily 1500mg over 4 days
-- daily 12-lead ECG to check QT interval prolongation
-- no more level determinations (target levels: 1,3-3,7
µmol/l or 0,7-2,5 mg/l) recommended (obsolete),
since there is no correlation between the plasma le-
vel and the antiarrhythmic effect
-- then maintenance dose of 200mg once daily
• anticoagulation:
-- After a successful cardioversion, anticoagulation
should always (regardless of whether atrial fibrilla-
tion lasted longer or shorter than 48 hours [reason:
"atrial stunning") for at least 4 weeks (exception:
CHADS2 score / CHA2DS2-Vascscore: 0P.). For this
also NOAC are appoved:
◦◦ rivaroxaban (for 4 weeks 1 x daily 20mg [X-VeRT
study])
◦◦ edoxaban (for 4 weeks 1 x daily 60mg [ENSURE-
AF study])
◦◦ apixaban (for 4 weeks 2 x daily 5mg [EMANAT
study])
-- Even after successful cardioversion in sinus rhythm
a lifelong oral anticoagulation is recommended in
case of an increased risk (p.d. CHADS2 score > 1P.
or CHA2DS2-Vasc score > 2P.)! Most recurrences of
atrial fibrillation are asymptomatic (PAFAC study:
70%).
electrical cardioversion: not only with
a sedative, but always with an
analgesic!
 ACUTE study

Use of Transesophageal Echocardiography to Guide Car-

dioversion in Patients with Atrial Fibrillation
Klein et al, N Engl J 2001

• multicenter prospective randomized controlled study

• 1222 patients with atrial fibrillation > 48h
-- previously 3 weeks of oral anticoagulation with warfa- Fig. 619  If you are unsure whether the left atrial appenda-
rin with INR in target area ge (LAA) is actually free of a thrombus, you can use a left
-- only TEE (exclusion of thrombus) heart contrast agent (here: SonoVue). The LAA is filled up
• results: completely with contrast medium, so that the cardioversion
can take place.
-- primary endpoint: ischemic stroke, TIA, peripheral
embolism → no difference
-- higher success rate by early cardioversion

RACE-7-ACWAS study

Early or Delayed Cardioversion in Recent-Onset Atrial Fi- Fig. 620  electrical cardioversion: application of the adhesi-
brillation ve electrodes (here conventional sternal-apical)
Pluymaekers et al, N Engl J 2019

• multicenter randomized non-inferiority study

• Rate Control versus Electrical Cardioversion Trial - Acu-
te Cardioversion versus Wait and See
• 437 patients with recent-onset (<36h) symptomatic at- Fig. 621  electrical cardioversion in atrial fibrillation (left
rial fibrillation (hemodynamically stable); cardioversion in the ECG): Here it was forgotten to press the synchro-
(pharmacological / electrical) nization button. The impulse fell into the vulnerable phase
-- early (ascending part of the T-wave) and triggered ventricular fi-
-- late (only > 48h ["wait & see"]; only frequency control) brillation (on the right in the ECG). If an attempt has failed
• results and the joule number is increased for the next attempt, the
synchronization button must be pressed again!
-- sinus rhythm after 4 weeks (primary endpoint): no dif-
ference
-- relapse rate: no difference
CHADS2-Score
-- symptoms / quality of life: no difference
-- in the late group in 69% spontaneous conversion
points
to sinus rhythm (i.e. in 69% unnecessary cardioversi-
on in the early group; note: "The slow horse reaches C: Congestive heart failure 1
the mill!")
H: Hypertension 1
A: Age > 75 years 1
D: Diabetes mellitus 1
S: Stroke / TIA 2

CHADS2 score > 1P. : indication for

oral anticoagulation!

Fig. 618  TEE: thrombus in the left atrium (i.a. in the LAA)

Cardiology 435
CHA2DS2-Vasc score

points
C: congestive heart failure (EF < 40%) 1
H: Hypertension 1
A: Age > 75 years 2
D: Diabetes mellitus 1
S: Stroke / TIA 2
V: Vascular disease (previous myocardial
infarction, PAD, aortic plaques) 1
A: Age 65-75 years 1
S: sex category (female; does not count at
age < 65 years) 1

CHA2DS2-Vasc score > 1P. (man)

respectively > 2P. (woman): indication
for oral anticoagulation!

HAS-BLED score
Every third patient with sepsis has atrial fibrillation. Co-
agulation disorders and thrombopenia often occur in
points
sepsis. In a retrospective cohort study (Walkey et al,
H: Hypertension 1 JAMA Cardiology 2016 [see box]), a fully therapeutic
A: abnormal kidney or liver function (1 anticoagulation showed no advantages, but rather dis-
point each) 1-2 advantages in the sense of an increased bleeding rate!
S: Stroke 1
B: Bleeding 1
L: Labile INR 1
E: Elderly (age > 65 years) 1
D: drugs or alcohol (1 point each) 1-2

Risc of bleeding:
• HAS-BLED score < 3P.: low
• HAS-BLED score ≥ 3P.: high

Even patients with a low CHA2DS2-Vasc score on the one

hand and a high HAS-BLED score on the other hand be-
nefit from oral anticoagulation in the long-term!

The only therapy for atrial fibrilla-

tion with prognostic relevance is
anticoagulation (and not rhythm
or frequency control)! The
non-induction of oral anticoagula-
tion must be justified!

436 Cardiology
Fig. 622  It is not uncommon for patients with atrial fibril-
lation to always be fully anticoagulated as standard in the
intensive care unit, as if they had suffered a fresh pulmona-
ry embolism the previous day, for example. In the intensi-
ve care unit, it is usually only an epiphenomenon of septic
cardiomyopathy in sepsis or a side effect of the catechola-
mines. The daily risk of suffering from an embolic stroke in
atrial fibrillation is only very low at 1: 10000 (with a high risk
also only 1: 5000), so that generally no full anticoagulation
is necessary. In the course of sepsis, coagulation disor-
ders and DIC with thrombopenia often occur, so that it can
bleed here. Furthermore, unscheduled invasive procedures
or even operations for infectious source control are often
necessary in the ICU, which can lead to pronounced blee-
ding under fully therapeutic anticoagulation. For example,
the risk of the lamp (see arrow) falling on the patient's head
in the ICU room and causing severe TBI is probably not
much lower either than the risk of suffering a stroke, es-
pecially during the short (usually only a few days) stay in
the intensive care unit with atrial fibrillation. So, if you al-
ways perform a full anticoagulation with ICU patients only
because of atrial fibrillation, you should consequently also
put on a helmet for the patient to protect him from severe
TBI from the possibly down falling lamp. Anticoagulation
is certainly important in the long term then even the most
important measure!), but not essential during the usually
short ICU stay. Exceptions (e.g. valvular atrial fibrillation or
atrial fibrillation with a high cardioembolic risk [e.g. recent
cerebral ischemia]), however, remain unaffected.
study
Practice Patterns and Outcomes Associated With Use of
Anticoagulation Among Patients With Atrial Fibrillation Dur-
ing Sepsis
Walkey et al, JAMA Cardiology 2016
• retrospective cohort study
• 38582 patients with sepsis and atrial fibrillation (without
any other reasons for full anticoagulation)
-- with fully therapeutic anticoagulation (parenteral)
-- without fully therapeutic anticoagulation
• results: fully therapeutic anticoagulation
-- ischemic stroke: no difference (neither with pre-
existing nor with new-onset atrial fibrillation)
-- bleeding: significantly increased
tely to antiarrhythmic drugs or who do not tolerate
them (Atrial fibrillation ablation is only the second
choice: It is only recommended if a class I or class III
antiarrhythmic drug does not succeed in stabilizing
the sinus rhythm.)
-- tachymyopathy (in permanent atrial fibrillation, i.e.
non-cardiovertable [not even after amiodarone sa-
turation])
-- tachycardia-bradycardia syndrome (sick sinus syn-
drome) to avoid a pacemaker implantation
-- The intention of terminating oral anticoagulation is
definitely not an indication for atrial fibrillation ablati-
on! Even after (clinically) successful ablation, there
is still an indication for oral anticoagulation due to the
possibility of asymptomatic relapses depending on
the CHA2DS2Vasc score.
• success rate:
-- paroxysmal atrial fibrillation: 80%
-- persistent atrial fibrillation: 60%
• assessment: a purely symptomatic therapy (therefore
only indicated in symptomatic patients), no mortality
advantage (CABANA study 2018 [see box]; mortality
advantage only demonstrated in atrial fibrillation with
heart failure [CASTLE-AF study: Marrouche et al, N
Engl J 2018])
• complications: i.a.
-- pericardial tamponade (the most frequent poten-
tially life-threatening complication)
-- lesion of the phrenic nerve (often spontaneous re-
mission)
-- pulmonary vein stenosis (scarred stricture; often
haemoptysis; <1%)
-- TIA, stroke
-- myocardial infarction
-- pulmonary embolism
-- atrioesophageal fistula (0.05%; most severe compli-
cation)

Atrial fibrillation ablation

• syn.: pulmonary vein isolation
• Impulses from the pulmonary veins can induce atrial
fibrillation (75% of foci localized there; triggers).
• electrical isolation
• techniques (both equivalent [i.e. FIRE & ICE study
2016]):
-- radiofrequency ablation (most frequent)
-- cryoballoon ablation
• indications:
-- young symptomatic patients with paroxysmal (less
persistent [here not so useful, e.g. STAR-AF study
2014]) atrial fibrillation who do not respond adequa-

Cardiology 437
 CABANA study

Catheter ablation vs antiarrhythmic drug therapy in atrial

fibrillation
Packer et al, ACC 2018

• multicenter randomized study

• 2204 patients with atrial fibrillation requiring treatment
(including anticoagulation in all patients)
-- with ablation (pulmonary vein isolation)
-- without ablation (only the best possible pharmacologi-
cal therapy [rhythm / fetquency control])
• result: ablation → no reduction in the combined pri-
mary endpoint (death, severe stroke, severe bleeding,
cardiovascular arrest [within 5 years])
• note: relatively high crossover rate (However, 27.5% of
all patients who were primarily in the purely pharmaco-
logical group still received an ablation. After a corres-
ponding "treatment received" analysis, a significant re-
duction in the primary endpoint could be shown for the
ablation.)

Closure of the left atrial appendage (LAA

closure)
Types
• For a long time now, the left atrial appendage has been
closed (resection, amputation; note: Ligation alone is
not sufficient.) in patients with atrial fibrillation who un-
dergo cardiothoracic surgery. The proximity to the left
circumflex artery should be noted.
• interventional
-- endocardial; occlusion systems (atrial occluder):
◦◦ Watchman (Boston Scientific; only for this rando-
mized controlled trials)
Fig. 623  Atrial fibrillation ablation (pulmonary vein isolati- ◦◦ Amplatzer Cardiac Plug (ACP; St. Jude Medical),
on): Yellow depicts the ablation catheter located in the re- successor: Amplatzer Amulet LAA-Occluder
gion of the ridge (between the left upper pulmonary vein ◦◦ Ultraseal (Cardia)
and the left atrial appendage); green the 10-pole mapping
catheter (so-called lasso catheter) and blue the reference
◦◦ LAA-Occluder (Occlutech)
catheter in the region of the coronary sinus (courtesy of Dr. ◦◦ WaveCrest (Johnson & Johnson)
Kurzidim, Medical Director of the Clinic for Rhythmology, ◦◦ PLAATO (percutaneous left atrial appendage
hospital Barmherzige Brüder, Regensburg [Germany]) transcatheter occlusion; from market)
-- epicardial (e.g.. LARIAT [SentreHEART]; very com-
plex [i.a. pericardial puncture necessary])

Definition
• Predilection site for thrombus formation in atrial fibrilla-
tion in the left atrium is the left atrial appendage (LAA).
90% of all thrombi in the left atrium in non-valvular at-
rial fibrillation are in the left atrial appendage (note: in
valvular atrial fibrillation only in 50%, so that a systemic
therapy [oral anticoagulation] is definitely necessary
here). This can be closed interventionally or surgically.
• indication: atrial fibrillation with increased thrombem-
bolic risk (CHADS2 score > 1P. or CHA2DS2-Vasc
score > 2P.) + contraindication / intolerance for oral

438 Cardiology
 anticoagulation / increased bleeding risk (HAS-BLED
score ≥ 3P.)
• recommendation grade IIb (ESC-Guidelines 2016 and
2020; only a weak recommendation; even if there are
contraindications to oral anticoagulation [e.g. after life-
threatening bleeding without a reversible cause, i.e. for
example not after upper gastrointestinal bleeding from
an ulcer that has been treated with a hemoclip])
• interventional placement (in the cardiac catheterizati-
on lab: puncture of the femoral vein, catheter advan-
ce into the right atrium, then transseptal puncture and
catheter advance into the left atrium; TEE-controlled)
• for 3 months after implantation dual antiplatelet thera-
py (ASA 100mg + Clopidogrel 75mg), then ASA 100mg
lifelong (If the risk of bleeding is increased, ASA can
also be stopped at any time, so that the patient then no Fig. 625  TEE: The Watchman device was placed in the left
longer has any anticoagulant medication.) atrial appendage (LAA).

• for 6 months endocarditis prophylaxis

Fig. 626  AGA Cardiac Plug [3]

Studies
• PROTECT AF study (see box)
• PREVAIL study (see box): The results of this some-
what comical and especially complicated study were
little convincing. There were no clear advantages.
• PRAGUE-17 study: comparison with NOAC (see box)

PROTECT AF study

Fig. 624  Watchman device [5]

Embolic Protection in Patients with Atrial Fibrillation

Holmes et al, Lancet 2009

• multicenter prospective randomized study

• 800 patients with non-valvular atrial fibrillation and
CHADS2 score > 1P.
-- oral anticoagulation with VKA (Vitamin K antagonist
[warfarin])
-- LAA closure (Watchman device)
• result: non-inferiority of the LAA closure to warfarin in
stroke rate (significantly less hemorrhagic strokes)

Cardiology 439
 PREVAIL study
Evaluation of the WATCHMAN LAA Closure Device in Pa-
tients With Atrial Fibrillation Versus Long Term Warfarin
Therapy
Holmes et al, J Am Coll Cardiol 2014
• multicenter prospective randomized study
• 407 patients with non-valvular atrial fibrillation and
CHADS2 score > 1P.
-- 269 patients: LAA closure (Watchman device)
-- 138 patients: oral anticoagulation with VKA (Vitamin K
antagonist [warfarin])
• results:
-- successful implantation in 95%
-- endpoints
◦◦ safety endpoint (within 7d: death, ischemic stroke,
systemic embolism, procedural or device associa-
ted complications): in 2.2% occurring (met)
◦◦ effectiveness endpoints (after 18 months)
▪▪ primary: combined endpoint of stroke, systemic
embolism, cardiovascular or unexplained death:
6.4% in both groups (no benefit)
▪▪ secondary: combined endpoint of stroke, syste-
mic embolism > 7d after implantation: 2.53% in
LAA group versus 2.01% in warfarin group (even
slightly more frequent)
PRAGUE-17 study
Left Atrial Appendage Closure Versus Direct Oral Antico-
agulants in High-Risk Patients With Atrial Fibrillation
Osmancik et al, J Am Coll Cardiol 2020
• multicenter prospective randomized controlled non-infe-
riority study
• 402 patients with non-valvular atrial fibrillation with one
of the following criteria: CHADS2Vasc score ≥ 3P., HAS-
BLED score > 2P., previous bleeding with need for hos-
pitalization or intervention, cardioembolic event under
oral anticoagulation
-- oral anticoagulation with NOAC (all substances; main-
ly apixaban)
-- LAA closure (Watchman or Amulet; DAPT for 3
months; if there was then no thrombus in the TEE:
ASA alone)
• result: non-inferiority of LAA closure to NOAC with
regard to the primary combined endpoint cardiovascu-
lar death, stroke / TIA, systemic embolism, significant
bleeding
440 Cardiology
APPLY study
Left atrial appendage closure versus medical therapy in
patients with atrial fibrillation
Gloekler et al, EuroIntervention 2020
• retrospective observational study (propensity score ana-
lysis; two centers in Switzerland)
• 1000 patients with non-valvular atrial fibrillation (median
CHADS2Vasc score: 4P., medianer HAS-BLED score:
3P.)
-- oral anticoagulation (VKA or NOAC)
-- LAA-closure (Amplatzer Cardiac Plug)
• results: LAA-closure
-- significant reduction of the primary composite end-
point (stroke, systemic embolism, cardiovascular or
unexplained death)
-- significant reduction of mortality
Complications
• pericardial tamponade
• ASD (due to the the transseptal puncture)
• stroke
• dislocation (hence TEE control post-interventionally on
day 1, after 4 weeks and 3 months)
• endocarditis (therefore endocarditis prophylaxis re-
commended for 6 months [then endothelialized])
Regular narrow complex tachycar-
dias
• types:
-- sinus tachycardia
-- atrial flutter
-- ectopic atrial tachycardia
-- AV node reentry tachycardia (AVNRT)
-- orthodrome AV reentry tachycardia (WPW syndro-
me)
-- permanent junctional reentry tachycardia (PJRT)
• guideline: ESC Guidelines for the management of pati-
ents with supraventricular tachycardia 2019 (previous-
ly from 2003)
Sinus tachycardia
Definition
• heart rate > 100/min (lying in bed mostly < 130/min!)
with evidence of a P wave that is positive in II, III and
aVF and negative or biphasic in V1
• "There is no sinus tachycardia in bed of 150/min" →
atrial flutter
• never sudden onset → AVNRT
Etiology • type II
• physiological -- flutter waves in II, III, aVF positive and in V1 negative
-- infants, toddlers -- reentry: clockwise
-- stress -- flutter frequency > 350/min
-- increased sympathetic tone -- poor response to atrial overstimulation and isthmus
-- pregnancy ablation
• pathological
Diagnostics
-- fever (1°C → increase of the heart rate by 10/min)
• ECG
-- pulmonary embolism (Sinus tachycardia is the
most sensitive ECG sign of pulmonary embolism -- flutter waves ("saw-teeth")
[and not the SIQIII type]!) -- no isoelectric line present (in contrast to ectopic at-
-- pain rial tachycardia)
-- lack of volume -- If atrial flutter is normofrequent, it is usually ea-
-- anemia (DO2 = CO x SO2 x Hb: The body tries to sily recognized. However, if it is tachycardic (usually
prevent a drop in the oxygen supply DO2 caused by heart rate around 150/min), it is almost always over-
the low hemoglobin by increasing the CO [= stroke looked in clinical routine (especially by non-internal
volume x heart rate] via the heart rate. Therefore, colleagues): The classic misdiagnosis is always si-
patients with a relevant anemia have mostly also ta- nus tachycardia. Almost always, under the idea of
chycardia.) "lack of volume", volume is also given, which can
quickly lead to cardiac decompensation with pulmo-
-- hyperthyroidism
nary edema, as a heart with tachycardic atrial flutter
-- heart failure, myocarditis, cor pulmonale usually only pumps insufficiently. If you are unsure
-- withdrawal, delirium whether a sinus tachycardia or atrial flutter is present
-- status post grand mal seizure (here mostly the sinus (especially with unclear hemodynamic instability),
tachycardia with the highest frequency) you should perform a carotid sinus massage or an
• pharmacological (medication [e.g. catecholamines], adenosine test to unmask the flutter waves and con-
drugs [e.g. amphetamines, cocaine]) firm the diagnosis of atrial flutter and then treat this
(if necessary with electrical cardioversion).
-- tip: The best way to assess atrial actions is in the
Lewis lead (see page 448)!
Memo: no therapy of sinus tachycar-
dia with β-blocker (on-demand • vagal manoeuvres (e.g. carotid sinus massage), ade-
tachycardia; no ECG cosmetics)! nosine (Adrekar) → demasking the flutter waves
note: The lowering of the heart rate
(with sinus tachycardia) with Atrial flutter is the most frequently
β-blockers corresponds in analogy overlooked rhythm disorder! regular
to the lowering of the respiratory narrow complex tachycardia of
rate of a tachypnoeic patient by approx. 140-160/min: almost always
holding nose and mouth shut! atrial flutter (2:1 transition)
classic misdiagnosis: sinus tachy-
cardia
Atrial flutter

Definition
• a macro-reentry (right atrial; in the area of the cavo-
tricuspid isthmus
• mostly underlying organic heart disease (most fre-
quent cause: CHD)
• often in intensive care (13% of all intensive care pa-
tients [Annane et al, Resp Crit Care Med 2007]) and
unfortunately often overlooked
• mostly protective block (AV-block II → 2:1/3:1-transiti-
on; the AV block in atrial flutter is physiological!)

Types
• type I (common type)
-- flutter waves in II, III, aVF negative and in V1 positive
-- reentry: counterclockwise Fig. 627  Atrial flutter: If it occurs at normal heart rate, the
-- flutter frequency < 350/min diagnosis is usually simple. The flutter waves are easy to
-- good response to atrial overstimulation and isthmus detect (3:1 transition).
ablation

Cardiology 441
 HR 150/min This is no P-wave!

Fig. 630  This is atrial flutter and no sinus tachycardia (most

common misdiagnosis): On the one hand there is no sinus
tachycardia at rest of 150/min, on the other hand this is not
Fig. 628  Atrial flutter in tachycardia: Diagnosis is much
a P wave: A P wave must be round and crescent-shaped. If
more difficult here, the flutter waves are difficult to detect
you are unsure, you can easily confirm the diagnosis with
(2:1 transition).
an adenosine test (unmasking of the flutter waves).

Fig. 631  tachycardic atrial flutter on the monitor (various

examples)

Fig. 629  coarse atrial fibrillation (no atrial flutter): no shape
constancy of the atrial actions
Therapy
• vagal manoeuvres (e.g. carotid sinus massage), ade-
nosine (Adrekar) → demasking of the flutter waves
(Vagal manoeuvres are usually only diagnostic and not
therapeutic for atrial flutter.)
• drugs: similar to Tachyarrhythmia absoluta
• electrical cardioversion in short anesthesia
-- 30 Joule biphasic mostly completely sufficient
-- especially immediately if haemodynamically unsta-
ble
-- if stable perform TEE first to exclude intracavitary
thrombus
• anticoagulation like in atrial fibrillation (The ESC
recommends [IIa] anticoagulation in atrial flutter for a
duration > 48h analogous to atrial fibrillation. According
to a retrospective study [Comparison of clinical outco-
mes among patients with atrial fibrillation or atrial flut-
ter stratified by CHA2DS2-VASc score; Lin et al, JAMA
2018] however, the risk of stroke in atrial flutter is si-
gnificantly lower, so that anticoagulation should only

442 Cardiology
 pe performed if the CHA2DS2-Vasc score is ≥ 5 points.
However, the ESC guideline 2019 does not specify a
corresponding threshold above which CHA2DS2-Vasc
score an anticoagulation in atrial flutter would be indi-
cated. The CHA2DS2-Vasc score is also not validated
for atrial flutter.)
• if necessary atrial overdrive-pacing
• curative therapy by isthmus ablation (success rate:
95%)
Fig. 632  patient with unclear hemodynamic instability ("si-
nus tachycardia", therefore volume administration already
performed): EThere is a regular narrow complex tachycar-
dia of 138/min. Carotid sinus massage clearly unmasks flut-
ter waves (atrial flutter). After electrical cardioversion with
30 Joule biphasic in sinus rhythm, the patient is completely
stable again.
adenosine
10mg
Fig. 633  After the administration of adenosine (Adrekar),
the flutter waves clearly unmask themselves and the dia-
gnosis of atrial flutter can be easily confirmed.
Fig. 634  The flutter waves (as here in I, II and aVL) should
not be confused with ST depressions!
Atrial overstimulation (overdrive-pacing)
• indication: We perform atrial overstimulation in our cli-
nic only in the (very rare) cases in which the electrical
cardioversion of the tachycardic atrial flutter was not
successful.
• installation of a 5F or 7F French sheath into the inter-
nal jugular vein
• - insertion of the electrode into the right atrium under
x-ray fluoroscopy and attachment to the lateral atrial
wall (tip: J-shaped pre-bending of the wire)
• The easiest case is when the patient is already ha-
ving a pacemaker (either a two-chamber pacemaker
or a single-chamber pacemaker [AAI; rare]): Here you
can simply over-stimulate via the programming device
using the atrial lead (also classe I recommendation in
the ESC guideline 2019). The programming head is
placed on the pacemaker unit. On the programming
device, go under "EPU" and then under "burst". Befo-
re this, the pacemaker must be reprogrammed to AAI
mode. Then you stimulate with decreasing cycle length
(= increasing heart rate)
• overstimulation:
-- start with 120% of the flutter frequency (e.g. 360/
min), then successively increase up to 800/min
-- overstimulation up to max. 30s
-- The overstimulation can trigger muscle and dia-
phragm twitching in the patient.
• success rate: 60% (Usually initial atrial fibrillation oc-
curs, which then usually converts to sinus rhythm after
a few hours.)
• only efficient for atrial flutter type I (common type)
• Due to the acceleration of the rhythm disorder, ventri-
cular fibrillation can occur as a complication, so that
overstimulation should only ever be performed with a
readiness to defibrillate.
• alternative: transesophageal overstimulation
-- Here a special electrode (6-pin, e.g. Alphacard-x) is
inserted into the esophagus.
-- higher amplitudes than with invasive overstimulati-
on and therefore an extra esophageal stimulator is
necessary
-- relatively unpleasant, therefore usually only possible
in intubated patients
-- common mainly in pediatrics
Cardiology 443
 Therapy
• verapamil (Isoptin)
-- means of choice (good response); alternatively,
however, are β-blockers possible
-- dosage: 3-4 x 120mg
• flecainid (Tambocor)
caution: -- 1 amp. = 50mg
only for atrium -- 1 Amp. slowly over 10min i.v.; then wait 2 hours, then
repeat if necessary (up to 3 amp.)
• amiodarone
• electrical cardioversion (mostly successful!)
• ablation (success rate: 85%)
• anticoagulation: recommended if atrial frequency >
160/min as for atrial fibrillation

AV node reentry tachycardia (AVNRT)

Definition
• syn.: Bouveret's tachycardia (named after the French
internist Leon Bouveret [1850-1929])
Fig. 635  The function of atrial overstimulation is integrated
(but mostly well hidden) in most pacemaker aggregates (
• presence of two functionally separated conduction pa-
for another example see page 489). thways in the AV node (functional longitudinal dissoci-
ation of the AV node)
-- α-pathway: slow (antegrade) conductive
Ectopic atrial tachycardia
-- β-pathway: fast (retrograde) conductive
• reentry mechanism (mostly slow → fast-type-tachycar-
Definition dia [α → β])
• syn.: • simultaneous excitation of atrium and ventricle
-- focal atrial tachycardia • mostly heart-healthy
-- paroxysmal atrial tachycardia (PAT) with block • mostly younger women
• etiology: i.a. • frequent!
-- digitalis intoxication
-- cor pulmonale (COPD!)
• slow (no sudden) onset („warming up - cooling down“)
• in contrast to atrial flutter
-- isoelectric line present
-- atrial frequency < 250/min (ventricular frequency
AV
mostly 160-200/min)
• If there is no tachycardia at all (i.e. ventricular fre- node
quency < 100/min), pseudoregularized atrial fibrillation
should also be considered for differential diagnosis.

α-pathway β-pathway
Fig. 637  AV node reentry tachycardia: Presence of two se-
parate pathways around the AV node; reentry mostly from
the slow (α) to the fast (β) pathway
Symptoms
• dizziness
• racing heart, palpitations
• typically sudden onset and end ("like turning the light
switch on and off")
• urge to urinate (ANP release due to atrial overstret-
Fig. 636  Ectopic atrial tachycardia: In contrast to atrial flut- ching due to atrial contraction against the closed AV
ter, the atrial actions are slower and there is an isoelectric valve)
line between them.

444 Cardiology
• frog sign (simultaneous contraction of atrium and ven-
tricle → grafting, "pulsating" jugular veins)
ECG
• regular narrow complex tachycardia with a heart rate
of 180-220/min
• no P waves detectable
• sudden onset („jump“)
• possibly electrical alternans
• no signs of preexcitation in tachycardia-free ECG
• aVL-notch (for AVNRT in 51%, for AVRT [in WPW syn-
drome] only in 7% [Toro et al, Europace 2009])
• types (electrophysiological):
-- typical AVNRT: HA (His-atrial) ≤ 70ms, VA (ventricu-
lo-atrial) ≤ 60ms
-- atypical AVNRT: HA (His-atrial) > 70ms, VA (ventri-
culo-atrial) > 60ms
Fig. 638  AV node reentry tachycardia
Fig. 639  AV node reentry tachycardia: The typical sudden
onset ("jump") is clearly visible in the long term ECG.
Therapy
• vagal maneuver → termination
• adenosine (Adrekar)
-- 1 amp. = 6mg (new: 1 amp. = 10mg)
-- dosage: 5, 10, then 15mg (children: 0,2 mg/kg)
-- only very short T½ → rapid injection
• curative: AV node modulation
-- ablation of the slow pathway
-- in symptomatic relapses and distress
-- success rate: 97%
-- complication: i.a. total AV block
• otherwise theoretically also effective: β- blocker, ver-
apamil
adenosine 10mg
Fig. 640  Termination of AV node reenty tachycardia by ade-
nosine
Cardiology 445

AVNRT: means of choice adenosine!
Treating an AVNRT with a another
drug than adenosine is a malpractice!
It is obligatory to keep adenosine on
the emergency vehicle!
The only thing that is dangerous and
can die from in AVNRT is the
physician's polypharmacy!
Orthodromic AV reenty tachycardia
Definition
• typical for WPW syndrome
• P wave behind QRS complex (retrograde; DD PJRT)
• PR interval > RP interval
• electrical alternans (An electrical alternans is also
found in a large pericardial effusion. A mechanical al-
ternans is found in sever aortic valve stenosis.)
• in tachycardia-free ECG then signs of preexcitation
• therapy: as with AVNRT
• bidirectionally conducting accessory bundle (conducts
faster than the HIS/AV bundle)
• localization of the pathway:
-- mostly left ventricular (more rarely right ventricular)
-- left free wall (lateral wall): 47% (most frequent loca-
lization)
-- right free wall: 17%
-- septum
◦◦ anterior: 9%
◦◦ posterior: 27%
-- possibly also multiple pathways
• concealed WPW syndrome: The accessory path,
which normally conducts in both directions (typically
bidirectionally), conducts only retrogradely (unidirec-
tionally; rarely). The ECG does not show a delta wave.
• therapy of choice: ablation

Classification according to Rosenbaum

Fig. 641  orthodromic AV reentry tachycardia: regular nar-
row complex tachycardia with retrograde P (P wave behind
the QRS complex)
• QRS (R > S) and delta wave in V1 positive: sternal
positive (type A), pathway on the left (QRS complex:
right bundle branch block)
• QRS (R < S) and delta wave in V1 negative: sternal
negative (type B), pathway on the right (QRS complex:
left bundle branch block))

V1

V1 positive (R > S) V1 negative (R < S)

pathway left pathway right

aVF R/S transition

Fig. 642  WPW syndrome: left orthodromic (narrow com- positive negative ≥ V4 ≤ V3
plex), right antidromic (wide complex) AV reenty tachycar-
dia lateral septal lateral septal
(most frequent
location)
Excursus: WPW syndrome Fig. 643  simplified scheme for localization of the pathway
in WPW syndrome
Definition
• Wolff-Parkinson-White syndrom Epidemiology
• a preexcitation syndrome (overview: see infobox) • 0.3% of the population
• atrio-ventricular pathway (Kent bundle) • m > w

446 Cardiology
• usually manifested between 20- 0 years of age
• most frequent cause of tachycardias in children
• Tachycardias become more frequent with increasing
age.
• in 7-20% associated with congenital vitium (e.g. VSD,
ASD, Ebstein anomaly, mitral valve prolapse)
ECG
• classical triad (can only been seen in the tachycardia-
free ECG):
-- delta wave (must be well recognizable in all leads)
with QRS broadening > 120ms
-- shortened PQ interval
-- ST deperessions (physiological; no indication of is-
chemia!)
• The morphology, however, can also typically change
(depending especially on heart rate, sympathetic tone;
so-called Concertina effect).
increased sympathetic tone with the result that the AV
pathway increases and thus conducts less along the
accessory pathway.
• ajmaline test
-- indication:
◦◦ risk stratification in WPW syndrome
◦◦ suspected Brugada syndrome
-- 1 mg/kg (e.g. 50mg) over 5min
-- always under monitor control
-- interpretation:
◦◦ If the delta wave disappears (positive ajmalin test),
the ERP > 250 msec and the risk of SCD is low.
◦◦ If the delta wave does not disappear (negative aj-
maline test), the ERP is < 250 msec and the risk
of SCD is high.
• electrophysiology (EPU):
-- recommended for risk stratification in asymptomatic
patients
-- testing with isoprenaline
-- effective refractory period (ERP) < 250msec → hifh
risk for SCD → ablation recommended

Tachycardia
in WPW syndrome

Fig. 644  ECG in WPW syndrome: delta wave (must be well

recognizable in all leads), shortened PQ interval, ST de-
pression (physiological; no indication of ischemia); note:
The ECG signs are, however, only present in tachycardia-
free ECG, in the context of tachycardia in WPW syndrome
they are not recognizable!

Risk assessment
• effective antegrade refractory time (effective refractory
period [ERP]): The longer it is, the less quickly the ac-
cessory pathway recovers and the less quickly it can
conduct, i.e. the lower the risk of ventricular fibrillation
and SCD (sudden cardiac death).
• exercise ECG (ergometry): If the delta wave disap-
pears under exercise, then the ERP is > 250 msec, i.e.
there is only a low risk for SCD. Exercise leads to an

Cardiology 447
Permanent junctional reciprocating
tachycardia (PJRT)
• syn.: Coumel tachykarda (named after the French phy-
sician Philippe Coumel [1935-2004])
• a reentry tachycardia accessory pathway (atrio-ventri-
cular) with exclusively (unidirectional) retrograde (slow
because decremental) conduction
• regular (relatively slow!) narrow complex tachycardia
-- retrograde P (PR interval > RP interval)
-- negative P waves in II, III, aVF (Note: An important
DD to negative P waves is the lead reversal by a
wrongly applied ECG.)
• frequently relatively slow tachycardia (not noticed →
runs permanently)
• main problem: danger of tachymyopathy (syn.: TIC [ta- The best way to assess atrial actions
chycardia induced cardiomyopathy]) is in the Lewis lead!
• therapy: ablation (only very poor response to antiar-
rhythmics; after the ablation, the reduced ejection frac-
tion in the context of tachymyopathy usually recovers
completely)

Fig. 645  PJRT (permanent junctional reciprocating tachy-

cardia): The relatively (for a tachycardia) slow heart rate,
the negative P waves in II, III and aVF as well as the retro-
grade P wave (behind the QRS complex) are conspicuous.

Fig. 646  PJRT (permanent junctional reciprocating tachy-

cardia): retrograde P waves which are negative in II, III, aVF
at (for tachycardia) relatively slow heart rate of 112/min

448 Cardiology

I -- A2 rezeptor: smooth musculature; activation leads to
III
II
Fig. 647  modified ECG derivation according to Lewis to
better assess atrial actions (a special atrial lead): 3 of the 4
limb leads are glued to a different location: on the sternum
manubrium, on the lower right edge of the sternum and on
the lower right costal arch. The Lewis lead is the lead I: It
runs directly through the atrium and is best suited for ana-
lysis of atrial actions.
Therapy (regular narrow complex ta-
chycardia)
• vagal maneuver (e.g. carotid sinus massage
-- terminates AV node reentry tachycardia and ortho-
dromic AV reentry tachycardia
-- demasks atrial flutter
• adenosine (Adrekar)
• digitalis
-- e.g. digoxin (Lanicor) 0.5mg, 0.25mg, 0.25mg
(30min interval)
-- effect more after clinic (less after drug level)
-- cave:
◦◦ ectopic atrial tachycardia (digitalis intoxication as
a frequent cause!)
◦◦ contraindication in atrial fibrillation in WPW syn-
drome
-- not listed at all in the ESC Guidelines 2019 for the
management of supraventricular tachycardia
• verapamil (Isoptin) 2.5-5mg (max. 20mg) slowly i.v.
(not in combination with β-blocker or in patients pretre-
ated with β-blocker and also not in systolic heart failure
[HFREF])
• β-Blocker
-- long-acting: metoprolol (Beloc) i.v. (slowly 1-3mg re-
petitively up to max. 15mg)
-- short-acting: esmolol (Brevibloc, Esmocard) 40-
50mg (exactly: 0.5 mg/kg; over 1min) i.v.
-- ultrashort-acting: landiolol (Rapibloc)
• amiodaron (Cordarex) 150-300mg i.v. or as short infu-
sion (in 250ml G5%)
• R-wave triggered cardioversion in short anesthesia
• with atrial flutter possibly atrial overdrive pacing
Adenosine (Adrekar)
• an endogenous purine nucleoside (a body's own sub-
stance)
• 1 amp. = 6mg; new: 1 amp. = 10mg
• agonist at the A1 and A2 receptor
-- A1 receptor: sinus and AV node; activation leads to
negative chrono- and dromotropy
vasodilation
• dosage: 5, 10, then 15mg (children: 0.2 mg/kg)
• One must see an AV block in the monitor ECG,
otherwise the applied dose was insufficient!
• application as close to the heart as possible (e.g. in
the cubital fossa or CVC [if available]) quickly i.v. (10ml
NaCl 0.9% immediately afterwards; T½ only 8 sec)
[Adenosine is rapidly deaminated to inosine, which is
no longer active.])
• side effects:
-- flush
-- bronchospasm (contraindication: bronchial asthma)
[but only relatively])
• antidote: theophylline 200mg
• also possible in pregnancy
• Be careful with heart transplant patients: The denerva-
ted heart reacts hypersensitively to adenosine, so that
significantly lower doses are required here!
• success rates (termination of tachycardia):
-- AV node reentry tachycardia: 90%
-- orthodromic AV reentry tachycardia: 90%
Fig. 648  1 amp. adenosine (Adrekar) = 2ml = 10mg
Vagal maneuvers
• blocking of the conduction in the AV node
• effects
-- therapeutic: termination
◦◦ AV node reentry tachycardia
◦◦ orthodromic AV reentry tachycardia
-- diagnostic: demasking of flutter waves (atrial flutter)
• types
-- carotid sinus massage (CSM)
◦◦ stimulation of baroreceptors in the carotid sinus
◦◦ risk of detachment of plaques with consecutive
stroke, therefore prior auscultation of both carotid
arteries (possibly even duplex sonography befo-
re), pressure for max. 5s
◦◦ not in patients with a history of TIA or stroke or with
known carotid plaques
-- Valsalva manoeuvre (pressing)
◦◦ named after the Italian anatomist Antonio Maria
Valsalva (1666-1723)
◦◦ practical tip: The patient should blow into a
10ml syringe until the piston moves.
Cardiology 449
 -- bulbus pressure (eyeball compression; cave: retinal
ablation; obsolete today)
-- fast drinking of cold water
-- dive reflex (dipping the face in cold water)
-- insertion of the finger into the pharynx so that the
patient chokes

REVERT study

Postural modification to the standard valsalva maneuvre

for emergency treatment of supraventricular tachycardias
Appelboam et al, Lancet 2015
• randomized controlled study (England)
• 428 patients with supraventricular tachycardia (without
atrial fibrillation and atrial flutter)
-- classic Valsalva maneuvre (blowing into a manometer
to generate a pressure of 40 mmHg for 15s)
-- modified Valsalva maneuvre: additional flat positio-
ning + lifting of the legs by 45° (increase in venous
return flow → vagal stimulus ↑)
• result: modified Valsalva maneuvre → significantly
higher cardioversion rate (43% versus 17%)
Fig. 649  ventricular tachycardia (VT)
Types
• according to morphology
-- monomorphic VT (anatomically induced; usually af-
ter myocardial infarction, DCM)
-- polymorphic VT (functionally induced)
• according to duration
-- < 30 sec: non sustained VT (nsVT)
-- > 30 sec: sustained VT (sVT)

The most common cause of

WIDE COMPLEX TACHY- ventricular tachycardia is cardiac
ischemia!
CARDIA (WCT)
Monomorphic VT
Classification • scar VT
• idiopathic right ventricular outflow tract tachycardia
• according to origin:
-- typical for arrhythmogenic right ventricular dysplasia
-- ventricular tachycardia (VT; 80%; origin distal of the
-- typically left bundle branch block (but unusual for
His bundle)
LBBB: aVL negative and steep/right type)
-- supraventricular tachycardia (SVT; 20%; origin pro-
-- steep/right type
ximal of the His bundle)
-- means of choice for suppression of VT in arrhyth-
• according to regularity of ventricular actions:
mogenic right ventricular dysplasia: sotalol (highly
-- regular wide complex tachycardia dosed up to 240mg)
-- irregular wide complex tachycardia → atrial fibrilla- -- therapy: ablation
tion
• repetitive monomorphic ventricular tachycardia (RMVT;
◦◦ atrial fibrillation with block (frequent) Gallavardin tachykardia)
◦◦ atrial fibrillation in WPW syndrome (rare) • bundle branch reentry tachycardia (BBRT)

Wide complex tachycardia is an

emergency until proven otherwi-
se!

Ventricular tachycardia

Guideline
2015 ESC Guidelines for the management of patients
with ventricular arrhythmias and the prevention of sud-
den cardiac death

450 Cardiology

Fig. 650  monomorphic VT
Repetitive monomorphic ventricular tachycar-
dia (RMVT)
• syn.: Gallavardin tachycarda (named after the French
cardiologist Louis-Bénédict Gallavardin [1875-1957])
• ventricular tachycardia from the right ventricle (exact-
ly: from the right ventricular outflow tract [RVOT]) →
LBBB configuration (similar to idiopathic right ventri-
cular outflow tract tachycardia [also aVL negative and
steep/right type])
• no structural heart disease presend
• typically salve-like (interrupted by sinus beats; "extra-
systole-like")
• prognosis: good (ablation or ICD almost never neces-
sary)
• therapy: β-blocker or verapamil (very good response)
Fig. 651  VES with LBBB (Striking and completely untypical
for a LBBB however is the right axis deviation [right type]
and the fact that aVL is negative!)
Bundle branch reentry tachycardia (BBRT)
• monomorphic ventricular tachycardia (5%)
• syn.: fascicular tachycardia
• reentry between both Tawara branches, therefore
bundle branch block configuration (left or right)
• Although BBRT is a ventricular tachycardia, the res-
pective block configurations (right or left bundle branch
block) are typical and not atypical. The definitive diag-
nosis is ultimately only possible through an electrophy-
siological examination.
• conduction disorders already detectable in sinus
rhythm (electrophysiological examination: extended
HV interval)
• structural heart disease present (typically with DCM)
• therapy: ablation (cave in 30% pacemaker required)
-- LBBB → ablation of the right Tawara branch
-- RBBB → ablation of the left Tawara branch
• special form: Belhassen tachycardia (named after the
Israeli cardiologist Bernard Belhassen)
-- reentry within the Purkinje fibers of the left posterior
fascicle
-- ECG: superior location type (aVR positive) and right
bundle branch block (typical RBBB, i.e. rsR´, hence
frequent misdiagnosis: supraventricular tachycardia
with right bundle branch block [due to aberrant con-
duction])
-- very good response to verapamil (therefore also
called verapamil-sensitive ventricular tachycardia)
-- mostly young men (15-40 years)
-- no structural heart disease present (hence also
called idiopathic fascicular ventricular tachycardia)
-- hemodynamically mostly well tolerated
-- therapy:
◦◦ Verapamil
◦◦ catheter ablation
Polymorphic VT
• torsade de pointes
• catecholaminergic polymorphic ventricular tachycardia
(CPVT; an ion channel disease; see page 468)
Torsade de pointes
Definition
• polymorphic VT in which the vector of the QRS com-
plexes moves sinusoidally around the isoelectric base-
Cardiology 451
 line -- drugs (especially sotalol, amiodarone, antibiotics
• first described in 1966 by the French cardiologist Fran- [especially macrolides, fluoroquinolones], psycho-
çois Dessertenne tropic drugs [tricyclic antidepressants, neuroleptics],
• syn.: fluconazole, propofol)
-- peak reversal tachycardia -- hypo-electrolytes (hypocalcemia, hypokalemia, hyp-
-- screw tachycardia onatremia, hypomagnesemia)
• w:m = 3:1 -- Tako-Tsubo cardiomyopathy
• age: 30-50 years -- citric acid intoxication (due to hypocalcaemia; e.g.
after transfusions of numerous RCC or FFP)
• onset from a long-short coupling interval
-- energy drinks (especially ingredients high-dose caf-
• ventricular frequency mostly 160-240/min
feine, taurine, L-carnitine; i.a. Fletcher et al, J Am
• mostly self-limiting (wait a few seconds with defibril- Heart Ass 2017)
lation)
-- neurogenic:
• cause: prolonged QT interval
◦◦ stroke: in 38%
◦◦ ICH: in 64%
◦◦ SAH: in 71%

Therapy
• magnesium: bolus 20-40 mval (2-4g), then 60 mval/24h
• balance hypo-electrolytes (especially hypokalaemia)
• increase of the heart rate of the basic rhythm (HR ↑ →
QT interval↓)
-- from HR < 60/min: atropine, orciprenaline, dobuta-
mine
-- possibly temporary pacemaker (target HR: 80-100/
min)
-- recurrence → permanent pacemaker (AAI with rapid
stimulation [up to 120/min]; rarely indicated)

Therapy (VT)
• without palpable pulse: defibrillation (pulseless VT;
therapy such as ventricular fibrillation)
• with palpable pulse:
-- R-wave triggered cardioversion in short anesthesia
(initially 200 J, dann 360 J)
-- stable: differentiation in 12-lead ECG → drugs:
Fig. 652  Torsade de pointes ◦◦ amiodarone (Cordarex) 300mg i.v. (2 amp.)
◦◦ ajmalin (Gilurytmal) 1 amp. = 50mg, 1 mg/kg over
10min i.v.
▪▪ no longer officially recommended (ESC, ERC),
but it is a very effective drug!
▪▪ contraindications: especially acute myocardial
infarction, decompensated heart failure
◦◦ procainamide
▪▪ class IA antiarrhythmic
Fig. 653  Torsade de pointes: It can usually be found in the
▪▪ dosage: 10 mg/kg over 20 min i.v.
context of a resuscitation situation. The situation is accor-
dingly hectic and there is not much time to look at the ECG ▪▪ recommended as the first choice in the Euro-
and explore the helical morphology. At first glance, torsa- pean guideline (IIa; amiodarone only IIb), alt-
des look like ventricular fibrillation. The absolutely decisive hough procainamide does not exist in Europe
distinguishing feature to ventricular fibrillation, however, is ▪▪ PROCAMIO study (Ortiz et al, Eur Heart J
the fact that torsades, like this one, often spontaneously
2017): procainamide in VT significantly better
cease, which is never the case with ventricular fibrillation
(only at some point then turns into an asystole).
than amiodarone (higher termination rate [67%
versus 38%], lower MACE rate [major advers
Cause (Long-QT syndrome; QT interval prolon- cardiac events; 9% versus 41%])
gation [QTc > 450ms]) ◦◦ acute coronary syndrome → amiodarone
◦◦ torsades de pointes → 2g magnesium sulfate i.v
• congenital (rare): long-QT syndromee (LQTS; see
page 474)
• acquired (frequently)

452 Cardiology

in general: no β-blockers for ventricu-
lar tachycardia (exception: RMVT)!
Memo for all cardiac arrhythmias: "The
more unstable, the more electrical
current!"
Amiodarone (Cordarex)
• class III antiarrhythmic
• 1 amp. = 3ml = 150 mg
• 300 mg (2 amp.) i.v. or as short infusion in 100 ml Glu-
cose 5%
• advantage: no negative inotropic effect (in contrast to
almost all other antiarrhythmics)
• cave
-- QT interval ↑ → possibly torsades de pointes
-- stimulus threshold ↑ → pacemaker-/ AICD dysfunc-
tion (exit block; amiodarone can lead to the pacema-
ker or AICD no longer functioning!)
-- blood pressure ↓
• im Notfall keine Kontraindikationen (Ausnahme: in an
emergency no contraindications (exception: pregnan-
cy, torsades de pointes)
If you have no idea at all, you can
always give amiodarone at any
tachycardia (no matter if VT or SVT)!
Supraventricular tachycardia (with
wide complexes)
In 20% of cases, a wide complex tachycardia is a supra-
ventricular tachycardia. Supraventricular tachycardias
usually show a narrow QRS complex. Wide ventricular
complexes in supraventricular tachycardia occur:
• supraventricular tachycardia with pre-existing bundle
branch block
• supraventricular tachycardia with functional (= fre-
quency dependent) bundle branch block ("fatigue"
block; mostly left bundle branch block; e.g. during
exercise ECG)
• supraventricular tachycardia with pacemaker-induced
left bundle branch block
• supraventricular tachycardia with aberrant conduction:
i.a.
-- phase III block (intraventricular conduction delay
based on change of RR interval, mostly affects right
bundle branch, therefore mostly right bundle branch
block configuration)
-- Several wide QRS complexes with RBBB configura-
tion appear in atrial fibrillation. After a long-short se-
quence, the refractory times are different, so that an
aberrant conduction with an intermittent conduction
block occurs during the following beat.
• antidromic AV reentry tachycardia (WPW syndrome)
• atrial fibrillation / atrial flutter in WPW syndrome
• supraventricular tachycardia in STEMI (QRS deforma-
tion → QRS width ↑­)
• supraventricular tachycardia in hyperkalaemia (Hyper-
kalaemia leads to QRS broadening! The QRS com-
plexes are usually even ultra-wide here [> 180ms; for
ECG example see page: follows]!)
• supraventricular tachycardia among drugs that lead to
QRS broadening (e.g. sodium channel blockers such
as class I antiarrhythmics or tricyclic antidepressants)
Fig. 654  antidromic AV reentry tachycardia in WPW syn-
drome (a supraventricular tachycardia with wide QRS com-
plexes)
Differentialdiagnosis VT / SVT
• anamnesis (known CHD, status post myocardial in-
farction/ CABG, DCM → VT)
• regularity of ventricular actions: An irregular wide
complex tachycardia is always only a supraventricu-
lar tachycardia (usually tachyarrhythmia absoluta with
block)!
• AV dissociation
-- independent beating of atrium and ventricle
-- comparison of PP and RR intervals
-- clinical signs
◦◦ different intensity of the fisrt heart tone
◦◦ different systolic BP amplitudes (invasive BP mea-
surement)
-- proving for VT (but only present in 25%)
-- P waves under tachycardia are often difficult to de-
tect, therefore as a tip: Use Lewis lead (see page
448) for better detection of P-waves!
• fusion beats, capture beats
-- normal antegrade conducted sinus node activity with
narrow QRS complex
-- especially with slow VT (heart rate < 150/min)
-- proving for VT (but only present in 30%)
Cardiology 453
• location type (axis): for VT mostly abnormal location is on the right!]) → SVT
type (axis deviation) ▪▪ Rsr´ (left rabbit ear; i.e. the first spike is larger
-- left or right axis deviation than the second spike; atypical RBBB) → VT
-- extreme axis deviation Nord-West-Typ (superior lo- ◦◦ V6:
cation type) ▪▪ S < R → SVT
◦◦ If you compare the Cabrera circle with a compass, ▪▪ S > R → VT
the location type at VT is often in the north-west -- left bundle branch block (LBBB):
area (north-west axis; "no-man´s land“). ◦◦ V1: R wave
◦◦ negative QRS complex in I, II and III ▪▪ narrow, rapid drop from RS (RS distance < 70ms
◦◦ sure sign for VT [Brugada´s sign negative]; typical LBBB) → SVT
-- change of localisation type (axis) compared to the ▪▪ broad, slow drop from RS (RS distance > 70ms
tachycardia-free ECG [Brugada´s sign positive]; atypical LBBB) → VT
• chest wall leads (specifity: 90%) ◦◦ V6: Q wave
-- concordance → VT ▪▪ not present (typical LBBB) → SVT
◦◦ negative concordance: consistently negative QRS ▪▪ present (atypical LBBB) → VT
complexes in all chest wall leads (missing RS • influenceability by Valsalva manoeuvre / adenosine →
complexes in V1-V6; origin of the VT: anterior wall) SVT (exception: 88% of ventricular tachycardia from
◦◦ positive concordance: consistently positive QRS the right ventricular and 78% of ventricular tachycardia
complexes in all chest wall leads (origin of the VT: from the left ventricular outlet tract can also be termina-
inferior or lateral wall); exception: antidromic AV ted by adenosine [Iwai et al, Electrophysiology 2006].)
reentry tachycardia in WPW syndrome (here also
positive concordance, but only SVT)
-- disconcordance → SVT
• QRS morphology:
-- number of phases (but not very reliable):
◦◦ biphasic → VT
◦◦ triphasic → SVT
-- Brugada´s sign (especially in V1/V2): RS distance >
70 ms → VT
-- Josephson's sign especially (in V1/V2): notch in de-
scending part of S wave → VT
-- aVR
◦◦ negative → SVT Fig. 655  wide QRS complex tachycardia at 180 / min: Howe-
ver, it is irregular, so that it is not a ventricular tachycardia,
◦◦ positive → VT (QRS vector points in the north-
but only an tachyarrhythmia absoluta with a block.
west direction!)
-- V(i) / V(t) ratio: quotient of the initial (amplitude of the
QRS complex in mV 40ms after the start of the QRS
complex) and terminal (amplitude in mV 40ms befo-
re the end of the QRS complex) activation velocity
(AVR: activation-velocity-ratio)
◦◦ > 1 → SVT
◦◦ < 1 → VT Fig. 656  capture beat (see arrow): It proves ventricular ta-
• QRS width (p.d. > 120 ms) chycardia in the presence of wide QRS compelx tachycar-
dia.
-- SVT < 140 ms
-- VT > 160 ms
-- note: If there is a bundle branch block with wide QRS
complex in the tachycardia-free ECG and the tachy-
cardia now has a narrower QRS complex,it is a VT.
• bundle branch block configuration: A typical bund-
le branch block configuration speaks for an SVT, an
atypical bundle branch block configuration for a VT
(exception to this rule: BBRT [bunde brunch reentry
tachycardia incl. Belhassen tachycardia]).
-- right bundle branch block (RBBB):
◦◦ V1: "rabbit ear" (rabbit viewed from behind]; i.e. 2
spikes available):
▪▪ rsR´ (right rabbit ear; i.e. the first spike is smaller
than the second spike; typical RBBB [remark: In
typical right bundle branch block, the rabbit ear

454 Cardiology
 north

LAD
pathological
aVR aVL
LAD
physiological

Fig. 659  The Josephson's sign is defined as a notch in the

west I east descending part of the S wave of the QRS complex. It indi-
cates a ventricular tachycardia in the presence of a wide
QRS complex tachycardia.
RAD
pathological

III II SVT VT
normal axis
RAD
physiological V1
aVF
rsR´ Rsr´
south

extreme
axis LAD

V6

RAD normal R>S R<S

axis
Fig. 657  Cabrera circle for determining the electrical axis
(location type) using the limb leads (LAD: left axis devia-
tion; RAD: right axis deviation): In ventricular tachycardia
you often find an extreme axis and especially often a com-
pletely different axis as in the tachycardia-free ECG. The
vector points to an area where the location type is normally
never found ("no man´s land"; yellow circle). If you com-
pare the Cabrera circle with a compass, the axis of a VT
is often located in the north-west. With a VT aVR is often
positive.
right bundle branch block
Fig. 660  Wide QRS complex tachycardia with right bundle
branch block: The chest wall leads V1 and V6 are consi-
dered. A rsR´-configuration in V1 (right rabbit ear, i.e. the
second spike is higher than the first spike [typical RBBB])
indicates a SVT, a Rsr´-configuration (left rabbit ear, i.e. the
first spike is hiherer than the second spike [atypical RBBB])
indicates VT. If the R wave in V6 is larger than the S wave, it
speaks for an SVT. If the R wave is smaller than the S wave,
this speaks for a VT.
SVT VT

V1

narrow R broad R
rapid drop slow drop

V6
Fig. 658  Brugada's sign is defined as an RS distance of >
70ms. It indicates a ventricular tachycardia in the presence without Q wave with Q wave
of a wide QRS complex tachycardia.
left bundle branch block
Fig. 661  Wide QRS complex tachycardia with left bundle
branch block: The chest wall leads V1 and V6 are consi-
dered. A narrow R wave with a rapid drop from RS in V1
speaks for an SVT, a wide R wave with a slow drop in RS
speaks for a VT. If there is a Q wave in V6, this speaks for a
VT. If this is not the case, this speaks for an SVT.

Cardiology 455
 the wider the QRS complexes → VT
the less serrated the QRS complexes
→ VT

wide QRS tachycardia: always (if

stable) derive a 12-lead ECG before
termination! is very often forgotten!

Fig. 663  ventricular tachycardia: The change in the axis,

which is typical of ventricular tachycardia, can be clearly
seen here

Fig. 664  ventricular tachycardia

Fig. 662  right bundle branch block with left rabbit ear (Rsr´-
configuration; 2 spikes in V1, of which the first spike is lar- Fig. 665  supraventricular tachycardia: This is supported
ger than the second spike [atypical RBBB]) and R < S in V6, by the triphasic configuration of the QRS complexes and
Josephson´s sign (see arrows), positive concordance (con- by the discordance (in V1 and V2 negative, in V3-V6 positi-
sistently positive QRS complexes in all chest wall leads) ve QRS complexes) over the chest wall.
and positive aVR: All of the criteria mentioned speak for
ventricular tachycardia. The tachycardia-free ECG (after
electrical cardioversion) also shows a right bundle branch
block, but here with a right rabbit ear (rsR´-configuration
[typical RBBB]). You can also see the significant change in
the axis: Whereas the tachycardia-free ECG shows a LAD
(left axis deviation), the tachycardia ECG shows a RAD
(right axis deviation).

456 Cardiology
Fig. 666  supraventricular tachycardia: atrial fibrillation
with the right bundle branch block
Fig. 669  supraventricular tachycardia: atrial flutter with ty-
pical right bundle branch block (in V1 rsR´ [right rabbit ear];
i.s. the first spike is smaller than the second spike; further-
more in V6 R > S)

Fig. 667  supraventricular tachycardia: atrial fibrillation

with the right bundle branch block
Fig. 670  supraventricular tachycardia: sinus tachycardia
in STEMI (The deformated QRS complex is also wide!)

Fig. 668  supraventricular tachycardia: tachyarrythmia ab-

soluta with an intermittent functional (frequeny depending)
block

Cardiology 457
 Fig. 671  typical PVC (premature ventricular contractions;
syn.: ventricular extrasystoles [VES]; here bigeminus)
from RVOT (right ventricular outflow tract; most common
localization): left bundle branch block (LBBB), inferior
axis (II, III, aVF positive) and late R/S transition (only in
V4-V6; R/S ratio in V3 < 1). A high PVC burden (> 15% in
the long-term ECG) can even lead to a reduced ejection
function (tachymyopathy [syn .: TIC: tachycardia-induced
cardiomyopathy]). PVC from the RVOT respond very well to
β-blocker. If this is not the case, it can also be ablated very
easily (catheter ablation).

AICD
Since my experience has shown that there are relatively
many uncertainties regarding the topic of AICD, I would
like to explain this topic in more detail here as an ex-
cursus. The subject is certainly somewhat complex, but
not only cardiologists or even electrophysiologists, but
actually all internists or intensive care physicians should
master the basics of AICD.

Definition
• - automatically implantable cardioverter-defibrillator
• first implanted by the Polish physician Michel Mirowski
(1924-1990) in 1980
• 5-year survival rate in heart failure: 50% (a serious di-
agnosis with extremely poor prognosis!)
• causes of death in heart failure:
-- NYHA I/II: especially sudden cardiac death (SCD)
-- NYHA III/IV: especially pump failure
• Due to the recommendation for primary prophylaxis,
the number of AICD implantations has increased sig-
nificantly (approx. 25000 AICD implantations annually,
approx. 100000 patients with an AICD in Germany).

Fig. 672  AICD [7]

Companies
• Medtronic
• Biotronik
• St. Jude Medical
• Boston-Scientific (formerly Guidant, CPI, Intermedics)
• Vitatron (can also be scanned with Medtronic device)
• ELA
• Sorin

458 Cardiology
Types
• single-chamber AICD (one lead [in right ventricle];
standard)
• dual-chamber AICD (two leads: one in right ventricle,
one in right atrium) electrode
-- only if an additional anti-bradycardia function is re-
quired, i.e. pacemaker indication
-- Frequent right ventricular stimulation should be avo-
ided (DAVID study [Wilkoff et al, JAMA 2002]: incre- RV LV
ased RV stimulation → increased mortality). There-
fore, two-chamber AICD should only be used in a shock
very restrictive way and a three-chamber AICD (CRT coil
system) should be installed instead!
• triple-chamber (= AICD + CRT [cardiac resynchroni-
zation therapy]):
-- In addition to the dual-chamber AICD, there is also
an electrode in the left ventricle, i.e. leads in two ven-
tricles (biventricular system).
-- This is indicated if there is also a complete LBBB ring tip
(QRS width > 150ms).
Fig. 673  AICD: structure of the electrode (lead) - ring and
tip represent the "eye of the AICD", here the sensing takes
Structure place; RV: right ventricle, LV: left ventricle
• aggregate (unit; weight: approx. 70g):
-- battery:
◦◦ made of silver vanadium oxide (in contrast to a
pacemaker in which the battery consists of lithium)
◦◦ voltage: 3.2V
◦◦ running time: 10 years (if combined with CRT sys-
tem: 4-5 years)
-- capacitors, transformers
-- current circuit, electronics
-- header (plug for electrode connection)
• leads (electrodes):
-- Shortly before the tip of the electrode (located in the
right ventricle) there is a shock coil through which
the shock is released. Standard today are electrodes
with one shock coil (single coil; completely suffici-
ent), electrodes with two shock coils (dual coil; addi-
tional shock coil located in the superior vena cava) Fig. 674  AICD: structure of the aggregate [7]
are almost no longer implanted today.
-- screw electrode
-- At the end of the electrode there is a ring and a tip:
Both together represent the "eye of the AICD", whe-
re sensing takes place (bipolar). Today, the sensitivi-
ty threshold is set automatically in modern devices.

Fig. 675  An AICD can be easily recognized by the left sided

location of the device (pacemaker devices are usually on
the right) and above all by the shock coil (see arrow), which
is significantly thicker than a pacemaker electrode.

Cardiology 459

Fig. 676  CRT system (cardiac resynchronization therapy,
"bivent" [biventricular pacemaker]): In addition to the elec-
trode in the right ventricle (and right atrium), an electrode
can be seen on the posterolateral wall of the left ventricle
(see arrow). This is insertd via the coronary sinus.
Implantation
• under local anaesthesia
• perioperative antibiotic prophylaxis with a 1st generati-
on cephalosporin, e.g. Cefazolin 2g 1-1-1 (over a total
of 24h, 1h before surgery antibiotic treatment should
be initiated
• left pectoral (because better defibrillation than on the
right side)
• analogous to pacemaker implantation, which usually
takes place on the right side
• implantation
-- single coil: suprapectoral (above the pectoral musc-
le)
-- dual coil (largely abandoned today): infrapectoral
(below the pectoral muscle)
• pre-preparation in the infraclavicular fossa (=
Mohrenheim's fossa) and free preparation of the ce-
phalic vein
• insertion of the lead(s) via the cephalic vein (vena sec-
tio) or via the subclavian vein (puncture [puncture set
9.5F])
• placement of the lead on the apex of the right ventricle
• screwing in of the electrode and fixation (sleaves)
• preparation of the pocket for the aggregate (unit)
• connection of the lead(s) to the header, placement of
the leads underneath (not above [otherwise danger of
lead injury when changing the unit!) the aggregate, fi-
xation of the aggregate
• intraoperative measurements (nominal values)
-- intrinsic signal > 8mV
-- sensing
◦◦ P-wave > 2mV
◦◦ R-wave > 6mV
-- slew-rate
460 Cardiology
◦◦ atrium: > 0.5 mV/s
◦◦ ventricle: > 1.0 mV/s
-- electrode impedance < 1000Ω
-- stimulus threshold < 1V
-- impedance
◦◦ stimulation impedance: 300-1800Ω
◦◦ defibrillation impedance: 30-80Ω
• intraoperative testing ("trial shock")
-- Ventricular fibrillation is generated under short
anaesthesia and it is checked whether the implanted
AICD terminates this properly.
-- indication:
◦◦ secondary prophylaxis: always
◦◦ primary prophylaxis: controversial (no mortality
advantage proven in previous studies; i.a. SIMP-
LE study [Jeff et al, Heart Rhythm Society 2014],
NORDIC-ICD study [Bänsch et al, Eur Heart J
2015]: no advantage for intraoperative testing;
note: We also do not perform testing in primary
prophylaxis.)
• complications
-- lead dislocation
-- pneumothorax (chest X-ray on the day of surgery
obligatory after puncture of the subclavian vein), he-
matothorax
-- myocardial perforation, pericardial tamponade
(cave especially in patients with dilated cardiomyo-
pathy due to the thin wall)
-- hematoma
-- thrombosis (subclavian vein)
-- infection, sepsis
-- therapy refractory ventricular fibrillation (if intraope-
rative "trial shock" testing)
• DRG proceeds: 11000-15000€ (relatively lucrative for
a hospital)
• AICD control
-- immediately postoperative
-- after 4 weeks
-- then every 6 months
Goals
• avoidance of sudden cardiac death by ventricular fibril-
lation by means of defibrillation (ultimate goal)
• avoidance of shocks (extremely painful and stressful!)
-- avoidance of inadequate shocks: Shock release
should only occur in VT but not in SVT (especially
tachyarrhythmia, sinus tachycardia). Inadequate
shock releases occur in 10% of cases (No.1 atrial
fibrillation, No.2 sinus tachycardia).
-- avoidance of adequate shocks: Shocks are extreme-
ly painful and can also lead to myocardial damage.
Therefore, an attempt should first be made to ter-
minate the VT by means of antitachycardia pacing
(ATP; syn.: ATS: antitachycardia stimulation), which
has the great advantage that it is painless. A shock
should only be triggered if this has not been achie-
ved by ATP.
Functions
An AICD has three functions:
• defibrillation (in ventricular fibrillation)
• antitachycardic stimulation (ATS; syn.: ATP: antitachy-
cardic pacing)
• cardioversion
Defibrillation
• charging of capacitor plates
• shock release with maximum energy (35-40 J; today
only high-output aggregates; during testing with 20 J)
• settings: first shock with 15 J above the DFT (defibril-
lation threshold [last successful energy level]) or 10 J
above the DFT+ (last energy level with two-time suc-
cess), then all shocks with maximum energy
• biphasic
• very short impulse duration (5-10ms)
• high current (15A)
• Detection of ventricular fibrillation is usually performed
according to the "X-out-of-Y-criterion" (= NID: number
of intervals to detect): With a setting e.g. of 18/24, 18
of 24 strokes must have a correspondingly high fre-
quency in order to release a shock ("fibrillation filter");
settings:
-- primary prophylaxis: 24/32 or 30/40
-- secondary prophylaxis: 12/16 or 18/24
• no more warning tones shortly before the shock re-
lease in modern devices
• Defibrillation is extremely painful for the patient (as if
a cobblestone drops onto the thorax from a height of
2 meters).
• If a patient with AICD is touched during the release of
the shock, nothing happens (harmless).
Fig. 677  AICD control: Ventricular fibrillation was detected
and terminated correctly with a shock delivery of 40 J (see
arrow).
Antitachycardia Pacing (ATP)
• overstimulation
-- slow VT:
◦◦ overstimulation with 70-80% (coupling interval) of
the cycle length of tachycardia
◦◦ 4 stimuli
◦◦ success rate: 90%
-- fast VT:
◦◦ overstimulation with 80-90% (coupling interval) of
the cycle length of the tachycardia
◦◦ 8 stimuli
◦◦ success rate: 80%
• pain-free (in contrast to defibrillation)
• best (The goal is to avoid shock release, i.e. defibrilla-
tion, which is extremely painful!)
• types:
-- burst (interval remains the same; less aggressive)
-- ramp (interval becomes shorter, i.e. the frequency
becomes higher; more aggressive [danger of ac-
celeration, i.e. that through overstimulation the VT
becomes faster and faster and even ventricular fib-
rillation occurs])
Cardioversion
• low energy only (1-2 J)
• R-wave triggered
• also painful
Zones (detection zones)
The classification is made according to the heart rate
HR or the cycle length CL (CL = 60000/HR). The cycle
length for the detection of ventricular fibrillation is called
FDI (fibrillation detection interval), the cycle length for the
detection of a tachycardia TDI (tachycardia detection in-
terval).
criterion for zoning: frequency in the
ventricle
• VF zone (ventricular fibrillation): Defibrillation is perfor-
med here.
-- content
◦◦ ventricular fibrillation
◦◦ haemodynamically non-tolerated VT (ventricular
tachycardia)
-- programming (according to HR or CL [= FDI here])
◦◦ EF > 60%: HR > 220/min (CL < 270ms)
◦◦ EF 30-60%: HR > 200/min (CL < 300ms)
◦◦ EF < 30%: HR > 180/min (CL < 330ms)
• VT zones (haemodynamically tolerated VT): ATS (anti-
tachycardia pacing) is performed here. One or two VT
zones can be programmed; programming according to
HR or CL (= TDI here; to determine the TDI long-term
ECG and ergometry where the maximum tolerated VT
is documented; TDI = CLVTmax + 60ms)
-- only one VT zone (HR 140-200/min; standard for pri-
mary prophylaxis)
-- two VT zones (standard for secondary prophylaxis)
◦◦ VT1 zone = FVT zone (f: fast; HR 160-220/min)
◦◦ VT2 zone: HR 140-160/min
• sinus zone (HR 40-140/min)
• Bradykardie (Hf < 40/min): bradycardia (HR < 40/min):
This is where pacemaker stimulation takes place (for
example VVI). Here, a low frequency (usually 40-50/
min) should be set to avoid stimulation (DAVID study
[Wilkoff et al, JAMA 2002]: increased RV stimulation →
increased mortality) and to ensure the patient's own
rhythm (exception Long-QT syndrome: here stimulati-
on with 80/min).
Increasingly, however, in primary prophylaxis (especially
according to the results of the MADIT-RIT study [see
box]), only the VF zone with the additional function "ATP
Cardiology 461
during the charging process" and no VT zone at all is ◦◦ low degree of agreement → VT (note: fails with
programmed. frequency-dependent [functional ]block)
• stability (protection against shock release in atrial fib-
rillation)
-- large variability of RR intervals (unstable) → SVT
MADIT-RIT study
(classic: tachyarrhythmia absoluta)
-- small variability of RR intervals (stable) → VT
There are additional criteria for dual-chamber AICD:
• comparison of the number of atrial (A) and ventricular
Reduction of inappropriate therapy and mortality through
ICD programming (V) signals
Moss et al, N Engl J 2012 -- A > V → SVT
-- A < V → VT
• MADIT-RIT: Multicenter Automatic Defibrillator Implanta-
• AV ratio
tion Trial–Reduce Inappropriate Therapy
• 1500 patients with AICD (primary prophylaxis); 3 diffe-
-- AV association → SVT
rent programmings: -- AV dissociation → VT
-- programming A (conventional) From this, various dual-chamber algorithms were de-
◦◦ VT zone: HR 170-200/min (2.5s) veloped by the respective companies for dual-chamber
◦◦ VF zone: HR > 200/min (1s) AICD, which are presented here as examples:
-- programming B ("high-rate") • SMART algorithm (Biotronik): comparison of the mean
◦◦ VT zone: HR > 170/min (not activated; monitor only) PP and RR intervals
◦◦ VF zone: HR > 200/min (2.5s) -- RR > PP (ventricle slower than atrium) → SVT
-- programming C ("duration delay") -- RR < PP (ventricle faster than atrium) → VT
◦◦ VT zone 1: HR 170-200/min (60s) • PARAD algorithm (Sorin)
◦◦ VT zone 2: HR 200-250/min (12s) -- stability (RR interval)
◦◦ VF zone: HR > 250/min (2.5s)
◦◦ unstable → SVT
• results: Both programming B and programming C
showed a significant reduction of inadequate shock deli-
◦◦ stabil → VT
very compared to conventional programming without an -- AV ratio
increase in mortality. On the contrary: The mortality rate ◦◦ AV association → SVT
was even significantly lower! ◦◦ AV dissociation → VT
-- onset
For purely electrical diseases (e.g. long / short QT syn- ◦◦ atrial ("atrium leads") → SVT
drome, ion channel diseases such as Brugada syndro- ◦◦ ventricular ("ventricle leads") → VT
me, idiopathic VT) the programming of only one zone is • Rhythm-ID (Boston Scientific)
completely sufficient (1-zone programming: only VF zone -- comparison of mean PP and RR intervals
is programmed [FDI 220/min]). ◦◦ RR > PP (ventricle slower than atrium) → SVT
Additional functions in the VT zone ◦◦ RR < PP (ventricle faster than atrium) → VT
-- stability (RR interval)
It is crucial that the AICD can distinguish between su-
praventricular (SVT) and ventricular tachycardia (VT). ◦◦ unstable → SVT
Shock should only be delivered in VT but not in case ◦◦ stable → VT
of SVT (e.g. sinus tachycardia, atrial flutter, atrial fibril- • AV-Detection Enhance Trial (St. Jude Medical): 3 cri-
lation). ). In SVT the therapy should be suppressed, alt- teria
hough the heart rate criterion is actually fulfilled. For this -- stability (RR Interval)
discrimination SVT / VT there are different criteria: -- QRS morphology
• onset (protection from shock release in sinus tachy- -- onset
cardia)
• PR-Logic (Medtronic): 6 criteria (complex)
-- slow increase in heart rate → SVT
-- frequency atrium / ventricle
-- rapid increase in heart rate ("sudden onset") → VT
-- PR pattern
(note: fails in AV node reentry tachycardia)
-- far field R-wave criterion
• QRS complex
-- stability
-- QRS width (largely abandoned today)
-- AF event counter
◦◦ narrow → SVT
-- AV ratio (AV association or AV dissociation)
◦◦ wide → VT
-- QRS morphology (now standard; e.g. "Wavelet" at
Medtronic): The QRS complex is compared with a
Indications
reference complex in sinus rhythm and the differen- • survived cardiovascular arrest after ventricular fibrillati-
tial area is determined. From this, the percentage on, ventricular flutter, VT + no reversible or no transient
degree of agreement is determined. cause (e.g. not < 48h after myocardial infarction)
◦◦ high degree of agreement → SVT • persistent VT ( > 30 sec) with hemodynamic effect + no

462 Cardiology
 reversible or no transient cause
• CHD (after myocardial infarction) + EF < 35% (primary
prophylaxis); note: however, AICD implantation at the
earliest 40 days after the infarction (i.a. DINAMIT study
[Hohnloser et al, N Engl J 2004: no mortality benefit
from early AICD implantation, i.e. already 6-40 days
after the infarction], Steinbeck et al, N Engl J 2009)
• DCM (EF < 35%) from NYHA II (primary prophylaxis)
• unclear syncopes + EF < 40% + inducible persistent
VT / ventricular fibrillation during EP examination
• specifically
-- Brugada syndrome (mainly for secondary preventi-
on; controversial for primary prevention [especially
when Brugada type I or inducible sustained VT du-
ring EP examination])
-- QT syndromes:
◦◦ Long-QT syndrome: recurrent syncope under
β-blocker
◦◦ Short-QT syndrome
-- H(O)CM:
◦◦ secondary prevention (always)
◦◦ primary prevention: in the presence of 2 risk fac-
tors
▪▪ SCD in family
▪▪ recurrent stress-inducible syncope
▪▪ hypertrophy > 30 mm
▪▪ ventricular tachycardia
▪▪ cardiac MRI: fibrosis centers
-- ARRVD (arrhythmogenic right ventricular dysplasia)
◦◦ secondary prevention (always)
◦◦ primary prevention: in the presence of risk factors
▪▪ SCD in family
▪▪ severe right ventricular dysplasia
▪▪ involvement of the left ventricle
• note for everyday practical use: When it comes to the
question of whether an AICD should be implanted or
not with regard to a wide QRS complex tachycardia, of
which you are completely unsure whether it is ventri-
cular or only supraventricular tachycardia, the decision
with a highly restricted pump function (EF < 35%) is
easy: Because here the indication for AICD implantati-
on is already given for primary prophylaxis alone.
No indications
• ventricular fibrillation / VT within < 48h after acute
myocardial infarction
• syncope without inducible VT and without structural
heart disease
• incessant VT (mostly relatively slow [120-160/min];
mostly patients with highly impaired pump function,
most frequent cause: ischemic cardiomyopathy; very
poor prognosis; antiarrhythmic agent of choice here:
β-blocker ["sympathetic blockade"]) → emergency ab-
lation
• ablatable arrhythmias (e.g. WPW syndrome, idiopathic
RVOT tachycardia)
Contraindications (for AICD carriers)
• MRI (For AICD carriers an MRI is contraindicated!
However, analog to the pacemakers, there are already
MRI-compatible AICD devices.)
• electronic welding (AICD carriers should not carry out
any welding work).)
• hyperbaric oxygenation (HBO is contraindicated in
patients with AICD or pacemaker, as the overpressu-
re can cause deformation of the unit with consecutive
loss of effectiveness.)
Emergencies
• dysfunction of the electrodes (lead; most frequent)
-- dislocation
◦◦ microdislocation (not yet visible in X-ray)
◦◦ macrodislocation (already visible in X-ray)
-- fracture
◦◦ Lead fractures occur more frequently in AICD than
in pacemakers (2% versus 0.4%).
◦◦ localization: mostly close to the aggregate
◦◦ strikingly high electrode impedance
-- insulation defect
◦◦ strikingly low electrode impedance
◦◦ strikingly many VT with very short cycle length (i.e.
high heart rate, e.g. 500/min) in the event counter
◦◦ causes
▪▪ injury of the lead by the fixation suture
▪▪ "subclavian-crush" syndrome (compression of
the lead between clavicle and first rib; especially
if the puncture of the subclavian vein was perfor-
med too far medially)
▪▪ degenerated insulation material
◦◦ problem: oversensing of artefacts with the conse-
quence of an inadequate shock release
• dysfunction of the aggregate (e.g. battery exhaustion,
physical damage [e.g. in the context of a thoracic trau-
ma], too long charging time of the capacitor)
• increase of the stimulus threshold (DFT: defibrillation
threshold) with the result that the AICD can no longer
defibrillate ventricular fibrillation; causes:
-- amiodarone (3-fold increase of the stimulus
threshold! note: decrease of the stimulus threshold
with β-Blocker or sotalol)
-- hyperkalemia
-- after cardioversion / defibrillation (mostly short term
massive increase of stimulation threshold!)
-- right ventricular myocardial infarction
• infection: In vegetations at the AICD lead the complete
system (i.e. lead and aggregate) must be explanted.
This is explicitly recommended (expert consensus
Wilkoff et al, Heart Rhythm 2009 and Kusumoto et al,
Heart Rhythm 2017: IB recommendation) in case of
endocarditis (e.g. vegetation on the valve without evi-
dence of vegetation on the lead) or in case of gram-
positive sepsis (blood culture), especially with staphy-
lococcus aureus: Due to the pronounced tendency to
biofilm formation, antibiotic therapy alone is usually
inefficient. With small vegetations (< 15mm) and an
implantation period of < 1 year, the lead can still be
Cardiology 463
 removed transvenously (so-called lead explantation;
cave pericardial tamponade → pericardial puncture
set within reach, with larger vegetations (> 15mm) or
implantation periods of > 1 year, this must be done by
cardiothoracic surgery (so-called lead extraction, using
extraction set). Alternatively, an interventional laser ex-
traction is performed in some specialized centers (for
lead removal see also infobox page 506). After 1-2
weeks (under monitor control), the implantation on the
opposite side can then take place if the inflammation
parameters are normal again. To protect the patient,
a wearable defibrillator vest (e.g. LifeVest [see page
469]) can be put on during this time temporarily. The
main cause are usually coagulase-negative staphylo-
cocci. Vancomycin or Daptomycin are suitable for em-
pirical antibiotic treatment.
• disturbance of sensing
-- oversensing
◦◦ AICD mistakes other events (T-wave, myopotenti-
als, electromagnetic interference signals [e.g. drill,
electrocautery]) than the R-wave for patient´s own
actions and triggers a shock.
◦◦ causes:
▪▪ electrocautery (operating with the electric knife):
see infobox
▪▪ electrode dysfunction (insulation defect of the
electrode, lead fracture [incomplete; here impul-
ses are often generated which are then incor-
rectly sensed by the AICD)
-- undersensing: AICD does not recognize the actions
and does therefore not trigger a shock despite VT /
ventricular fibrillation.
• resuscitation: A patient with AICD is basically resusci-
tated in the same way as a patient without AICD.
• frequent discharges ("electric storm")

464 Cardiology
perioperative AICD deactivation only
necessary for surgeries above the
navel AND monopolar electrocautery!

Cardiology 465

preoperative measures in pacemaker
patients only necessary for surgeries
above the navel AND monopolar
electrocautery!
Frequent discharges ("electric storm", VT
storm)
Definition
• more than 3 shocks from the AICD per day
• mortality: 2%
• occurrence: in 25% of AICD carriers; especially in pa-
tients with
-- ischemic cardiomyopathy (76%)
-- dilated cardiomyopathy (8%)
-- arrhythmogenic right ventricular dysplasia (8%)
• cave i.a. premature battery depletion
Causes
• inadequate (30%)
-- electrode defect
-- supraventricular tachycardia (especially atrial fibrilla-
tion, sinus tachycardia)
-- nicht-anhaltende ventrikuläre Tachykardie
-- oversensing
• adequate (70%)
-- proarrhythmic drugs (→ discontinuation)
-- electrolyte disorder (especially hypokalemia)
-- infection
-- progression of coronary artery disease / heart failure
(frequent) → possible interventional (PCI) or surgical
(CABG) myocardial revascularization
Therapy
• analgosedation (e.g. fentanyl + propofol / midazolam)
• magnetic application (ring magnet; closes the Reed
switch)
-- The magnet terminates the anti-tachycardic function
in the AICD, the anti-bradycardic function (pacema-
ker stimulation) remains intact. An AICD does not
have a transition from a magnetic application to a
magnetic frequency (rigid-frequency stimulation with
a manufacturer-specific heart rate) such as a pace-
maker.
-- tip: best to stick it on!
• determination of potassium/magnesium and, if neces-
sary, raise electrolyte levels
• antiarrhythmic therapy
-- amiodarone
◦◦ means of choice
◦◦ cave: Amiodarone leads to an increase in the sti-
mulus threshold. If the patient was saturated with
amiodarone during the inpatient stay, the AICD
should be tested before discharge (trial shock un-
der short anaesthesia).
-- β-blocker
◦◦ It is best here to use a non-selective β-blocker
466 Cardiology
(e.g. propranolol 2-5mg i.v.): They are lipophilic
and therefore can pass the blood-brain barrier,
where they can reduce the already increased sym-
pathetic tone in patients. They are more effective
than selective β-blockers in electric storm (Chatzi-
dou et al, J Am Coll Cardiol 2018).
◦◦ best in combination with amiodarone
-- VT storm in Brugada syndrome:
◦◦ no amiodarone, no β-blocker
◦◦ These patients benefit from an increase in sympa-
thetic tone. Means of choice here is orciprenalin
(also possible isoprosterenol, quinidine).
-- cave class I antiarrhythmics: Most AICD carriers
have a reduced ejection fraction. Class I antiarrhyth-
mics are contraindicated here due to their negative
inotropic effect!
• AICD control (programming device)
-- possibly increase fibrillation counter (e.g. from 8/12
to max. 30/40)
-- no shock for non-sustained VT
-- in case of inadequate shock delivery (i.e. shock in
case of SVT): activation of the additional func-
tions of the VT zone (especially onset, stability, QRS
width)
-- preferably ATP (overstimulation) instead of shock,
possibly cardioversion
-- program FVT zone (e.g. 180-250/min) with 1 x ATP, ,
then only shock (so-called "pain-free" programming)
-- options in case of ineffective ATP
◦◦ decrease of the cycle length (increase of the over-
stimulation frequency, the therapy becomes more
aggressive as a result)
◦◦ increase of the number of stimuli (e.g. from 4 to 8)
◦◦ conversion from burst to ramp (is the more ag-
gressive therapy)
• maybe cardiac catheter examination
-- generous (especially in ischemic cardiomyopathy)
-- to rule out renewed ischemia as a cause (ischemic
correlate as a trigger), possibly PCI
• electrode defect → surgical lead revision
• if necessary ablation (electrophysiology; very effective
[especially with ischemic, but less with dilated cardio-
myopathy])
-- emergency: in VT (VT ablation)
◦◦ only in individual cases
◦◦ a relatively complex and long lasting (4-6 hours)
procedure, maybe periprocedural even ECMO
(especially in hemodynamically unstable patients
to save time [e.g. to create a three-dimensional
activation map])
-- elective:
◦◦ AV node reentrant tachycardia → AV node modu-
lation
◦◦ atrial flutter → isthmus ablation
◦◦ atrial fibrillation → pulmonary vein isolation (atrial
fibrillation ablation), if necessary AV node ablation

Fig. 678  ring magnet
best antiarrhythmic therapy for
electrical storm: amiodarone +
β-blocker!
Legal aspects
• restricted driving license (according to the ESC Con-
sensus Statement of European Heart Rhythm Associa-
tion: updated recommendations for driving by patients
with implantable cardioverter defibrillators 2009); it is
important that the physician informs the patient about
this and documents it (otherwise liability risk for the
physician!)
-- private driving (group 1)
◦◦ after AICD implantation
▪▪ secondary prophylaxis: 3 months restriction for
driving after implantation
▪▪ primary prophylaxis: 1 month restriction for dri-
ving after implantation
◦◦ patient refusing AICD implantation:
▪▪ secondary prophylaxis: 6 months restriction for
driving
▪▪ primary prophylaxis: no restriction for driving
◦◦ after AICD therapy (defibrillation, ATP):
▪▪ after appropriate therapy: 3 months restriction
for driving
▪▪ after inappropriate therapy: restriction for dri-
ving, until measures to prevent inappropriate
therapy are taken
-- professional driving (group 2): generally perma-
nent restriction for driving (both primary and secon-
dary prophylaxis; without exception! also applies if
the patient refuses the AICD implantation [for both
primary and secondary prophylaxis])
-- annotations:
◦◦ after pacemaker implantation
▪▪ private driving: for 1 week (only until wound
healing is completed)
▪▪ professional driving: for 3 months
◦◦ after a syncope (Assessment guidelines on the
suitability of the Federal Highway Research Insti-
tute in Germany [BAST] 2018)
▪▪ first syncope: no restriction both for private and
professional driving, provided there is no evi-
dence of a high risk of recurrence (e.g. severe
aortic valve stenosis aortic stenosis (It should be
explained to the patient that the ride should be
interrupted when prodromi occur. A defensive
driving style is recommended)
▪▪ repeated (unclear) syncope: with private driving
restriction for driving for at least 6 months (then
recheck of the ability to drive), professional dri-
ving generally restriction for driving
• degree of the handicap (with AICD): 50% (with pace-
maker: 10%)
Ethical aspects
• One should certainly consider critically the indication
for the AICD implantation in older patients with highly
limited pump function (e.g. EF 15% in a 83-year-old
patient): By the implantation of an AICD one takes the
patient off the option of sudden cardiac death and on
the other hand there is a high probability of painful suf-
focation death (pump failure), which should be consi-
dered ethically. If, by the way, you were to implant an
AICD into any person (i.e. healthy, even without heart
failure) > 60 years of age, the survival rate could also
be significantly increased. The only question is whe-
ther that makes sense.
• If a patient with an AICD is in the dying process in the
intensive care unit, the defibrillation function (shock
release) should be deactivated in order to avoid un-
necessary stressful and painful shock releases in the
dying process. The deactivation should be done here
by programming with the control unit and not by pure-
ly by putting a magnet above the aggregate. The ATP
function should only be deactivated in ventilated pati-
ents, not in spontaneously breathing awake patients:
On the one hand, antitachycardia pacing is not painful
at all, on the other hand, ventricular tachycardia, if not
terminated, is highly likely to lead to cardiac decom-
pensation with pulmonary edema, which is absolutely
excruciating for spontaneously breathing awake pati-
ents (dyspnea, anxiety of suffocation). However, deac-
tivation against the actual or presumed patient's will is
out of the question.
Sudden cardiac death (SCD)
Definition
• unexpected death of cardiac cause
• usually as a result of ventricular fibrillation
Epidemiology
• the most frequent form of death ("We usually die
suddenly!")
• in Germany approx. 150000-200000 cases annually
• incidence (Germany): 81/100000 (Martens et al, Euro-
space 2014)
• frequency of SCD in the EU per year ≈ crash of two
fully occupied jumbo jets per day
• m:w = 2:1 (Bogle et al, J Am Heart Assoc 2016)
• successful resuscitation: in 30%
Cardiology 467
Causes
• younger patients (< 40 years)
-- HOCM (No.1) AVID study
-- coronary anomalies (No.2; prevalence 0.1-0.3%; es-
pecially right coronary artery; diagnosis: CT angio-
graphy)
-- ARRVD (arrhythmogenic right ventricular dysplasia) A Comparison of Antiarrhythmic-Drug Therapy with Im-
-- ion channel diseases (especially Brugada syndro- plantable Defibrillators in Patients Resuscitated from Near-
me, Long-QT syndrome) Fatal Ventricular Arrhythmias
-- myocarditis AVID-Study (Antiarrhythmics versus Implantable Defibrilla-
tors), N Engl J 1997
-- idiopathic VT
-- WPW syndrome • multicenter randomized controlled study
• elderly patients (> 40 years) • 1016 patients with status post ventricular fibrillation or
-- CHD cardioversion with sustained VT and EF < 40%
-- pulmonary embolism -- ICD (507 patients)
-- DCM -- Amiodaron (509 patients)
• result: ICD implantation was clearly superior to amiodar-
one! survival after 3 years:
Prevention -- ICD: 75%
• secondary prevention -- amiodarone: 64%
• primary prevention (indication AICD; prerequisite: EF
< 35%)
-- ischemic cardiomyopathy: clear indication (at least 4
weeks after myocardial infarction) MADIT I study
-- non-ischemic cardiomyopathy (e.g. DCM)
◦◦ asymptomatic (NYHA I): no indication
◦◦ symptomatic (NYHA II-IV): indication
Improved Survival with an Implanted Defibrillator in Pa-
tients with Coronary Disease at High Risk for Ventricular
drugs or devices?
Arrhythmia - MADIT (Multicenter Automatic Defibrillator
Implantation Trial) I
Moss et al, N Engl J 1996

Studies • multicenter randomized controlled study

• 196 patients with
• on secondary prevention:
-- status post myocardial infarction (ischemic cardio-
-- AVID (see box) myopathy)
-- CASH (Kuck et al, Circulation 2000) -- EF < 35%
-- CIDS (Connolly et al, Circulation 2000) -- documented non-sustained VT and EP-inducible and
• on primary prevention: non-suppressible VT
-- MUSST (Klein et al, J Interv Card Electrophysiol • groups
2000) -- 95 patients: ICD implantation
-- MADIT I /II (see box) -- 101 patients: conventional pharmacological therapy
• results
-- DINAMIT (Hohnloser et al, N Engl J 2004)
-- 54% reduction in mortality by ICD implantation
-- COMPANION (Bristow et al, N Engl J 2004)
-- Amiodarone had no effect at all on mortality.
-- DEFINITE (Kadish et al, N Engl J 2004)
-- SCDHeft (see box)
-- DANISH (see box)
-- EU-CERT-ICD 2020 (Zabel et a, Eur Heart J 2020):
significant reduction in mortality (but only a cohort
study)

468 Cardiology
 MADIT II study DANISH study

Prophylactic Implantation of a Defibrillator in Patients with Defibrillator Implantation in Patients with Nonischemic Sys-
Myocardial Infarction and Reduced Ejection Fraction - MA- tolic Heart Failure
DIT (Multicenter Automatic Defibrillator Implantation Trial) Kober et al, N Engl J 2016
II
Moss et al, N Engl J 2002 • multicenter randomized controlled study
• 1116 patients with non-ischemic cardiomyopathy (DCM)
• multicenter randomized controlled study -- with ICD implantation
• 1232 patients with status post myocardial infarction -- without ICD implantation
(ischemic cardiomyopathy) and EF < 30%
• result: no difference in mortality (note: In the sub-
-- 742 patients: ICD implantation
group analysis, however, in patients < 68 years ICD im-
-- 490 patients: conventional therapy plantation showed a significant reduction in mortality.)
• no EP examination for risk stratification, no documenta-
tion of VT necessary
• results: LifeVest
-- mortality after 20 months
◦◦ ICD group: 14.7% Definition
◦◦ conventional group: 19.8% • wearable cardioverter defibrillator (WCD) vest
-- Prophylactic ICD implantation reduced mortality • company Zoll
by 31%.
• construction:
-- Patients with wide QRS complexes (> 120 ms) and EF
< 25% benefited particularly (mortality reduction by -- belt with 4 electrodes
49%!) from this treatment. -- 3 defibrillator plates (2 rear, 1 front left under chest)
-- aggregate (monitor, battery)
• The vest detects ventricular fibrillation and ventricu-
lar tachycardia and gives alarm. If this is not acknow-
ledged within 25s for ventricular fibrillation or 90s for
SCD-Heft study
VT, defibrillation takes place with 150J (biphasic).
• as bridging to a potential AICD implantation (not as re-
placement)
• financing through medical and aids ordinance (no
Amiodarone or an implantable cardioverter-defibrillator for
congestive heart failure costs for patient or clinic)
Bardy et al, N Engl J 2005 • average wearing period: 2-3 months
• recommended daily wearing time: at least 20 hours
• multicenter randomized controlled study
• default settings:
• largest ICD study (to date)
-- VT zone: 150/min
• 2521 patients with heart failure NYHA II, III and EF 35%
(both ischemic [CHD] and dilated cardiomyopathy) and -- VF zone: 200/min
conventional therapy; 3 arms: • telemedicine possible via the LifeVest network
-- placebo
-- amiodarone
-- ICD
• results:
-- ICD → significant reduction in mortality
-- amiodarone: not better than placebo (in NYHA III even
excess mortality!)

Cardiology 469
 Fig. 679  LifeVest [34]

Indications: EF < 35%

• time after initiation / increase of heart failure therapy to
re-evaluation (most common indication): If a new heart
failure with an EF < 35% was detected and a relevant
CHD is ruled out by coronary angiography, medication
for heart failure is started. This must then be increased
on an outpatient basis. Only if EF remains < 35% after
three months despite the maximum possible drug the-
rapy for heart failure, an AICD is implanted. During this
time (3 months), however, the patient is unprotected,
so that he can be equipped with a defibrillator vest for
bridging.
• status post myocardial infarction in the first 40 days
• waiting time until CABG surgery or in the first 90 days
after CABG surgery
• myocarditis
• peripartum cardiomyopathy
• Tako-Tsubo cardiomyopathy
• waiting list for heart transplantation
• AICD explantation (e.g. due to infection) until reimplan-
tation
• rejection of AICD implantation

470 Cardiology
 study
Experience with the Wearable Cardioverter-Defibrillator in
Patients at High Risk for Sudden Cardiac Death
Waessnig et al, Circulation 2016
• retrospective cohort study
• 6043 patients with WCD (wearable cardioverter defibril-
lator); 404 centers (in Germany)
• median age: 57 years, 78% men
• most frequent indications:
-- DCM (37%)
-- ischemic cardiomyopathy (27%)
-- AICD explantation (e.g. due to infection)
• shock release in 1.6% (in case of persistent VT / ventri-
cular fibrillation; survival after 24h: 93%)
PROLONG study
Avoiding Untimely Implantable Cardioverter/Defibrillator
Implantation by Intensified Heart Failure Therapy Optimi-
zation Supported by the Wearable Cardioverter/Defibrilla-
tor
Duncker et al, JAHA 2017
• monocenter (medical high school of Hannover) retros-
pective study
• 156 patients with EF < 35%
• after 3 months under optimal pharmacological heart fai-
lure therapy under WCD protection in 42% again EF >
35% (i.e. no more AICD necessary), in case of an exten-
sion of another 3 months in a further 35%
• after 6 months in 62% EF > 35% again, i.e. in 2/3 of
all patients there was no indication for AICD implantation
after half a year
VEST study
Efficacy of a Wearable Cardioverter-Defibrillator after Myo-
cardial Infarction: Results of the Vest Prevention of Early
Sudden Death Trial
Olgin et al, N Engl J 2018
• first randomized controlled study on the topic WCD
(wearable cardioverter defibrillator)
• 2303 patients with status post recent myocardial infarc-
tion and EF < 35% (early post-infarction phase); 7 days
after discharge from hospital:
-- with WCD (LifeVest; over 90 days)
-- without WCD (only standard therapy)
• results: WCD
-- primary endpoint: no reduction in the rate of sud-
den cardiac death
-- secondary endpoints: i.a. all-cause mortality → signi-
ficantly reduced (since there were more fatal strokes
in the control group)
• Anm.: average daily wearing time only 18h (Only a quar-
ter of the patients who died in the WCD group were wea-
ring their vest at the time of death!)
Recommendations
• national
-- statement of the German Society for Cardiology
(DGK) 2015: IIa recommendation for AICD implan-
tation (e.g. due to infection), for the rest IIb recom-
mendation
-- recommendations of the German Society for Cardio-
logy (DGK) 2019 (see infobox)
• international (ESC-Guidelines 2015 for the manage-
ment of patients with ventricular arrhythmias and the
prevention of sudden cardiac death): IIa recommen-
dation for myocarditis, for the rest IIb recommendation
Cardiology 471
 Ventricular tachycardias
• ajmaline
• amiodarone: strictly contraindicated (only in case
of absolute danger to life [e.g. therapy refractory ven-
tricular fibrillation])
• R-wave triggered cardioversion
• after resuscitation in case of ventricular arrhythmia/
ventricular fibrillation (after exclusion of an recoverab-
le or temporary cause [e.g. myocardial infarction]) →
ICD implantation (shocks → no damage to the unborn
child [Natale et al, Cirulation 1997]); alternative: WCD
vest (e.g. LifeVest) during pregnancy and AICD im-
plantation only after delivery

Ion channel diseases

• syn.:
-- channelopathies
-- primarily electrical diseases of the heart
• types:
-- Brugada syndrome (sodium channel)
Therapy options in pregnancy -- QT syndromes (potassium channel):
◦◦ long-QT syndrome
◦◦ short-QT syndrome
-- catecholaminergic polymorphic ventricular tachycar-
dia (CPVT; calcium channel)
• overwiew: ventricular tachycardia / ventricular fibrilla-
tion
-- 95% with structural heart disease
-- 5% without structural heart disease ("idiopathic"
Supraventricular tachycardias ventricular fibrillation; typically ion channel diseases)
• vagal maneuvers
• adenosine Brugada syndrome
• digoxine
• verapamil: just very careful (reduction of blood flow in Definition
the uterus), ESC guidelines 2019: IIa recommendation • first described in 1992 by the brothers Pedro and Jo-
(previously IIb recommendation) sep Brugada in a small number (11) of patients who
• diltiazem: contraindicated suddenly suffered from cardiac arrest, were success-
• β-blocker (especially β1-selective [but not atenolol]) fully resuscitated, had no structural heart disease and
• class IC antiarrhythmics (propafenone, flecainide) all showed a typical ECG picture
• R-wave triggered cardioversion (relatively unprob- • syncope in the own anamnesis
lematic [fetus outside the current field]) • sudden cardiac death in the family anamnesis

472 Cardiology
• in 30% sudden cardiac death as first manifestation -- ventricular tachycardia
• absence of a structural heart disease ◦◦ frequently polymorphic
◦◦ origin: right ventricular outflow tract (RVOT)
Epidemiology -- ventricular fibrillation
• prevalence: 0.1-0.4% of the population (just as fre- • new risk markers:
quent as WPW syndrome!) -- fragmented QRS complexes (fQRS) in V1-V3 (i.e.
• m:w = 8:1 ≥ 2 spikes)
• first manifestation mostly in the 4th decade of life -- early repolarisation (recognizable as late potential
• 30% of all SCD in structurally heart-healthy people [especially in signal-amplified ECG]) in the inferola-
• high prevalence especially in Asia, there partly synony- teral leads
mous with SCD in men < 50 years (especially at night
during sleep; SUNDS [sudden unexplained nocturnal
death syndrome]):
-- "Lai Tai" (Thailand)
-- "Bangungut" (Philippines)
-- "Pokkuri" (Japan)
Fig. 680  Brugada ECG: shoulder-shaped elevated ST seg-
Etiology ment
• partially autosomal dominant inheritance, in 30% posi-
tive family anamnesis
• mutation in SCN5A gene (coded for cardiac sodium
channel) on chromosome 3 (possibly genetic testing)

Symptoms
• syncope
• palpitations
• SCD or after successful resuscitation in ventricular fi-
brillation
• often at rest / at night during sleep
• nocturnal agonal breathing
• frequent triggers:
-- fever
-- excessive alcohol consumption
-- large (opulent) meals
-- medication (see below), drugs (i.a. cannabis, coca-
ine)

ECG
• right bundle branch block (complete / incomplete)
• descending (saddleback / coved-type; "children's sli-
de") ST elevation in the right precordial leads (V1-V3)
• shoulder-shaped elevation of ST segment (J-point)
• The ECG changes exclusively affect the leads V1-V3.
• The corresponding ECG changes are often easier to
detect if the right ventricular leads (V1 and V2) are ap-
plicated one ICS higher (2nd / 3rd ICS).
• The ECG morphology typically changes..
• concealed Brugada syndrome → provocation test with
ajmaline
-- As a sodium channel blocker, Ajmalin can unmask
the typical ECG findings.
-- ajmalin test: gilurytmal 1 mg/kg over 5min i.v.
-- possible complications: ventricular tachycardia, pos-
sibly ventricular fibrillation (therefore defibrillator rea-
diness; cave: monitoring for at least 2hours!)
• possibly PQ interval↑
• malignant arrhythmias:

Cardiology 473

Fig. 681  Brugada ECG type I: shoulder-shaped elevated ST
segment, especially in V1 and V2 (various examples)
Fig. 682  Brugada ECG type II: saddleback-type ST seg-
ment, elevated especially in V2, the isoelectric line is not
yet reached
Therapy
• general measures
-- avoidance of excessive alcohol consumption and
large (opulent) meals
-- immediate treatment of fever with antipyretic drugs
(e.g. paracetamol)
-- avoidance of certain drugs (see especially http://
www.brugadadrugs.org): especially Class IC antiar-
rhythmics, β-blockers, antidepressants (especially
amitriptyline [Tricyclic antidepressants are sodium
channel blockers], lithium), propofol, antihistamines
• drugs
-- amiodarone: ineffective
-- β-blocker: contraindicated (even increased inci-
dence of ventricular fibrillation)
-- therapy for VT storm in Brugada syndrome:
◦◦ no amiodarone, no β-blocker
◦◦ Very effective here is orciprenalin (also possible
isoprosterenol or quinidine [class IA antiarrhyth-
mic]).
474 Cardiology
◦◦ if applicable, catheter ablation in recurrent VT
storms
• AICD
-- symptomatic (resuscitation, syncope, documented
sustained VT) → secondary prevention (clear indi-
cation)
-- asymptomatic
◦◦ primary prevention: indication controversial
▪▪ if applicable, electrophysiological risk stratifica-
tion (programmed ventricular stimulation; but no
general recommendation)
▪▪ Patients with a high risk should receive an AICD
(class IC recommendation). High risk is defined
as follows: Brugada type I (spontaneous, i.e.
without ajmaline provocation test) or sustained
inducible VT during EP examination
◦◦ no survival benefit versus symptomatic patients
◦◦ A positive family history for SCD or Brugada syn-
drome is surprisingly not prognostically relevant
according to previous findings (Gehi et al, J Cardi-
ovasc Electrophysiol 2006; Probst et al, Circ 2010;
Sarkozy et al, Eur Heart J 2011) and is therefore
not considered in the current recommendations
(Class III recommendation) on risk stratification.
◦◦ possibly prophylactic administration of quinidine
or hydroquinidine in asymptomatic patients with
spontaneous type I ECG or in patients with a con-
traindication for AICD (IIb recommendation [Pri-
ori et al, Heart Rhythm 2013]; i.a. QUIDAM study
[Probst et al, Eur Heart J 2013])
Prognosis
• mortality:
-- mortality without any therapy: 30% risk of sudden
cardiac death within 2 years after syncope or after
surviving cardiac arrest
-- mortality with AICD: almost 0%
• In a patient with newly diagnosed Brugada syndro-
me a family screening should be performed urgently.
If the ECG of the family members is inconspicuous,
an ajmaline test should also be generously performed.
Genetic testing is recommended for first-degree family
members.
• genetic testing:
-- only minor diagnostic (sensitivity only 25%) and pro-
gnostic (no genotype-based risk stratification) impor-
tance
-- possibly as a confirmation test to confirm the diagno-
sis in case of clinical doubt
-- only recommended as an option (IIa recommandati-
on; especially for first-degree family members)
Long-QT syndromes (LQTS)
Definition
• congenital prolongation of the QT interval
• ion channel disease (especially potassium channel,
but also sodium channel)
• genetic (various gene mutations described [all on the
 short arm of chromosome 11]) Fig. 683  determination of the frequency-corrected QT inter-
val with the Bazett formula (According to agreement, the
• delayed cardiac repolarization
QT interval is always measured in V2/V3, since it is the lon-
• frequent ventricular tachycardia (especially torsade de gest there.)
pointes), maybe even ventricular fibrillation with SCD
• key symptom: syncope; typically triggered by stress /
exercise (activation of the sympathetic nervous sys-
tem, which triggers the torsade de pointes):
-- psychical stress (especially fright [e.g. suddenly loud
noise like ringing the alarm clock], fear, excitement,
anger)
-- physical stress (especially sport, jump into the water)
• frequent misdiagnoses:
-- vasovagal syncope
-- epilepsy (hence often convulsive syncope)

LQTS: recurrent stress-induced Fig. 684  ECG: prolonged QT interval

syncope in childhood and
adolescence, QT interval ↑ +
positive family history!

Epidemiology
• especially in children and adolescents
• prevalence: 1: 2000 live births
• w>m
• mortality:
-- 20% within 1 year after the first syncope
-- 50% after 5 years (untreated)

Diagnosis
• ECG:
-- QTc interval ↑ (The frequency-corrected QT interval
should always be determined. The lower the heart
rate, the longer the relaive QT interval. There are
various formulas for this [i.a. Fridericia, Hegglin, Fra-
mingham]. The most common is the Bazett formula.)
-- T wave:
◦◦ notches
◦◦ alternans (change of the morphology of the T-
wave with regard to amplitude or alignment [po-
larity; e.g. positive on one stroke, negative on the
next stroke])
• diagnostic criteria: Schwartz score (see infobox [accor-
ding to Schwartz et al, Circ 1993; updated 2011]; note:
According to this score, an LQTS can also present if
the QT interval is not extended!)
• genetic testing (recommendation grade I)
• note: EP examination (programmed ventricular stimu-
lation) unsuitable for risk stratification

QT (ms) Types
QTc = • previous classification (according to the first descrip-
tors):
RR (s) -- Romano-Ward syndrome (autosomal dominant; wit-
hout inner ear deafness; more often)
-- Jervell-Lange-Nielson syndrome (autosomal reces-
sive; withinner ear deafness; less often)
• current classification (according to genetics; mean-

Cardiology 475
 while 8 different types described): especially
-- LQTS I (most common)
◦◦ mutation in the KCNQ1 gene
◦◦ disorder of the potassium channel
◦◦ very good response to β-blocker
◦◦ trigger: stress
-- LQTS II
◦◦ mutation in the KCNQ2 gene
◦◦ disorder of the potassium channel
Fig. 685  Short QT syndrome: short QT interval and remar-
◦◦ questionable response to β-blocker kably high peak T wave
◦◦ trigger: stress
-- LQTS III
◦◦ mutation in the SCN5A gene
◦◦ disorder of the sodium channel
◦◦ no response to β-blocker (here even disadvanta-
geous because the QT interval increases due to
bradycardia; option here: AAI pacemaker to incre-
ase the heart rate of the basic rhythm)
◦◦ trigger: rest
Fig. 686  Short QT syndrome: short QT interval (here 308
Therapy ms) and high peak T wave
• general measures
-- avoidance of the triggers (e.g. no competitive sport, Catecholaminergic polymorphic ventri-
no swimming / diving, no loud acoustic signal tones cular tachycardia (CPVT)
[especially no alarm clock]) • especially in children (danger of SCD)
-- no drugs that prolong the QT interval • congenital (ion channel disease [calcium channel, es-
-- compensation of hypo-electrolytes (especially hypo- pecially ryanodine receptor [RYR-2 gene], calseques-
kalemia) trin])
• β-Blocker • genetic testing recommended (recommendation grade
-- to reduce the activity of the sympathetic nervous I)
system and thus the trigger • prevalence: 1:10000
-- in 75% sufficient • polymorphic VT
• AAI pacemaker in LQTS III • QT interval normal
• possibly AICD (especially after resuscitation or recur- • mainly occurring during exercise (mental, physical
rent syncope despite β-blocker) [e.g. ergometry])
• if necessary surgical denervation of the heart: LCSD • normal ECG at rest, but conspicuous exercise ECG
(left cardiac sympathetic denervation) • can also be triggered by exogenously supplied cate-
-- to reduce sympathetic activity cholamines in the intensive care unit with a correspon-
-- surgical removal of the stellate ganglion ding genetic predisposition
• in 30% sudden cardiac death as first manifestation
Short-QT syndrome • therapy: β-blocker (high dose)
• p.d. QTc < 320 ms
• congenital (autosomal dominant)
• mutation in the potassium channel → accelerated re-
polarization
• 5 types (different gene mutations: KCNH2, KCNQ1,
KCNJ2, CACNA1C, CACNB2b)
• frequent atrial fibrillation and syncope in childhood,
SCD in family
• ECG: shortened QT interval and high peak T wave
(DD hyperkalemia or hyperacute myocardial infarction)
• other clinically important DD of a QT interval shorte-
ning: digitalis intoxication!
• therapy: AICD
Fig. 687  CPVT: catecholaminergic polymorphic ventricular
tachycardia (here occurred during ergometry)

476 Cardiology
 Fig. 690  Another example of an artifact: Here, the patient
allegedly had "self-limiting" ventricular fibrillation again
and again (note: Ventricular fibrillation is never self-limiting
and only turns into asystole at some point.). Ultimately, it
was just trembling artifacts in a patient with Parkinson's
disease.

Fig. 688  One should always think of iatrogenic tachycardia:

Here, for example, shortly after a Port-a-Cath implantation
(left subclavian vein), a wide QRS tachycardia with LBBB
occurred, which indicates the right ventricular origin. It tur-
ned out that the port tip was not, as it should have been,
at the cavoatrial transition, but much too far in the right
heart (here in the right ventricle), which ultimately caused
the rhythm disturbances. The "antiarrhythmic therapy" in
this case is very simple: Under local anesthesia only the Fig. 691  Another example of an artifact: there is an alleged
skin has to be opened briefly, the tube has to be disconnec- broad QRS complex tachycardia. This was only due to the
ted from the port, shortened by a few centimetres and then patient's restlessness. Lead III shows a normofrequency
reconnected. sinus rhythm. You would have recognized that by feeling
your pulse!

bradycardic cardiac
arrhythmias

Causes
• primary (15%; idiopathic [degenerative])
• secondary (85%)
Fig. 689  Artefacts should also always be considered: This -- ischemic (No.1; 40%; especially acute coronary syn-
is not a tachycardia, but only artefacts of a sacral neuro- drome)
stimulator. -- pharmacological-toxic (No.2; 20%; especially.
β-blocker [note: Even eye drops containing
β-blockers can also cause a relevant bradycardia!],
verapamil, digitalis)
-- metabolic (5%)
-- neurological (5%)
-- pacemaker failure (2%)
-- other (13%)

Cardiology 477
Types
• sinus bradycardia
• sick sinus syndrome (SSS)
• AV block
• bradyarrhythmia absoluta
Sick sinus syndrome (SSS)
Definition
• syndrome of the sick sinus node
• most common indication for pacemaker implantati-
on (DDD pacemaker)
Forms
• symptomatic sinus bradycardia (often the earliest sign)
• intermittent sinus arrest / SA block
• tachycardia-bradycardia syndrome:
-- paroxysmal atrial fibrillation
-- pre-automatic pause after termination before sinus
rhythm resumes (with dizziness, syncope)
• chronic atrial fibrillation (often misjudged as "idiopa-
thic" atrial fibrillation)
Causes
• idiopathic degeneration (fibrosis) of the conduction
system (most common cause; can affect both the si-
nus and AV node)
-- M. Lenegre (concerns especially the distal conduc-
tion system and younger patients)
-- M. Lev (concerns especially the proximal conduction
system and elderly patients)
• CHD (The sinus node artery originates in 70% from the
right coronary artery and in 30% from the left circum-
flex artery.)
• cardiomyopathy, myocarditis
Diagnosis
• long-term ECG (Holter)
• exercise ECG: typically completely insufficient heart
rate increase under exercise(not more than 110/min
[usually not even more than 90/ min]; chronotropic in-
competence)
• atropine test: After injection of 1mg atropine the heart
rate does not increase > 80/min.
• EP examination: extended sinus node recovery time
(> 1500 ms; = time to restore sinus rhythm after rapid
atrial stimulation)
478 Cardiology
Fig. 692  pre-automatic pause
Therapy
• pacemaker implantation (Theoretically a single-cham-
ber pacemaker [AAI] would be sufficient, but in 10% of
the cases, disease of the AV node in the sense of two
node disease also occurs in the course, so that usually
a two-chamber pacemaker [DDD] is implanted.)
• possibly atrial fibrillation ablation to avoid pacemaker
implantation in tachcardia-bradycardia syndrome (This
option is often not considered!)
SA block (sinu-atrial)
SA block grade I
• not recognizable in normal (surface) ECG
• only in intracardiac (electrophysiological examination)
ECG (p.d. sinoatrial conduction time > 120ms)
SA block grade II
• intermittent dropping of the QRS complex without prior
P wave
• types
-- SA block grade II type Wenckebach
◦◦ The PP distance becomes smaller.
◦◦ The pause is smaller than the double PP interval.
-- SA block grade II type Mobitz
◦◦ The PP distance remains the same.
◦◦ The pause is as long as the double PP interval.
SA block grade III
• continuous dropping of the QRS complexes without
prior P wave
• complete absence of the sinoatrial transition (total SA
block)
• The pause does not correspond to a multiple of the PP
interval.
• In the normal (surface) ECG it cannot be distinguished
from sinus arrest.
• possibly escape rhythm up to complete asystole with
Adams-Stokes attack
Fig. 693  top: SA-Block grade II type Wenckebach, middle:
SA-Block grade II type Mobitz; bottom: SA-Block grade III
(courtesy of Mr. U. Follmann, former Deputy Director of the
Clinic for Internal Medicine I, Caritas-Krankenhaus St. Jo-
sef Regensburg [Germany])
AV block (atrio-ventricular)
First degree AV block
• extended PR interval (> 200 ms)
• harmless (no indication for pacemaker implantation)
Fig. 694  first degree AV Block
Second degree AV block
• type Wenckebach (named after the Dutch internist
Karel Frederik Wenckebach [1864-1940]); note: also
called (in anothter classification) Mobitz I
• type Mobitz (named after the German internist Wolde-
mar Mobitz [1889-1951]); note: also called (in anothter
classification) Mobitz II
second degree AV block: A QRS
complex does not follow every P wave!
Second degree AV block type Wenckebach
• progressive prolongation of PR interval periodically
due to increasing fatigue of the AV node until total
dropping of the conduction through the AV node
• harmless; frequent in adolescents, athletes and digita-
lis intoxication
• no indication for pacemaker implantation
Fig. 695  second degree AV block type Wenckebach
Second degree AV block type Mobitz
• partial AV block with regular dropping of the chamber
complexes in a fixed ratio
• constant PQ interval
• mostly an indication for pacemaker implantation
Fig. 696  second degree AV block type Mobitz
A special form of second degree AV-Block is the AV-Block
with 2:1 blocking ratio: Here, the atrial excitation is alter-
nately conducted and not conducted to the chamber (2
P waves, 1 QRS complex). This can be a second degree
AV block type Wenckebach (Mobitz I; harmless) as well
as type Mobitz (Mobitz II; harmful). The differential diag-
nosis is often not easy, a longer ECG recording (rhythm
strips) can be helpful. If you are lucky, the conduction
changes and you can make a further differentiation:
• proof of a 3:1 blocking ratio (3 P waves, 1 QRS com-
plex) → second degree AV block type Mobitz (PR inter-
val remains the same)
• proof of a 3:2 blocking ratio (3 P waves, 2 QRS com-
plexes) → second degree AV block type Wenckebach
(PR interval increases; note: The shortest Wencke-
bach block is the 2:1 block.)
If an increase of the sympathetic tone (e.g. ergometry)
increases the blockage (3:1) or an increase of the vagal
tone (e.g. Valsalva maneuver) decreases the blockage
(normal conduction again), it is an second degree AV
block type Mobitz. A second degree AV block type Wen-
ckebach often disappears under stress / exercise.
Cardiology 479

Fig. 697  This shows a second degree AV block with a 2:1
blocking ratio: It can be either second degree AV block type
Wenckebach or type Mobitz. This can only be differentiated
if the conduction changes in a longer ECG recording (e.g.
rhythm strips, long-term ECG).
Fig. 698  long-term ECG: A 2:1 block can be seen on the left
side of the picture. On the right, the conduction changes to
a 3:2 block and the PR interval increases, i.e. it is a second
degree AV block type Wenckebach.
480 Cardiology
Fig. 699  2:1 block (here second degree AV block type
Wenckebach)
Fig. 700  first 2:1 block, then the conduction changes to 3:2
and the PQ interval increases, so that it is a second degree
AV block type Wenckebach
Third degree AV block
Definition
• total (complete) AV block
• atrium and ventricle beat independently (AV dissocia-
tion [ the crucial criterion!]),whereas in the first and
second degree AV atrium and ventricle still beat de-
pendently on each other (AV association)
• P-waves "pass through".
• ventricular escape rhythm (secondary or tertiary cen-
tre)
• The atrial frequency is higher than the ventricular fre-
quency
• DD to second degree AV block:
-- type Mobitz: in third degree AV block no constant PR
interval (in second degree AV-Block II type Mobitz
constant PR interval)
-- type Wenckebach: in third degree AV-Block regular
ventricular actions (escape rhythm; caused by the
AV dissociation; in second degree AV block type
Wenckebach irregular ventricular actions)
• possible Adams-Stokes attacks
• absolute indication for pacemaker implantation

Fig. 701  third degree AV block (cause here: acute inferior
myocardial infarction, recognizable by the ST elevations in
II, III, aVF)
Fig. 702  third degree AV block: Only P waves without QRS
complexes (ventricular asystole) can be detected.
Fig. 703  regular wide QRS bradycardia without P waves:
third degree AV block in atrial fibrillation (very often over-
looked!)
regular wide QRS bradycardia without
detectable P waves: atrial fibrillation in
third degree AV block!
Adams-Stokes attack
• exactly: Morgagni-Adams-Stokes attack (MAS)
• named after the Dublin physicians Robert Adams
(1791-1875) and William Stokes (1804-1878)
• state of short unconsciousness, which is caused by
a paroxysmal short asystole as a result of a total AV
block, SA block or sinus arrest
• unconscious out of complete well-being without pro-
dromi
• very often therefore by fall injuries (typical: facial skull
injuries!)
• often also seizures (similar to an epileptic seizure; so-
called convulsive syncope; to distinguish a convulsive
syncope from a real epileptic seizure see page: fol-
lows)
• therapy: pacemaker implantation (dual-chamber PM;
DDD)
There are only two causes of syncope
that cause facial injury: epileptic
seizure and MAS attack! classic
without prodromi!
Causes
• degenerative (No.1, 50%): idiopathic fibrosis of the
conduction system (can affect both the sinus and AV
node)
-- M. Lenegre (concerns especially the distal conduc-
tion system and younger patients)
-- M. Lev (concerns especially the proximal conduction
system and elderly patients)
• ischemic (No.2; 40%)
-- stenosing CAD or acute myocardial infarction (espe-
cially inferior wall myocardial infarction [When regar-
ding the 12-lead ECG, one is often very focused on
the rhythm. One should not forget to check whether
there are ST elevations in II, III and aVF!])
-- The AV node is supplied predominantly by the right
coronary artery (RCA). The AV node artery arises
in 90% from the right coronary artery (RCA) and in
10% from the left circumflex artery (LCX). Therefore
a cardiac catheter examination should generously be
performed especially in unclear cases (even if there
are no signs of ischemia in the ECG and laboratory):
By intervention (PCI + stent implantation) of a higher
grade RCA stenosis the implantation of a permanent
pacemaker may be avoided for the patient!
• pharmacological (No.3; e.g. β-blocker, digitalis, vera-
pamil), toxic (e.g. organophosphates)
• metabolic (especially hyperkalemia, amyloidosis)
• inflammatory
-- myocarditis (especially borreliosis [Lyme disease],
rheumatic fever, sarcoidosis)
-- endocarditis
Cardiology 481
• iatrogenic
-- post-operative (after cardiac thoracic surgery)
-- post-interventional, especially after
◦◦ TAVI (transcatheter aortic valve implantation): in
17%
◦◦ TASH (transcoronary ablation of septal hypertro-
phy; with HOCM [hypertrophic obstructive cardio-
myopathy]): in 10%
◦◦ ablation (e.g. AV node reentry tachycardia, WPW
syndrome)
third degree AV-Block: generous
cardiac catheterization to rule out
higher grade RCA stenosis!
Fig. 704  STEMI of the inferior wall (ST elevations in III and
aVF) with consecutive third degree AV block
Localisation
• according to His bundle (named after the German in-
ternist Wilhelm His [1863-1934]):
-- infrahisarian
◦◦ wide QRS complex
◦◦ intensive care unit
-- suprahisarian
◦◦ narrow QRS complex
◦◦ possibly normal ward (IMC)
• according to AV node:
-- intranodal (syn.: AV-nodal; withinin the AV node)
◦◦ AV stimulation (e.g. atropine, catecholamines) im-
proves the conduction here.
◦◦ AV inhibition (e.g. vagal maneuvers such as ca-
rotid sinus massage, adenosine, verapamil,
β-blocker) worsens the conduction here.
-- infranodal (below the AV node)
◦◦ AV stimulation (e.g. atropine, catecholamines)
worsens the conduction here (cave cardiovascular
arrest due to ventricular asystole!).
◦◦ AV inhibition (e.g. vagal maneuvers such as caro-
tid sinus massage, adenosine, verapamil, β blo-
cker) paradoxically even improves the conduction
here.
482 Cardiology
Therapy
• pharmacological (drugs)
• electrical (pacemaker)
Drugs
• atropine
-- inhibition of the release of acetylcholine by blocking
muscarinic receptors (a parasympathicolytic agent)
-- 1 amp. = 0.5mg; max. 3mg = 6 ampoules
-- cave for second degree AV-Block type Mobitz and
third degree AV-Block → paradoxical effect
◦◦ decrease in heart rate by atropine
◦◦ The paradoxical effect is due to the fact that at
certain muscarinergic receptors atropine causes
activation instead of inhibition and thus a release
of acetylcholine.
◦◦ Classically the paradoxic effect occurs almost
only with slow application and with small dosage
(0.25mg). The paradoxical effect is terminated by
increasing the dose. Alternatively, adrenalin can
also be given.
◦◦ Atropine only acts at the AV node. Atropine no
longer acts on the pathways below the AV node
(infranodal; e.g. His bundle). The refractory time
is extended in the area of the infranodal blocka-
ge, so that the excitation waves from the atrium
now reach the refractory phase of the diseased
pathway and are therefore no longer transmitted.
The higher the atrial frequency (e.g. by administra-
tion of atropine), the longer the refractory time and
the less excitation waves are transmitted. The
blocking ratio increases. There is a risk of comple-
te ventricular asystole.
◦◦ If the AV block type Mobitz is of infranodal loca-
tion (recognizable by wide chamber complexes),
atropine causes an increase in the blocking ratio
due to an increase in the sinus frequency, with the
result that a complete AV block up to ventricular
asystole (i.e. only P waves without QRS comple-
xes) can occur! Here adrenaline (diluted) is the
treatment of choice.
-- Atropine is usually ineffective in third degree AV
block, and even contraindicated in infranodal third
degree AV block, i.e. with wide chamber complexes!
-- contraindicated (relatively) in glaucoma (narrow-
angle glaucoma)
• glycopyrronium bromide (Robinul)
-- a parasympathicolytic agent
-- 1 amp. = 1ml = 0.2mg; dosage: 0.2mg i.v.
-- in contrast to atropine no crossing of blood-brain bar-
rier (therefore good especially in geriatric patients)
-- off-lable-use (note: Main indication is bronchial hy-
persecretion.)
• orciprenaline (Alupent)
-- 1 amp. = 5mg
-- perfusor: 1 large ampoule (10ml = 5mg) + 40ml NaCl
0.9% → 0.1 mg/ml, infusion rate: 6-18 ml/h
-- no longer approved for this purpose since 2009 (off-
label-use; officially only approved for the treatment
 of asthma attack)
-- but still recommended in the ERC guidelines 2015
• diluted adrenaline 1:100000 (e.g. 1 ampoule Sup-
rarenin [= 1ml = 1mg] in 100ml NaCl 0.9% → of which
1ml repetitively)
• theophylline
-- 1 amp. = 10ml = 200mg; dosage: 100-200mg slowly
i.v.
-- as the second choice drug recommended by the
ERC 2015 for bradycardia do to:
◦◦ inferior wall myocardial infarction
◦◦ heart transplantation
◦◦ spinal cord injury
• select energy (current: 120-200 mA)
• pulse control
• Iindications: An external pacemaker stimulation is very
rarely necessary. It is only performed in the case of
severe AV blocks or severe bradycardia and especially
when the patient is really unstable, which is rarely the
case. Then an external pacemaker stimulation is car-
ried out bridging (especially preclinically) until a tem-
porary internal pacemaker is implanted.

Atropine is contraindicated in
infranodal third degree AV-Block
(increase of blocking ratio with
risk of complete ventricular
asystole)!

Patients with bradycardia (e.g. third degree AV block with

a heart rate of 28/min) are often hypertensive (e.g. BP
of 210/130mmHg). However, this is completely normal
and physiological: The cardiac output is composed of the
product of stroke volume and heart rate. In order to ge-
nerate a sufficient cardiac output for organ perfusion, the
stroke volume is automatically increased. The lower the
heart rate, the higher the stroke volume and thus also
the blood pressure. The increased blood pressure must
not be lowered here (up to an upper limit of systolic BP
of 240mmHg), because otherwise the patient's cardiac
output is lowered and he is transferred into shock!

third degree AV-Block: often hyper-

tensive → physiological (Do not lower
BP!)
Fig. 705  Pacing (here LIFEPAK 15): First the adhesive
electrodes are glued on. Additionally the ECG derivation
via the ECG cable of the device is also required. Then you
Pacemaker press the "stimulation" button and select an appropriate
frequency (e.g. 60/min). Then you go up with the current
• temporary pacemaker ("current" button) until the spike is followed by a QRS com-
-- external plex. The stimulation is performed automatically as long as
-- internal the patient's own frequency is below the set frequency (on-
demand mode).
• permanent pacemaker (always internal)

Temporary external pacemaker Temporary internal pacemaker

• transthoracic
• short anaesthesia (analgosedation, e.g. fentanyl + pro-
pofol)
• by means of paddles or adhesive electrodes
• positioning:
-- sternal-apical (as with defibrillation )
-- anterior-posterior ("sandwich" technique)
• set ECG to synchronisation mode (SYNC)
• In contrast to cardioversion, in pacing the ECG
must also be derived via ECG electrodes in addition to
the paddles / adhesive electrodes.
• select stimulation frequency (approx. 60-90/min)
Indications
• higher degree AV blocks in acute inferior myocardial
infarction (for permanent pacemaker implantation wait
at least 10 days [monitoring → logistic problem!])
• alternating bundle branch blocks (alternation of LBBB
and RBBB)
• bridging of symptomatic bradycardia
-- until the effect of bradycardic medication subsides;
note: If the patient is stable, it is sometimes not so
bad to do nothing at all and simply wait until the ef-
fect of the bradycardic medication [e.g. β-blocker in
the premedication] has subsided. If, for example, a

Cardiology 483
 stable patient with a third degree AV block with nar- pacemaker. However, if the patient has a permanent
row QRS complexes and an HR of 32/min is implan- pacemaker anyway, the heart rate can simply be set
ted a temporary pacemaker with overzealousness higher with the programming device without much ef-
and then stimulated, for example, with 50/min, it is fort.
possible that as a result of the artificial stimulation
there is no rhythm at all left. If there is a disloca-
tion (e.g. at night due to an abrupt movement of the
patient) of the stimulation lead with the result that
the stimulation no longer functions, the patient can
then become completely ventricular asystolic. Here
the saying applies: "Do not accelerate the patient,
but rather slow down the doctor!). In such situations,
we usually already insert a temporary pacemaker for
safety, but we only set this to a relatively low backup
frequency (e.g. 30-40/min) so that the patient conti-
nues to have his own rhythm.
-- until implantation of a permanent pacemaker system
• complications in case of infectious endocarditis or acu-
te myocarditis (septal edema) with involvement of the
cardiac conduction system
• protection in the postoperative phase of cardiac surge- Fig. 706  alternating bundle branch blocks: change from
ry (standard at the end of a cardiac surgery: epicardial LBBB to RBBB
electrode)
• change of aggegate in completely pacemaker-depen-
dent patients (Alternatively, it is also possible to stimu-
late intraoperatively via the alligator clamps.)
• In the context of TASH (transcoronary ablation of sep-
tal hypertrophy) for the therapy of HOCM (hypertrophic
obstructive cardiomyopathy) a third degree AV block
occurs in 10%, so that as a rule a temporary pacema-
ker is placed prophylactically before TASH.
• if necessary (very rarely) prophylactically before right
heart catheter / pulmonary artery catheter in patients
with complete LBBB: In 4% a RBBB develops during
implantation of a pulmonary artery catheter. In case of
a pre-existing LBBB this can then lead to a total block!
• borreliosis (Lyme disease), sarcoidosis
• intoxication (e.g. β-blocker, digitalis)
• Guillain-Barré syndrome
• electrolyte imbalance (e.g. hyperkalemia in dialysis
patients)
• torsades de pointes (to increase the heart rate of the
basic rhythm to shorten the QT interval [e.g. until sota-
lol is degraded]) Fig. 707  various pacemaker aggregates (unit) [7, 23]
• increase of the heart rate of the basic rhythm in acute
severe aortic valve regurgitation (to reduce the regur-
gitation volume; bridging until surgery; e.g. in endocar-
ditis)
• increase of cardiac output (CO): If a patient beco-
mes bradycardic (e.g. 40-50/min) in the course of a
shock (e.g. in the case of septic shock), a temporary
pacemaker can be used to increase the cardiac output
(CO = stroke volume x heart rate) and stimulate it with
a higher heart rate (90-100/min). The right ventricular
stimulation reduces the ejection fraction and thus the
stroke volume due to desynchronization between the
right and left ventricle. However, CO increases signi-
ficantly due to the increase in heart rate, so that the
decrease in stroke volume is more than compensated.
For the sole purpose of increasing the heart rate in
shock patients, we only cautiously implant a temporary Fig. 708  pacemaker leads (electrodes) [7]

484 Cardiology
Fig. 709  By default, the temporary pacemaker uses only
one lead (for the right ventricle). It is an anchor electrode
(no screw electrode). This has two connections for the sti-
mulation device. Here a wire guidance for the placement is
possible.
Fig. 710  Alternatively, a flow-directed balloon electrode can
also be used: Here an auxiliary balloon (see arrow), which
is blocked with air, is attached shortly before the end. The
electrode (lead) is placed like a flow-directed catheter (ana-
logous to a pulmonary artery catheter) following the blood
flow. The advantage here is that X-ray fluoroscopy is not
necessary, so that it goes faster. In an absolute emergency
(e.g. resuscitation), where there is no more time for x-ray
fluoroscopy, this is certainly a good option. A disadvantage
is that no wire guidance for the placement is possible. Tip:
The balloon electrode can be inserted very well and without
great effort under echo control (transthoracic sufficient)!
Fig. 711  Using echocardiography (here a subcostal
4-chamber view), the pacemaker electrode (see arrows; es-
pecially the balloon electrode, which is usually placed wit-
hout X-ray fluoroscopy) can be inserted on the bedside at
the apex of the right ventricle.
Placement
• sterile covering
• insertion of a sheath (5F completely sufficient; 7F: too
large and sucks air]) as with CVC
• i.a. local anaesthesia, puncture of the internal jugular
vein (preferably sonographic), dilator, insert guidewire,
Seldinger technique
• advance the lead through the sheath (via sterile protec-
tive cover [SeptiShield]; if possible under fluoroscopy
[alternatives: flow-directed balloon electrode or echo-
cardiographically]) into the apex of the right ventricle
• connect the electrode to the pulse generator (pacema-
ker aggregate)
-- red in plus
-- black in minus
• settings
-- parameters
◦◦ frequency (e.g. 60/min)
◦◦ pacing (stimulation, output)
▪▪ pulse amplitude (0.3-12V): The stimulation
threshold is determined, i.e. the lowest pulse
amplitude with which regular stimulation is still
performed. You turn back the pulse amplitude
starting at 12V and observe on the monitor up
to which pulse amplitude the pacemaker is still
stimulating properly. At the device then the 2-3-
fold stimulation threshold is set.
▪▪ pulse duration: The pulse duration for a tem-
porary pacemaker is fixed (at 0.75ms) and can-
not be changed.
Cardiology 485
 ◦◦ sensing (sensivity)
▪▪ memo: decrease of sensivity = increase of sen-
sing treshold, i.e. increase of the mV-number
▪▪ procedure: You determine the threshold in mV
at which the pacemaker starts to stimulate and
then set half of it on the device (e.g. 2 mV).
▪▪ cave: The sensing threshold must never be
set to the maximum value (e.g. 20mV; complete-
ly insensitive then). Here the pacemaker would
work in a rigid frequency mode (V00), so that a
stimulus can fall into the vulnerable phase (as-
cending phase of the T wave; R to T phenome- Fig. 712  7F sheath [14]
non) and can trigger ventricular fibrillation.
-- mode: VVI (standard)
• lamps
-- green: sensing
-- red: stimulation
• fixation of the pacemaker electrode
• chest X-ray
• determination of the stimulation and sensing threshold
at least once per shift (and after each repositioning)
• maximum duration of use: 14 days
• The implantation of the electrode(s) is always painless.
If chest pain occurs, there is always the suspicion of a
perforation and an echocardiography must be perfor-
med immediately. If a pericardial effusion appears, it
must always be punctured, even if it is small (for pe-
ricardial puncture see page 523)! Even the slightest
amount is sufficient to cause the patient to go into car-
diogenic shock. Despite the presence of a pericardial
tamponade, most patients here are not tachycardic
either, as many pacemaker patients are often chrono-
tropically incompetent anyway and there is also often
severe pain, so that the heart rate does not increase
for vagal reasons.
• antibiotic prophylaxis
-- e.g. cefazolin 2g 3x daily or ceftriaxon 2g 1x daily i.v.
-- for the duration of the temporary pacemaker
-- no general recommendation, however (We usually
already carry out antibiotic prophylaxis, especially if Fig. 713  The internal jugular vein is punctured under sono-
the patient needs a permanent pacemaker.) graphic control (sterile transducer cover).
• removal of the temporary pacemaker: If it is no lon-
ger needed, the lead can simply be pulled out of the
sheath. If the patient was subsequently provided with
a permanent pacemaker, the electrode of the tempora-
ry pacemaker should be pulled under X-ray fluorosco-
py, so that the electrode of the permanent pacemaker
does not dislocate. It is best to do this right away on the
operating table shortly before suturing, because if the
permanent electrode is dislocated when pulling out the
temporary electrode, the permanent electrode can be
repositioned immediately.

486 Cardiology
 Fig. 716  Under fluoroscopy, the lead is correctly positioned
at the apex of the right ventricle with a slightly S-shaped
course.
Fig. 714  A 7F sheath is inserted via a guide wire (Seldinger
technique).

Fig. 715  The pacemaker lead (electrode) is now inserted via Fig. 717  After the electrode has been correctly placed, its
the 7F sheath and advanced into the right ventricle (apex of two plugs are connected to the pacemaker aggregate (red
the heart) under X-ray fluoroscopy. in plus, black in minus).

Cardiology 487
 setting of pacing
(pulse amplitude;
setting of sensing output) in Volt
in mVolt

on / off
standard-
pacing mode: VVI
frequency

low battery warning

(Battery lasts ap-
prox. 1000 hours.) for atrial overpacing (e.g.
atrial flutter; key must be
pressed continuously)

Fig. 718  The electrode is fixed lengthwise in the sheath

with a plaster strip.

lamp: sensing
(If it flashes, the pacema-
ker recognizes the patient's lamp: stimulation
own actions and does not (If it flashes, the pacema-
stimulate.) ker stimulates.)

Fig. 719  The electrode is fixed circularly to the forehead

with plaster strips.

488 Cardiology

Only one electrode is used. This has two connec-
tions that have to be plugged into the pacemaker
aggregate and screwed tight:
red in plus, black in minus.
Fig. 720  displays and settings on the pacemaker aggregate
temporary PM: wait briefly with the
resuscitation (chest compressions) in
case of asystole: first check whether
the plugs are connected, then set the
output to maximum; only if asystole
continues, then chest compressions
(otherwise mostly complete disloca-
tion of the electrode by chest
compressions)!
Excursus: Emergencies in patients
with permanent pacemaker
place place operating frequency
stimulation sensing mode adaptation
V V I R
A A T 0 (none)
D D D
0 (none) 0 (none) 0 (none)
Fig. 721  NBG code (NASPE/BPEG Generic Pacemaker
Code [NASPE: North American Society of Pacing and Elec-
trophysiology, BPEG: British Pacing and Electrophysiology
Group]); V: ventricle, A: atrium, D: dual (both); I: inhibition,
T: triggering; R: rate-response
Disturbance of stimulation (pacing)
• failure to output
• failure to capture (= exit block)
Failure to output
• definition: no spikes at all, no more impulse delivery by
the pacemaker
• causes
-- fixing screw not properly tightened intraoperatively
-- lead fracture
-- battery depletion (EOS [end of service], here emer-
gency aggregate change); note: principled replace-
ment indications (ERI: elective replacement indica-
tion):
◦◦ decrease of battery voltage (e.g. < 2.5V; displayed
automatically in modern devices)
◦◦ increase of battery impedance (e.g. > 4000Ω; dis-
played automatically in modern devices)
◦◦ decrease of magnetic frequency with magnet ap-
plication: The magnetic application causes a fixed-
rate stimulation with cancellation of sensing and
triggering regardless of the patient's own rhythm,
i.e. V00 mode for single-chamber pacemakers
and D00 mode for dual-chamber pacemakers. A
decrease in the magnetic frequency indicates bat-
tery depletion. The magnetic frequency is manu-
facturer-specific (e.g. Medtronic 85/min, Biotronik
90/min [note: note: Here, the fixed-rate stimulation
only takes place for 10 cycles.], St. Jude Medical
96/min, Boston-Scientific 100/min, Guidant 100/
min). In the context of fixed-rate stimulation,
a stimulus can fall into the vulnerable phase (R on
T phenomenon; ascending phase of the T wave)
and trigger ventricular fibrillation, so that in prin-
ciple magnet application must always be perfor-
med in readiness for defibrillation and not for an
unnecessarily long time. If the magnet is placed
on an AICD, there is no magnetic frequency, only
the anti-tachycardic therapies are switched off. If
the magnet is placed on a CCM device (cardiac
contractility modulation), the device is switched off
completely and must be restarted using the pro-
gramming device.
Cardiology 489

Fig. 722  Here, after magnet application, a regular fixed-rate
stimulation (here D00 for two-chamber pacemaker) with the
manufacturer-specific heart rate (here Biotronik: 90/min)
can be seen. So there is no evidence of battery depletion
here.
cave magnet application to pacema-
ker: always only in readiness for
defibrillation (Ventricular fibrillation
can be triggered!)
Failure to capture (exit block)
• definition: spikes still visible, but no more stimulated
QRS complex (ineffective spike ["naked spike"]: no de-
polarization and thus no more myocardial contraction)
• causes
-- electrode (lead):
◦◦ lead dislocation
▪▪ types: macrodislocation (also visible in X-ray) /
microdislocation
▪▪ causes: e.g. Twiddler's syndrome (The pacema-
ker aggregate rotates in the pacemaker pocket
with the result that the electrode rolls up spirally
and thus dislocates from the myocardium.), e.g.
pneumothorax (Especially in tension pneumo-
thorax, the mediastinal shift can cause a lead
dislocation), e.g. lead dislocation by insertion of
a CVC (central venous catheter) or PAC (pulmo-
nary artery catheter)
◦◦ lead fracture
▪▪ strikingly high electrode impedance (> 2000Ω)
▪▪ e.g. subclavian crush syndrome (SCS): Here
the electrode is crushed like by a pliers between
the clavicle and the first rib. This occurs above
all if the subclavian vein is punctured too far me-
dially Therefore the subclavian vein should be
punctured as far as possible laterally.
-- increase of stimulation treshold:
◦◦ fibrosation at the electrode tip (This is also the ra-
tional reason why some lead heads contain stero-
ids to prevent fibrosation.).
◦◦ drugs (e.g. amiodarone, sotalol, propafenone, fle-
cainide
◦◦ hyperkalemia
◦◦ right ventricular myocardial infarction (Myocar-
dium can no longer be excited there due to the
infarction.)
◦◦ after cardioversion / defibrillation (mostly short-
490 Cardiology
term massive increase in stimulation threshold!)
• therapy
-- magnet application: ineffective (does not increase
the output)
-- pharmacological increase in heart rate (e.g. atropi-
ne, orciprenaline)
-- increase in pulse amplitude or extension of pulse
duration (Here you should immediately fetch the
pacemaker control device from the respective com-
pany of the implanted pacemaker and increase the
output!)
-- possibly temporary pacemaker
-- in case of a lead problem surgical lead revision
Fig. 723  Exit block: spikes still recognizable, but no stimu-
lated QRS complex recognizable (ineffective spike ["naked"
spike])
common causes for an exit block
in ICU: cardioversion / defibrillati-
on, amiodarone, hyperkalemia,
right ventricular MI!
Pacemaker syndrome
• definition: Occasionally it happens that a VVI pacema-
ker is implanted in supposedly permanent atrial fibrilla-
tion and then sinus rhythm shows up again. Then the
retrograde pathway causes atrial excitation and atrial
contraction against the closed AV valve. The result is
a reflectory drop in blood pressure with dizziness and
possibly even syncope.
• occurrence: in 20% of all patients with a VVI pacema-
ker
• symptoms:
-- palpitations
-- reduced resilience
-- dizziness, possibly syncope (despite pacemaker im-
plantation!)
-- dyspnea (up to pulmonary edema)
• therapy:
-- reduction of the stimulation frequency (e.g. from 60/
min [mostly set like this] to 50/min), in order to gu-
arantee patient´s own (intrinsic) rhythm, so that no
stimulation takes place; alternatively, you can also
program the hysteresis function (Greek "hysteros":
later, afterwards) to e.g. 50/min, i.e. the stimulation
frequency of the pacemaker is officially still 60/min,
 but the pacemaker starts to stimulate actually only if
the patient´s own frequency is < 50/min.
-- possibly upgrading to a dual-chamber pacemaker
(DDD)
Patient with VVI pacemaker, sinus
rhythm (instead of atrial fibrillation) and
syncope: think of pacemaker syndro-
me!
Disturbances of sensing
Oversensing
• definition
-- The pacemaker mistakes other events (T wave, af-
terpotentials, myopotentials [e.g. contraction of the
pectoral muscle; perform provocation maneuvers!
e.g. muscle fasciculations triggered by succinylcho-
line], electromagnetic interference signals [e.g. drill,
electrocautery, Vibrax]) than the P wave or R wave
for own actions. The sensitivity is too high.
-- The consequence of oversensing is underpacing.
• causes
-- insulation defect of the electrode (No.1)
◦◦ strikingly low electrode impedance (< 200Ω)
◦◦ causes:
▪▪ injury of the lead by the fixation suture
▪▪ subclavian crush syndrome (SCS)
▪▪ degenerated insulation material
-- lead fracture (incomplete; here impulses are often
generated which are then incorrectly sensed by the
pacemaker)
• behavior of the pacemaker during oversensing
-- single chamber pacemaker
◦◦ inhibition (up to asystole; ; no pacemaker impulses
despite bradycardia)
◦◦ asynchronous (fixed-rate) stimulation: V00 (In mo-
dern pacemakers this option is implemented as
interference protection.)
-- dual chamber pacemaker
◦◦ atrial oversensing: tachycardia or mode-switch
◦◦ ventricular oversensing:
▪▪ inhibition (up to asystole; no pacemaker impul-
ses despite bradycardia)
▪▪ asynchronous (fixed-rate) stimulation: D00 (In
modern pacemakers this option is implemented
as interference protection.)
• types
-- far-field-sensing:
◦◦ sensing of the R wave through the atrial channel
◦◦ hints:
▪▪ many mode-switch episodes
▪▪ event counter (atrial refractory sensing) > 50%
▪▪ atrial frequency histogram with a high (> 50%)
content at "> 180 ppm"
▪▪ atrial frequency = double ventricular frequency
◦◦ therapy: reprogramming
▪▪ extension of the PVAB (postventricular atrial
blanking time; syn.: FFB: farfield blanking time;
e.g. from 100ms to 150ms)
▪▪ possibly increase of the atrial sensing threshold
-- cross-talk (AV-cross-talk):
◦◦ sensing of the atrial impulse by the ventricular
channel (The atrial stimulation is misinterpreted as
R wave in the ventricle, so that no more stimulati-
on takes place.)
◦◦ With pre-existing third degree AV block, this can
even lead to asystole (dangerous!).
◦◦ therapy: extension of the ventricular blanking time
-- T wave oversensing
◦◦ sensing of the T wave through the ventricular
channel
◦◦ This extends the stimulation interval with the result
that a frequency is found which is lower than the
programmed frequency.
• therapy
-- magnet application: This cancels the sensing and
a fixed-rate stimulation takes place.
-- reprogramming
◦◦ Since the sensitivity is too high, it must be redu-
ced (decrease of sensitivity = increase of sensing
treshold, i.e. the mV-number must be increased).
◦◦ setting a bipolar sensing (usually set anyway; note:
standard setting for pacemakers: sensing always
bipolar, stimulation always unipolar [because you
just see the spike better])
◦◦ extension of refractory time
Undersensing
• definition
-- syn.: entrance block
-- Own actions (P wave, R wave) are not recognized
by the pacemaker. The sensitivity is too low.
-- The consequence of undersensing is overpacing
-- Ventricular fibrillation can be triggered by stimulation
into the vulnerable phase (ascending part of the T
wave).
• causes
-- sensing threshold too high (most common cause)
-- lead problem: lead dislocation, lead fracture (strikin-
gly high electrode impedance [> 2000Ω]), insulation
defect (strikingly low electrode impedance [< 200Ω])
-- after cardioversion / defibrillation
• therapy
-- magnet application
-- reprogramming: Since the sensitivity is too low, it
must be increased (increase of sensitivity = decrea-
se of sensing treshold, i.e. the mV-number must be
decreased)
-- in case of lead problem surgical lead revision
Pacemaker tachycardias
• endless-loop tachycardia (ELT):
-- pacemaker-related tachycardia
-- only in DDD pacemaker
-- syn.: pacemaker reentrant tachycardia (analogous
Cardiology 491
 to WPW syndrome, retrograde P wave
-- After ventricular stimulation, retrograde atrial excita-
tion occurs via the AV node. The atrial excitation is
detected and answered in the ventricle, which in turn
leads to retrograde atrial excitation.
-- In contrast to pacemaker-mediated tachycardia
(PMT), ELT has the frequency maximum as high as
the upper limit frequency set in the pacemaker (usu-
ally 120-150/min), at PMT it can be higher.
-- prerequisite: retrogradely conductive AV node (pre-
sent in 60% of all people)
-- types
◦◦ antidromic ELT: retrograde conduction (VA con-
duction; extrinsic; more frequent)
◦◦ orthodromic ELT: antegrade conduction (AV con-
duction; intrinsic; less frequent)
-- therapy
◦◦ vagal maneuvers (e.g. carotid sinus massage:
terminates the ELT by interrupting the retrograde
conduction
◦◦ adenosine
◦◦ magnet application
◦◦ reprogramming (extension of the PVARP [post-
ventricular atrial refractory period], e.g. to 350ms;
switching on PMT option [automatic extension of
PVARP to terminate an ELT])
• pacemaker-mediated tachycardia (PMT)
-- only in DDD pacemaker
-- An atrial tachycardia (especially atrial fibrillation,
atrial flutter) or atrial interference signals are ventri-
cularly conducted in a DDD pacemaker. The atrial
tachycardia is incorrectly misinterpreted as sinus ta-
chycardia.
-- therapy
◦◦ therapy of atrial tachycardia
◦◦ reprogramming (switching on the mode-switch [=
automatic change of mode in atrial tachycardia
from DDD to DDI, i.e. change from triggering to
inhibition]); problem: 2:1-lock-in (example: In case
of atrial flutter with an atrial frequency of 240/min
it can happen with a too long PVAB [postventricu-
lar atrial blanking time] that the pacemaker only
detects every second P-wave because it is in the
blanking with the consequence that the mode-
switch is not activated because the pacemaker
only registers an atrial frequency of 120/min. The
pacemaker behaves here like in a 2:1 block. Here,
the PVAB should be shortened (e.g. 150ms). With
modern pacemaker devices, the option of 2:1 lock-
in protection can also be activated.
Pacemaker-specific tachycardias (ELT,
PMT) are only possible with a 2-cham-
ber pacemaker (not 1-chamber
pacemaker), since only here the
atrial-chamber interaction is possible!
492 Cardiology
Fig. 724  pacemaker-induced tachycardia: During the (very
juddery) blue light ride with the emergency vehicle, the
accelerator of the DDD-R pacemaker is activated, causing
tachycardia. The therapy here is simply to ask the driver of
the emergency vehicle to slow down.
Others
• resuscitation in patients with pacemakerse
-- defibrillation in ventricular fibrillation
◦◦ inverted or anterior-posterior attachment of the de-
fibrillator pads
◦◦ cave increase in stimulation threshold after defib-
rillation: After successful defibrillation of ventricular
fibrillation in a completely pacemaker-dependent
patient (e.g. in third degree AV block), this can
lead to the patient becoming asystolic (ventricular
asystole, i.e. only P waves without QRS comple-
xes). Therefore a pacemaker control (checkup) is
obligatory afterwards.
◦◦ possibly even complete destruction of the system
by defibrillation (leads to [ventricular] asystole in
completely pacemaker-dependent patients)
-- Here the missing cardiac ejection is often not detec-
ted or only very late, because a deceptive heart rate
of 60/min appears on the monitor: However, this is
only the pacemaker stimulation. Here chest com-
pressions should have taken place long ago. Here,
too, it is absolutely necessary to palpate the pulse
and best to verify by echocardiography or invasive
BP measurement whether there is an ejection at all!
• If a patient with a pacemaker shows a reduced cardiac
output, the stimulation frequency can simply be incre-
ased by reprogramming to increase the cardiac output
(CO = stroke volume x heart rate). This is particularly
the case if the patient is chronotropically incompetent,
i.e. he can no longer increase his heart rate himself.
The stimulation frequency can be increased easily
and quickly without a programming device by repea-
ted quick tapping of the aggregate. This activates the
accelerometer.
• electrocautery in pacemaker patients: see page 465
• pacemaker endocarditis (see page 505)
• lead removal (i.a. indicationen, types): see page 506
• MRI: Most of the pacemakers implanted today are
MRI-compatible. MRI suitability is only important for
the aggregate (unit), it does not matter for the elect-
rodes (MRI always possible here). When performing
an MRI, the pacemaker must be reprogrammed to
asynchronous fixed-rate stimulation mode beforehand,
i.e. in a single-chamber pacemaker to V00 and in a
dual-chamber pacemaker to D00. Due to the fixed-rate
stimulation stimulation, there is a possibility that ventri-
cular fibrillation is triggered by stimulation into the vul-
 nerable phase. ECG monitoring during the MRI scan
is therefore mandatory. A pacemaker control (checkup)
must be carried out after the MRI examination. It is the
case with us that during the MRI examination, which
must take place outside the hospital, since we do not
have our own MRI, there is always a cardiologist with
the programming device persent.
• If a patient suffers atrial flutter with a dual-chamber
pacemaker, it is relatively easy to perform atrial over-
drive pacing with the programming device using the
atrial lead, thereby eliminating atrial flutter (for atrial
overdrive pacing see page 443).
• If there is no information about the pacemaker (inclu-
ding no pacemaker ID, no previous documents), you
can put on the magnet for further information:
-- number of probes (also visible from the chest x-ray)
◦◦ V00 stimulation → single-chamber pacemaker
◦◦ D00 stimulation → dual-chamber pacemaker
-- manufacturing company (derivable from the manu-
facturer-specific magnetic frequency; then you can
check the pacemaker with the company's program-
ming device and, if necessary, reprogram it)
• If you have decided on a therapy reduction for a patient
in the dying process, you can always completely switch
off an AICD, but usually not a pacemaker. This is only
possible with (few) newer devices. But especially if the
patient is completely pacemaker-dependent (e.g. with
third degree AV block without a replacement rhythm),
this procedure is discussed controversially, since death
occurs immediately after switching off.
• death detection in a patient with pacemaker: A pace-
maker can usually not be switched off. Frequently the-
re is uncertainty regarding the diagnosis of death, as
it is not possible to print out a zero line ECG for docu-
mentation as usual. But this is not necessary either.
The usual criteria for determining death (postmortem
lividity, rigidity, putrefaction) are sufficient as usual. In
case of uncertainty, the asystole can also be detected
via the SpO2 curve, the arterial pressure curve or echo-
cardiographically. It is only important to mark the pas-
sage "pacemaker carrier" on the certificate of death, as
it must possibly (depending on the crematorium) then
be removed before a desired cremation (but not by the
physician, but by the undertaker), because otherwi-
se the battery in the oven could explode. In modern
crematoriums, this is often no longer necessary: After
the cremation, the device is removed with a magnet
like other implants.

Cardiology 493
 fever licks the joints and bites the heart!"
INFLAMMATORY HEART ◦◦ skin (erythema annulare, subcutaneous nodules)
◦◦ CNS (Chorea minor)
DISEASES -- laboratory (antibodies against metabolic products of
group A streptococci)
◦◦ ASL (anti-streptolysin; especially increased in in-
fections of the respiratory tract [pharyngitis])
◦◦ ADB (anti-deoxyriboncelotidase B; especially in-
creased in infections of the skin [erysipelas])
• infective (bacterial) endocarditis

infective Endocarditis

Definition
• The correct term is "infective" and not "infectious", be-
Endocarditis cause the disease is not contagious. A less misleading
designation is actually microbial or microbially caused
endocarditis.
• an inflammation caused by germs:
-- endocardium (mainly in the valve area; there is usu-
ally previous endocardial damage)
-- intracardially implanted polymer material (polymer-
associated endocarditis: e.g. valve prostheses, elec-
trodes [pacemaker, ICD], port catheters, atrial dialy-
sis catheters)
• affected valves:
-- No.1: mitral valve
-- No.2: aortic valve
-- No.3: tricuspidal valve
-- No.4: pulmonal valve

• non-infective (abacterial) endocarditis: rheumatic fever
-- definition:
◦◦ second illness 10-20 days after a streptococcal
infection (tonsillitis, pharyngitis, scarlet fever, ery-
sipelas)
◦◦ antibodies not only against bacteria, but also
against the body's own tissue (heart, joints, skin,
CNS)
◦◦ only very rarely in industrialized countries today,
more often in developing countries (e.g. with re-
fugees)
-- involvement :
◦◦ heart (especially the endocardium [especially mit-
ral valve → mitral valve stenosis])
◦◦ joints (acute polyarthritis); memo: „The rheumatic
Guidelines
• international: ESC-Guidelines for the management of
infective endocarditis 2015
• national (Germany):
-- S2 guideline for the diagnosis and treatment of infec-
tive endocarditis 2004 of the PEG (Paul Ehrlich Soci-
ety), DGK (German Society for Cardiology), DGTHG
(German Society for Thoracic, Cardiac and Vascular
Surgery) and DGI (German Society for Infectious Di-
seases)
-- recommendations for the calculated parenteral initial
therapy of bacterial diseases in adults - Update 2010
of PEG (Paul Ehrlich Society)
Epidemiology
• incidence 10/100000 (age > 65 years even 31/10000),
increasing
• m > w (70% men, 30% women)
• mean diagnostic latency: 29 days (about 1 month!)
• mean duration of hospital stay: 42 days
• surgery in 50% necessary (Endocarditis is more
and more a surgical disease!)

494 Cardiology

study
Clinical Presentation, Etiology, and Outcome of Infective
Endocarditis in the 21st Century
The International Collaboration on Endocarditis–Prospec-
tive Cohort Study
Murdoch et al, Arch Int Med 2009
Terminology
• active (positive blood cultures, fever) / cured
• first / recurrent infection
• diagnostic probability: certain / possible / excluded
• mitral/ aortic/ tricuspid/ pulmonary valve
• native valve / artificial (prosthetic) valve (early / late)
• pathogen
e.g. "active first confirmed mitral valve native endocardi-
tis by enterococcus faecalis"

• prospective cohort study

• 2781 patients with infective endocarditis Types
• mean age: 58 years • subacute endocarditis (= endocarditis lenta):
• in 72% native valve endocarditis
-- mainly viridans streptococci
• most commonly affected valves:
-- incidence ↓
-- mitral valve (41%)
-- aortic valve (38%)
• acute endocarditis:
• most frequent pathogen: S. aureus -- mainly staphylococci (S. aureus)
• need for surgery in 48% -- incidence ↑­
• mortality: 17.7%
Germs
• bacteria
• fungi
study
Bacteria
• gram-positive bacteria (mostly)
Clinical presentation, aetiology and outcome of infective -- streptococci
endocarditis. Results of the ESC-EORP EURO-ENDO ◦◦ viridans streptococci (No.2)
(European infective endocarditis) registry ◦◦ streptococcus gallolyticus
Habib et al, European Heart Journal 2019
◦◦ streptococcus pneumoniae (pneumococci)
• European IE register EURO-ENDO (European infective -- staphylococci
endocarditis) ◦◦ staphylococcus aureus (No.1)
• prospective cohort study between 2016-2018 (156 hos- ◦◦ coagulase-negative staphylococcus (CoNS)
pitals in 40 countries)
-- enterocococci (No.3)
• 3116 patients with infective endocarditis
-- propionibacterium acnes
• mean age: years
• allocation: • gram-negative bacteria
-- native valve: 57% -- HACEK group
-- artificial valve (mechanical, biological): 30% -- pseudomonas aeruginosa
-- intracardially implanted polymer material (especially -- enterobacteriaceae
pacemaker, ICD): 10%
• community acquired in 66% Viridans streptococci
• pathogens:
-- No.1: staphylococcus aureus (44%)
-- No.2: enterococci (16%)
-- No.3: streptococci
◦◦ viridans streptococci (12%)
◦◦ streptococcus gallolyticus (6%)
• complications:
-- embolism: in 21%
-- acute kidney failure: in 18%
-- heart failure: in 14%
• need for surgery: indicated in 69%, but performed
only in 51% (i.e. only 75%)
• mortality (hospital): 17.1%

Cardiology 495
Definition Staphylococcus aureus
• second most common pathogen (formerly No.1)
• physiological colonization of the oropharynx (therefore
syn.: oral streptococci)
• types:
-- S. mutans, S. mitis
-- S. sanguinis, S. anginonsus, S. salivarius
• lethality: < 10%
• penicillin resistance: only 1%

Therapy

Viridans streptococci

Definition
• meanwhile the most common pathogen
• types:
-- MSSA: 75%
-- MRSA: 25%
• course: mostly acute
• in 40% cerebral embolisms
• often large vegetations
• risk factors:
-- i.v. drug abuse
-- haemodialysis
-- diabetes mellitus
• lethality: 40%

Therapy

Other streptococci
• S. gallolyticus (former name: S. bovis)
-- physiological colonization of the gastrointestinal MSSA
tract (tooth extractions!)
-- especially in gastrointestinal malignancies (therefo-
re, if detected, prompt gastroscopy and colonoscopy
to search for tumors), colonic polyps (after polypec-
tomy)
-- good penicillin sensitivity
-- therapy as with viridans streoptococci
• S. pneumoniae (pneumococci)
-- only rarely pathogens of endocarditis (2%)
-- more frequent in
◦◦ alcoholics, accompanying pneumonia or meningi-
tis
◦◦ aortic valve (rapid destruction)
◦◦ intramyocardial abscesses
-- lethality: 40%

496 Cardiology
 MRSA Enterococci

Coagulase-negative staphylococci (CoNS)

• main pathogen:
-- early prosthesis endocarditis (incl. TAVI; p.d. < 1
year postoperatively)
-- pacemaker endocarditis
-- nosocomial endocarditis (p.d. > 48h after hospital
admission)
• types:
-- S. epidermidis
-- S. lugdunensis
• course: mostly subacute
• often only contamination in the blood culture (must
therefore be positive in several blood cultures; suspi- Propionibacterium acnes
cious, however, e.g. in case of already long lying CVC) • part of the skin flora and thus, if detected in the blood
• often complications (especially embolism, heart failu- culture, usually to be regarded as contamination
re) • However, it can also cause endocarditis that is difficult
• mostly methicillin-resistant (to 90%) to treat (almost exclusively in the presence of intra-
cardiac foreign bodies such as mechanical valves or
pacemakers / AICD)
• therapy: penicillin G + possibly gentamycin
CoNS • Lindell et al, Eur J Clin Micribiol Infect Dis 2018: 8% of
all prosthetic valve endocarditis, mostly late endocar-
ditis (on average 3 years after valve operation), in 63%
reoperation necessary, in 98% men

HACEK group
• members
-- Haemophilus parainfluenzae and aphrophilus
-- Actinobacillus actinomycescomitans
-- Cardiobacterium hominis
-- Eikanella corrodens
Enterococci -- Kingella kingae
• third most common endocarditis pathogen (already • physiological colonization of the upper respiratory tract
No.2 according to recent studies) and oropharynx
• types: • 2% of all cases of endocarditis
-- enterococcus faecalis (90%; E. faecalis in blood cul- • often difficult microbiological diagnosis (very slow
ture → in 17% endocarditis [with S. aureus „only“ growth, long incubation period → incubation up to 3
in 10%]!) weeks necessary)
-- Enterococcus faecium (10%) • mostly subacute course
• physiological colonization of the gastrointestinal tract • often large vegetations (but without increased risk of
• often infections of the urogenital tract embolism)
• enterococcal endocarditis: often older men with uri- • low virulence, good prognosis
nary tract infection / urosepsis • therapy:
• high recurrence rate (28%) -- ceftriaxone 2g/d as monotherapy for 4 weeks (for

Cardiology 497
 prosthetic valves 6 weeks) • types:
-- alternatives: -- candida (yeast fungi)
◦◦ fluoroquinolone ◦◦ C. albicans
◦◦ trimethoprim / sulfamethoxazole ◦◦ C. glabrata
◦◦ C. krusei
Rarer germs ◦◦ C. tropicalis
• Coxiella burnetii ◦◦ C. parapsilosis
• Bartonella (therapy: doxycycline 200mg/24h p.o. for 4 -- aspergillus (mould)
weeks + gentamycin 3mg/kg/24h i.v. for 2 weeks) • risk factors:
• Brucella (therapy: doxycycline 200mg/24h p.o. + cotri- -- immunosuppression
moxazol 960mg/12h p.o. + rifampicin 300-600mg/24h -- protracted antibiotic therapy
p.o. for 3-6 months) -- drug consumption
• Chlamydia psittaci -- CVC
• Tropheryma whipplei (M. Whipple; therapy: doxycy- -- status post cardiosurgical interventions
cline 200mg/24h p.o. + hydroxychloroquine 200-600
• often large vegetations
mg/24h p.o. for 18 months)
• high lethality (50%)
Coxiella burnetii • therapy
• Q-fever (Q: "query", since earlier the cause of the fever -- early surgery (even in native valve endocarditis no
was questionable / doubtful) conservative [i.e. purely antifungal with echinocan-
• a zoonosis (especially cattle, sheep, goats) dins] therapy attempt)
• infection: by inhalation (especially via infected barn -- antifungal therapy for 6 weeks postoperatively
animals or infected hay) ◦◦ candida: echinocandins (e.g. Caspofungin, Anidul-
• animal contact (e.g. farmers, butchers, veterinarians, afungin); for candida parapsilosis: azol
shepherds) ◦◦ aspergillus: voriconazole, posaconazole
• in 30% granulomatous hepatitis • high recurrence rate → secondary prophylaxis for 2
• diagnosis: years
-- cultural (blood culture: almost always negative, as -- candida: fluconazole
coxiella burnetti cannot be grown in conventional -- aspergillus: itraconazole
blood cultures)
-- serological (standard; IgM or IgG > 1:800)
• therapy:
Symptoms
-- doxycycline 200mg/24h p.o + hydroxychloroquine • fever (unclear; 80%)
200-600mg/24h p.o.for 3 months (in pregnancy: • chills
cotrimoxazol 960mg/12h p.o.); annot.: Combination • recurrent sweating
therapy is only recommended for Q fever with en- • fatigue, tiredness
docarditis, otherwise monotherapy with doxycycline
• cardiac:
(then only for 3 weeks) is sufficient.
-- tachycardia
-- mostly however indication for surgery
-- heart murmur
-- after surgery long-term antibiotics (up to 3 years)
necessary ◦◦ newly occured (85%)
◦◦ indication that the valve has already been dama-
ged
Fungi
◦◦ DD functional heart murmurs in fever, sepsis,
anaemia
• splenomegaly
• skin lesions
• drumstick fingers (subacute endocarditis)
• weight loss
• arthralgias, myalgias
• renal:
-- proteinuria
-- haematuria
• anaemia
• neurological symptoms, cerebral embolisms (e.g. hea-
daches, meningoencephalitis, stroke)
• septic encephalopathy (Sepsis caused by endocarditis
is often accompanied by severe encephalopathy!)
• heart failure (especially newly occured)

498 Cardiology
• unclear abscesses, i.a. spleen, kidney, spine (e.g.
spondylodiscitis: in 30% endocarditis as cause [Pales-
tro et al, Best Pract Res 2006]!), skin
• unclear sepsis

Fig. 726  Osler's nodes

Fig. 727  Osler's nodes on the toe

Fig. 725  Osler's nodes on the finger (courtesy of Dr. Bern-

hard Kaiser, cardiologist at the Clinic for Neurology at the
University of Regensburg [Germany])

Fig. 728  Janeway lesions

Cardiology 499
 Anamnesis
• status post infective endocarditis
• known heart valve defect
• presence of valve prosthesis
• i.v. drug abuse
• tooth extractions, surgery (e.g. tonsillectomy)

Fig. 729  splinter hemorrhages: bleeding under the nails
(courtesy of Dr. Bernhard Kaiser, cardiologist at the Clinic
for Neurology at the University of Regensburg [Germany])
Laboratory
• leukocytosis, CRP­: A normal CRP practically rules
out endocarditis! If the CRP is < 10 mg/dl, endocarditis
is present in only 2% and if it is CRP < 7 mg/dl in only
0.1% (Horstkotte et al, Internist 2008)!
• anemia (infectious anemia: ferritin ↑­, transferrin ↓)
• thrombocytopenia (often pronounced!)
• rheumatoid factor in 30% positive (immunological ac-
companying reaction)
• procalcitonin (PCT): in endocarditis despite sepsis ty-
pically mostly negative

Blood culture
• always prior to initiation of antibiotics
• collection independent of body temperature
-- even when there is no fever
-- no waiting for fever
-- The bacteremia is continuous! So don't write into the
fever curve: "Take blood cultures if fever > 39°C", but
immediately take blood cultures regardless of body
temperature!
-- The collection of blood cultures in the fever peaks
even reduces the chances of success for a positive
blood culture, since fever peaks are caused mainly
by pyogenically decaying bacteria, which have al-
ready died and therefore no longer grow on the agar
plate!
Fig. 730  epidural abscess in the lumbar spine • disinfection of skin and plug of the blood culture bottle
• no post-palpation
• from peripheral vein (not from central venous catheter
Diagnostics [unless it has just been freshly placed] or cannula)
• anamnesis, clinical examination • arterially worse than venous
• ECG (possibly ST segment changes in septic coronary • change needle before inoculating the blood culture
embolism) bottle
• laboratory • 3 pairs in 3 hours (ESC 2015: 3 pairs in 1.5 hours)
• microbiological diagnostics • notification on microbiology requisition slip (especially
-- blood culture infective endocarditis) → extended incubation time
(slow-growing pathogens, e.g. HACEK- group)
-- serology if necessary (especially with culture negati-
ve infective endocarditis) • in case of intermediate storage: no cooling (not in refri-
gerator), no warming, but storage at room temperature
• echocardiography
• determination of resistance, determination of MIC (mi-
-- transthoracic
nimum inhibitory concentration) in the microbiological
-- transesophageal
institute
• abdominal sonography
• procedure in case of antibiotic pre-treatment
• if necessary multislice cardio-CT (especially for para-
-- stable (mostly) → 48h antibiotic break, then 3 blood
valvular abscesses, pseudoaneurysm)
culture pairs in 3h
-- unstable (rarely) → immediately switch to the correct
ascertained diagnosis of endocar- calculated antibiotic
ditis = positive blood culture + • Positive blood cultures in endocarditis should be kept
positive TEE! by the microbiological institute for one year, in order
to be able to use them if necessary to be able to carry

500 Cardiology
 out special follow-up examinations to optimise the an-
tibiotic therapy.
Echocardiography
• transthoracic (TTE)
-- usually the primary examination
-- sensitivity: 63% (TEE: 95%)
-- to assess the tricuspid valve usually better than
TEE: In the question of endocarditis, a transthoracic
echocardiography should always be performed in
addition to the transesophageal echo, because the
tricuspid valve can be assessed much better here.
The posterior leaflet, which is only visible in an atypi-
cal section in the parasternal long axis, must always
be assessed as well.
-- weekly follow-up
• transesophageal (TEE)
Vegetations
• TEE: high sensitivity (95%), but only low specificity
• negative predictive value of TEE: 95%
• vegetations < 2mm mostly not detectable
• large vegetations especially in:
-- S. aureus
-- fungi
-- HACEK group
• localization:
-- mitral valve
◦◦ mainly anterior mitral leaflet (AML)
◦◦ on the atrial side
-- aortic valve: on the ventricular side
• should become smaller (but usually never completely
disappear) and denser under antibiosis

TEE
• detection of vegetations
• detection of complications (therefore do not miss the
TEE even in case of positive TTE!)
-- abscesses
◦◦ especially in case of aortic valve endocarditis
◦◦ typical: central brightening
◦◦ in case of difficulties in TEE possibly multislice-CT
-- fistulas (especially in case of aortic valve endocardi-
tis, e.g. from the left ventricle into the right atrium [=
Gerbode shunt])
-- pericardial effusion (also clearly recognizable in the
TTE)
◦◦ often small effusion
◦◦ cave larger effusion:
▪▪ haemopericardium
▪▪ pyopericardium (due to a purulent fistula)
-- multiple valve involvement (kissing vegetations; e.g.
frequent secondary involvement of the anterior mit-
ral leaflet by the regurgitation jet in severe aortic val-
ve regurgitation in primary aortic valve endocarditis)
• assessment of ventricular function
• assessment of the severity of valve regurgitation
-- The absence of valve regurgitation practically rules
out endocarditis!
-- The severity of valve regurgitation does not decrea-
se even after successful antibiotic therapy!
• possibly 3D-TEE (if available):
Fig. 731  TEE: mitral valve endocarditis with corresponding
-- In 2D-TEE the size of the vegetation is regularly un-
mitral valve regurgitation
derestimated compared to 3D-TEE (Berdejo et al,
JACC Img 2014).
-- detection of paravalvular leakage, fistulas, perfora-
tion

initially inconspicuous TEE, but

still clinically high-grade suspec-
ted infective endocarditis →
repeat TEE after 1 week!

Cardiology 501
 Fig. 733  Lambl's excrescence on the aortic valve (no ve-
getation!)
Fig. 732  TEE: aortic valve endocarditis

Fig. 734  Noduli arantii (see arrow) like here on the aortic
valve can sometimes appear quite prominent. However,
they are completely normal and should not be confused
with endocarditis.

Characteristics
endocarditic vegetation

There is no endocarditis without valve

regurgitation!

Duke criteria
• specificity 80%, sensitivity 80% (both apply to the nati-
ve valve endocarditis of the left heart)
• named after Duke University in the USA (1994, revised
and updated last in 2015; see infobox
• In addition, the ESC Guidelines 2015 include the fol-

502 Cardiology
lowing new major criteria (as equivalent imaging to
echocardiography):
-- cardiac CT (multislice, ECG triggered; especially for
the detection of paravalvular abscesses [anular ab-
scess], pseudoaneurysm)
-- nuclear medicine imaging (18F-FDG PET-CT or leu-
kocyte SPECT-CT): pathological activity in the area
of valve replacement (but not in the first 3 months
after implantation, as postoperative accumulation of-
ten occurs without endocarditis being present);
-- also suitable for the question of pacemaker / AICD
endocarditis

Complications
• severe sepsis, septic shock, multi-organ failure
• paravalvular spread (abscesses, fistulas)
• intracranial hemorrhage (mycotic aneurysm)
• embolism
• with artificial valves:
-- avulsion of prosthesis
-- obstruction of opening of the prosthesis
• severe valve regurgitation → left heart failure, pulmo-
nary oedema, cardiogenic shock
• acute kidney failure (acute kidney injury); possible cau-
ses:
-- immune complex glomerulonephritis (15%)
-- renal infarction (by a septic embolism)
-- reduced perfusion in the context of septic shock or
after cardiac surgery
-- nephrotoxicity
◦◦ antibiotics (especially gentamicin, vancomycin)
◦◦ contrast agents (e.g. CT, preoperative coronary
angiography)

Paravalvular spread

Risk factors
• aortic valve endocarditis
• prosthetic valve endocarditis
• S. aureus

Types
• paravalvular (perianular) abscess
-- locus minoris resistentiae: AV node, membranous
septum
-- remember this if a new AV block / bundle branch
block occurs (predictive value: 88%, sensitivity only
45%)
-- in the echocardiography typical central brightening
in the anular area (cave: Do not confuse it with a
transverse cut coronary artery!)

Cardiology 503
 -- very good option also for the detection of an anu-
lar abscess (especially if unclear in the TEE): CT
(multislice, ECG-triggered)
-- always indication for surgery
• valve ring, valve pocket
• septum → bundle branch block, third degree AV block
• pericardium → pericarditis, hemopericardium, pyope-
ricardium
• sinus valsalvae (= (= the slightly dilated part of the as-
cending aorta immediately following the aortic valve;
origin of the coronary vessels); rupture of a sinus val-
salvae aneurysm → acute right heart failure (ausculta-
tion: machine noise!)
• Gerbode shunt
-- named after the American cardiac surgeon Frank
Gerbode (1907-1984; first description: 1958)
-- connection between left ventricle and right atrium
(LV-RA fistula)
-- etiology
◦◦ congenital (most frequent)
◦◦ acquired (e.g. endocarditis, thoracic trauma, cardi-
ac surgery, myocardial infarction)
-- imaging
◦◦ echocardiography (TTE, TEE)
▪▪ dilated right atrium
▪▪ shunt detection in color Doppler
▪▪ high pressure gradient between left ventricle and
right atrium (up to 150mmHg; mean 95mmHg)
◦◦ sectional imaging: cardio CT or MRI
-- therapy: surgical patch closure
• right heart
• coronary arteries (in aortic valve endocarditis) → sep-
tic coronary embolism (→ myocardial infarction!)
• pulmonary artery (in aortic valve endocarditis) → pul-
monary embolisms, recurrent pneumonias (also in left
heart endocarditis!)
• myocardium → myocarditis (consequence: i.a. ventri-
cular arrhythmias)
Fig. 735  The central brightening in the anulus of the aortic
valve (see arrow) is not an abscess, but only the cross-cut
left coronary artery.
504 Cardiology
Intracranial hemorrhage
• mycotic aneurysms
-- consequence of septic embolisms
-- mortality: 60% (in rupture even 80%)
-- especially in i.v.drug abuse
-- therapy:
◦◦ interventional (endovascular)
◦◦ neurosurgical
• After an intracranial haemorrhage the valve operation
can take place at the earliest after 4 weeks, because
otherwise the risk of intraoperative enlargement of int-
racranial haemorrhage is increased.
• intracranial haemorrhage (SAH, intracerebral blee-
ding in young patients → think of endocarditis!)
Embolisms
• the most frequent complication (33%) of endocar-
ditis
• especially occurring in the early phase (highest risk in
the first two weeks!)
• Organ infarcts and consecutive organ abscesses oc-
cur.
• risk factors
-- size of vegetation > 10 mm (especially mitral valve)
-- mitral valve endocarditis (embolism occurs more
frequently in mitral valve endocarditis than in aortic
valve endocarditis; furthermore more frequent in ve-
getation on the anterior than on the posterior leaflet);
reasons:
◦◦ The mitral valve has a larger valve surface than
the aortic valve.
◦◦ The pressure jumps between diastole and systo-
le are larger at the mitral valve than at the aortic
valve.
◦◦ The opening and closing movements of the mitral
valve leaflets, which are very mobile, cause a high-
er acceleration of the vegetation than the opening
and closing movements of the aortic valve leaflets.
-- germs: S. aureus, enterococci, fungi
• abdominal sonography obligatory in case of endocar-
ditis
in case of a confirmed endocarditis:
generous CT diagnostics on the
question of septic embolisms: CCT
(necessarily with contrast medium), CT
chest and abdomen
Organs
• kidney (60%; renal infarction; symptom: flank pain)
• spleen
-- 44% splenic infarctions, 5% splenic abscesses (typi-
cal for staphylococcal endocarditis)
-- symptoms: left flank and shoulder pain, singultus (ty-
pical hiccup!)
-- spleen abscess → increased risk of rupture
 -- Spleen abscesses are difficult to treat conserva-
tively, usually only surgically (splenectomy [before
valve surgery to avoid reinfection]).
• liver (e.g. liver abscess)
• brain (40%)
-- localization: especially middle cerebral artery
-- symptom: stroke
-- diagnosis: CCT (in case of abscess with contrast
agent), if necessary MRI
-- therapy: Fibrinolytic therapy is absolutely cont-
raindicated in case of endocarditis due to the risk of
cerebral bleeding! However, mechanical recanaliza- Fig. 737  CT abdomen: renal infarction (wedge-shaped; ar-
tion would be possible. row)
• spinal column (e.g. paravertebral abscess
• coronary vessels (30%)
• pulmonary artery (in tricuspid valve endocarditis; con-
sequence: pulmonary infarction, possibly pulmonary
abscess)
• limb arteries

Fig. 738  CT abdomen: splenic infarction (wedge-shaped;

arrow)

Fig. 736  abdominal sonography: splenomegaly with sple-

nic abscesses (arrows)

Fig. 739  CT abdomen: liver abscesses

Cardiology 505
 Fig. 742  Angiography: embolic occlusion of the popliteal
artery (P3 segment)

Left heart failure

• the decisive prognostic parameter and the most fre-
quent surgical indication
• frequency:
-- aortic valve endocarditis: in 29%
-- mitral valve endocarditis: in 20%
• causes:
-- perforation of valve leaflets
-- tendinous chord rupture
-- prosthetic valves:
◦◦ prosthetic dehiscence
◦◦ obstructive vegetations
• laboratory: increase in pro-BNP
• therapy: (almost) always indication for surgery
Fig. 740  MRI: paravertebral abscess (arrows)
Therapiy
• antibiotics
• surgery (necessary in 50%)

Antibiotics (calculated; empirical)

• native valve
• artificial valve

Fig. 741  Angiography of the left leg: acute occlusion of the

superficial femoral artery (typical dome sign indicating an
acute embolic occlusion; see arrow) by a large embolism in
aortic valve endocarditis

506 Cardiology

Calculated antibiosis
native valve
Calculated antibiosis
artificial valve
Gentamycin
• Normally, aminoglycosides are only given once a day
due to the "first dose phenomenon". They have a pro-
nounced post-antibiotic effect, i.e. they are still bacte-
ricidal, even though the peak level has already fallen
In cases of endocarditis, the daily dose (gentamycin 3
mg/kg based on the ideal weight) is divided into three
single doses as an exception! In endocarditis, amino-
glycosides are only given as a comedication in addition
to aminopenicillin (e.g. ampicillin), as this leads to an
increased effect. Since ampicillin is also given several
times a day, gentamycin, which only acts as an en-
hancer, is also given several times a day. The amino-
glycoside should always been administered after the
penicillin. In the European guidelines (ESC-Guidelines
2015), however, only once daily administration (gen-
tamycin 3 mg / kg) is now recommended, while the
American guidelines continue to recommend three
times daily administration. In MSSA, aminoglycosides
are now no longer recommended for the therapy of na-
tive valve endocarditis, as an advantage could not be
proven and the risk of kidney failure is increased by ne-
phrotoxicity. In the case of artificial valve endocarditis
due to MSSA or endocarditis due to MRSA (regardless
of whether native or artificial valve) aminoglycosides
are still recommended
• dose reduction in renal insufficiency (see table; half of
all patients with acute endocarditis have an impaired
renal function! The nephrotoxicity is lower with the
administration in one dose than with the division into
three doses per day.)
• therapeutic drug monitoring; target level:
-- trough level (immediately before administration; pre-
dose)
◦◦ when administered one time a day (currently re-
commended [ESC]): < 1 mg/l (< 1 µg/ml)
◦◦ when administered three times a day (currently no
longer recommended [ESC]): < 2 mg/l
-- peak level (1h after administration; post-dose)
◦◦ when administered one time a day (currently re-
commended [ESC]): 10-12 mg/l
◦◦ when administered three times a day (currently no
longer recommended [ESC]): 3-4 mg/l
Creatinine clearance Percent of normal dose
(ml/min) (3 mg/kg bw)
> 70 100
60 98
50 97
40 94
30 88
20 75
< 10 50
Principles ("rules of the game")
• The treatment of endocarditis (especially when com-
plications have occurred) should be carried out on an
interdisciplinary basis by or in consultation with an en-
docarditis team (cardiologist, heart surgeon, infectio-
logist) at a reference centre (ESC Guidelines 2015 IIa
recommendation). In a French study (Botelho-Nevers
et al, Arch Intern Med 2009), this dramatically reduced
mortality (after 1 year 8.2% versus 18.5%).
• Antibiosis should always be administered parenterally
(via peripheral cannulae; no central venous catheter in
infectious endocarditis [if possible, but often unavoida-
ble in septic patients with intensive care). The POET
study (see box) showed, however, that in the second
half the antibiosis can also be given orally without
endangering the patient, so that a more rapid dischar-
ge from hospital is possible.
• always abdominal sonography (especially splenic in-
farction)
• positive blood culture with S.aureus → always TEE (in
15% endocarditis; note: The VIRSTA score is helpful in
deciding which patient with S. aureus bacteremia actu-
ally needs a TEE (see infobox on page 827).
• Defervescence should occur after 7 days at the latest.
• initial bed rest
• duration of antibiosis
Cardiology 507
 -- native valves: at least 4 weeks
-- artificial valves: at least 6 weeks (day of surgery
counts as day 1 [also applies to other polymer-asso-
ciated endocarditis]!)
• antibiosis at least until leukocytes and CRP have nor-
malized
• artificial valves → always additionally rifampicin
-- Rifampicin is the best biofilm-penetrating antibiotic
available. It is actively enriched in granulocytes
and thus accelerates the sterilization of abscesses,
which are often formed in artificial valves.
-- The ESC Guidelines 2015 recommend that therapy
with rifampicin should only be started with a delay
(after 3 days) in addition to the effective antibiotic
therapy already initiated, as otherwise antagonizing
effects may occur.
• weekly echocardiographic controls (TTE: mainly to
evaluate valve reguritation, pump function)
• blood cultures once or twice a week (also under anti-
biotic treatment!)
• Extracardiac abscesses should be surgically removed
prior to valve surgery (e.g. splenectomy in multiple
splenic abscesses [vaccination against pneumococ-
cus / H. influenzae for OPSI prophylaxis]).
• 4 and then 8 weeks after the end of therapy, blood cul-
tures should be drawn again to detect early recurrence
(especially important in enterococci).
• continuation of antibiosis even after surgery (pre- and
post-operative antibiotics: 6 weeks in total)
POET study
Partial Oral versus Intravenous Antibiotic Treatment of En-
docarditis
Iversen et al, N Engl J 2018
• prospective randomized controlled multicenter (Den-
mark) non-inferiority study
• POET: Partial Oral Treatment of Endocarditis
• 400 patients with infective endocarditis (caused by S.
aureus, streptococci, enterococcus faecalis or CoNS),
stable (i.e. no more fever, leukocytes < 15000/μl, low
CRP [< 2 mg/dl or drop to < 25% of the maximum value],
no abscess in the TEE, heart surgery > 7 days ago);
antibiosis for at least 10 days i.v., then
-- change to p.o. (oralization; on average 17 days; i.a.
after 3 days discharge from hospital)
-- further i.v. (19 days on average)
• result: oralization → no difference in the primary com-
bined endpoint (death, unplanned cardiac surgery, em-
bolism or recurrence of bacteremia), i.e. equivalent (also
applied to valve prostheses [1/4 of all patients])
• note: overall low-risk patients (very selective patient
population [From the 2000 patients screened only 400
patients were suitable.])
508 Cardiology
Anticoagulation
• no full anticoagulation in endocarditis (common
mistake! increased risk of intracerebral hemorrhage
[Hart et al 1987, Kanter et al 1991])
• low dose anticoagulation (for thrombosis prophylaxis)
allowed (but also only indicated in cases of bedridden-
ness, sepsis, DIC)
• The most effective protection against embolization of
a large vegetation is the immediate start of adequate
antibiosis!
• no ASA / thienopyridine (if possible discontinue; ESC
2015: discontinuation only in case of bleeding)
• embolism
-- before the start of an adequate antibiosis → antibio-
sis (no full anticoagulation!)
-- after the start of an adequate antibiosis → no full
anticoagulation, but immediate surgery
• other reason for full anticoagulation (e.g. mechanical
valve prosthesis, pulmonary embolism / thrombosis <
6 months) → change from VKA / NOAC to heparin-
perfusor
• cerebral complications under anticoagulation → ge-
nerous CCT to rule out intracranial hemorrhage
An embolism under (test-adapted)
antibiosis is not an indication for
anticoagulation, but an indication for
surgery!
Timing of surgery for cerebral embolism
under antibiosis
• early! within 72h (ESC guidelines)
• In the past, latency was often recommended (from 8
days up to 3 weeks): However, it is known that the
maximum of the disturbance of the blood-brain barrier
usually occurs after 8 days, so that the rate of intra-
cerebral hemorrhage is then greatly increased during
surgery!
• An exception is intracranial hemorrhage: In this case
cardiac surgery should be performed after 4 weeks
at the earliest. According to the ESC guideline 2015,
however, if there is a small hemorrhage, the cardiac
surgery can be carried out earlier (within 2 weeks), i.e.
 a urgently indicated (or even as an emergency) cardi- -- increase in vegetation size
ac surgery should not be postponed if there is a small • acute kidney failure (only relative)
cerebral hemorrhage. • persistent fever / bacteremia (positive blood culture)
for 8 days despite adequate antibiotic therapy
A cerebral embolism is not a • evidence of local complications: abscess, fistula (e.g.
contraindication for surgery! newly appeared bundle branch block)
• kissing vegetations on the mitral valve in primary aortic
valve endocarditis
Surgery • prosthetic valve endocarditis: Artificial valves usually
cannot be restored by antibiotics. In the case of pros-
thetic valve endocarditis caused by penicillin-sensitive
streptococci, a conservative approach is initially justi-
fied. Especially early prosthetic valve endocarditis (< 1
year) almost always requires surgery. This applies to
both mechanical and biological valves (The biological
material is not supplied with blood.).

The most common indication for

surgery in endocarditis is mani-
fest heart failure!

Types
• valve reconstruction (especially for mitral valve: In the
case of the mitral valve, reconstruction should always
be the goal, as it shows much better long-term results
than the replacement.)
• valve replacement (especially for aortic valve: Here,
reconstruction is of very little importance.)

Indications
• septic shock > 48h
• haemodynamically relevant valve regurgitation (pul-
monary oedema, acute left heart failure, cardiogenic
shock)
• germs: MRSA (note: early even in MSSA if there is no
rapid response of conservative therapy), VRE, coxiella
burnetii, brucella, fungi (even in native valve endocar-
ditis no conservative [i.e. purely antifungal with echino-
candins] therapy attempt)
• embolisms under (adequate) antibiosis
• size of vegetation
-- > 10 mm at the mitral valve (relative; risk of embo-
lism in 30d: 76%)
-- The larger the vegetation, the longer the diffusion
distance gets from the blood into the vegetation. Es-
pecially with a MIC (minimal inhibition concentration)
> 4 mg/l, no success is to be expected even with
prolonged antibiotic therapy, so that in this case, with
a constant size vegetation > 10 mm, surgery should
be performed early.
-- The ESC Guidelines 2015 recommend surgery (IIa
recommendation) for mitral or aortic valve vegetati-
on > 30 mm.

Cardiology 509
 EASE study

Early Surgery Versus Conventional Treatment in Infective

Endocarditis
Kang et al, N Engl J 2012

• prospective randomized study (Korea)

• EASE: endovascular atherectomy safety and effective-
ness
• 76 patients with infective endocarditis and vegetations >
10mm (aortic or mitral valve)
-- conservative (in 77% but then still in the course [i.e.
after 48h] surgery; [note: a very unusual "conserva-
tive" group])
-- surgical (surgery within 48h)
• results: surgical
-- significantly reduced combined endpoint of hospital
mortality and embolism (especially less embolism!)
-- no difference in mortality

Fig. 743  different surgical images in endocarditis: in the

first image vegetation on the mitral valve, then on the aortic
valve (bicuspid, below tricuspid), finally on an aortic valve
prosthesis (courtesy of PD Dr. med. Florian Wagner, deputy
director of the Clinic for Cardiovascular Surgery, University
Heart Center Hamburg [Germany])

Coronary angiography

• Preoperative coronary angiography is recommended

in the ESC guidelines before urgent (1-3 days) and
elective surgery, but not before emergency surgery (<
24h) in the following:
-- men > 40 years of age
-- postmenopausal women
-- at least one cardiovascular risk factor
-- known CHD
• rationale: If a cardic surgery with a sternotomy takes
place anyway, then it would make sense to provide the
patient with appropriate bypass grafts (CABG [corona-
ry artery bypass graft]) at the same time if necessary.
• cave: triggering of a septic embolism by coronary
angiography (especially in aortic valve endocarditis:
Here, instead of conventional coronary angiography,
CT coronary angiography should be performed pre-
operatively.)

510 Cardiology
Special forms
• microbiologically negative (culture-negative) infective
endocarditis
• polymicrobial infective endocarditis
-- in 3-4%
-- risk factors
◦◦ i.v. drug abuse
◦◦ artificial valves
• right heart endocarditis
• artificial valve endocarditis
• pacemaker endocarditis
• endocarditis in pregnancy
-- incidence: 6/100000
-- cause: mostly pre-existing heart disease or i.v. drug
abuse
-- mortality:
◦◦ mother: 33%
◦◦ child: 29%
Culture-negative infective endocarditis
• blood culture-negative infective endocarditis (BCNIE)
• in 15%
• causes:
-- antibiotic pre-treatment (mostly)
-- rare, difficult to cultivate pathogens (e.g. coxiella bur-
netii [the most frequent pathogen of culture-negative
infective endocarditis, because it cannot be cultiva-
ted using conventional blood cultures; diagnosis via
serology only], HACEK group)
-- non-infective cause (e.g. autoimmune)
• Here an extended diagnosis should always be car-
ried out: serology
-- infectious serology: coxiella burnetii, brucella, barto-
nella, chlamydia psittaci, mycoplasma pneumonia,
legionella pneumophila, tropheryma whipplei
-- autoimmune serology
◦◦ antinuclear antibodies (ANA), double-stranded
DNA antibodies (ds-DNA) → SLE (endocarditis
Libman-Sacks
◦◦ lupus antioagulans, cardiolipin antibodies, anti-β2-
microglobulin → antiphospholipid Syndrome
• therapy:
-- vancomycin for 4-6 weeks + gentamicin for 2 weeks
-- for artificial valve additionally rifampicin
fusobacteria)
• prognosis: relatively favourable (surgery rarely neces-
sary)
Risk factors
• i.v. drug abuse („Hippie“ endocarditis; especially HIV
patients); distribution: endocarditis in i.v. drug addicts:
-- 2/3 right heart endocarditis (especially tricuspid val-
ve endocarditis)
-- 1/3 left heart endocarditis
• pacemaker/ AICD carriers, CVC, pulmonary artery ca-
theter
• dialysis patients
• congenital vitia
Imaging
• radiology: in the chest X-ray or CToften multiple or
changing pulmonary infiltrates
• echocardiography:
-- often huge vegetations
-- The tricuspid valve is usually easier to assess in the
TTE than in the TEE (exception: transgastric view).
But even with a positive TTE, you should always
also perform a TEE to rule out complications (espe-
cially abscesses).
-- annotation for transthoracic echocardiography:
Normally only two leaflets of the tricuspid valve can
be seen: e.g. in the apical 4-chamber view laterally
the anterior and septally the septal leaflet. However,
the tricuspid valve, as the name suggests, has three
leaflets ("tri-cuspid"): To view the third (i.e. posterior)
leaflet, an atypical section must be made: You set
the parasternal long axis and then tilt the transducer
down: This is the only section where you can see the
posterior leaflet!

Right heart endocarditis

Definition
• mostly tricuspid valve endocarditis (But also the pul-
monary valve and the Eustachian valve can be affec-
ted.)
• most common pathogen: S. aureus Fig. 744  chest X-ray: multiple lung infiltrates in tricuspid
• typically i.v. drug addicts with respiratory thoracic pain, valve endocarditis
cough, pneumonia
• differential diagnosis: Lemierre syndrome (see page
827; similar symptoms as in tricuspid valve endo-
carditis with multiple lung infiltrates; main germ here:

Cardiology 511
 Fig. 747  echocardiography with subcostal view: tricuspid
valve endocarditis (vegetation on the anterior leaflet)

Therapy
• antibiotics
-- means:
◦◦ i.v. (first choice):
▪▪ flucloxacillin + gentamycin or
▪▪ daptomycin (monotherapy
◦◦ p.o (second choice): ciprofloxacin 750mg/24h +
rifampicin 300mg/24h
-- duration: 2 weeks sufficient if
◦◦ only tricuspid valve affected (i.e. no kissing vege-
tations on other valves)
◦◦ MSSA
Fig. 745  CT thorax: multiple lung infiltrates in tricuspid val- ◦◦ vegetation size < 20mm
ve endocarditis (different examples)
• surgery (tricuspid valve endocarditis):
-- indication:
◦◦ persistent vegetation > 20mm with pulmonary em-
bolisms
anterior
leaflet ◦◦ severe tricuspid valve regurgitation, which does
not respond sufficiently to diuretics
-- types:
posterior ◦◦ valve reconstruction
leaflet ▪▪ anuloraphy (suture): Kay technique (bicuspidi-
zation of the tricuspid valve), deVega technique
[gathering by continuous suture; problem: The
suture often tears out due to the enormous ten-
sile forces resulting from the right ventricular
dilation.])
▪▪ anuloplasty (mplantation of a Carpentier ring;
Fig. 746  important atypical parasternal section: the only standard today)
setting in which the posterior leaflet of the tricuspid valve ◦◦ valve replacement
is also visible (The posterior leaflet is the smallest of the
3 leaflets of the tricuspid valve, but its assessment is still ▪▪ overall very rarely necessary in the case of tri-
important!) cuspid valve regurgitation, but more often in en-
docarditis
▪▪ preferably biological valve (beware of thrombo-
sis with mechanical valve due to the very low
flows)
-- mortality (with severe tricuspid valveregurgitation):
20% (The high surgical mortality is due to the fact
that the patients are asymptomatic for a long time
despite severe tricuspid valve regurgitation. When
they become symptomatic, they often already have
further end organ damage [especially hepatic insuf-
ficiency], so that they are already in a relatively poor
functional status.)

512 Cardiology
Daptomycin (Cubicin) by penicillin-sensitive streptococci, a conservative
• In a study (Fowler et al, N Engl J 2006) of patients with trial is initially also justified.
right heart endocarditis and positive blood culture with • For TAVI valves (TAVI: transcatheter aortic valve im-
S.aureus (both MSSA and MRSA), monotherapy with plantation), which are also biological valves, in prin-
daptomycin was not inferior to the usual combination ciple the same recommendations apply as for surgi-
therapy of flucloxacillin/ vancomycin + gentamycin. cally implanted biological valves. However, the role of
• approved for the treatment of right-heart endocarditis surgery is still unclear here. In a retrospective study
caused by S. aureus (6 mg/kg i.v. once a day; note: (Mangner et al, J Am Heart Assoc 2018) after one year,
in the case of endocarditis the ESC Guidelines 2015 after surgery the mortality was just as high (60%) as
recommend a higher dosage: 10 mg/kg!) with the purely conservative therapy.
• postoperative: antibiosis (for a total of 6 weeks; day of
surgery counts as day 1)
Artificial valve endocarditis
• syn.: prosthetic valve endocarditis (PVE)
• 20% of all endocarditis unclear fever in patients with artificial
• distribution: valve → always blood cultures and
-- 50% mechanical valves TEE!
-- 50% biological valves
• highest risk of endocarditis in the first 6 months after
surgery physiolocigal patholocigal
• types: course transvalvular paravalvular
-- early endocarditis: < 1 year after surgery (most com- localization centric eccentric
mon germ: CoNS [coagulase negative staphylococ-
pattern typical atypical
ci; especially S. epidermidis])
-- late endocarditis: > 1 year after surgery (germs and flow velocity low high
therapy as in native valve endocarditis) aliasing near the valve far from the valve
• In the TEE one often sees physiological flushing jets
with mechanical valves: These are completely normal
and not indicate a pathological insufficiency. They are
consciously implemented in by the manufacturer to re-
duce the risk of valve thrombosis. The jet is always
located within the valve apparatus (transvalvular). If it
is paravalvular, i.e. outside the valve apparatus, this is
always pathological and a sign of a paravalvular leaka-
ge (e.g. as a complication of endocarditis). As a tip, in
addition to the color Doppler, you can add the M-mode
and thus better assess whether the jet is inside or out-
side the valve apparatus (for DD see also the following
table).
• signs:
-- paravalvular leakage
-- valve obstruction by vegetation (x-ray fluoroscopy:
obstruction of opening movement) Fig. 748  TEE of a mechanical valve in mitral position: Two
• if necessary nuclear medicine imaging (18F-FDG PET- physiological flushing jets are shown. These are located in-
side (transvalvular) the valve apparatus.
CT or leukocyte-SPECT-CT) on the question of a pa-
thological activity in the area of valve replacement (i.a.
Tornos et al, Circ 2015; very good option [especially if
unclear in the TEE]; but not in the first three months
after surgery, since physiological accumulation often
also occurs here)
• almost always surgery necessary
-- especially in case of early prosthetic valve endocar-
ditis
-- This applies to both mechanical and biological
valves: The bio-material is not supplied with blood
and therefore inert, so that the antibiotics almost ne-
ver reach the vegetation. In the case of endocarditis
of a biological valve (especially if it is not caused by
S. aureus or fungi), a purely conservative attempt at
therapy is justified.
-- In the case of prosthetic valve endocarditis caused

Cardiology 513
Fig. 749  TEE: vegetation at a double-wing prosthesis in
aortic position (first in longitudinal section, then in cross
section)
Pacemaker endocarditis
Definition
• infection of the lead(s; syn.: probe) or the aggregate
• most frequent germ: staphylococci (especially coagu-
lase-negative staphylococci)
• incidence: 1.4/1000 pacemaker years
• The same applies analogously to an AICD. Here the
infection rate is even higher than with a pacemaker.
• note on TEE: If you see a lesion on the lead, you are
often not sure whether it is a thrombus or vegetation
("ghost"). The further procedure then depends mainly
on the symptoms and the laboratory: If there is no fe-
ver and the inflammation parameters (e.g. CRP) ​​are
not increased, a thrombus is assumed, anticoagulation
is performed and the finding is controlled at interval.
Tip for discrimination between thrombus and vegetati-
on: indicative for a vegetation is if
-- lime splashes are present
-- the lesion lights up after administration of left heart
contrast agent (e.g. SonoVue)
514 Cardiology
Fig. 750  pacemaker endocarditis: vegetation on the lead
Therapy
• empirical antibiosis with vancomycin or daptomycin
• In case of vegetation on the pacemaker lead, the
complete pacemaker system (i.e. lead and aggregate;
analogous to an AICD) must be removed. This is also
explicitly recommended (expert consensus Wilkoff et
al, Heart Rhythm 2009; IB recommendation) in case of
endocarditis (e.g. vegetation on the valve without ve-
getation on the lead) or also in case of a gram-positive
(blood culture) sepsis, especially with S. aureus: Due
to the pronounced tendency to biofilm formation, a sole
antibiotic therapy is usually inefficient here. We do not
immediately remove the entire system from every pati-
ent because he has a S. aureus bacteremia. This only
takes place if the conservative attempt at therapy (with
antibiotics) has failed (e.g. repeatedly positive blood
cultures).
• With small vegetations (< 15mm) and an implantation
period < 1 year, the lead removal can still be performed
transvenously (so-called lead explantation; cave peri-
cardial tamponade → pericardial puncture set within
reach), with larger vegetations (> 15mm) or implanta-
tion period > 1 year, this must be performed by car-
diothoracic surgery (so-called lead extraction, using
 extraction set). Alternatively, interventional laser ext-
raction is also performed in some specialised centres.
• The electrode in the coronary sinus (in a CRT system)
can be removed by a simple pull.
• After 1-2 weeks (under monitor control) the implanta-
tion on the opposite side can then be performed if the
inflammation parameters are normal. If the patient is
completely pacemaker-dependent, a temporary pace-
maker must transitionally be inserted.
Excursus: Lead removal
• types:
-- lead explantation (< 1 year; screw leads are easier
to remove than anchor leads): removal of the lead
(transvenous) via the implantation route (cephalical /
subclavial vein ) without using special tools
-- lead extraction (> 1 year)
◦◦ with using special tools (e.g. locking stylets, elec-
trosurgical sheats, laser) or
◦◦ removal of the lead by a route other than the im-
plantation route
▪▪ interventional: transvenous (femoral / jugular
vein)
▪▪ surgical: transthoracic (thoracoscopy, thoracoto-
my [mini thoracotomy or sternotomy])
◦◦ Today, laser extraction is mostly carried out trans-
venously via the implantation route in a hybrid
surgical room (cardiothoracic surgical room with
option of coronary catheterization) with additional
TEE monitoring.
• Indications (Byrd criteria; updated according to Wilkoff
et al, Heart Rhythm 2009 and Kusumoto et al, Heart
Rhythm 2017):
-- infections (most common; the entire system, i.e. lead
and aggregate, must be removed here)
◦◦ pacemaker / AICD endocarditis (detection of vege-
tation on the lead)
◦◦ valvular endocarditis (without evidence of vegeta-
tion on the lead [IB recommendation])
◦◦ gram-positive blood culture (especially staphylo-
coccus aureus [IB recommendation]; note: We do
not automatically remove the device including the
probes, for every patient who has a pacemaker,
just because of a S. aureus bacteriemia.)
-- thromboembolism: detection of a thrombus on the
lead and detection of a clinically relevant embolism
(e.g. pulmonary embolism; here only the ead has to
be removed)
-- complications of a decommissioned lead:
◦◦ life-threatening arrhythmias
◦◦ acute danger from probe fragments (e.g. broken
wire)
◦◦ disturbance of treatment of a a malignancy (e.g.
radiation)
• complications:
-- main complication: pericardial tamponade (Therefo-
re the possibility of an emergency sternotomy must
be guaranteed within 10 minutes. Lead removal
should actually only be carried out in hospitals where
there is also cardiothoracic surgery.)
-- complication rate:
◦◦ ELECTRa study (Bongiorni et al, Eur Heart J
2017): serious complications (especially pericar-
dial tamponade, hemorrhage) in 1.7%, mortality
0.5%
◦◦ Hosseini et al, JACC Clinical Electrophysiology
2019: serious complications in 10.4%, mortality
4.1%
Prophylaxis
• aseptic surgery (surgical room)
• no implantation of a permanent pacemaker in the case
of a current bacterial infection (CRP should be < 10
mg/dl and PCT < 1 ng/ml.)
• For prophylaxis, the patient should therefore receive
perioperative antibiosis with a first generation cepha-
losporin, e.g. cefazolin 2g q8h, as part of a pacemaker
or AICD implantation (the antibiotics should be started
24 hours, 1 hour before surgery).
Prognosis
• untreated with lethal course (a "malignant" disease)
• lethality:
-- on average 18% (staphylococcal endocarditis: 40%,
fungal endocarditis 50%)
-- in decompensated heart failure: 40%
-- with CNS involvement: 41%
-- mitral valve endocarditis > aortic valve endocarditis
(almost twice as high mortality because of more fre-
quent embolisations)
• recurrent endocarditis (usually in the first 2 months af-
ter end of therapy)
-- S. viridans: 2%
-- S. aureus: 4%
-- enterococci: 28%
• general rules of conduct: oral hygiene, regular dental
checkups, no tattoos / piercings
Prophylaxis (endocarditis prophyla-
xis)
The recommendations have changed radically according
to the currently valid guidelines (national: DGK 2007, in-
ternational ESC 2009 and 2015). Endocarditis prophy-
laxis is almost no longer necessary today, endocarditis
passports are a thing of the past. note: Do not confuse
endocarditis prophylaxis with wound infection prophyla-
xis (often applied preoperatively [e.g. Cefazolin 2g i.v.
30min before pacemaker or AICD implantation])!
Cardiology 515
Risk groups Procedures

Patients

Endocarditis prophylaxis is now only recommended

for patients with high (no longer for low or intermediate)
risk!

516 Cardiology
 It is more important than the prophylactic administration
of antibiotics that high-risk patients adhere to certain ge-
neral measures (see box).
study

Dental procedures, antibiotic prophylaxis, and endocardi-

tis among people with prosthetic heart valves: nationwide
population based cohort and a case crossover study
Tubiana et al, BMJ 2017

• population-based cohort study (France)

• 138 876 patients with artificial valves and invasive dental
procedures (manipulation of the gingiva and the periapi-
cal tooth region; furthermore interventions in which the
oral mucosa is perforated [not: local anesthesia])
• antibiotic prophylaxis (carried out in 50.1%) → no
difference in the incidence of oral streptococcal endo-
carditis after 3 months

Endocarditis prophylaxis is only recommended for

procedures with high (no longer for low or medium) risk,
i.e. among other things, no more endocarditis prophy-
laxis for gastroscopy, colonoscopy, TEE, bronchoscopy
etc.!

In the ESC Guidelines 2015, endocarditis prophylaxis is

almost exclusively recommended only for dental proce-
dures (focus: oral streptococci). It is explicitly no longer
recommended (IIIC) for the following procedures:
• respiratory: bronchoscopy, laryngoscopy, intubation
• gastrointestinal: gastroscopy, colonoscopy, TEE
• urogenital: cystoscopy, delivery (whether vaginal deli-
very or cesarian)
• dermatological: interventions on the skin / soft tissue
(not even with abscesses or boils)

endocarditis prophylaxis: only very

rarely indicated!

endocarditis prophylaxis only necessa-

ry for patients with high risk (artificial
valves [mechanical, biological]) and
only for intervejtions with high risk
(especially dental procedures)!

Antibiotics
• amoxicillin 2g p.o. or Ampicillin 2g i.v. (children: 50 mg/
kg p.o./i.v.), alternatively ceftriaxone 1g i.v. (children:
50 mg/kg)
• One dose is sufficient (before the procedure).
• 30-60 min before the procedure
• penicillin allergy: clindamycin 600mg p.o./i.v. (children:
20 mg/kg)

Cardiology 517

MYOCARDITIS
Definition
• inflammation of the myocardium
• usually also pericardium is involved (perimyocarditis)
• usually caused by viruses
• usually cross antigenicity ("antigen-mimicry") between
viral and myocardial structures
• triphasic course (3 phases)
Epidemiology
• especially in childhood and adolescence
• m > w (typically in young men!)
• prevalence: 22/100000
• responsible for 10% of all sudden deaths in adole-
scents
• third most frequent cause of death in competitive ath-
letes (after hypertrophic cardiomyopathy and coronary
anomalies [especially RCA])
Etiology
• infectious
-- viruses (50%; No.1; coxsackie [formerly the most
common pathogen; B1-B5, A], parvovirus B19 [to-
day the most common pathogen; it usually does not
attack the myocytes, but the endothelial cells of the
vessels], adenoviruses, echoviruses, influenza viru-
ses A/B, SARS-CoV-2 [COVID-19], herpes viruses
[especially HHV 6; also HSV, CMV, EBV, VCV], he-
patitis C, mumps virus, measles virus, rubella virus,
poliovirus, HIV, hantavirus)
-- bacteria (especially Borrelia [in 8% of cases of Lyme
disease cardiac involvement in the sense of Lyme
carditis], staphylococci, enterococci, corynebacteria
[diphtheria], salmonella, brucella, rickettsia, coxiella
burnetii [Q fever], β-haemolytic group A streptococci
[angina tonsillaris, scarlet fever, erysipelas], menin-
gococcus, pneumococcus, gonococcus, clostridia,
chlamydia, mycoplasma, legionella, haemophilus
influenzae, leptospires [treponema pallidum → lues,
leptospira interrogans → Weil's disease], Mycobac-
terium tuberculosis [tuberculosis])
-- protozoa (e.g. trypanosoma cruzi [Chagas disease:
most frequent cause of myocarditis in South Ameri-
ca; see infobox], toxoplasma gondii)
-- fungi
518 Cardiology
◦◦ especially in immunosuppression
◦◦ candida, cspergillus, cryptococci, histoplasms,
mucormycosis
-- helminths (e.g. echinocococci, trichinae, ascaris)
• autoimmune
-- collagenoses (e.g. systemic lupus erythematosus,
Sjögren's syndrome, scleroderma [systemic sclero-
sis], dermatomyositis)
-- vasculitides (e.g. panarteriitis nodosa [Kussmaul-
Maier´s disease], Wegener's disease [Granuloma-
tosis with polyangiitis], Churg-Strauss syndrome
[EGPA: eosinophilic granulomatosis with polyangii-
tis], Takayasu's disease, giant cell arteritis)
-- sarcoidosis (Boeck´s disease)
-- rheumatoid arthritis
-- celiac disease, IBD (inflammatory bowel disease
[Crohn's disease, ulcerative colitis])
-- Kawasaki syndrome
-- immune checkpoint inhibitors
-- giant cell myocarditis (syn.: Fiedler's myocarditis)
◦◦ often lethal (mortality 90% within 6 months
◦◦ rapidly progressive heart failure and malignant ar-
rhythmias
◦◦ median age: 43 years, especially women
◦◦ in 20% associated with systemic diseases (espe-
cially sarcoidosis, SLE), thymoma, reaction to me-
dication (i.a. immune checkpoint inhibitors)
◦◦ diagnosis: myocardial biopsy ( aim immediate-
ly)
◦◦ therapy: immunosuppression (e.g. prednisolone
+ azathioprine; alternatively anti-CD3 antibodies
[muromonab; OKT3], ciclosporin), if necessary
heart transplantation
• allergic: hypersensitivity myocarditis (eosinophilic
myocarditis; Loeffler syndrome)
-- trigger:
◦◦ drugs: e.g. NSAID, mesalazine, benzodiazepi-
nes, diuretics, antibiotics (especially ampicillin,
penicillin, sulfonamides, cephalosporins, tetracy-
clines), anticonvulsants (e.g. phenytoin), tricyclic
antidepressants (e.g. amitriptyline), sulfonylureas,
clozapine, isoniazid, colchicine, methyldopa
◦◦ vaccinations (e.g. tetanus)
◦◦ insect bites, snake bites
-- typically exanthema of the skin and eosinophilia in
the differential blood count
-- therapy: immunosuppression (prednisolone, possib-
ly additionally azathioprine
• toxic (i.a. alcohol, catecholamines, cocaine, ampheta-
mines, chemotherapeutics [especially anthracyclines,
herceptin, cyclophosphamide], lithium, arsenic, heavy
metals [copper, cobalt, chromium, iron, lead], carbon
monoxide)
main cause of myocarditis: viral
(most common pathogens:
formerly Coxsackie B virus, today
parvovirus B19 and HHV 6)
Fig. 751  Chagas disease: It is caused by the protozoon
rypanosoma cruzi (first picture), which is transmitted by
blood-sucking predatory bugs (triatoma infestans; second
picture), which hang from the ceiling (from mostly simple
dwellings such as mud huts) and fall on sleeping people
at night.

Cardiology 519
Course
ECG in myocarditis: mostly
• asymptomatic (mostly)
pathological! typical: sinus
• symptomatic: tachycardia, T-negativations
-- mild (often)
-- fulminant (rarely):
◦◦ rapidly progressive heart failure with cardiogenic
shock or malignant arrhythmias
◦◦ However, if the acute phase has been overcome
(e.g. by aggressive intensive therapy), patients
have an excellent long-term prognosis!

Symptoms
• fever
• prior (shortly before) infection (mainly respiratory or
gastrointestinal) with unspecific symptoms (e.g. tired-
ness, fatigue, performance dip, myalgia, arthralgia)
• tachycardia (at rest)
• palpitations
• angina pectoris (especially with concomitant pericardi-
tis, but also due to coronary spasms in the context of
myocarditis)
• possibly signs of heart failure (including dyspnea, or-
thopnea, jugular vein congestion)
Diagnosis
• anamnesis (especially previous infections, tick bites,
arthralgias, medication [drugs]), clinical examination
(accidental heart murmur, possibly 3rd heartbeat in
heart failure, possibly basal fine crackles in pulmonary
congestion, possibly pericardial rubbing with concomi-
tant pericarditis)
• ECG ( mostly pathological!), Holter ECG
• chest X-ray (i.a. question of congestion, cardiomegaly)
• laboratory
• echocardiography
• cardiac MRI
• possibly cardiac catheter examination (if necessary
with endomyocardial biopsy
ECG
• sinus tachycardia (classic)
• tachyarrhythmia absoluta
• premature ventricular contractions
• supraventricular and ventricular tachycardia
• AV block (especially in Lyme disease, sarcoidosis, gi-
ant cell myocarditis, diphtheria)
• ST segment changes
-- ST elevation (especially in additional pericarditis)
-- ST-depresison, T-negativations ( the most sensiti-
ve ECG sign of myocarditis, i.e. missing T-negativa-
tions make myocarditis unlikely!)
• bundle branch block (e.g. LBBB)
• QT interval ↑ (unfavourable prognosis)
• possibly low voltage (in case of concomitant pericardi-
tis with pericardial effusion)
Fig. 752  typical ECG in myocarditis: sinus tachycardia with
T-negativations in the chest wall leads
Laboratory
• leukocytosis (in case of viral myocarditis mostly leuko-
penia), CRP ↑, BSR (blood sedimentation rate) ↑
• CK, CK-MB ↑, troponin ↑ (in 40%)
• possobly proBNP ↑ (in case of heart failure)
• differential blood count (question eosinophilia as an in-
dication of hypersensitivity myocarditis or EGPA)
• infectiology:
-- virology
◦◦ virus detection in stool, oral-throat wash speci-
mens
◦◦ maybe virus-serology (IgM)
▪▪ relatively expensive, usually no therapeutic re-
levance
▪▪ high infestation rate in Germany (among others,
70% of all people in Germany have IgG-antibo-
dies against Parvovirus B19), therefore not ne-
cessary!
◦◦ useful: testing for influenza (during the flu season)
and SARS-CoV-2 (during the pandemic)
-- microbiology (e.g. borrelia)
• sarcoidosis: ACE, neopterin, sIL-2-receptors (sIL: so-
luble interleukin)
• cardiac autoantibodies (of type IgM; mostly detectable
only in special laboratories)
-- AMLA (antimyolemmal antibodies)
-- ASA (antisacrolemmal antibodies)
-- antibodies against β1-receptor
Do not determine virus serology any
longer (expensive and useless)!

520 Cardiology
Echocardiography
• reduced systolic left ventricular pump function (in
70%), possibly also right ventricular involvement (in
32%)
• typically diastolic dysfunction at an early stage
• possibly dilated left ventricle, possibly relative mitral
valve insufficiency
• pericardial effusion (in 25%)
• regional wall motion abnormalities
-- often in myocarditis (in 80%), as the inflammation is
often only present focally
-- usually septal and apical
• lumpy reflex pattern ("sparkling septum"; "pepper and
salt aspect", "milk glass"; as in amyloidosis)
• thickened septum (due to myocardial oedema; in 10%)
• wall adherent thrombi (in 15%)

Cardiac MRI
• today means of choice in the diagnostic (for myo-
carditis sensitivity 100% and specificity 90%)
• findings (Lake-Louise criteria):
-- presentation of tissue edema (in the T2-weighted
uptake; best in the STIR sequences [STIR: short-tau Fig. 754  Cardiac MRI in myocarditis: The typical local
inversion recovery]) ("spotty") edema with intramural and also subepicardial
contrast medium enrichment (arrows) is visible.
-- contrast medium enrichment (gadolinium)
◦◦ early enhancement (enrichment in the heart musc-
le earlier than in the skeletal muscle) myocarditis: generous cardiac MRI!
◦◦ late enhancement (syn.: late gadolinium enhance-
ment [LGE]; as an indication of focal scars) not
only subendocardially (as in ischemia), but typi-
cally intramurally and subepicardially
-- possibly reduced left ventricular systolic function,
Cardiac catheterization
detection of regional wall motion abnormalities, pe-
ricardial effusion (analogous to echocardiography)
• Im Kardio-MRT kann man auch erkennen, ob die Ent-
zündung vorwiegend im linken oder rechten Ventrikel
lokalisiert ist und somit entscheiden, ob man die Myo-
kardbiopsie links- oder rechtsventrikulär durchführt.
• Cardio-MRI can also detect whether the inflammation
is predominantly localized in the left or right ventricle
and thus decide whether to perform myocardial biopsy
of either the right or the left ventricle.
• indications:
-- absolutely necessary in case of unclear left or right
ventricular dysfunction or life-threatening ventricular
arrhythmias
-- in case of unclear differential diagnosis to acute
coronary syndrome (angina pectoris, ST segment
changes, positive troponin)
A B C • i.a. exclusion of CHD (possibly slow-flow phenomenon
Fig. 753  Different forms of late enhancement in cardiac as an expression of the disturbed microcirculation)
MRI: Subendothelial accumulation (A) is typical for ische- • possibly vasculitic changes of the coronaries (e.g.
mia (CHD, infarction), intramural (B) and subepicardial ac- small aneurysms) in case of vasculitis as an underly-
cumulation (C) is typical for myocarditis. ing disease
• if necessary endomyocardial biopsy

Cardiology 521
Endomyocardial biopsy (EMB)
• indications:
-- see infobox
-- In case of myocarditis, a myocardial biopsy is still the
gold standard, but not always absolutely necessary.
It is usually only performed in the case of limited left
ventricular function (EF < 45%) if there is no impro-
vement within 14 days. However, it should be per-
formed immediately in haemodynamically unstable
patients (e.g. in cardiogenic shock) with the question
of giant cell myocarditis, as in this case immunosup-
pressive therapy must be initiated immediately.
-- In 30% of cases it is false negative ("sampling er-
ror"), especially if the inflammation is only locally
pronounced, so that a negative biopsy by no means
rules out myocarditis.
• procedure: At least 6 biopsies should be taken. Die
Biopsie ist immer schmerzfrei: The biopsy is always
painless: If chest pain occurs, an error has occurred!
The biopsy can be taken either from the right (disa-
dvantage: higher risk of perforation) or from the left
ventricle (disadvantage: arterial puncture necessary). myocarditis: diagnostic of choice
-- right ventricular biopsy: puncture of the femoral vein Today cardiac MRI! possibly cardiac
(8F-sheath), insertion into the right ventricle, punc- cath to exclude myocardial infarction;
ture of the septum (never of the free wall of the right EMB only rarely necessary
ventricle, because it is very thin, so that the risk of
myocardial rupture with consecutive pericardial tam-
ponade is very high)
-- left ventricular biopsy: puncture of the femoral artery Complications
(6F-sheath), retrograde passage of the aortic valve,
insertion into the left ventricle, heparinization • acute:
• histology: -- cardiac arrhythmia
-- methods: ◦◦ tachycardia (especially ventricular tachycardia
[especially on exertion], ventricular fibrillation;
◦◦ standard histology
note: However, an AICD implantation should not
◦◦ immunohistochemistry (especially CD54, VCAM- be carried out prematurely, as myocarditis has a
1, ICAM-1, HLA class I/II antigens high spontaneous healing rate.)
◦◦ electron microscopy ◦◦ bradycardia (especially third-degree AV block)
◦◦ molecular biology (PCR, in-situ hybridization) -- acute heart failure, pump failure, cardiac pulmonary
-- definition: For the diagnosis of myocarditis at least edema, cardiogenic shock
14 lymphocytes/mm2 or the detection of viral DNA / • chronic: development of dilated cardiomyopathy
RNA are required. (DCM; in 10%)
-- types (according to the Dallas criteria [controversial
because of high interobserver variability and no de-
tection of non-cellular inflammation]): Phases
◦◦ active myocarditis: infiltrate with necroses (myo-
• phase I: viral infection
cytolysis
-- entry of the viruses into the myocytes, virus replica-
◦◦ borderline myocarditis: infiltrate without necroses
tion and destruction of the myocytes
(no myocytolysis)
-- Viral myocarditis heals within a few weeks in 90%
• therapy guidance:
without consequences.
-- virus positive: antiviral (e.g. immunoglobulins)
• phase II: virus persistence or autoimmune (autoreacti-
-- virus negative: immunosuppressive ve, post-viral) reaction (renewed biopsy may be neces-
sary after 3-4 months)
• phase III: inflammatory dilated cardiomyopathy (iDCM)

522 Cardiology
Therapy
• causal
• symptomatic
Causal therapy
• anti-infective
-- antiviral (in case of virus persistence with detection
of viral DNA / RNA; only within the scope of studies;
ggf. Ganciclovir bei Herpesviren [HHV 6])
◦◦ detection of RNA: interferon β (BICC study [Schul-
theiss et al, Clin Res Cardiol 2015]: significant im-
provement in NYHA class
◦◦ detection of DNA: immunoglobulins (1-2 mg/kg
over 48h)
-- antibacterial (e.g. ceftriaxone for Lyme disease)
-- antiparasitic (e.g. nifurtimox for Chagas disease
-- antifungal
• immunological (no general recommendation; only
within the scope of studies):
-- immune suppression (especially in autoreactive ca-
ses after exclusion of virus persistence; however, no
immunosuppressive therapy in cases of virus persis-
tence [deterioration!])
◦◦ representatives: steroids, azathioprine, ciclospo-
rin, anti-CD3 antibodies (muromonab [OKT3])
◦◦ evaluation:
▪▪ steroids: with immunohistologically diagnosed
iDCM in 64% of patients significant improve-
ment of symptoms and increase in ejection frac-
tion (Kuehl al, Eur Heart J 1995)
▪▪ Myocarditis Treatment Trial (Mason et al, Eur
Heart J 1995): The immunosuppressive therapy
with steroids and azathioprine or cyclosporine
showed no benefit.
▪▪ TIMIC study (Frustaci et al, Eur Heart J 2009): In
patients with chronic myocarditis and excluded
virus persistence, immunosuppressive therapy
with steroids and azathioprine led to an increase
in the ejection fraction and a decrease in LVEDD
(left ventricular end diastolic diameter).
◦◦ indications: especially
▪▪ giant cell myocarditis
▪▪ eosinophilic myocarditis
▪▪ sarcoidosis (cardiac sarcoidosis: clear indica-
tion for steroids!)
▪▪ underlying autoimmune disease (especially
eosinophilic granulomatosis with polyangiitis
[Churg-Strauss syndrome])
-- immune adsorption:
◦◦ rationale: frequent cardiac autoantibodies (e.g.
against β1 receptors, AMLA, ASA)
◦◦ removal by plasma separation and immunaphere-
sis
In case of clear viremia (phase I)
and reduced left ventricular
function, an immunosuppressive
therapy with immunoglobulins 1-2
mg/kg over 48h can be tried.
EF < 45% and no improvement within
2 weeks → endomyocardial biopsy:
- virus positive → antiviral
- virus negative → immunosuppressive
Symptomatic therapy
• always hospital admission and initially also monitoring
(especially if troponin is positive [in our house until
troponin-I < 30 pg/ml])
• physical rest, ban on sports (for 6 months)
• alcohol abstinence
• no NSAID (contraindicated because they increase
myocardial cell damage [even increased mortality in
animal experiments]; only in perimyocarditis with se-
vere chest pain and normal ventricular function at the
lowest possible dose); note: In many places, NSAID
therapy (e.g. ibuprofen 3 x 600mg for 3 weeks) is car-
ried out if the ventricular function is normal.
• therapy of heart failure
-- therapy of acute heart failure (i.a. loop diuretics, do-
butamine, if necessary va-ECMO, if necessary LVAD
[left ventricular assist device; include cardiothoracic
surgery at an early stage!])
-- therapy of chronic heart failure
◦◦ i.a. early initiation of heart failure therapy in ac-
cordance with the guidelines consisting of ACE in-
hibitors or in case of intolerance ARBs, β-blocker,
diuretics and mineralocorticoid receptor antago-
nist
◦◦ in 60% improvement of systolic ventricular func-
tion
◦◦ if after 3 months despite maximum heart failure
therapy EF is still less than 35%: primary prophyl-
actic AICD implantation (optional bridging with de-
fibrillator vest [e.g. LifeVest])
• higher degree of AV-block: temporary pacemaker
• ultima ratio: heart transplantation (if no recovery under
an LVAD)
Prognosis
• mortality: 20% (after 5 years)
• depending on the persistence or elimination of the vi-
rus
• Myocarditis heals in 90% without consequences, in
10% heart failure remains in the form of dilated cardio-
myopathy (iDCM: inflammatory DCM).
• If the acute phase is survived, the fulminant form of the
disease with rapid onset of heart failure has a better
long-term prognosis ("the worst are the best"; excellent
long-term prognosis) than the insidious inflammation
Cardiology 523
 (e.g. without inflammation values). Therefore, in fulmi- -- bacteria (e.g. tuberculosis [No.1 in developing coun-
nant myocarditis an aggressive intensive medical the- tries], Lyme disease)
rapy (incl. LVAD) is crucial and absolutely worthwhile! -- protozoa (e.g. trypanosoma cruzi [Chagas disease])
• autoimmune
-- rheumatoid arthritis
-- Reiter's disease
Pericarditis -- collagenosis (e.g. SLE, Sjögren's syndrome, sclero-
derma [systemic sclerosis], dermatomyositis)
-- vasculitis
-- immune checkpoint inhibitors (e.g. ipilimumab, nivo-
lumab)
• congenital: familial Mediterranean fever (see infobox)
• - after myocardial infarction (see page 389)
-- pericarditis epistenocardica (early; < 1 week)
-- Dressler's syndrome (late; > 1 week)
• uremic

Definition
• inflammation of the pericardium (pericardial sac)
• usually caused by viruses
• the most common pericardial disease
• 5% of all causes of chest pain
• recurrence rate: 15-30% within 18 months
• risk of developing a constriction (pericarditis constricti-
va) depending on the etiology:
-- low (< 1%): viral, idiopathic
-- intermediate (2-5%): autoimmune, neoplastic
-- high (20-30%): bacterial (mainly tuberculosis, puru-
lent pericarditis)
• guidelines: ESC-Guidelines for the diagnosis and ma-
nagement of pericardial diseases 2015

Anatomy
• pericardium: double-walled connective tissue envelo-
pe
• structure
-- Lamina visceralis (epicardium; serous)
-- Lamina parietalis (pericardium; fibrous)
• pericardial cavity (max. 50ml fluid; sliding layer)

Epidemiology
• incidence: 28/100000
• m > w
• especially younger people

Etiology
• infectious
-- viruses (No.1 in industrial countries; especially cox-
sackie, adenoviruses, echoviruses, HIV; similar to
myocarditis)

524 Cardiology
Symptoms
• pericarditic chest pain (increases with inspiration,
but does not stop with respiratory pause in contrast to
pleuritic pain)
• possibly fever

Diagnosis
• anamnesis, physical examination (possibly pericardial
friction rub in the auscultation)
• ECG
• laboratory: i.a.
-- inflammation parameters (leukocytosis, CRP ↑)
-- troponin (increased in perimyocarditis)
-- virus serology: not necessary
• chest X-ray
• echocardiography (often pericardial effusion; in case
of additional myocarditis possibly EF ↓)
• diagnostic pericardiocentesis: usually not necessary

ECG (stages)
• stage I:
-- ST elevation; distinguishing features from ST eleva-
tion in myocardial infarction:
◦◦ not from the R-, but from the S-wave
◦◦ concave (not convex)
◦◦ The leads with the ST elevations cannot be assig-
ned to a coronary vessel.
◦◦ no reciprocal changes (typically missing)
-- PQ depression
◦◦ descending course of the segment between the
end of the P wave and the beginning of the QRS Fig. 756  acute pericarditis
complex
◦◦ due to the subepicardial injury pattern
◦◦ best recognizable in lead II
◦◦ present in 50%
◦◦ the most specific sign of pericarditis!
• stage II: decrease of the ST elevation, flattening of the
T wave
• stage III: isosceles negative T-waves
• stage IV: normal ECG again (postpericarditic)

Fig. 757  acute pericarditis with PQ depression: This is best

seen in II (see arrow) and is the ECG criterion with the high-
est specificity for pericarditis. The deperssed PQ segment
often gives the wrong impression that there is an ST ele-
vation. However, if you compare the ST segment with the
segment between the end of the T wave and the beginning
of the P wave (and not with the PQ segment, which is de-
pressed), you can see that the ST segment is not elevated.

Fig. 755  acute pericarditis: The typical concave ST elevati-

on from the S-wave in V2 and V3 can be seen.

Cardiology 525
 (standard)
◦◦ < 5 mm: small pericardial effusion
◦◦ 5-10 mm: moderate pericardial effusion
◦◦ > 10 mm: large pericardial effusion
• Doppler: in the spectral Doppler (pw-Doppler) diastolic
dysfunction (E < A; due to the disturbed filling)
• differential diagnosis
-- epicardial fat (adeps)
◦◦ often ventral to the right ventricle (small effusions
preferred posterior)
◦◦ hypoechoic (but not echo-free; maximum gain)
◦◦ no variation of thickness in the cardiac cycle
-- pleural effusion (left side); differentiation by:
Fig. 758  acute pericarditis with PQ deperssion (best reco-
◦◦ spreading
gnizable again in lead II)
▪▪ no circular spreading
▪▪ crossing of the atrial-ventricular junction (sulcus
atrioventricularis), i.e. also behind the left atrium
◦◦ position to the descending aorta (in parasternal
long axis below the left atrium)
▪▪ pericardial effusion: ventral to the descending
aorta
▪▪ pleural effusion: dorsal to the descending aorta
-- ascites

Echocardiography (pericardial effusi-

on)
• B-mode
-- acoustic window with the most sensitive evidence:
substernal
-- echo-free epicardial space
-- no crossing of the atrial-ventricular junction (= sulcus Fig. 759  This is not a pericardial effusion, but only a (left-si-
atrioventricularis; there is no more pericardial effusi- ded) pleural effusion, since the effusion crosses the atrial-
on behind the left atrium [exception: status post car- ventricular junction (sulcus atrioventricularis [see arrow]).
diothoracic surgery]; in contrast to pleural effusion)
-- parasternal basal often minimal fluid is recognizable
during systole (physiological; a diastolic persistent
fluid space is always pathological!)
-- extension
small atelectasis
◦◦ localized (mainly posterior) descending aorta
◦◦ circular
-- possibly "swinging heart" in case of large pericardial
effusion
-- possibly septation / chambering in case of chronic
effusion
• M-mode
-- separation of the epicardium during systole and dia-
stole (A separation detectable only during systole is
Fig. 760  This is not a pericardial effusion, but only a (left-
physiological.) sided) pleural effusion, since the effusion is located dorsal
-- The effusion removes the contact, so that the peri- to the aorta decendens in the parasternal long axis. Fur-
cardium can no longer be represented as a wave, thermore, a small atelectasis (typical of a pleural effusion)
but as a straight line (lack of systolic forward move- can be seen.
ment of the pericardium).
-- quantification according to diastolic separation

526 Cardiology
Prognostic factors
The factors listed below indicate an increased risk. If
none of the factors is fulfilled, outpatient treatment can
be performed. If one factor is fulfilled, inpatient treatment
(i.e. hospital admission) should be carried out.
• fever > 38ºC
• subacute course
• large pericardial effusion (enddiastolic > 20mm)
• myocardial involvement (troponin ↑)
• insufficient response to outpatient therapy
• immunosuppression
• oral anticoagulation therapy
Therapy
• combination of
-- antiphlogistic (with gastric protection)
◦◦ high dosage ASA (750-1000mg p.o. 3 x daily for
1-2 weeks, then dose reduction by 250-500mg
every 1-2 weeks) or
◦◦ high dosage NSAID (e.g. ibuprofen 600mg p.o. 3
x daily for 1-2 weeks, then dose reduction by 200-
400mg every 1-2 weeks; contraindicated in renal
failure with GFR < 30 ml/min) and
-- colchicine
◦◦ evaluation: today an integral part of first-line the-
rapy (ESC 2015: IA recommendation), as it halves
the risk of recurrence (CORP-2 study [see box])!
◦◦ dosage: 0,5mg p.o.
▪▪ < 70kg: 1 x daily
▪▪ ≥ 70kg: 2 x daily
◦◦ dose reduction for renal insufficiency:
▪▪ GFR 35-50 ml/min: 1 x 0,5mg daily
▪▪ GFR 10-35 ml/min: 1 x 0,5mg every 2 days
▪▪ GFR < 10 ml/min: contraindicated
◦◦ duration: for 3 months (no tapering)
◦◦ side effect: mainly diarrhoea
◦◦ contraindication: i.a. pregnancy and lactation
(Contraception during and up to 3 months [in men
even 6 months due to potential damage to the
sperm cells] after therapy is mandatory.)
• steroids
-- only second choice
-- indications:
◦◦ failure of first-line therapy
◦◦ contraindication against ASA or NSAID (e.g. al-
lergy, peptic ulcer, gastrointestinal bleeding, oral
anticoagulation with high risk of bleeding, renal
insufficiency)
◦◦ autoimmune disease
-- dosage: only low doses (0.2-0.5mg prednisone /
day; cave excess mortality with high-dose therapy)
-- only after exclusion of an infectious cause
-- preferably always in combination with colchicine
-- additional osteoporosis prophylaxis (calcium and vi-
tamin D)
-- tapering according to the scheme
◦◦ > 50 mg/d: 10 mg/d every 1-2 weeks
◦◦ 25-50 mg/d: 5-10 mg/d every 1-2 weeks
◦◦ 15-25 mg/d: 2.5 mg/d every 2-4 weeks
◦◦ < 15 mg/d: 1.25-2.5 mg/d every 2-6 weeks
-- optional intrapericardial administration (of non-ab-
sorbable steroids) also possible
• The duration of therapy depends on the symptoms and
on the course of CRP level.
• physical rest (at least 3 months; until the symptoms
have subsided and CRP level has normalized)
• therapy of recurrent disease:
-- again similar the first disease (ASA/NSAID + colchi-
cine) Steroide
-- immunosuppressive therapy (if steroid-dependent;
non-infectious)
◦◦ azathioprine
◦◦ immunoglobulins i.v.
◦◦ anakinra (IL1 receptor antagonist)
-- ultima ratio: pericardectomy
• therapy of pericarditis in pregnancy:
-- ASA: only < 20 WOP allowed (but here first choice
[also during lactation])
-- NSAID: from > 20. WOP contraindicated
-- paracetamol and steroids (prednisone 2.5-10mg dai-
ly): allowed both in pregnancy and lactation
-- colchicine: contraindicated both in pregnancy and
lactation
CORP-2 study
Efficacy and safety of colchicine for treatment of multiple
recurrences of pericarditis (CORP-2)
Imazio et al, Lancet 2014
• multicentre double-blind placebo-controlled randomised
study
• 240 patients with a repeated recurrence of pericarditis
-- NSAID
-- NSAID + colchicine (< 70kg: 1 x 0.5mg; > 70kg: 2 x
0.5mg)
• result: The additional administration of colchicine led to a
halving of the risk of recurrence (after 18 months; 21.6%
vs. 42.5%).
Therapy of choice for pericarditis:
combination of ASA / NSAID and
colchicine!
Cardiology 527
Excursus: Pericardial tamponade
Definition
• cardiogenic shock due to obstruction of filling
• most frequent cause: malignoma
• critical effusion quantity depending on the duration of
the development of pericardial effusion (elasticity of
the pericardium)
pressure
tamponade
volume
Fig. 761  The haemodynamically critical effusion rate de-
pends crucially on the duration of the pericardial effusion.
The pericardium is in fact dilatable. The relationship bet-
ween intrapericardial volume and intrapericardial pressure
is shown here, on the one hand, in the case of a rapidly
(red) and, on the other hand, in the case of a slowly (blue)
developing pericardial effusion. In the case of a rapidly
developing effusion, 50-100ml are often sufficient for the
development of a tamponade. Conversely, the amount re-
moved at the beginning of the pericardial puncture has the
greatest relative relieving effect!
Etiology
• neoplastic (No.1): pleural mesothelioma, breast
cancer, lung cancer, esophageal cancer, malignant
lymphomas, plasmocytoma (note: However, 2/3 of all
pericardial effusions in malignant patients are non-
malignant effusions [e.g. after radiation, opportunistic
infections!])
• idiopathic (No.2)
• inflammatory (pericarditis)
• metabolic
-- renal: uremic (chronic renal insufficiency; echocardi-
ography: typical radial segmentation)
-- hepatic: liver cirrhosis (hypalbuminemia)
• circulatory: pulmonary hypertension (due to the re-
duced reabsorption of pericardial fluid due to the in-
creased venous pressure; note: difficult diagnosis of
tamponade, because the right ventricle collapses very
lately due to the high pressure)
• traumatic
-- internal
◦◦ acute aortic dissection
◦◦ myocardial rupture
◦◦ ruptured sinus valsalvae aneurysm
◦◦ coronary perforation in PCI
528 Cardiology
◦◦ iatrogenic:
▪▪ perforated pacemaker / AICD electrode: perfo-
ration of the ventricular lead in the context of
pacemaker or AICD implantation (If hemodyna-
mic instability occurs after implantation, a peri-
cardial tamponade should always be considered
immediately in addition to a tension pneumotho-
rax and an echocardiography should be perfor-
med immediately. The implantation of the elec-
trodes is always painless. If chest pain occurs,
perforation is always suspected and echocar-
diography must be performed immediately. If a
pericardial effusion then appears, it must always
be punctured, even if it is very small! Even the
smallest amounts are sufficient to put the pati-
ent into cardiogenic shock and make him or her
liable to resuscitation. Patients here are usually
not tachycardic despite the presence of a peri-
cardial tamponade, since on the one hand many
pacemaker patients are often chronotropically
incompetent anyway, and on the other hand the-
re is often severe pain, so that the heart rate
does not increase due to vagal conditions.
▪▪ ablation (e.g. isolation of pulmonary veins)
▪▪ MitraClip procedure (mainly due to injury to the
atrial wall by the rigid catheter)
▪▪ implantation of an LAA occluder (occlusion of
the left atrial appendage)
-- external
◦◦ blunt (e.g. thoracic trauma as part of a polyrauma:
A pericardial tamponade is the cause of a trau-
matic cardiac arrest in 10% of cases [Kleber et al,
Resuscitation 2014] and is a reversible (treatable)
cause of cardiac arrest!)
◦◦ penetrating (e.g. stabbing)
• postoperative (after cardiothoracic surgery)
• endocrinological (e.g. hypothyroidism [myxoedema
heart], Addison's disease)
After a pacemaker / AICD implantation
or an atrial fibrillation ablation, an
echocardiography should always be
performed as a standard to exclude
pericardial effusion!
Symptoms
• dyspnea
• Beck's triad (named after the American cardiothoracic
surgeon Claude Beck [1894-1971])
-- upper venous congestion (i.e. venous hypertension
[i.a. CVD ↑])
-- arterial hypotension
-- quiet heart sounds
• tachycardia
• pulsus paradoxus
Pulsus paradoxus
• definition:
-- Normally, the systolic BP (invasive BP measure-
ment) would decrease by a maximum of 10 mmHg
during inspiration (inspiration → negative intrathora-
cic pressure ↑­ → filling of the right ventricle ­↑ → dila-
tation of the right ventricle → septum shift to the left
[Bonnheim effect] → left ventricular ejection ↓ → BP
↓). In pulsus paradoxus, the systolic BP decreases
by more than 10 mmHg: In pericardial tamponade,
the septum shift is even more pronounced, since
the right ventricle is almost unable to expand to the
lateral side due to the tamponade, so that the BP
Fig. 763  ECG: low voltage (most common differential dia-
decrease is even more pronounced here.
gnosis: obesity)
-- This applies to spontaneous breathing. With positive
pressure ventilation, the behavior is opposite (rever-
se pulsus paradoxus).
-- can also be recognozed in the pulse oximetry curve
• occurrence:
-- Perikardtamponade (note: The pulsus paradoxus
can be absent in the case of a sever aortic valve
regurgitation present at the same time as pericardial
tamponade [e.g. acute aortic dissection Stanford A
with pericardial tamponade and aortic valve regur- Fig. 764  ECG: electrical alternans
gitation].)
-- pericarditis constrictiva
-- status asthmaticus
-- tension pneumothorax

Fig. 762  Pulsus paradoxus [14]

Diagnosis
• ECG:
-- low voltage
-- electrical alternans ("swinging heart")
◦◦ fluctuation of the height or direction of the QRS
complexes
◦◦ often half the heart rate
◦◦ the electrocardiographic tamponade sign
• chest X-ray: "Bocksbeutel" heart (named after a type
of wine bottle with the form of a flattened ellipsoid
which is commonly used for wines from Franconia in
Germany tent-shaped; note: A "Bocksbeutel" heart is
also classic in Ebstein's anomaly.)
• echocardiography
• possibly CT thorax
• haemodynamic pressure curves: The atrial pressure
curves (CVP, wedge) show a loss of the y-descent with
a preserved x-descent (ad RA pressure curve for pe-
ricardial tamponade see page 26; ad LA pressure
curve for pericardial tamponade see page 203).

Cardiology 529
 Fig. 767  CT: pronounced pericardial effusion
Fig. 765  “Bocksbeutel” heart (tent-shaped; different ex-
amples): A large heart in the chest X-ray in the absence of
pulmonary congestion in a patient with pronounced dys-
pnea is almost pathognomonic for a (large) pericardial ef-
fusion!

Fig. 768  The most frequent cause of a pericardial tampona-

de is a malignancy (here left-sided lung bronchial cancer).
Tamponade criteria
• clinical:
-- Beck triad
◦◦ upper venous congestion (i.e. venous hypertensi-
on [i.a. CVD ↑])
◦◦ arterial hypotension
◦◦ quiet heart sounds
-- dyspnea
-- tachycardia
-- pulsus paradoxus
• electrocardiographic: electrical alternans
• echocardiographic:
-- dilated inferior vena cava without respiratory modu-
lation
-- diastolic collapse (invagination, inversion) of the
heart cavities (especially of the heart cavities, as the
pressure in these is significantly lower than in the left
heart cavities)
◦◦ right atrium first, then right ventricle
◦◦ right atrial collapse > 1/3 cardiac cycle
-- respiratory variability of the ventricle diameter (espe-
Fig. 766  echocardiography (subcostal view): pericardial
tamponade cially of the right ventricle)

530 Cardiology
 -- increased respiratory variability of the transvalvular
flow profiles (pw-Doppler; set low recording speed
["sweep speed"]; applies only to spontaneous brea-
thing, not to ventilated patients)
◦◦ inspiratory decrease of the transmitral inflow ve-
locity > 25%
◦◦ inspiratory increase of the transtricuspid inflow ve-
locity > 40%
-- inspiratory increase of the reflux in the hepatic veins
inspiration expiration
Fig. 769  Echocardiography: significant decrease of the
transmitral flow during inspiration
haemodynamic relevance/ tamponade:
clinical diagnosis!
Therapy
• hemodynamic stabilization ( volume administration
[to increase the right ventricular preload], no diuretics
[are contraindicated here; in contrast to pleural effusi-
on or ascites]!)
• PEEP as low as possible during ventilation (A too high
a PEEP lowers the right ventricular preload and incre-
ases the right ventricular afterload.)
• pericardial puncture (pericardiocentesis; emergency!);
first described by Naloleon's personal physician Jean-
Dominique Larrey (1766-1842) in soldiers with thoracic
gunshot wounds
• Pericardiocentesis (emergency!) - Pericardiocentesis
(mainly performed preclinically) in the case of trauma-
induced pericardial tamponade (e.g. traffic accident)
is usually not a meaningful intervention and only de-
lays the necessary thoracotomy (Penetrating cardiac
wounds: Principles for surgical management; Gao et
al, World J Surg 2004). Since there is often already co-
agulated blood in the pericardium, pericardiocentesis
is also often ineffective. However, pericardiocentesis
can be used as a bridging procedure in haemodyna-
mically unstable patients until the patient is treated
surgically.
• in case of septation or purulent / tuberculous pericar-
ditis
• unclear recurrent pericardial effusion → possibly peri-
cardioscopy (possibly with biopsy)
• malignant pericardial effusion:
-- pericardiodesis (e.g. 30mg bleomycin in 50ml NaCl
0.9% i.p.; note: The ESC Guidelines 2015 recom-
mend cisplatin for pulmonary and thiotepa for breast
cancer.)
-- oncological therapy (i.a. systemic chemotherapy,
radiotherapy [especially for lymphomas and leuka-
emias])
-- possibly pericardial fenestration (A window is crea-
ted in the pericardium so that the pericardial effusion
drains into the pleural space, where there is consi-
derably more space than in the pericardial space.)
◦◦ interventional (percutaneous balloon pericardio-
tomy: via wire under x-ray fluoroscopy expanding
the puncture site in the pericardium using a bal-
loon [e.g. valvuloplasty balloon])
◦◦ surgical (cardiothoracic; via a left-sided mini-tho-
racotomy)
-- possibly pericardectomys (ultima ratio; but usually
no more operable)
• special cases:
-- autoimmune: triamcinolone 300-600 mg/m2 i.p.
-- purulent: gentamycin 80mg i.p. (via irrigation draina-
ge)
Pericardiocentesis (pericardial puncture)
Puncture sites
• subcostal:
-- 2-3cm left and 2-3cm below the xiphoid (Larrey
point)
-- direction of puncture: left shoulder (tip: flat stitch [al-
most parallel to the sternum!])
-- standard
• apical:
-- apex in MCL
-- direction of puncture: right shoulder
-- intercostal (upper edge of the rib)
-- especially in obese patients
Procedure
• flat position of the upper body
• analgosedation (e.g. 0.05mg fentanyl, 50-100mg pro-
pofol)
• best invasive blood pressure measurement (insert ar-
terial line before if possible; but not absolutely neces-
sary
• sterile gown, sterile gloves, mouth protection, hood
• sterile covering, disinfection
• local anaesthesia
• insertion of the wire via Seldinger-technique, dilator,
5F-sheath
• via the sheath pigtail up to the left apex of the heart
• control
-- fluoroscopy (only very rarely necessary)
-- echocardiography (sterile cover)
• connection to drainage system (tip: Redon drainage
with suction)
Cardiology 531
 5
1

4 8

532 Cardiology
9 13

14
10

15

11

16

12

Cardiology 533
 been advanced, it must not be removed under any
17 circumstances, as otherwise the bleeding into the
pericardial space may cause the tamponade to in-
crease. In this case, a drainage must first be cor-
rectly inserted into the pericardial space. Once this
has been done, the drainage misplaced in the right
ventricle can be removed.
• vascular injury (internal thoracic artery, coronary ar-
teries [especially right coronary artery; therefore, re-
member this in case of a inferior wall infarction after
pericardiocentesis!)
• injury to the left lobe of the liver (possibly abdominal
sonography)
• pulmonary oedema with pre-existing reduced left ven-
18 tricular ejection fraction (Pericardiocentesis increases
the right ventricular ejection fraction again. Now sud-
denly increased blood comes to the left ventricle again.
If the left ventricle is previously insufficient, pulmonary
oedema may occur.)
• pneumothorax )complication especially in apical punc-
ture)
• pericardial pleural fistula (complication especially in
apical puncture)

Examination (pericardial effusion)

Fig. 770  The individual steps of pericardiocentesis (pe-
ricardial puncture): After sterile wiping and masking with
adhesive tissues (1), local anesthesia with xylocaine (2) is
performed. Then a conventional Seldinger needle is used to
puncture (3) from subxiphoidal position in the direction of
the left shoulder almost parallel to the sternum, until finally
fluid can be aspirated (4). A Seldinger wire is now advanced
over the lying Seldinger needle (5) and the needle is finally
pulled out. A small stab incision is made with the scalpel
at the point of the entry of the wire. Then a 5F sheath is
inserted over the wire (7, 8). Before this, the dilator is in-
serted into the sheath. After the sheath is inserted, the wire
and dilator are removed. Pericardial effusion can already be
removed on a trial basis using the side instruments of the
sheath (9). A pigtail catheter is advanced through the check
valve of the sheath (10-12). Then the sheath is retracted to
skin level (13) while the pigtail catheter is completely ad-
vanced. Pericardial effusion can now be punctured via the
pigtail catheter (14). The pigtail catheter is connected to a • laboratory:
Redon bottle. A connection adapter is necessary for this.
We use the Urotech catheter (15 [see arrow]; alternative- -- LDH, protein, cell count (differentiation of transudate
ly also possible: e.g. Can adapter, Renodrain). The sheath / exudate [Light criteria])
is sutured proximally and distally (16) and the connection -- BGA (incl. hemoglobin, pH value)
point between pigtail catheter and sheath is secured with -- possibly tumour markers (ESC-Guidelines 2015 IIa-
a patch strip (17). Finally, the suction of the Redon drain is
recommendation; CEA < 5 ng/ml, CYFRA 21-1 < 100
opened and the pericardial effusion drains off (18).
ng/ml; furthermore NSE, CA 19-9, CA 72-7)
Complications -- possibly adenosine deaminase (ADA; norm < 40
• puncture of the ventricles (mostky right ventricle): U/l; if increased: indicative for tuberculosis), possibly
unstimulated INFγ (if increased: indicative for tuber-
-- in case of uncertainty (especially in haemorrhagic
culosis)
pericardial effusions), whether one is actually in the
pericardium or the heart (e.g. in the ventricular cavi- -- triglycerides > 500 mg/dl (note: in the pleural effusi-
ty) or in a vein on limit value already at 110 mg/dl) → chylopericar-
dium (usually due to an injury of the thoracic duct;
◦◦ 2ml syringe (BGA): hemoglobin, oxagen saturati-
therapy trial with octerotide 100μg s.c. three times
on; comparison with previously taken values
a day for 2 weeks to reduce production of chyle, but
◦◦ injection of X-ray/echo contrast medium (e.g. often surgery is necessary)
5-10ml shaken NaCl 0.9%)
• microbiological (it is best to inoculate additionally blood
-- If it is confirmed that the right ventricle has been culture bottles; examination for pus, including myco-
punctured, this is usually harmless, but one should bacterium tuberculosis)
not advance the sheath. If the sheath has already
• cytological (Here you should not only send in one sin-

534 Cardiology
gle tube of the effusion, but the complete effusion. The
pathologist will then perform a centrifugation, so that
the diasgnostic yield [positive result on malignant cells]
can be increased significantly. It is best to fill the com-
plete effusion into a urine collection container: This can
be screwed up and is sufficiently stable for transport.)

Cardiology 535

HYPERTENSIVE CRISIS
Definitions
• hypertensive crisis: BP > 230/130 mmHg without acute
organ damage
• hypertensive emergency: BP > 230/130 mmHg with
acute organ damage:
-- cardiac:
◦◦ acute left heart failure
◦◦ angina pectoris, possibly myocardial infarction (in-
creased myocardial wall tension → increased O2
consumption)
-- pulmonal: pulmonary edema
-- renal: acute kidney failure (due to malignant neph-
rosclerosis)
-- cerebral:
◦◦ stroke (ischemic / hemorrhagic)
◦◦ hypertensive encephalopathy, PRES (posterior re-
versible encephalopathy syndrome)
-- vascular: acute aortic dissection, aneurysm rupture
-- ophthalmological: congestive papilla (papillary ede-
ma), retinal hemorrhage
Causes
• mostly insufficient compliance (independent disconti-
nuation of antihypertensive drugs)
• new concomitant medication (e.g. NSAID, steroids)
• unusually high-salt diet
• crisis-like blood pressure increases:
-- pheochromocytoma (see excursus)
-- renal
◦◦ renoparenchymatous (e.g. rapid-progressive glo-
merulonephritis)
◦◦ renovascular (renal artery stenosis)
-- primary hyperaldosteronism (Conn syndrome)
-- intoxications (e.g. cocaine, amphetamines, LSD)
536 Cardiology
-- scleroderma crisis (agent of choice here: ACE inhi-
bitors)
-- acute intermittent porphyria (AIP)
Annotations
• Pain can also lead to a pronounced rise in blood pres-
sure. In this case, however, an analgesic and not a
hypertensive therapy should be used primarily!
• Patients with bradycardic cardiac arrhythmias (e.g.
third degree AV block with a heart rate of 28/min) are
often hypertensive (e.g. BP 210/130mmHg). However,
this is completely normal and physiological: The cardi-
ac output is composed of the product of stroke volume
and heart rate. In order to generate sufficient cardiac
output for organ perfusion, the stroke volume is au-
tomatically increased here. The lower the heart rate,
the higher the stroke volume and thus also the blood
pressure. The increased blood pressure must not be
lowered here (up to an upper limit of systolic BP of
240mmHg), because otherwise the patient's cardiac
output will be lowered and he will be transferred into
shock!
• In obese patients (BMI > 30 kg/m2) the blood pressure
may only be measured with the wide (15-18cm) and
not with the normal (12-13cm) cuff, as otherwise in-
correctly too high blood pressure values are measured
• With the invasive BP measurement it is always impor-
tant to ensure that the pressure transducer (see also
page 37) is at heart level.
-- pressure transducer too low: BP ↑ ("hypertensive
crisis")
-- pressure transducer too high: BP ↓ ("shock")
Symptoms
• angina pectoris (frequent; possibly even troponin
elevation, even without CHD!)
• headaches
• nausea
• epistaxis
• dizziness
• confusion
• loss of consciousness up to coma (Think of cerebral
hemorrhage [especially for oral anticoagulation in me-
dication]!)
• neurological deficits (pareses, paraesthesias)
• visual field disturbances (scotomas), deterioration of
visual acuity
• hypertensive encephalopathy (PRES: posterior rever-
sible encephalopathy syndrome; see page 540)
• dyspnea
• cyanosis
Medication (drugs)
cave calcium antagonists: often
excessive BP decrease and
contraindicated in angina pectoris
and myocardial infarction!

Nitroglycerin (Perlinganit)
• dosage
-- puff: 0.4 mg
-- capsule: 0.8 mg
-- perfusor: 50 IE/50ml; 1-5 ml/h
• contraindications:
-- severe valve stenosis, HOCM
-- right ventricular myocardial infarction (in every
third inferior wall infarction!)
-- intake of phosphodiesterase 5 inhibitors (due to the
increased risk of a pronounced drop in blood pres-
sure): :
◦◦ sildenafil (Viagra, Revatio; in the last 24h)
◦◦ vardenafil (Levitra; in the last 24h)
◦◦ tadalafil (Adcirca; in the last 48h)
-- increased intracranial pressure (ICP; because nitro-
glycerin increases the intracranial pressure)
Calcium antagonists
• Dihydropyridines are used to lower blood pressure:
These lead to reflex tachycardia with consecutively
reduced coronary perfusion (including intracoronary
"steal" phenomenon), so that they are contraindicated
in acute coronary syndrome (up to 4 weeks later).
• representatives:
-- nifedipine (Adalat 5mg/ 10mg; cave excessive BP
drop, i.a. cardiac and cerebral ischemia are descri-
bed as side effects)
-- nitrendipine (Bayotensin vial 1ml = 5mg)
-- clevidipin (Cleviprex)
◦◦ a new ultra-short-acting (T1/2 only 1 min) calcium
antagonist of the dihydropyridine type
◦◦ fat-soluble (lipid emulsion), so that a separate ac-
cess is necessary
◦◦ dosage:
▪▪ lipid emulsion 0,5 mg/ml
▪▪ start with 4 ml/h (2 mg/h), then the dose can be
doubled every 90 seconds up to a maximum of
64 ml/h (32 mg/h)
Urapidil (Ebrantil)
• α1-receptor antagonist
• 1 amp. = 50 mg
• 10-25 mg slowly i.v.
• perfusor: 5 mg/ml; 1-6 ml/h
• advantages:
-- no reflex tachycardia
-- no increase in intracranial pressure (ICP)
Clonidine (Catapresan)
• α2-rezeptor agonist (inhibition of the release of norad-
renaline in the CNS [Locus coeruleus])
• 1 amp. = 0.15 mg
• perfusor: 0.03 mg/ml; 0.5-3 ml/h
• if necessary combination with dihydralazine (Ne-
presol)
• side effects:
-- bradycardia (contraindicated at heart rate < 50/min;
catecholamines are ineffective in clonidine-related
bradycardia → temporary pacemaker necessary!)
-- dry mouth
-- sedation
-- seizure threshold ↓
Dihydralazine (Nepresol)
• a peripheral vasodilator with direct attack on the
smooth muscles
• 1 amp. = 25 mg dry substance
• bolus: 5 mg i.v.
• perfusor: 1 mg/ml → 1-16 ml/h
• very effective in combination with clonidine
• only approved drug for hypertensive crisis in pregnan-
cy (indication: i.a. pre-eclampsia, eclampsia)
• side effects:
-- angina pectoris (frequent!)
-- reflex tachycardia
-- headache, dizziness, nausea
-- drug-induced SLE (systemic lupus erythematosus;
especially with long-term use)
Sodium nitroprusside (SNP; Nipruss)
• indication: therapy-refractory hypertensive crisis
• NO-releasing substance
• very short duration of action
• perfusor: 1 amp. (= 60 mg); 0.6-2.4 mg/h
• always invasive BP measurement
• light protection
• contraindication: increased intracranial pressure (ICP;
because SNP [just like nitroglycerin] increases the int-

Cardiology 537
 racranial pressure [ICP])
• for further details see page Seite 407
Emergency therapy only necessary if
symptoms are present, otherwise
initiation / increase of oral therapy is
sufficient!
Memo
Excursus: Pheochromocytoma
538 Cardiology
Definition
• catecholamine-producing (adrenaline, noradrenaline)
neuroendocrine tumor of the chromaffin tissue (mostly
of the adrenal medulla)
• etymology: Greek "phaios chroma": dark color (In
1912, the Berlin pathologist Ludwig Pick described
for the first time a tumor of the adrenal medulla which,
after adding a fixation solution containing chromate,
showed a strikingly dark color.)
• a secondary form of hypertension
• high cardiovascular risk (potentially fatal due to cate-
cholamine excess)
• hormonal activity:
-- 2/3 adredaline and 1/3 noradrenaline
-- extraadrenal pheochromocytomas above the dia-
phragm: only noradrenaline
-- malignant pheochromocytomas: also dopamine
• size mostly > 2cm
• „90%-tumor“ :
-- localization:
◦◦ 90% in the adrenal medulla (intraadrenal), 10% in
paraganglia (extraadrenal [paragangliomas; more
common in children]) the trunk or intra-abdominal
organs (e.g. urinary bladder)
◦◦ 90% one-sided, 10% both-sided (especially in fa-
milial forms)
-- dignity: 90% benign, 10% malignant (more frequent
in extraadrenal locations [in 40%], familial forms [in
25%] and in children)
-- genesis: 90% sporadic, 10% familial (MENII syndro-
me [Sipple´s disease; additionally medullary thyro-
id carcinoma, primary hyperparathyroidism], von-
Hippel-Lindau syndrome, neurofibromatosis type I
[Recklinhausen], familial paraganglioma)
Epidemiology
• prevalence: 0.2% of all hypertensive patients
• incidence 1:100000
• 5% of all incidentaliomas
• mostly 40.-50. age
• m=w
Symptoms
• arterial hypertension ( leading symptom)
-- difficult to adjust ("therapy refractory")
-- types:
◦◦ persistent(60%)
◦◦ paroxysmal (40%)
-- often fluctuating blood pressure values
-- often also orthostatic hypotension (despite otherwi-
se existing hypertension)
-- often already severe retinopathy
-- typically paradoxical rise in blood pressure on
β-blockers (Due to the constantly released cate-
cholamines, almost all β-receptors are already oc-
cupied. If the remaining β-receptors are blocked
by β-blockers, the vasodilation via β2-receptors is
completely eliminated and vasoconstriction via the
α-receptors can now fully penetrate, so that the
 blood pressure can rise.)
-- paradoxical blood pressure reactions during anest-
hesia or surgery
-- missing reduction of the blood pressure during the
night ("non-dipper") in the 24h long-term blood pres-
sure measurement
• tachycardia
• paplitations
• headache
• pallor (especially in the face)
• sweating (hyperhidrosis)
• nervousness, fear, panic (misdiagnosis: anxiety disor-
der, panic disorder)
• angina pectoris
• tremor
• nausea, vomiting
• abdominal pain
• weight loss
• hyperglycemia (diabetes mellitus)
• leukocytosis
classic triad (sensitivity of 90%,
specificity 65%) in pheochromo-
cytoma: headache, palpitations,
sweats!
Complications
• hypertensive crisis ("pheochromocytoma crisis"; cate-
cholamine excess); trigger:
-- palpation of the abdomen (i.a. massage), manipu-
lation at the tumor (e.g. intraoperatively), increase
of intra-abdominal pressure (coughing, sneezing,
compression of the tumor by an enlarged uterus in
pregnancy [DD pre-eclampsia!], labor pain)
-- operations, anesthesia
-- drugs: mainly β-blockers, clonidine, tricyclic antide-
pressants, MCP, steroids, contrast media
• cardiogenic shock: The massive increase in blood
pressure leads to an increase in the afterload and, ac-
cording to Laplace's law (T = P x r/2d), to an increase
in wall tension. The higher the wall tension, the lower
the contractility, so that patients in the context of a
pheochromocytoma crisis can have a massive reduc-
tion in the ejection fraction (EF <20%). As a result of
the increased wall tension, the oxygen consumption is
increased: Myocardial ischemia occurs (especially of
the small vessels).
• Tako-Tsubo cardiomyopathy
• acute abdomen
• malignant degeneration
-- border-crossing growth
-- especially with a size > 5cm
-- metastases especially in the skeleton, liver, CNS,
pleura, kidneys
Diagnosis
• anamnesis, clinical examination
• laboratory
-- serum
◦◦ preanalytics:
▪▪ bed rest for 30 minutes beforehand (otherwise
pseudo-pheochromocytoma), insert i.v. access
30 minutes beforehand
▪▪ blood sampling while lying
▪▪ sober
◦◦ determination of the metanephrines (Metane-
phrines are methylation products of the cate-
cholamines. The metanephrine of adrenaline is
metaphrine, the metanephrine of noradrenaline
is normetaphrine. Metanephrines have a signi-
ficantly longer half-life than catecholamines.); if,
as an exception, a hypertensive crisis is present,
then additional determination of the catecholami-
nes (adrenaline, noradrenaline; detection is much
more difficult due to the very short half-life, and
also relatively expensive)
◦◦ interpretation:
▪▪ > 2000 ng/l: pathological
▪▪ < 500 ng/l: normal
◦◦ interferences: tricyclic antidepressants, L-DOPA,
theophylline, sympathomimetics, α-blockers, clo-
nidine, nicotine (no smoking), coffee, alcohol
◦◦ permitted blood pressure drugs: ACE inhibitors,
angiotensin II antagonists, diuretics, calcium an-
tagonists
-- urine: 24-hour urine collection (no longer absolutely
necessary)
◦◦ acidified with 10ml of 25% hydrochloric acid after
the first portion
◦◦ two measurements recommended
◦◦ determination:
▪▪ catecholamines (adrenaline, noradrenaline)
▪▪ metanephrines (metaphrin, normetaphrin)
▪▪ note: Vanilin-mandelic acid is no longer neces-
sary (often false positive [e.g. in panic attacks])
◦◦ standard values:
▪▪ adrenaline: < 20 µg/d
▪▪ noradrenaline: < 110 µg/d
▪▪ metanephrines: < 1000 µg/d
◦◦ interpretation (catecholamines):
▪▪ > 200 ng/l: pathological
▪▪ < 50 ng/l: normal
◦◦ interferences and permitted blood pressure drugs:
as for the determination in the serum
-- confirmatory test (especially in the case of borderline
findings): clonidine inhibition test
◦◦ As a central α2-agonist, clonidine is a central sym-
patholytic agent, so that normally (in healthy peo-
ple) the catecholamine levels drop after administ-
ration of clonidine (suppression test).
◦◦ procedure (monitoring): collect urine from 7 a.m.
to 7 p.m., at 7 p.m. 0.3mg (300µg) clonidine p.o.
(always take the non-retarded form), then go on
collecting from 7 p.m. to 7 a.m.
Cardiology 539
 ◦◦ determination of the catecholamines in the urine
(before and after administration of clonidine); al-
ternatively or additionally, determination of cate-
cholamines and metanephrines in the serum befo-
re and after administration of clonidine
◦◦ interpretation:
▪▪ decrease of catecholamines > 50%: exclusion
▪▪ no decrease (< 50%): pheochromocytoma (of-
ten even increase!)
• imaging (for localization)
-- sonography
-- sectional imaging: CT, MRI
-- nuclear medicine imaging (only if no clear localizati-
on is possible in the sectional imaging; especially for
the detection of extraadrenal pheochromocytomas
and metastases)
◦◦ scintigraphy
▪▪ MIBG (metaiodobenzylguanidine; fisrt choive)
▪▪ somatostatin receptor (octreotide)
◦◦ PET (DOPA), SPECT
• if necessary genetic analysis (in the case of familial
forms)
• note: A biopsy is contraindicated because it can lead
to the release of catecholamines with a subsequent
pheochromocytoma crisis
Pheochromocytoma diagnostics
(screening): determination of the
metanephrines in the serum sufficient
(no more 24h urine collection necessa-
ry)
Fig. 771  CT abdomen: huge pheochromocytoma of the
right adrenal gland
Differentialdiagnoses
• other forms of secondary hypertension
• hyperthyroidism
• intoxication with amphetamine / cocaine
• anxiety or panic disorder
• withdrawal (e.g. alcohol)
• neuroblastoma (especially in children)
• pre-eclampsia (during pregnancy)
540 Cardiology
Therapy
• surgery: adrenalectomy
-- mostly laparoscopic
-- "no touch" technique (cave triggering a pheochro-
mocytoma crisis by manipulating at the tumor with
the subsequent release of catecholamines)
-- Sufficient α-blockade must be carried out preopera-
tively. The patient should be admitted to the hospital
7-10 days before the planned surgery.
◦◦ agent of choice: phenoxybenzamine (dibenzyran;
a non-selective α-blocker); dosage: start with 2 x
10mg daily p.o., then increase to 100-150mg dai-
ly (in 4 doses; dailye increase by 20-30mg); the
aim is to have orthostatic hypotension (target BP:
slightly hypotonic) and swelling of the nasal mu-
cosa ("blocked" nose; vasodilation of the vessels
of the nasal mucosa as a typical side effect of the
adequately dosed α-blocker).
◦◦ alternative α-blockers: doxazosin, prazosin
◦◦ β-blockers are only administered if there is tachy-
cardia and only after α-blockade.
◦◦ adequate volume administration (high volume re-
quirement due to vasodilation; e.g. 2000ml crystal-
loid daily over three days preoperatively)
-- renewed determination of the metanephrine in the
serum 2 weeks postoperatively, then annually (for
the question of a relapse [relapse rate: 15%])
• drugs
-- phenoxybenzamine (Dibenzyran; non-selective
α-blocker)
-- α- before β-blockade: The high blood pressure is
mainly caused by the vasoconstriction as a result of
the stimulation of the α-receptors. If you now give
β-blockers (before an α-blocker), the inotropy decre-
ases with already existing massive vasoconstriction
and decompensation occurs. The same applies to
intoxication with amphetamines and cocaine.
-- calcium antagonist
-- in hypertensive crisis:
◦◦ phentolamine (non-selective α-blocker) 2-5mg i.v.
◦◦ sodium nitroprusside (SNP; Nipruss)
• malignant pheochromocytoma
-- surgical (to reduce the tumor mass)
-- nuclearmedicinical: Iodine-131-MIBG
-- pharmacological: chemotherapy (Averbuch scheme
[cyclophosphamide, vincristine, dacarbazine])
Excursus: PRES (posterior reversible en-
cephalopathy syndrome)
Definition
• syn.: hypertensive encephalopathy
• a syndrome (especially seizures, visual impairment)
that is associated with radiological (MRI) changes pos-
teriorly and is reversible (benign course)
• classic trigger: hypertensive crisis
• first described by Hinchey in 1996 in the New England
Journal of Medicine
• a disease of the endothelium of the small brain vessels
 (vasogenic edema with capillary leakage; exceed of
the upper cerebral autoregulation limit)

Epidemiology
• average age: 35 years
• w > m

Etiology
• hypertensive crisis (classic!)
• eclampsia, pre-eclampsia
• drugs (i.a. cocaine, amphetamines)
• immunosuppressants (especially tacrolimus, ciclospo-
rin), cytostatics (i.a. angiogenesis inhibitors [bevaci-
zumab, sunitinib, sorafenib])
• status post transplantation
• kidney disease
Fig. 772  MRI of a patient with PRES: Hyperdense lesions
• blood transfusion are visible posteriorly (courtesy of Prof. Dr. Gerhard F. Ha-
• Guillain-Barré-Strohl syndrome mann, Medical Director of the Clinic for Neurology, clinic
• acute intermittent porphyria (AIP) Wiesbaden [Germany]).
• tetanus

Symptoms
• seizures (89%)
• visual impairment, possibly cortical blindness (rever-
sible
• nausea, vomiting
• headaches
• disturbance of consciousness
-- quantitative (somnolence, coma)
-- qualitative (delirium)

hypertensive crisis with seizure and

visual impairment: PRES!

Complications
• status epilepticus
• intracranial hemorrhage

Diagnostics
• cerebrospinal fluid puncture: obligatory to exclude
other diseases
• imaging:
-- CCT: posterior hypodensities (in 50% unremarkable)
-- MRI:
◦◦ means of choice
◦◦ typically posterior changes (bilateral parieto-occi-
pital)

Cardiology 541
Angiology

PULMONARY EMBOLISM
Definition
• acute obstruction of the pulmonary tract with a drag-
ging thrombus (= embolus)
• thrombus mostly from pelvic / leg veins (deep vein
thrombosis)
Guidelines
• international (Europe): ESC-Guidelines on the diagno-
sis and management of acute pulmonary embolism
2019
• national (Germany): S2k-guideline diagnostics and
therapy of deep vein thrombosis and pulmonary em-
bolism 2015 (lead: German Society of Angiology - So-
ciety of Vascular Medicine)
Epidemiology
• incidence 150-200/100000
• 8 x higher incidence at age > 80 years
• estimatation: approx. 350000 pulmonary embolisms
per year in Germany (more frequent than myocardial
infarction [approx. 280000 per year]), of which approx.
40000 deaths
• overlooked in 70% of clinical cases (post-mortem stu-
dies, i.a. VITAE study [Cohen et al, Thromb Haemost
2007]), only 1/3 of all pulmonary embolisms are diag-
nosed before death
• the most common undiagnosed cause of death in hos-
pitalised patients
• average age: 62 years
• w > m (In the age between 15-55 years, twice as many
women as men die from pulmonary embolism [Barco
et al, Lancet Respir Med 2020; probably due to oral
contraception]!)
544 Angiology
• decrease in lethal pulmonary embolisms
• 10% of all SCD (sudden cardiac death
• second most frequent cause of cardiovascular arrest
(after myocardial infarction
• third most common cardiovascular disease (after myo-
cardial infarction and stroke)
Pathophysiology
• The increase in pressure in the small circulatory sys-
tem increases the pulmonary arterial pressure (PAP)
and thus the right ventricular afterload.
• An increase in pulmonary pressure only occurs when
more than 50% of the entire pulmonary artery tract is
occluded. This is almost never the case. However, pul-
monary embolism releases mediators (e.g. thrombo-
xane, serotonin, leukotrienes) which lead to pulmonary
vasoconstriction and thus to an increase in pulmonary
pressure. The amount of cytokine release cannot be
measured in everyday clinical practice. Therefore, the
extent of the occlusion of the pulmonary artery tract in
the CT does not correlate sufficiently with the degree
of severity!
• The right ventricle is very sensitive to pressure (PAP;
afterload), but not very sensitive to volume (preload).
The increased right ventricular afterload leads to a
reduced right ventricular ejection (obstructive shock;
acute right heart failure).
• The increased pressure in the right ventricle causes a
septum shift to the left side (Bonnheim effect) with the
result that the left ventricle can no longer fill properly
(severe diastolic dysfunction of the left ventricle). The
left ventricular preload decreases and the left ventri-
cular ejection is reduced. As a result, there is a drop
in systemic blood pressure, reduced perfusion of the
organs and finally cardiogenic shock.
• desynchronization of the ventricles (interventricular
asynchrony) by the development of a right bundle
branch block
• reduced coronary perfusion pressure (Due to the in-
creased pressure in the right atrium, the inflow of coro-
nary veins via the coronary sinus is reduced; coronary
perfusion pressure = DBP - RA pressure) → aggravati-
on of right heart failure
Fig. 773  Bonnheim effect (syn.: LV-RV-crosstalk): The right
ventricular load causes a septum shift to the left. Therefore,
the left ventricular filling is reduced and the left ventricular
ejection fraction is decreased consecutively (interventricu-
lar dependence of both ventricles over the common sep-
tum!) [14]
Risk factors
• immobilization
-- bedriddenness
-- paralysis (e.g. after stroke)
-- heart failure, myocardial infarction
-- surgery (especially in the first two postoperative
weeks; especially hip / knee TEP
-- trauma (especially fractures of the lower extremities,
injury to the spinal cord)
• obesity
• older age (> 75 years)
• nicotine abuse
• thrombocytosis
• increased blood viscosity (e.g. polyglobulism, forced
diuresis)
• oral contraception ("pill"; risk of thromboembolism in-
creased by 6 times; main risk factor in women of child-
bearing age), pregnancy (especially in the last trimes-
ter), postpartum, in vitro fertilization
• nephrotic syndrome (proteinuria [> 3.5 g/d] + hypopro-
teinemia + hyperlipidaemia + edema; increased risk of
thromboembolism due to antithrombin deficiency)
• malignancies
• infections, i.a. SARS-CoV-2: Here there is an exces-
sive activation of the coagulation (hypercoagulability;
CIC: COVID-19 associated coagulopathy). Every third
patient suffers a thrombotic complication (especially
pulmonary embolism; Klok et al, Thrombosis Research
2020)!
• hematological diseases (e.g. polycythaemia vera, es-
sential thrombocythemia, paroxysmal nocturnal hemo-
globinuria)
• blood transfusion, administration of erythropoietin
• thrombophilia
Thrombophilia
Parameters
• APC resistance (No.1)
-- syn.: Factor V Leiden mutation (FVL; named after
the Dutch city of Leiden, where the mutation was first
described in 1994)
-- Factor V can no longer be inactivated by protein C
due to a genetic change (point mutation in the fac-
tor V protein on chromosome 1, in which arginine
is replaced by glutamine at position 506). There is
resistance to activated protein C (APC).
-- autosomal-dominant inheritance:
◦◦ heterozygous (90%; 5% of all people in Europe
[note: The Factor V Leiden mutation is almost non-
existent in America, Africa and Australia!]; risk of
thromboembolism increased by 5-10 times)
◦◦ homozygous (10%; 0.02-0.1% of all people in Eu-
rope; risk of thromboembolism increased by 50-
100 times)
-- procedure:
◦◦ asymptomatic (i.e. no thombembolic event): no
prophylaxis
▪▪ prophylaxis only in risk situations (e.g. immo-
bilization, surgery, serious infectious diseases,
air travel; note: In the case of the heterozygous
form, prophylaxis during pregnancy is only ne-
cessary in the presence of additional risk factors
[e.g. obesity, status after Thromboembolism]. In
case of the homozygous form, however, prophy-
laxis (with LMWH s.c.) must always be perfor-
med during pregnancy (up to the sixth postpar-
tum week).
▪▪ control of risk factors (especially smoking, obe-
sity; note: oral contraceptives are possible and
not contraindicated for the heterozygous factor
V Leiden mutation, but are contraindicated for
the homozygous form.)
◦◦ symptomatic (i.e. previous thombembolic event)
▪▪ heterozygous: associated with no increased risk
of recurrence and therefore not a reason for pro-
longed or even lifelong anticoagulation
▪▪ homozygous: lifelong anticoagulation
• prothrombin mutation (No.2; syn.: FII mutation [pro-
thrombin = factor II])
-- The mutation (G20210A [point mutation on chromo-
some 11, in which guanine is replaced by adenine in
position 20210]) leads to an increased formation of
prothrombin and thus activation of coagulation via
thrombin. Measuring the prothrombin level in the
serum alone is not sufficient, since the prothrombin
level can also be normal especially in the heterozy-
gous form. A genetic analysis is necessary.
-- in contrast to the factor V Leiden mutation, not only
an increased risk of venous, but also of arterial
thromboembolism (myocardial infarction, stroke)
-- types:
◦◦ heterozygous
▪▪ 2% of all people; risk of thromboembolism incre-
ased by 3-4 times
▪▪ associated with no increased risk of recurrence
and therefore not a reason for prolonged or
Angiology 545
 even lifelong anticoagulation
▪▪ in 20% associated with a heterozygous factor V
Leiden mutation (risk of thromboembolism then
increased by 30 times)
◦◦ homozygous (0.008% of all people [very rare-
ly]; risk of thromboembolism increased by 15-20
times)
• antithrombin deficiency (i.e. activity < 60%; Antithrom-
bin is the strongest inhibitor of the coagulation system!
highest risk of thromboembolism among all thrombo-
philia! Antithrombin is often reduced in the acute phase
of venous thromboembolism.)
-- congenital (rare)
◦◦ homozygous (very rare; often fatal neonatal
thromboembolism)
◦◦ heterozygous (0.16% of all people; risk of throm-
boembolism increased by 20-50 times)
▪▪ type I: antithrombin concentration reduced
(most common; quantitative deficiency)
▪▪ type II: Antithrombin concentration not reduced
(only the activity; qualitative deficiency)
-- acquired (often)
◦◦ acute thromboembolism
◦◦ therapy with heparin
◦◦ liver disease (decreased synthesis in the liver)
◦◦ consumption: sepsis, DIC, shock, surgery, myo-
cardial infarction
◦◦ loss: nephrotic syndrome, exudative enteropathy
(Gordon´s disease)
• protein C/S deficiency (note: Protein S is physiologi-
cally reduced during pregnancy, and protein S and C
are often also reduced in the acute phase of a venous
thromboembolism)
-- congenital (less often)
-- acquired (more often)
• antiphospholipid syndrome; parameters: lupus antico-
agulant, anti-cardiolipin antibodies, anti-β2-glycoprotein
antibodies Classification (according to risk)
• HIT II (relevant if the patient has previously received • low-risk thrombophilia
heparin [especially UFH]; one of the strongest throm- -- heterozygous factor V Leiden mutation
bophilia ever!)
-- heterozygous prothrombin mutation
• Blood group non-0 (the most common congenital
• high-risk thrombophilia
thrombophilia): Patients with blood group 0 have phy-
siologically lower levels of von-Willebrand factor and -- homozygous factor V Leiden mutation
factor VIII. Therefore, patients with a different blood -- homozygous prothrombin mutation
group (non-0, i.e. A, B or AB) have a two times hig- -- combination of heterozygous factor V Leiden mutati-
her risk of thromboembolism than patients with blood on and heterozygous prothrombin mutation
group 0. -- deficiency (pronounced) of inhibitors
• possibly homocysteinemia (MTHFR mutation [methy- ◦◦ antithrombin
lene tetrahydrofolate reductase]; homocysteine > 15 ◦◦ protein C, protein S
μmol/l; no longer recommended) -- antiphospholipid Syndrome
• possibly plasminogen activator inhibitor mutation (no
longer recommended)
Genetic Diagnostics Act (since
2009: written informed consent
required!

546 Angiology
Assessment Excursus: Deep vein thrombosis (DVT;
• no more general screening recommended any lon- leg)
ger
• very high costs (5% of the total laboratory costs) Localization
• no association with an increased risk of recurrence; • levels
studies: i.a.
-- iliacal vein (10%)
-- MEGA study (Coppens et al, J Thromb Haemost
-- femoral vein (50%)
2008): no difference in recurrence rate of thrombosis
with or without thrombophilia screening -- popliteal vein (20%)
-- RIETE register (RIETE: registry of patients with ve- -- lower leg veins (20%)
nous thromembolism), Roldan et al, Thromb Res • side
2009: 21367 patients with venous thromboembolism -- left: 2/3 (disturbed drainage at the junction of the iliac
(VTE), in 21% thrombophilia diagnostics was con- vein and the iliac artery through the existing ridge
ducted, in 32% thrombophilia has been diagnosed; in the iliac vein [May-Thurner syndrome; 20% of all
thrombophilia rate in patients with provoked venous adults, mostly women; descending thrombosis])
thromboembolism was as high as in patients with -- right: 1/3
unprovoked (idiopathic) VTE • spreading
-- Lijfering et al, Circulation 2010 -- ascending (most common)
• indicationen (only): -- descending (rarely; usually originating from the left
-- age < 45 yeras (In later life, thrombophilia is no lon- common iliac vein)
ger a relevant cause of VTE.) -- transfascial (transition from a superficial to a deep
-- positive family history vein thrombosis)
-- recurrence of VTE
-- recurrent abortions (especially antiphospholipid syn-
drome)
-- unusual localization (e.g. upper extremity, portal vein
thrombosis, sinus vein thrombosis)
• no (general) significance
• no significance at all for the diagnosis and initial thera-
py of acute venous thrombosis, can only influence the
duration of anticoagulation in very few cases

Timing
In the initial phase of an acute venous thromboembolism,
thrombophilia screening is completely irrelevant (the only
exception: antiphospholipid syndrome [APS]: Here no
NOAC should be given [TRAPS study 2018: increased
thromboembolism with rivaroxaban compared to war-
farin]. However, you do not need to rule out APS with
every venous thromboembolism before starting a NOAC
therapy, but only if you really have a strong suspicion of
APS [especially arterial thrombosis, thrombopenia, PTT
prolongation, known systemic lupus erythematosus]).
Anticoagulation must be carried out for three months
anyway. In the initial phase, the inhibitors (antithrombin, Fig. 774  deep vein thrombosis of the right leg
protein C / S) are often reduced, which can lead to misin-
terpretation. The thrombophilia screening should only be
performed after three months. Oral anticoagulation falsi-
fies the measured values, so that this has to be paused
(necessary break: for NOAC 2 days, for VKA 10 days
[in case of a high risk of recurrence LMWH for bridging
as soon as INR < 2; LMWH do not affect the measured
values.]).

Angiology 547

Fig. 775  thrombosis of the proximal superficial femoral
vein: lack of compressibility, no flow in the color Doppler,
direct detection of the thrombus in the B mode
Fig. 776  thrombosis of the popliteal vein (first cross sec-
tion, then longitudinal section): lack of compressibility, no
flow in the color Doppler, direct detection of the thrombus
in the B mode
Differential diagnoses
• Baker's cyst
-- named after the English surgeon William Morrant
Baker (1839-1896)
-- syn.: poplietal cyst
-- protuberance of the synovia in the hollow of the knee
-- location: medial
-- Connection to the joint space can be shown.
-- possibly with bleeding
-- can cause thrombosis of the popliteal vein due to
vascular compression
548 Angiology
-- therapy:
◦◦ mostly watch & wait
◦◦ puncture pointless (The cyst fills up again imme-
diately.)
◦◦ possibly surgery in case of vascular compression
• joint effusion
• torn muscle fibers, post-traumatic swelling
• hematoma (post-traumatic, post-operative)
• abscess
• tumor
• popliteal aneurysm (of the popliteal artery; in 60% of all
patients with abdominal aortic aneurysm)
• acute arterial occlusion of the lower limb (acute limb
ischaemia; 6P according to Pratt: pain, pallor, pulse-
lessness, paralysis, paresthesia, prostration)
• post-thrombotic syndrome (chronic venous insufficien-
cy)
• sciatica pain
• Sudeck´s disease
-- syn.: complex regional pain syndrome (CRPS)
-- especially post-traumatic, post-operative (e.g. after
knee surgery)
-- symptoms: pain, repeatedly cold leg (disturbed va-
somotion), swelling, skin changes, paralysis, hy-
pesthesia (similar to the 6P according to Pratt with
arterial occlusion!)
• Lymphedema
-- not indentable
-- positive Stemmer sign (also toes swollen)
Fig. 777  Baker's cyst in the hollow of the knee (poplitea;
different examples; in the second picture you can see the
connection to the joint space [arrow])
 -- cyanosis
-- cool / cold leg
-- missing foot pulses, possibly gangrene
• diagnostics
-- anamnesis, clinical examination
-- Doppler measurement of the occlusion pressure:
ABI (ankle brachial index) < 0.5 (critical ischemia)
-- duplex sonography of the arteries
-- if necessary CT angiography
• therapy
-- treatment of shock
-- full anticoagulation (especially unfractionated hepa-
Fig. 778  aneurysm of the popliteal artery (pulsatile flow in rin 10000E i.v.)
colour Doppler; here partially thrombosed)
-- immediate surgery (thrombectomy, fasciotomy)

Therapy
• full anticoagulation
-- LMWH
-- OAK (oral anticoagulation with VKA or NOAC)
• compression therapy
• possibly recanalizing measures (in the case of ilio-fe-
moral thrombosis) for the prophylaxis of a post-throm-
botic syndrome: thrombectomy
-- surgical
-- interventional (possibly combined with local lysis
[pharmaco-mechanical])

Therapy
DVT

Fig. 779  Most patients (60%) with a poplietal aneurysm

also have an abdominal aortic aneurysm (shown here; par-
tially thrombosed).
Bed rest in DVT
Complications (DVT)
• pulmonary embolism (10%)
• post-thrombotic syndrome )chronic venous insufficien-
cy; 50%)
• phlegmasia coerulea dolens
• Bed rest is not (any longer) necessary (i.a.
Phlegmasia coerulea dolens Aschwanden et al, Thromb Haemost 2001; S2k gui-
• definition deline 2015).
-- acute occlusion of all leg veins with edema formation • independent of:
and secondary compression of the arteries -- localization (pelvis, thigh or lower leg)
-- angiological or vascular surgery emergency (high -- morphology (floating, adherent)
amputation rate!) • only indication for bed rest (then with elevation of the
• symptoms leg) still in DVT: painful swelling of the leg to alleviate
-- strongest pain symptoms
-- leg swelling • Bed rest is harmful as it increases the recurrence rate!

Angiology 549

No more bed rest with DVT (regard-
less of localization or morphology)!
Compression therapy
• effects:
-- faster reduction of swelling → pain ↓
-- progression of DVT ↓
-- prophylaxis of post-thrombotic syndrome (most
important [main effect])
• phases:
-- initially elastic compression bandage with short-
stretch bandages until the swelling decreases (wrap-
ping the leg up to the groin; relatively prone to failure)
-- maintenance phase: then compression stocking of
class II (lifelong); note: classification of compression
classes according to the pressure (GZG norm [qua-
lity mark of the association of medical compression
stockings in Germany])
◦◦ compression class I: 18-21 mmHg
◦◦ compression class II: 23-32 mmHg
◦◦ compression class III: 36-46 mmHg
◦◦ compression class IV: > 49 mmHg
• only on the affected leg (not on both sides)
• lower leg stocking (calf compression stocking)
mostly sufficient (also for thigh / pelvic vein thrombosis)
• contraindications:
-- PAD (peripheral arterial disease; Doppler occlusi-
on pressure < 50mmHg; is unfortunately often igno-
red! always determine the Doppler occlusion pressu-
re before starting compression therapy!)
-- phlegmasia coerulea dolens
-- decompensated heart failure (The additional mobili-
zation of water from the legs can lead to pulmonary
edema and even cardiogenic shock.)
-- septic phlebitis, initial phase of erysipelas (first three
days)
-- polyneuropathy
◦◦ Due to the polyneuropathy, the patient has no pain
sensation and pressure ulcers or lacing can occur.
◦◦ however only a relative contraindication (possible
under close clinical control)
• without evidence of DVT in pulmonary embolism
no compression therapy in intensive care unit (too time
consuming
• assessment:
-- meta-analyses:
◦◦ Cochrane Database of Systematic Reviews 2014
(Graduated compression stockings for prevention
of deep vein thrombosis during a hospital stay):
reduction of the risk for deep vein thrombosis by
one third (However, the meta-analysis studies
were relatively old and LMWH were only used in
one study.)
◦◦ Metaanalysis of randomized trials comparing com-
bined compression and anticoagulation with either
modality alone for prevention of venous thrombo-
embolism after surgery; Zarebra et al, Br J Surg
550 Angiology
2014: reduction of the risk of deep vein thrombosis
by half (49%)
◦◦ Berntsen et al, AJM 2015 (see box)
-- studies:
◦◦ reduction of the incidence and severity of post-
thrombotic syndrome by 50% (i.a. Bandjes et al,
Lancet 1997; Prandoni et al, Ann Int Med 2004)
◦◦ CLOTS study (CLOTS Trials Collaboration, Lan-
cet 2009): Compression stockings do not reduce
the risk of thrombosis in stroke patients.
◦◦ A further, but often criticized study (SOX study
[see box]) could not prove any benefit of compres-
sion stockings after deep vein thrombosis.
-- S2k guideline 2015: still clear recommendation for
(early) compression therapy; note: not recommen-
ded for deep vein thrombosis of the upper extremity
(Kearon et al, Chest 2012: no benefit)
meta-analysis
Compression stockings for preventing the post-thrombotic
syndrome in patients with deep vein thombosis
Berntsen et al, AJM 2015
• 1418 patients (5 RCT) with deep vein thrombosis
• results: compression stockings
-- no reduction of incidence or severity of post-throm-
botic syndrome
-- no reduction of recurrence rate of deep vein throm-
bosis
-- no reduction of mortality
SOX study
Compression stockings to prevent post-thrombotic syn-
drome: a randomised placebo-controlled trial
Kahn et al, Lancet 2013
• multicenter randomised placebo-controlled study
• 806 patients with deep vein thrombosis; for 2 years:
-- 410 patients: genuine compression stockings (30-40
mmHg)
-- 396 patients: placebo compression stockings (i.e. sto-
ckings without compression effect [< 5 mmHg])
• results: genuine compression stockings
-- no reduction of incidence or severity of post-throm-
botic syndrome
-- no reduction of recurrence rate of deep vein throm-
bosis
-- no reduction of mortality
• critical remarks:
-- poor compliance (only 56%)
-- doubts about a sufficiently controlled study design
Therapy of superficial leg vein thrombosis
• POST study (Decousus et al, N Engl J 2010)
-- in 30% deep thrombosis (transfascial spreading)
-- in 4% pulmonary embolism
• The therapy of the superficial thrombosis is carried out
in the same way as the thrombosis of the deep veins if
it is a thrombosis of a trunk vein (great / small saphe-
nous vein) and
-- length of the thrombus > 5cm or
-- distance of the thrombus < 3cm from the mouth val-
ve
• Otherwise, patients with superficial leg vein thrombo-
sis should receive for 45 days:
-- fondaparinux (Arixtra) 1 x 2,5mg s.c. (CALISTO stu-
dy [see box]) or
-- rivaroxaban (Xarelto) 1 x 10mg (SURPRISE studie
[Beyer-Westendorf et al, Lancet 2017]: Rivaroxaban
1 x 10mg versus fondaparinux 1 x 2.5mg not inferior)
• muscle vein thrombosis: LMWH + compression thera-
py for 10 days
CALISTO study
Fondaparinux for the Treatment of Superficial-Vein Throm-
bosis in the Legs
Decousus et al, N Engl J 2010
• multicenter, randomised, double-blind study
• CALISTO: Comparison of Arixtra in Lower Limb Superfi-
cial Vein Thrombosis with Placebo
• 3002 patients with superficial leg vein thrombosis
-- fondaparinux 1 x 2,5mg (i.e. prophylactic dosage) s.c.
for 45d
-- placebo
• result: fondaparinux → significant reduction in the
primary composite endpoint of death, deep vein throm-
bosis, and pulmonary embolism
Fig. 780  thrombosis of the great saphenous vein (arrow)
Symptoms
• dyspnea (85%; typically sudden onset)
• chest pain (75%; angina pectoris: the coronary veins
in the coronary sinus flow into the right atrium. If the
pressure is increased there, the drainage into the tight
atrium is reduced [coronary perfusion pressure = DBP
- RA pressure] and angina pectoris occurs. Therefo-
re, pulmonary embolisms usually leads only to angina
pectoris if there is also a right ventricular dysfunction.
Peripheral pulmonary embolism can lead to chest pain
through pleuritic complaints [increase in inspiration].)
• tachypnea (respiratory rate > 20/min; 88%)
• tachycardia (very sensitive sign)
• syncope (14%)
-- almost only in central pulmonary embolism
-- independent of hemodynamic instability
-- Pulmonary embolism is a frequent cause of syncope:
The incidence of pulmonary embolism as a cause of
syncope was reported in earlier studies (Sarasin et
al, Am J Med 2001; Soteriades et al, N Engl J 2002)
to be 5-10%. In the PESIT study (Prandoni et al, N
Engl J 2016 [see box]) every sixth patient (17%)
admitted to a hospital for diagnostic evaluation of a
syncope had a pulmonary embolism! In a retrospec-
tive observational study (Constantino et al, JAMA In-
tern Med 2018), however, pulmonary embolism was
found to be the cause in only 0.5-1% of all syncopes.
• pain during inspiration (indication of pleural involve-
ment; typical for peripheral pulmonary embolism)
• sweating
• fever (7%)
• hemoptysis (30%) in lung infarction (with additional left
heart failure)
• cough (20%)
• cyanosis (18%)
• jugular vein congestion
Angiology 551
 ment; Ann Intern Med 2006)
• PERC score (according Kline et al, Clinical criteria to
prevent unnecessary diagnostic testing in emergency
PESIT study department patients with suspected pulmonary embo-
lism; J Thromb Haemost 2004)

Prevalence of Pulmonary Embolism among Patients Hos-

pitalized for Syncope
Prandoni et al, N Engl J 2016

• PESIT: Pulmonary Embolism in Syncope Italian Trial

• prevalence study from Italy (11 hospitals)
• 560 patients who were hospitalized for syncope evalu-
ation (first event) (note: Most [72%] of the initially 2584
patients were not hospitalized.)
-- 330 patients (59%): rule-out regarding pulmonary
embolism (Wells score ≤ 4P. and negative D-dimer),
i.e. no further diagnosis of pulmonary embolism was
carried out here
-- 230 patients (31%; either only positive D-dimer
[58.7%], only Wells score > 4P. [1.3%] or both [40%]):
chest CT or scintigraphy → in 42% pulmonary em-
bolism
• altogether pulmonary embolism in 17.3% ( in every
6th patient!), even in 12.7% of the patients who had a
supposed explanation for the syncope

syncope evaluation: generously

determine D-dimers; with increased
D-dimers generous chest CT to
exclude pulmonary embolism (Every
6th person has a pulmonary embolism!)

BASEL IX study

Prevalence of Pulmonary Embolism in Patients With Syn-

cope
Badertscher et al, JACC 2019

• prospective multicenter international prevalence study

• 1,397 patients presenting to the emergency department
with syncope
• altogether pulmonary embolism only in 1.4%, so that the
authors do not recommend a general pulmonary embo-
lism screening for syncope

Scores (see infoboxes)

• Wells score (according Wells et al, Use of a clinical
model for safe management of patients with suspected
pulmonary embolism; Ann Intern Med 1998)
• Geneva score (according Iles et al, Clinical experience
and pre-test probability scores in the diagnosis of pul-
monary embolism; QJM 2003)
• revised Geneva score (according Le Gal et al, Predic-
tion of pulmonary embolism in the emergency depart-

552 Angiology
 -- unsuitable (still too many movement artefacts)
-- not recommended (maybe optional for pregnant wo-
men)
-- PIOPED-III study (Repplinger et al, Emerg Radiol
2018): In this retrospective study, the MRI was found
to be equivalent to the CT.
• perfusion-ventilation scintigraphy
• pulmonary angiography (formerly "gold standard"; ra-
rely indicated today)

Clinical examination
• clinical signs of thrombosis
• tachycardia, possibly blood pressure ↓
• congested jugular veins
• accentuated 2nd heart sound
• systolic murmur p.m. 4th intercostal space right paras-
ternal (in case of tricuspid valve regurgitation; typically
increase in inspiration [Carvallo´s sign])
• pleural rub (in case of peripheral pulmonary embolism
with pleuritis)
• tachypnea
• Auscultation of the lungs: This is typically normal.A
conspicuous auscultation finding (e.g. expiratory spas-
ticity → exacerbated COPD; wet rattling noises basally
on both sides → pulmonary edema) clearly speaks
against the diagnosis of pulmonary embolism as the
cause of the dyspnea! Unfortunately, it is not uncom-
mon in everyday clinical practice that, for example,
despite wet rattling noises basally on both sides, just
because the D-dimers are increased, a chest CT is
performed to exclude a pulmonary embolism, in which
the cardiac decompensation then can be seen with
pleural effusions and a dilated inferior vena cava, what
is absolutely embarrassing! The argument that both
could be present at the same time, is also an expres-
sion of an irrational fear-laden medicine. If you have
discovered a pneumonic infiltrate in the chest X-ray of
a patient who has been admitted to hospital to find the
cause for fever, you do not perform an additional CSF
puncture to rule out meningitis either..

pulmonary embolism: normal

pulmonary auscultation findings!

Diagnosis
• anamnesis, clinical examination
• ECG
• laboratory
• blood gas analysis (BGA)
• chest X-ray
• ultrasound (sonography)
-- echocardiography
-- leg veins
-- lung
• computertomography
• MRI

Angiology 553
Fig. 781  Unfortunately, it happens again and again in eve-
ryday clinical practice that despite the clear genesis of the
dyspnea (as here cardiac decompensation with orthopnea,
leg edema and wet rattling noises over the lungs), a chest
CT (a so-called " D-Dimer-CT ") is performed to rule out
pulmonary embolism, in which one then sees the cardiac
decompensation with bilateral pleural effusions, as here.
important DD for pulmonary embolism
(PE): acute right ventricular myocardial
infarction (RVMI)
DD based on heart rate:
- RVMI: bradycardic
- PE: tachycardic
Laboratory
x 0.01 mg/l or age x 10 μg/l
-- This can increase the diagnostic value of the D-di-
mers (ADJUST-PE study [Righini et al, JAMA 2014]).
• D-dimers are not just a purely dichotomous decision
aid (positive / negative). The higher the value, the hig-
her the probability of a venous thromboembolism.
• biological half-life: 8 hours (D-dimers are normal again
two weeks after a venous thromboembolism.)
• not recommended with high clinical probability (be-
cause here the negative predictive value is low; even
dangerous here if the necessary imaging is omitted
due to a negative D-dimer and the pulmonary embo-
lism is overlooked; with high clinical probability ima-
ging is always indicated [even with negative D-dimer]!)
• algorithms (D-Dimer based diagnostic algorithms to
rule out pulmonary embolism):
-- YEARS algorithm (YEARS study: van der Hulle et al,
Lancet 2017; see infobox)
-- PEGeD algorithm (PEGeD study: Kearon et al, N
Engl J 2019; see infobox)

D-dimers: from age > 50 years age

adjustment (age in years x 10 μg/l

• D-dimers
• LDH­ ↑
• leukocytes ↑, thrombocytes­ ↑
• biomarker of right ventricular dysfunction (troponin,
pro-BNP)
• lactate: > 5 mmol/l → high-risk patient (i.a. Vanni et
al, Thorax 2015)

pulmonary embolism → additional

determination of: troponin, pro-BNP
(most sensitive for right ventricular
dysfunction), lactate

D-dimers
• fibrinogen-fibrin cleavage product
• determination by ELISA test (Enzyme-linked Immuno-
sorbent Assay)
• assessment:
-- high sensitivity: negative D-dimer → 95% no
venous thromboembolism (high negative predictive
value!)
-- low specificity (only 39%): There are numerous cau-
ses for a D-dimer increase (see infobox), therefore
D-dimers should never be part of a routine labora-
tory!
• cut-off value: 500 μg/l
• age-adjusted determination of the D-dimer cut-off va-
lue (The specificity of the D-dimer decreases with in-
creasing age. Therefore, an age adjustment should be
carried out from the age > 50 years. This is i.a. now
also recommended in the ESC guidelines 2019 [IIa].)
-- formula according to Douma: D-dimer cut-off = age

554 Angiology
 BNP is not increased (cut-off values: troponin T <
0.1 μg/l, troponin I < 0.4 μg/l; NT-proBNP < 500 pg/
ml [i.a. Becattini, Circulation 2007]):
◦◦ no right ventricular dysfunction
◦◦ good prognosis
-- low positive predictive value

BGA

• respiratory partial insufficiency (pO2↑, pCO2 normal/

low with spontaneous breathing [hyperventilation])
• completely unreliable (insufficient negative predictive
value and specificity [i.a. Rodger et al, Am J Respir Crit
Care Med 2000])
• ETCO2 (end-tidal CO2 concentration): If after intubation
of a dyspnoeic, hemodynamically unstable patient the
capnometry is low (e.g. ETCO2 5-10 mmHg), but the
capnogram is normal (i.e. the tube is correctly positi-
oned), this is typical for a pulmonary embolism!
• mechanical ventilation (This is how a pulmonary embo-
lism can be recognized intraoperatively, for example.)
-- decrease in end-tidal CO2 concentration (ETCO2):
caused by the decrease in the cardiac output due
to the pulmonary embolism (The pulmonary arteries
are clogged, so that less blood and thus less carbon
dioxide can be transported to the alveoli and thus
less carbon dioxide can be released into the bronchi
via the alveoli.)
-- increase in pCO2: Pulmonary embolism leads to an
increase in the dead space, i.e. the alveoli are still
ventilated, but no longer perfused. The increase in
dead space ventilation leads to a decrease in alve-
olar (effective) ventilation, so that pCO2 increases.
• determination of the alveolar dead space fraction
(AVDSF):
-- Bohr formula: AVDSF = (paCO2 - ETCO2) / paCO2
-- interpretation: An alveolar dead space fraction < 0.1
speaks against a pulmonary embolism (but does not
exclude it for sure).
Biomarkers of right ventricular dysfunc-
-- This requires on the one hand the paCO2 (BGA arte-
tion rial or alternatively also capillary), on the other hand
• parameters: the end-tidal CO2 concentration ETCO2: It can be
-- troponin determined not only in ventilated patients, but also in
-- pro-BNP (better than troponin [higher sensitivity spontaneously breathing patients (via a [tight-fitting]
[Vuilleumier et al, PLOSone 2016]; cut-off-value for ventilation mask with connector and measuring sen-
NT-pro-BNP: 600 pg/ml) sor). ETCO2 can be measured and displayed both
-- new: via the respirator and via the monitor (i.e. no respi-
◦◦ H-FABP (heart-type fatty acid-binding protein; cut- rator required at all). The end-tidal CO2 concentra-
off-value < 6 ng/ml → in 99% good prognosis) tion can now also be measured with the Lifepak 15
in spontaneously breathing patients using a special
◦◦ copeptin
nasal cannula.
◦◦ pro-ADM (adrenomedullin)
-- The alveolar dead space concentration can be de-
• evaluation: termided especially in pregnant women, when the
-- high negative predictive value; if troponin / pro- question of pulmonary embolism is raised, where an

Angiology 555
 alveolar dead space fraction < 0.1 in connection with
an inconspicuous finding in leg vein duplex sonogra-
phy makes a pulmonary embolism (very) unlikely.
-- studies:
◦◦ Roy et al, BMJ 2005
◦◦ Verschuren et al, J Thromb Haemostas 2009
◦◦ Ozlem et al, Am J Emerg Med 2010

Fig. 782  Measurement of end-tidal CO2 concentration in

spontaneously breathing patients: A conventional respi-
ratory mask is placed as tightly as possible (e.g. patient
can hold it by himself). Then he spontaneously breathes
through the mask (room air) for approx. 1-2 minutes. The
ETCO2 is then measured either on the monitor or alterna-
tively on the ventilator.

ECG
• sinus tachycardia
-- the most sensitive sign
-- Sinus tachycardia must be left unchanged and
not treated with a β-blocker: It is an important com-
pensation mechanism to still achieve a sufficient car-
diac output with a reduced stroke volume (cardiac
ouptut = stroke volume x heart rate). A pre-existing
β-blocker therapy should be paused (especially in
case of right ventricular dysfunction).
• SI-QIII type (Mc Ginn-White syndrome; note: Strictly
speaking, the SI-QIII type is defined by the indetermi-
nable heart axis and the delayed R-progression over
the chest wall. A deep and wide S-wave in I is physio-
logically always found in right bundle branch block.),
SISIISIII type
• change of the electrical axis (location type) to right axis
deviation (RAD)
• right bundle branch block (RBBB; new)
• ST elevation with terminal negative T in III (DD inferior
myocardial infarction [possibly even with right ventricu-
lar myocardial infarction!] in intermediate stage
• negative T waves in V1-V3, I, III
• P-pulmonale (P-wave > 0,25 mV)
• possibly extrasystoles (premature ventricular contrac-
tions)
• atrial fibrillation
-- pulmonary embolism as a cause of new tachyar-
rhythmia absoluta (Especially in the case of newly
occured tachyarrhythmia absoluta postoperatively,
one should always think of pulmonary embolism!)
-- PERGO register (Pulmonary Embolism Registry
Göttingen; Ebner et al, J Intern Med 2019):
◦◦ atrial fibrillation at diagnosis of pulmonary embo-
lism in 11% (new occurrence in 60%)
◦◦ however, not prognostically relevant
• shift of the R/S transition point to the right

556 Angiology
• resuscitation
-- frequently PEA (pulseless electrical activity; syn.:
EMD [electromechanical dissociation])
-- cardiovascular arrest + PEA + age < 65 years → In
57% pulmonary embolism was the cause in the au-
topsy (Courtney et al, Resuscitation 2001).
-- cardiovascular arrest + PEA + (automatic) lysis →
no reduction in mortality (Abu-Laban, N Engl J,
2002)

The most sensitive ECG sign of pulmo-

nary embolism is sinus tachycardia
(and not the SI-QIII type)! A missing
sinus tachycardia excludes a pulmona-
ry embolism in 90%!
Fig. 784  ECG: ST elevation with T negative in III and aVF
(as in a inferior wall infarction in the intermediate stage),
sinus tachycardia and complete right bundle branch block

Fig. 785  ECG: negative T-waves right precardial in V1-V3

Fig. 783  SI-QIII type (different examples)

Fig. 786  ECG: sinus tachycardia, ST depression with pre-

terminal T in III and V1-V4

Angiology 557
 • dilated right heart cavities
• dilated inferior vena cava (IVC) with lack of respiratory
modulation; dilated central hepatic veins (1 cm prior to
IVC > 10 mm)
• increased pulmonary arterial pressure (note: A PAP >
50 mmHg, however, clearly speaks against acute right
ventricular dysfunction as in acute pulmonary embo-
lism. The right ventricle would never acutely cope with
such a high afterload. Such high PAP values in ​​ an acu-
te pulmonary embolism are only possible in the case
of additional pre-existing conditions such as COPD or
recurrent pulmonary embolism [CTEPH].)
• paradoxical septum movement (i.e. the septum does
not move dorsally in the parasternal long axis, but ven-
trally in the systole in M-mode)
• tricuspid valve insufficiency
• flow reversal in the hepatic veins (sign of a severe tri-
cuspid valve insufficiency)
• hypokinesia of the free (lateral) wall of the right ven-
tricle
• decreased systolic right ventricular function (TAPSE,
TASV)
• Mc Connell's sign
-- akinesia of the right ventricle in normokinesia of the
RV apex (via the common septum!)
-- contraction only apical, rest of right ventricle akinetic
-- sign of acute right ventricular dysfunction
-- also possible in right ventricular myocardial infarc-
tion
Fig. 787  ECG: sinus tachycardia, SI-QIII type, premature R/
S transmission right precardial • shortened acceleration time (AT < 60ms); i.a. 60/60-
sign: acceleration time < 60ms + PAP < 60mmHg
Echokardiography • possibly left ventricle is pumping empty
• posibly direct visualization of the embolus in the pul-
monary artery in TTE (that rarely succeeds; for better
assessment contrast agent can be used (e.g. agitated
NaCl 0.9%):
-- representation of the pulmonary artery (main trunk
and bifurcation) in a longitudinal section in the para-
sternal short axis at the level of the aortic valve
-- representation of the right pulmonary artery in cross
section from the suprasternal view (via the jugular
fossa)
• if necessary TEE (generally not indicated)
-- identification of patients with patent foramen ovale
(PFO)
-- visualization of the embolus in the right heart or pul-
monary artery
• The negative predictive value of echocardiography is
only 45% (Roy et al, BMJ 2005), i.e. an inconspicuous
echocardiography does not exclude pulmonary embo-
lism.
• 80% of aller patients with pulmonary embolism have
no right ventricular dysfunction.
• If a patient is hemodynamically unstable and there is
no right ventricular dysfunction in the echocardiogra-
phy, a pulmonary embolism is very likely to be exclu-
ded as the cause (i.a. Nazerian et al, Intern Emerg
Med 2018: in 96% no pulmonary embolism if there is
no right ventricular dysfunction in the echocardiogra-
phy and no proximal deep vein thrombosis in the ultra-

558 Angiology
 sound), i.e. a chest CT no longer has to be performed
to rule out a pulmonary embolism!
• Routine echocardiographic follow-up after pulmonary
embolism is not necessary. Only if the patient conti-
nues to suffer from dyspnea or reduced resilience af-
ter three months, echocardiography should be carried
out questioning CTEPH (ES guidelines 2019 class I
recommendation).

Only 20% of all patients with

pulmonary embolism have RV
dysfunction!

Fig. 788  apical four-chamber view: dilated right heart ca- Fig. 790  dilated IVC and dilated central hepatic veins
vities

Fig. 791  tricuspid valve insufficiency

Fig. 789  subcostal four-chamber view (different examples):

dilated right heart cavities (The right ventricle is larger than
the left ventricle!)

Angiology 559
Fig. 792  measurement of pulmonary arterial pressure
(PAP) in the apical four-chamber view using cw-Doppler
(here moderately elevated)
Fig. 793  paradoxical septal movement: The septum (arrow)
moves not dorsally (to the left ventrcile), but ventrally (to
the right ventricle) during systole. The common septum
supports the right ventricle here.
Fig. 794  severe tricuspid valve insufficiency with systolic
reflux into the IVC and the hepatic veins
560 Angiology
Fig. 795  representation of the main pulmonary trunk inclu-
ding the bifurcation in the TTE in the parasternal short axis
at the level of the aortic valve (here normal finding): For
better illustration, contrast agent (10 ml agitated NaCl 0.9%)
was given i.v. An embolus can be detected directly here, but
this is only possible very rarely.
The echocardiography (in the hemodynamically stable
patient) is not a diagnostic agent for pulmonary embo-
lism and has no business in the diagnostics of pulmonary
embolism: If one sees a right ventricular dysfunction in
the echo, one must perform a chest CT. If you do not
see a right ventricular dysfunction in the echo, this does
not exclude a pulmonary embolism at all, so that you still
have to perform a chest CT. Echocardiography is only
performed after the CT (for risk stratification)! In the he-
modynamically unstable patient (especially cardiogenic
shock, resuscitation), on the other hand, the echocardio-
graphy is completely sufficient for the indication of lysis,
a chest CT (time delay due to transport of an intubated
patient into the CT, possibly even waiting for TSH and
creatinine) is not necessary.
Practical tip
• cross section of upper abdomen (echo / abdominal
probe)
-- inferior vena cava dilated (> 2.2cm)? reduced / ab-
sent respiratory modulation?
-- central hepatic veins dilated (> 1cm at the conflu-
ence)?
• echo: subcostal view
RV
LV
Fig. 796  subcostal four-chamber view: This shows a com-
pletely inconspicuous finding. The right ventricle (RV) is
significantly smaller than the left ventricle (LV). If a hemo-
dynamically unstable patient (e.g. in the emergency room,
intubated with mechanical ventilation, BP 60/30mmHg, HR
128/min, requiring high doses of catecholamines) shows
this (normal) finding, then pulmonary embolism is defini-
tely excluded as the cause, i.e. you no longer need to carry
out a CT! Because if a pulmonary embolism should explain
this poor hemodynamic condition, then the subcostal four-
chamber view would have to look quite different, namely
pathological: Here the right ventricle would then be at least
as large or larger than the left ventricle!

If the echo shows no right ventricular

dysfunction in a hemodynamically
unstable patient (shock), pulmonary
embolism is definitely excluded as
Fig. 798  acceleration time (AT): time between beginning
the cause (CT no longer required)!
and maximum of the transpulmonary outflow (The sample
volume of the pw Doppler has to be placed in the pulmona-
ry valve in the parasternal short axis.)
DD right ventricular dysfunction
acute chronic
Echocardiography in pulmonary
PAP < 50 mmHg > 50 mmHg embolism:
right ventricular stable patient: no business in the
hypertrophy - + diagnosis!
acceleration time (AT) < 60 ms > 60 ms unstable patient: sufficient for
indication of lysis (CT not absolutely
Mc Connel´s sign + -
necessary)
respiratory modulati-
on of VCI - +
pericardial effusion - + Echocardiography score
1 point 2 points 3 points
size of right RV < LV RV = LV RV > LV
ventricle RV < 30mm RV 30-40mm RV > 40mm
size of right
atrium RA < LA RA = LA RA > LA
contractility of
the RV wall normokinesia hypokinesia akinesia
paradoxical paradoxical
orthodoxical (systolic to (systolic to
movement of (systolic to ventral) - ventral) -
the septum dorsal) partial complete

• addition of points, then division of total score by 4

Fig. 797  subcostal four-chamber view: A clearly dilated
right ventricle can be seen (as wide as the left ventricle).
Furthermore, you can see a right ventricular hypertrophy
(wall of the right ventricle just as thick as the intraventri-
cular septum; here 11mm [normal value end-diastolic <
6mm]), so that it is a chronic right ventricular dysfunction
in the sense of chronic cor pulmonale.
• interpretation:
-- possible values: 1P. (normal finding [no right ventri-
cular dysfunction]) up to max. 3P. (severe right ven-
tricular dysfunction)
-- > 2.25P.: right ventricular dysfunction with increased
mortality
• modified according to Wacker et al, Intensivmed 2003
(Acute pulmonary embolism: a new scale for the quan-
tification of right heart strain)

Echocardiography is not a diagnostic

tool for pulmonary embolism (in
stable patients), but a prognostic tool!

Angiology 561
Pulmonary embolism & PFO
• high risk patients Thromboembolism (thrombosis or
embolism) is one entity!
• The increased pulmonary arterial pressure also leads
to an increase in pressure in the right ventricle and
right atrium. The pressure in the right atrium is then
higher than the pressure in the left atrium, so that a Lung sonography
right-to-left shunt occurs via the open foramen ovale
• pleural sonography with the linear transducer (syste-
in the atrial septum. As a result, not enough blood is
matic screening)
reaching the lungs and oxygenation is reduced. Fur-
• detection of at least two triangular or round subpleural
thermore, due to the increased pressure in the right
lesions in the lung parenchyma
atrium, the risk of paradoxical embolism (e.g. stroke;
especially if a deep vein thrombosis is simultaneously • valence (Mathis et al, Chest 2005):
present as the cause of the pulmonary embolism) is -- positive predictive value: 95%
significantly increased. -- negative predictive value: 75%
• Patients with pulmonary embolism and a patent fora- • possible additional administration of contrast medium
men ovale therefore have a higher mortality rate than (SonoVue)
patients with a closed foramen ovale. • can detect pulmonary embolism, but not exclude it
• if necessary, emergency interventional closure • especially a good option for "vulnerable" patients (ado-
lescents, pregnant women)
Sonography of the leg veins • combination of all three ultrasound procedures (sono-
• compression sonography graphy leg veins, echocardiography, lung ultrasound)
to detect VTE (Mathis et al, Chest 2005):
• 70% of patients with ascertained pulmonary embolism
have deep vein thrombosis of the leg at the same time. -- sensitivity: 90%
• If there is a ascertained DVT (e.g. DVT of proxi- -- specificity: 86%
mal leg vein in the sonography) and if there is also a
suspicion on pulmonary embolism (e.g. dyspnea, ta-
chycardia), a chest CT is no longer necessary. A chest
CT has no further therapeutic consequence. A chest
CT should only be performed in case of a distal deep
vein thrombosis (if pulmonary embolism is suspected).
There is also no difference in the duration of antico-
agulation: After pulmonary embolism anticoagulation
is not any longer than after DVT! In this case a CT
is definitely not indicated, the performance of a non-
indexed CT is a physical injury (e.g. radiation expo-
sure: 1 radiation-induced malignancy on 5000 CTs, in
adolescents even on 1800 CTs [Mattews, JAMA Pedi-
atrics 2013])! The only difference is the DRG reimbur-
sement (in Germany), which increases by 44% when a
pulmonary embolism is coded: If only the diagnosis of
deep vein thrombosis (I80.28) is coded, the proceeds Fig. 799  lung sonography in pulmonary embolism: Three
amount to 2040€ (cw value 0.64). If the pulmonary em- subpleural round lesions (see arrows) are visible.
bolism is additionally encoded (without indication of an
acute pulmonary heart disease; I26.9), the proceeds Chest X-ray
amount to 3615€ (cw value 1.13). However, this should • often normal in pulmonary embolism
not and must not be a reason to carry out medically
• a differential diagnostic indication (mainly indicated to
non-indicated measures!
exclude other differential diagnoses of acute dyspnea)
• Sonography of the leg veins should also be performed
• findings in pulmonary embolism:
as soon as the acute danger to the patient has been
overcome in the case of secured pulmonary embolism -- atelectasis (most common X-ray finding in pul-
(e.g. in the chest CT). This has no consequence with monary embolism!)
regard to anticoagulation, but with regard to the initi- -- pleural effusion
ation of compression therapy for the prophylaxis of a -- one-sided diaphragmatic elevation (on the em-
post-thrombotic syndrome. bolism side
• Sonography of the leg veins is also an option for -- caliber jump of the vessels; Palla sign: ballooned
pregnant women with suspected pulmonary embolism pulmonary artery in the hilum area with a jump in
if chest CT is not possible (e.g. due to the radiation caliber ("amputated hilus")
exposure of the unborn child): If the sonography shows -- Westermark sign: peripheral local brightening after
a thrombus (e.g. in a proximal leg vein), the diagnosis vascular (peripheral oligemia)
of pulmonary embolism and thus the indication for full -- Hampton's hump: wedge-shaped infiltrate (for pul-
anticoagulation are considered confirmed. monary infarction)

562 Angiology
Fig. 800  plate atelectases (arrows) in bilateral pulmonary
embolism

Fig. 803  wedge-shaped infiltrate on the left

Fig. 801  atelectasis and elevated diaphragm on the right

with right-sided pulmonary embolism

Fig. 804  left-sided diaphragmatic elevation with infarct

pneumonia

Fig. 802  wedge-shaped infiltrate on the right

Angiology 563
 same therapy is recommended as for symptomatic
pulmonary embolisms (i.e. LMWH s.c. for the duration
of the active cancer, i.e. especially in cancer patients in
palliative situations for the rest of their life)
• Occasionally it happens that the contrast was too poor,
so that the radiologist cannot determine (e.g. pulmona-
ry embolism in the left lower lobe cannot be excluded
with certainty). Due to the double radiation exposure,
repetition is reluctant. Then the pulmonary embolism
should then be secured or excluded with a scintigra-
phy, especially with regard to the indication of long-
term anticoagulation.

Fig. 805  Palla sign: clearly enlarged (" ballooned") left pul-
monary artery (main trunk) with pronounced jump in caliber
("amputated hilus")

Chest CT
• with contrast medium (CTPA: CT pulmonary angiogra-
phy)
• today the method of choice for the diagnosis of pul-
monary embolism
Fig. 806  chest CT: detection of embolus in the right main
• sensitivity 83%, specificity 96% (PIOPED II study
trunk of the pulmonary artery
[Stein et al, N Engl J 2006])
• radiation exposure: approx. 50 x chest X-ray
• diameter right / left ventricle (RV/ LV; i.a. meta-ana-
lysos Meinel et al, AJM 2015: The quotient RV/LV has
considerable prognostic significance!)
-- < 1: no right ventricular dysfunction; good prognosis
-- > 1: right ventricular dysfunction; poor prognosis
• not necessary in case of hemodynamic instability
(especially cardiogenic shock, resuscitation): Echocar-
diography is completely sufficient for indication of lysis!
After hemodynamic stabilization, however, CT should
be performed immediately for final confirmation.
• The severity is always a clinical and not a radiologi-
cal diagnosis. It depends on the amount of cytokine
release that causes pulmonary artery vasoconstric-
tion, not the amount of obstruction in the pulmonary
vascular system on CT. Therefore, on the one hand,
a central pulmonary embolism on the CT does not ne-
cessarily have to be massive. On the other hand, an
only small peripheral pulmonary embolism on the CT
can be quite massive (hemodynamic instability up to
cardiogenic shock).
• maybe additionally in the same session CT pelvis/leg
(so-called CT-venography to determine whether pelvic
or leg vein thrombosis is present; is not recommended,
as on the one hand the radiation exposure is too high
and on the other hand this has no therapeutic conse-
quence)
• in 1-2% accidentally discovered pulmonary embo-
lisms (so-called incident pulmonary embolisms) in the
chest CT (above all for patients with malignancy in the
staging CT); for incidental pulmonary embolisms the Fig. 807  chest CT: detection of an embolus in the left main
trunk of the pulmonary artery

564 Angiology
Fig. 808  chest CT: detection of an embolus spanning over Fig. 810  chest CT: The massively dilated inferior vena cava
the bifurcation into the left and right main trunk of the pul- and the significantly dilated three liver veins (classic right-
monary artery heart strain) are visible.

Fig. 811  chest CT: various examples of infarct pneumonia

(right in the first picture, left in the second picture; typically
triangular with the base facing peripherally)

Scintigraphy
• types:
-- perfusion scintigraphy (i.v.- application of Tc-99m-
labelled macroaggregated albumin [MAA]): conspi-
cuous in pulmonary embolism (but also pathological
in many other lung diseases [i.a. COPD] due to the
Euler-Liljestrand reflex)
-- ventilation scintigraphy (inhalation of Tc-99m-la-
Fig. 809  diameter of right ventricle (RV) to left ventricle (LV) belled aerosols or nanoparticles): inconspicuous in
> 1: CT morphology of right ventricular dysfunction pulmonary embolism

Angiology 565
• findings:
-- perfusion scintigraphy inconspicuous (no evidence
of a perfusion deficit): pulmonary embolism excluded
-- perfusion scintigraphy conspicuous (evidence of a
perfusion deficit):
◦◦ ventilation scintigraphy inconspicuous (mismatch):
pulmonary embolism
◦◦ ventilation scintigraphy conspicuous (match): no
pulmonary embolism (other cause such as COPD)
• typical for pulmonary embolism: pathological perfusion
and normal ventilation scintigraphy (mismatch V/Q)
• During the high phase of the corona pandemic, in many
places no ventilation scintigraphy is performed due to
the aerosols and the associated risk of infection. If the
perfusion scintigraphy is abnormal, a chest CT should
be performed to exclude a structural lung disease (to
assess match or mismatch). It is sufficient to do this
natively, i.e. without contrast agent. Most of the time,
you decided against a CT and for scintigraphy anyway
because of the contrast medium. Fig. 812  perfusion scintigraphy: perfusion defect on the
• radiation exposure: 1.1 mSv (if combined perfusion left side
and ventilation scintigraphy; lower than for chest CT:
2-6 mSv; if only perfusion scintigraphy: 0.2-0.6 mSv)
• only indicated in exceptional cases:
-- renal insufficiency
-- contrast agent allergy (although chest CT is also
possible possible here after appropriate pre-medica-
tionwith prednisolone, H1- and H2-blockers)
-- manifest hyperthyroidism (although chest CT thorax
is also possible here after appropriate pre-medica-
tion with Irenat and thyreostatics)
-- plasmacytoma (multiple myeloma): The adminis-
tration of contrast agent is only contraindicated in
light chain plasmacytomas (20% all plasmacytomas;
syn.: Bence-Jones plasmacytoma). This is because Fig. 813  perfusion scintigraphy: two perfusion defects (see
the light chains precipitate in the presence of a con- arrows)
trast agent, so that they fail and block the kidney
tubules. This also applies when kidney function is Pulmonary angiography
normal.
-- pregnant woman (cave: higher radiation exposure
for uterus than CT [Schaefer-Prokop et al, Eur Ra-
diol 2008], but only with a combination of perfusion
and ventilation scintigraphy)
-- young (especially female) patients
• Scintigraphy can methodically conditioned only detect
occluding emboli. It is therefore the better, the further
peripheral (smaller lumen of the pulmonary artery
branches) the embolism is located and the worse the
further central (larger lumen of the pulmonary artery
branches) the pulmonary embolism is located. For ex-
ample, in the case of a non-occluding embolus in the • formerly "gold standard" (historical [first description by
main trunc, it can be false negative (but overall very Sasahara in the New England Journal in 1961]); only
rarely). rarely indicated today (e.g. preoperatively before pul-
monary endarterectomy in CTEPH)
• We perform pulmonary angiography especially in pati-
diagnostic of the first choice for young ents with pulmonary hypertension due to recurrent pul-
(especially female) patients: scintigra- monary embolisms (CTEPH: chronic thromboembolic
phy (not CT!) pulmonary hypertension) to evaluate whether the pati-
ent is suitable for pulmonary endarterectomy.
• If a coronary angiography is performed in an emergen-

566 Angiology
 cy (e.g. under resuscitation conditions) and the exami-
nation is not groundbreaking, right heart catheter with
pulmonary angiography can be performed immediately
in the cardiac catheterization lab. Alternatively, a chest
CT chest also be performed.
• access: 7F sheath
-- internal jugular vein
-- femoral vein (previously sonography to exclude
DVT)
• 7F pigtail catheter via guide wire (e.g. Terumo 0,018´´)
under fluoroscopy
• injection of contrast medium
-- non-selective: 40ml into the right ventricle (via high
pressure syringe 20ml/s or by hand)
-- selective: each 40ml into the right and left main trunc
• a.p.-projection
• in DSA technique (DSA: digital subtraction angiogra-
phy)
• Miller score to quantify the extent of obstruction
• mortality of pulmonary angiography: 0.5% (procedural
[Stein et al, Circulation 1997])
• Alternatively, pulmonary angiography can also be per-
formed over a inlying pulmonary catheter: The catheter
is placed in the RV position (right ventricle) and then
the contrast medium is injected over the lumen “PA Fig. 814  selective pulmonary angiography: first image left
distal”. The result is an unselective pulmonary angio- pulmonary artery, second image right pulmonary artery
graphy. (here no evidence of pulmonary embolism)

Classifications
• according to Grosser (Klaus D. Grosser et al, Deut-
sches Ärzteblatt 1988: Acute pulmonary embolism -
treatment by severity)
• according to ESC

Stage classification according to Gros-

ser

stage I stage II stage III stage IV

pronounced
dyspnea,
only inter- chest pain
mittently; persistent; cyanosis,
slight moderate restless- shock, car-
symp- dyspnea, dyspnoea, ness, diovascular
toms chest pain chest pain syncope arrest

systemic
arterial
pressure normal normal ↓ ↓↓
mean PA
pressure
(mmHg) < 15 15-25 25-30 > 30
paO2
(mmHg) > 75 70-75 70-60 < 60

vascular right or left

oblitera- a periphe- a segmen- pulmonary truncus
tion ral branch tal artery artery pulmonalis
letality < 10% 10-25% 25-50% > 50%

Angiology 567

Staging of the pulmonary embolism
according to Grosser: abandoned
today!
ESC classification
ESC guidelines 2000
• mild pulmonary embolism (80%)
• submassive pulmonary embolism (15%)
• massive pulmonary embolism (5%)
Mild pulmonary embolism
• hemodynamically stable
• no RV dysfunction
Submassive pulmonary embolism
• already RV dysfunction
• but hemodynamically not yet unstable, i.e. SBP > 90
mmHg (without catecholamines)
Massive pulmonary embolism
• hemodynamically unstable: p.d. SBP < 90 mmHg lon-
ger than 15min (p.d. not caused by cardiac arrhythmia,
hypovolemia or sepsis)
• mortality: 25-30%
• i.a. cardiogenic shock, resuscitation
• no radiological (e.g. CT: central pulmonary embolism
on both sides), but a clinical diagnosis
ESC guidelines 2008
• high risk group: hypotensive (persistent hypotension /
shock; 15%)
• non-high risk group: normotensive (85%)
Furthermore, a group with intermediate risk is described:
Here the blood pressure is still normal, but RV dysfunc-
tion is already detectable (morphologically [echocardi-
ography or CT] or biochemically [especially increased
troponin]).
• anticoagulation with heparin
• lysis (in case of massive pulmonary embolism [high-
risk group])
• circulatory therapy
• hypoxemia (SpO2 < 90%) → administration of oxygen,
possibly also HFNOT (high-flow nasal oxygen therapy)
• if necessary intubation and mechanical ventilation
( use as little PEEP as possible [PEEP improves
left ventricular function, but worsens right ventricular
function!])
• embolectomy
-- interventional: thrombus fragmentation (right heart
catheter; possibly with local lysis [alteplase 15mg])
-- surgical
Procedure
• low risk group (mild pulmonary embolism):
-- only anticoagulation with heparin
-- no lysis
-- transfer to intensive care unit not absolutely neces-
sary; note: According to the current ESC guidelines,
in the absence of RV dysfunction in the echocardi-
ography and negative troponin, even an outpatient
therapy is also possible (studies: i.a. Aujesky et al,
Lancet 2011; CVRN-VTE study [Fang et al, JAMA In-
tern Med 2015]; HoT-PE study [Konstantinides et al,
ACC 2019]), which we do not practice. This is also
possible in the low-risk group after the PESI score
(see page 578), i.e. PESI class I or sPESI 0 points.
Outpatient therapy is not possible if one of the Hestia
criteria (see infobox; according to the HESTIA study
[Zondag et al, J Thromb Haemost 2011]) is met.
• intermediate risk group (submassive pulmonary embo-
lism)
• high risk group (massive pulmonary embolism):
-- lysis + heparin (UFH, i.e. heparin perfusor)
-- in case of contraindications for lysis: embolectomy

ESC guidelines 2014 + 2019

• high risk group: hypotensive (persistent hypotension or
shock)
• intermediate risk group: normotensive, but with RV
dysfunction
-- intermediate high risk group: RV dysfunction mor-
phologically (echo / CT) and biochemically (espe-
cially increased troponin)
-- intermediate low risk group: RV dysfunction morpho-
logically (echo / CT) or biochemically (especially in-
creased troponin)
• low risk group: normotensive (without RV dysfunction)

Therapy
• monitoring:
-- without RV dysfunction: for 24h
-- with RV dysfunction: for 48h

568 Angiology
Intermediate risk group (submassive pul-
monary embolism)
• no general recommendation for lysis (also not appo-
ved here)
• studies:
-- Pulmonary Embolism-3 study (Konstandinidis et al,
N Engl J 2002; see box): lysis → significantly redu-
ced combined endpoint of mortality and therapy es-
calation, but mortality alone not reduced!
-- MOPETT study 2012 (see box)
-- TOPCOAT study 2013 (USA; 83 patients with sub-
massive pulmonary embolism and therapy with
LMWH randomized to additional lysis [tenecteplase]
or placebo; result: lysis → higher survival rate after 5
days, shorter hospital length of stay, better quality of
life after 90 days)
-- PEITHO study 2013 (Europe; see box)
-- meta-analyses:
◦◦ Chatterjee et al, JAMA 2014: (scarcely) significant
survival benefit for lysis in submassive pulmonary
embolism, but with an NNT of 65 (i.e. not very ef-
fective)
◦◦ Marti et al, Eur Heart J 2014: no significant survi-
val benefit for lysis in submassive pulmonary em-
bolism
• our approach: lysis "drawn up and ready to use" and
immediate administration in case of hemodynamic de-
terioration
Pulmonary Embolism-
3-study
Heparin plus Alteplase Compared with Heparin Alone in
Patients with Submassive Pulmonary Embolism
Konstantinides et al, N Engl J 2002
• multizentrische randomisiert-kontrollierte Studie
• 256 patients with pulmonary embolism with RV dysfunc-
tion without arterial hypotension / shock
-- 118 patients: heparin + alteplase 100mg für 2h
-- 138 patients: heparin + placebo
• results: heparin + alteplase
-- significant reduction of the composite endpoint:
◦◦ death (hospital) or
◦◦ necessity of therapy escalation (catecholamine the-
rapy, intubation, second lysis, resuscitation, mecha-
nical thrombus fragmentation, surgery)
-- less escalation of therapy
-- no difference in mortality
MOPETT study
Moderate Pulmonary Embolism Treated With Thromboly-
sis
Sharifi et al, Am J Cardiol 2012
• single center prospective randomized controlled study
• 121 patients with submassive pulmonary embolism
-- without lysis (anticoagulation only)
-- with lysis (alteplase, but only half dose)
• results: lysis (half dose)
-- significantly less pulmonary hypertension in the
course (after 28 months)
-- no increased rate of ICH (intracranial hemorrhage)
-- significantly lower hospital length of stay
-- no difference in mortality
• note: The study had too little power and the quality cri-
teria of a "clinical trial" were not met (thus generating
hypothesis at best)
PEITHO study
Fibrinolysis for patients with intermediate-risk pulmonary
embolism
Meyer et al (The PEITHO-Investigators), N Engl J 2014
• multicenter prospective randomized study
• PEITHO: Pulmonary Embolism Thrombolysis
• 1005 patients with submassive pulmonary embolism
(hemodynamically stable, but already RV dysfunction
in echo / CT and troponin ↑), i.e. intermediate high risk
group
-- 499 patients: without lysis (anticoagulation only)
-- 506 patients: with lysis (tenecteplase)
• endpoints:
-- primary endpoint (combined):
◦◦ all-cause mortality or
◦◦ hemodynamic collapse (i.e. resuscitation, SBP <
90mmHg > 15min or decline > 40mmHg with end-
organ hypoperfusion [i.e. cold extremities, urinary
excretion < 30ml/h, mental confusion] or need for
catecholamines)
-- secondary endpoints
• results: lysis
-- primary endpoint: significantly reduced (2.6% vs.
5.6%; significant only for hemodynamic collapse, not
for all-cause mortality)
-- secondary endpoints:
◦◦ all-cause mortality (7 and 30 days): no difference
◦◦ pulmonary embolism recurrence within 7 days: no
difference
◦◦ need for intubation and mechanical ventilation: no
difference
◦◦ bleeding and stroke (ischemic / hemorrhagic):
significantly increased
Angiology 569

study
• Anticoagulation should already be startet in case of
Impact of Thrombolytic Therapy on  the  Long-Term Out-
come of Intermediate-Risk Pulmonary Embolism
Konstadinides et al, JACC 2017
-- fondaparinux (Arixtra)
◦◦ dosage: 7.5mg s.c. (> 100kg: 10mg; < 50kg: 5mg)
◦◦ control via anti-factor Xa possible
◦◦ also possible during pregnancy
◦◦ contraindication: i.a. GFR < 20 ml/min
(urgent) suspicion of pulmonary embolism (in case of
high clinical probability already before confirmatory di-
agnosis e.g. by means of CT).

• long-term data from the PEITHO study (3 years) Unfractionated heparin

• lysis in the intermediate high-risk group: • application:
-- no difference in mortality
-- i.v. (heparin perfusor)
-- no difference in resilience (dyspnea)
-- s.c. (The administration of unfractionated heparin
-- no difference in echo parameters (pulmonary hyper-
tension, RV function)
s.c. is obsolete today!)
-- no difference in frequency of developing CTEPH • PTT
-- target: 60-80 sec
-- control from "top down" (e.g. bolus 10000 IU)
submassive pulmonary embolism -- PTT-controls several times daily
(intermediate risk group): due to the • daily platelet control (risk of HIT II)
increased bleeding rate no general • after 1-2 days possibly switch to LMWH (stop heparin-
recommendation for lysis! especially perfusor 3h after s.c. administration of the LMWH)
not at age > 75 years! • dosage weight-adapted according to Raschke (Ann
Int Med 1993): 80 IU/kg bw as bolus, then 18 IU/kg bw
per hour
Right ventricular dysfunction • significance: rarely used today; only for:
• morphological (imaging): -- high risk group (massive pulmonary embolism, i.e.
-- echocardiography (gold standard) hemodynamically unstable)
-- CT (RV/LV > 1,0) -- renal insufficiency with a GFR < 30 ml/min (alterna-
• laboratory chemical: tively, however, LMWH with antifactor Xa monitoring
-- troponin ↑ also possible)
-- pro-BNP ↑ -- severe obesity with a BMI > 40 kg/m2 (ESC gui-
• hemodynamic: blood pressure index (BPI = SBP / DBP delines 2019: recommended here)
< 1,7 [SBP: systolic blood pressure; DBP: diastolic
blood pressure]: predictive value for right ventricular
dysfunction (Ates et al, American Journal of Emergen-
cy Medicine 2017)
-- positive predictive value: 100% (explanation: The
increased pressure in the right ventricle results in a
septum shift to the left. This leads to a decreased LV
filling so that the ejection decreases, i.e. SBP ↓. The
septum shift increases the left ventricular endiastolic Fig. 815  unfractionated heparin (UFH) [8]
pressure (LVEDP) and thus also the blood pressure
during diastole, i.e.. DBP ↑).
PTT dosage
-- negative predictive value: only 42%
bolus 80 E/kg
< 40 s rate ↑ by 4 E/kg/h
Troponin + pro BNP: high negative bolus 40 E/kg
predictive value for RV dysfunction 40-60 s rate ↑ by 2 E/kg/h
60-80 s ok
80-100 s rate ↓ by 2 E/kg/h
Anticoagulation
stop for 1h
• types > 100 s then rate ↓ by 3 E/kg/h
-- heparin
Fig. 816  dose-adjustment scheme for UFH: Start with bolus
◦◦ reduction of mortality by 25% of 80 IU/kg, then start perfusor with 18 IU/kg/h, then accor-
◦◦ types ding to PTT.
▪▪ unfractionated heparin (UFH; heparin perfusor)
▪▪ low molecular weight heparins (LMWH)

570 Angiology
Low molecular weight heparins (LMWH)
• syn.: fractionated heparins
• conversion: 1000 I.E. = 10mg = 0.1ml
• for at least 5 days, then overlapping onset with VKA
(e.g. marcumar)
-- overlapping necessary, as otherwise coumarin-in-
duced skin necrosis may occur (Marcumar inhibits
protein C initially, which has anticoagulatory effects,
and only later the procoagulatory coagulation factors
of the prothrombin complex [II, VII, IX, X], so that
hypercoagulability may occur in the initial phase [es-
pecially with thrombosis of small skin veins]).
-- Do not stop heparin until INR is in target range (INR
2-3) for two days.
-- note: The novel anticoagulants (NOAC; but only ap-
plies to rivaroxaban and apixaban) do not require
overlapping.
• advantages of LMWH over UFH:
-- constant bioavailability
-- less (major) bleeding (Erkens et al, Cochrane Data-
base Syst Rev 2010; Cossette et al, Ann Pharmaco-
ther 2010) Lysis (fibrinolytic therapy)
-- much less HIT II than under UFH (i.a. Stein et al, Am
J Med 2009) Assessment
-- no need for multiple blood samples (for PTT control)
• significant advantage of lysis in massive pulmonary
• dose reduction in renal insufficiency : embolism (high risk group)
-- from creatinine > 2 mg/dl or GFR < 30 ml/min (ex- • lysis much more effective in pulmonary embolism than
ception: tinzaparin [only from GFR < 20 ml/min]) in myocardial infarction (92% responder [Meneveau et
-- control via anti-factor Xa al, Chest 2006])
◦◦ determination 4h after s.c. administration of the • By far the most common indication for lysis is pulmo-
LMWH (citrate tube) nary embolism (well before stroke or myocardial infarc-
◦◦ target level: tion).
▪▪ with twice daily administration of the LMWH: • MAPPET II study (N Engl J 2002):
0.6-1.0 U/l -- alteplase (Actilyse) → highly significant advantage
▪▪ with once daily administration of the LMWH: 1.0- for the lysis group
2.0 U/l -- no significant difference in major bleeding complica-
◦◦ further indications: tions between heparin and heparin + lysis (e.g. ICH
▪▪ pregnancy in each case in 3%)
▪▪ weight < 50kg or > 100kg • There is no lysis time window in pulmonary embolism
◦◦ note: The commercially available tests are only in contrast to myocardial infarction (< 12h) or in stroke
calibrated for a one specific low molecular weight (< 4.5h): Relevant events occur in pulmonary embo-
heparin. One should inquire in his laboratory, on lism almost exclusively within the first 3 hours.
which! For example, it is not possible to determine
the anti-factor Xa under dalteparin or certoparin Indications
with a test set that has been calibrated for eno-
• massive pulmonary embolism (high-risk group): i.e.
xaparin.
SBP persistent (> 15min) < 90 mmHg or decrease by
• massive pulmonary embolism (high risk group) → UFH more than 40mmHg from baseline (not caused by car-
-- LMWH not approved here diac arrhythmia, hypovolemia, sepsis) or need for ca-
-- reasons: techolamines (in the ESC guidelines 2019 meanwhile
◦◦ unclear resorption in s.c. administration in shock class I indication [ESC 2014 still IIa])
◦◦ faster discontinuation in case of bleeding in lysis • possibly submassive pulmonary embolism (especially
and possibility of antagonization with protamine in intermediate high-risk group, i.e. RV dysfunction in the
UFH echocardiography and increased troponin; here lysis
can be performed optionally, especially if the right ven-
tricle is to be relieved quickly; but only at age < 75 ye-
ars, off-label use in this case!) +
-- comorbidities
-- heart failure
-- respiratory failure

Angiology 571
• floating (mobile) thrombus in the right heart (right atri-
um or right ventricle)
-- frequency (with confirmed pulmonary embolism)
◦◦ 4% (Pierre-Justin et al, Int J Cardiol 2005)
◦◦ 5% (Ferrari et al, Chest 2005)
-- mostly worm-shaped (Chartier et al, Circ 1999)
-- lysis very effective here (i.a. Chartier et al, Circ 1999,
Pierre-Justin et al, Int J Cardiol 2005; no surgery ne-
cessary; 50% of the thrombi dissolve within 2 hours
after the start of the lysis, 25% after 12 hours and
25% after 24 hours [Ferrari et al, Chest 2005])
-- Lysis is mandatory here (otherwise increased morta-
lity [Torbicki et al, J Am Coll Cardiol 2003]; is unfor-
tunately very often not performed)!
-- lysis here also according to the Mappet scheme, but
without a bolus, i.e. 100mg alteplase (rt-PA) over
120min
-- A frequently cited counter-argument for lysis in floa-
ting thrombi in the right heart is that the lysis incre-
ases the risk of thrombus fragmentation. The risk of
thrombus fragmentation is already very high here,
however, since the thrombus (usually worm-shaped)
is located in a moving organ (right atrium or right
ventricle) and the pulmonary valve is usually not se-
verely stenosed. The only way to reduce the risk of
thrombus fragmentation is to dissolve the thrombus
there on site (at the place of highest risk)! Otherwi-
se, the thrombus may remain in the right heart and
represent a "ticking time bomb".
-- Lysis is indicated here regardless of the circula-
tory situation, i.e. definitely also in hemodynamically
stable patients!
-- Lysis not only dissolves the thrombus in the right
heart, but also that in the pulmonary artery and deep Fig. 817  embolus in the inferior vena cava and in the right
leg vein (in 3 places!). atrium: independent indication for lysis (independent of the
-- In the case of contraindications to the lysis, tsurgery hemodynamic situation; lysis here obligatory, unfortunate-
is a theoretical option, albeit a very large interventi- ly frequently omitted! No surgery is necessary here [cave
over-therapy]!)
on, so that, provided the patient is hemodynamically
stable, we only perform full anticoagulation with a
heparin perfusor (UFH). If there are contraindica-
tions for lysis in hemodynamically unstable patients
with pulmonary embolism, embolectomy (surgical or
interventional) is carried out anyway, regardless of
whether there is also a thrombus in the right heart
or not.
-- cave: The moderator band should not be confused
with a thrombus in the right ventricle: This is a norm
variant and not a pathology. The moderator band is a
muscle branch between the septal and lateral wall of
the right ventricle and recognizable as a transverse
structure in the area of the tip of the right ventricle.
It is relatively frequently seen in the ultrasound and
contains the right Tawara branch.
Fig. 818  pitfall: Here the echocardiography in the right ven-
tricle shows no thrombus, but only the moderator band,
which is completely normal (norm variant).

572 Angiology

Fig. 819  embolus (lower arrow) in the right ventricle, above
the moderator band (upper arrow): Here, too (as with an
embolus in the right atrium), lysis is indicated even in pati-
ents with stable circulation, if pulmonary embolism is con-
firmed!
massive pulmonary embolism (high
risk group) → lysis "under all circum-
stances" (contraindications only: acute
ICH and active internal bleeding)
While you should always check the list of contraindica-
tions for lysis for lysis after a stroke or myocardial in-
farction, you do not usually need to do this for lysis after
pulmonary embolism: There is practically no contraindi-
cation here. Even if a surgical procedure (e.g. hip TEP)
has only recently taken place, there is no need to call the
surgeon to ask him if it can bleed: Of course it can! The
alternative, however, is circulatory failure and consecu-
tive death of the patient. If bleeding occurs, supportive
therapy (volume administration, RCC administration,
possibly massive transfusion via a rapid infusion system
[e.g. Level One]) is administered. By the way, most of the
court proceedings are not conducted because bleeding
occurred during the lysis, but because the lysis was not
carried out.
study
Thrombolytic therapy in unstable patients with acute pul-
monary embolism: saves lives but underused
Stein et al, Am J Med 2012
• epidemiological investigation in the USA
• 72230 hemodynamically unstable patients with pulmo-
nary embolism
• Lysis was performed only in 30%!
• mortality:
-- without lysis: 47%
-- with lysis: 15%
meta-analysis
Systemic thrombolytic therapy for acute pulmonary embo-
lism: a systematic review and meta-analysis
Marti et al, Eur Heart J 2015
• meta-analysis (15 RCT)
• 2057 patients with pulmonary embolism and anticoagu-
lation
-- with lysis
-- without lysis
• results: lysis
-- significant reduction of mortality (but only in hemody-
namically unstable patients)
-- significant reduction of combined endpoint mortality
and need for therapy escalation
-- significantly fewer recurrences of pulmonary embo-
lism
-- - significantly more major bleeding (severe bleeding in
9.9%, i.a. ICH in 1.7%)
Lysis in pulmonary embolism is the
most frequently omitted vital therapy
in intensive care medicine!
Substances (fibrinolytics)
• non-fibrin-specific (no longer relevant today)
-- streptokinase
-- urokinase
• fibrin-specific:
-- alteplase
-- reteplase (Rapilysin; not approved for pulmonary
embolism [off-label-use]): 2 bolus injections a 10U in
30min; resuscitation: 20U i.v.
-- tenecteplase (Metalyse; not approved in Germany
for the treatment of pulmonary embolism [off-label-
use]): 0.5 mg/kg i.v. (single shot)
Alteplase (rtPA, Actilyse)
• 10mg as bolus, then 90mg over 120min (MAPPET II
study [N Engl J 2002]; Mappet scheme)
• alternative:
-- accelerated scheme: 0.6 mg/kg in 15min (max.
50mg)
-- 50mg over 50ml perfusor syringe in 5min i.v., if ne-
cessary repetition after 15-30 min
• in case of resuscitation 50mg (ERC guidelines), but
then continue resuscitation for at least 30 minutes
(ESC guideline 2019: 60 minutes)
• postoperative: bolus delivery of 10-20mg i.v., mainte-
nance dose of 10 mg/h for 2-4h
• heparin: UFH (no LMWH) before (5000E as bolus i.v.)
and after (heparin perfusor: start with 1000E/h, then
according to PTT) the lysis (no heparin during lysis;
Angiology 573
 note: If LMWH has been administered before, switch
to UFH (with twice daily doses of LMWH after 12h, with
once daily doses of LMWH only after 24h).
• T1/2 = 15min (Due to the relatively short half-life an
emergency surgery is possible relatively soon. To be
on the safe side, fibrinogen should be determined pri-
or to the surgery: If it is not lowered, no relevant lysis
effect can be assumed [cave however falsely high fib-
rinogen values in inflammation, since fibrinogen is an
acute phase protein].)
Bed rest
If the patient has no RV dysfunction (morphologically: no
RV dysfunction in the echocardiogram, laboratory che-
mical: troponin and pro-BNP negative) and is circulatory
stable, no bed rest is required. According to the current
ESC guidelines, outpatient therapy can even be consi-
dered. However, this procedure is not usual in our clinic.
We admit the patient to hospital and monitor him for 24
hours at the IMC. A bed rest is clearly indicated for pati-
ents with circulatory instability.
Circulatory therapy
• volume administration (moderate [500-1000ml], no
aggressive volume therapy [Ghginone et al, Anesthe-
siology 1984])
• catecholamines
-- vasopressors:
◦◦ noradrenaline: Noradrenaline is repeatedly promo-
ted as the catecholamine of choice for pulmonary
embolism, as it improves right ventricular function
through a positive inotropic effect and improves
coronary perfusion of the right ventricle. One must
be very careful here, however, as noradrenaline
also increases the pulmonary artery pressure and
the pulmonary vascular resistance. Dobutamine is
a good option (especially if the cardiac output is
low): It lowers the pulmonary artery pressure and
the pulmonary vascular resistance.
◦◦ vasopressin
▪▪ MAP (mean arterial pressure) ↑, SVR (systemic
vascular resistance) ↑
▪▪ PAP (pulmonary artery pressure) ↓, PVR (pul-
monary vascular resistance) ↓
-- inotropics (especially for reduced cardiac output)
◦◦ dobutamine: PAP (pulmonary artery pressure) ↓,
PVR (pulmonary vascular resistance) ↓
◦◦ levosimendan
574 Angiology
▪▪ individual case reports (bolus 24 μg/kg over
10min, then 0.1 μg/kg/min over 24h)
▪▪ Levosimendan reduces the pulmonary arterial
pressure and the pulmonary vascular resistance
(Russ et al, Crit Care Med 2009).
▪▪ problem: peripheral vasodilatation → no general
recommendation for pulmonary embolism
▪▪ ESC guidelines 2016 recommended for acute
right heart failure
• massive pulmonary embolism (high risk group) → ex-
tended hemodynamic monitoring (domain of the pul-
monary catheter, here is clearly superior to the PiCCO
system!)
• preferably no preload-decreasing drugs (nitrates, diu-
retics)
• possibly ECMO (va-ECMO for circulatory support)
-- especially in therapy-refractory cardiogenic shock
and cardiovascular arrest
-- possibly in combination with embolectomy (surgical
or interventional)
Embolectomy
Indications
• contraindication for lysis
• unsuccessful lysis (wait until a maximum of 2h; mortali-
ty of renewed lysis 38%, of surgery only 7%)
• possibly in combination with va-ECMO
Types
• interventional (radiological)
• surgical
Interventional embolectomy
• via right heart catheter
• class IIa recommendation (ESC guidelines 2014 +
2019 [surgical embolectomy: class I recommendation!)
• fragmentation (e.g. with Pigtail Rotation Catheter
[Cook], e.g. Greenfield Embolectomy Catheter [Boston
Scientific], e.g. Amplatz Thrombectomy Device), aspi-
ration embolectomy (with thrombus aspiration catheter
[e.g. Pronto])
• possibly rheolytic embolectomy (fragmentation of the
embolus using water-jet, e.g. Angiojet, Hydrolyser)
• possibly ultrasound accelerated
-- definition: so-called pharmacomechanical thrombo-
lysis (hybrid procedure; USAT [ultrasound-assisted
catheter directed thrombolysis])
 -- example: EcoSonic-Device (catheter with transdu-
cer at the tip and local lysis, fragmentation of the
embolus by means of ultrasound waves)
-- studies:
◦◦ improvement of hemodynamic parameters (Engel-
hardt et al, Thromb Res 2011)
◦◦ significant improvement of RV dysfunction (in
echocardiography) without increase in bleeding
rate in patients with intermediate risk compared to
patients who were only anticoagulated (Kucher et
al, Circulation 2014)
• studies:
-- ULTIMA (Kucher et al, Circulation 2014)
-- PERFECT (Kuo et al, Chest 2015)
-- SEATTLE II (Piazza et al, JACC 2015)
• meta-analysis (Catheter-directed therapy for the treat-
ment of massive pulmonary embolism: systematic re-
view and meta-analysis of modern techniques; Kou et
al, J Vasc Interv Radiol 2009):
-- success rate: 87%
-- complication rate: 7.9%
• possibly with local lysis
-- alteplase (Actilyse) 15mg into the pulmonary artery
-- Jaff et al, Circ 2011: no advantages for local lysis,
only increased bleeding at the puncture site
• very good also under fluoroscopy with the C-arm,
as possible at the intensive care bed and no transport
is necessary!
• our procedure: installation of a 7F sheath, then inser-
tion of 7F guiding catheter with wire (Terumo 0, 018"),
then pigtail catheter (e.g. 5F)

Fig. 820  Interventional embolectomy: After a sheath (7F)

has been established in the internal jugular vein, the right
ventricle and then the right pulmonary artery, which is al-
most subtotally obstructed by an embolus (DSA pulmonary
angiography), are probed with a pigtail catheter (7F) via a
guidewire (e.g. Terumo 0,018"). Then the guidewire passa-
ge takes place. The lying wire is now used for splinting and
the catheter is moved back and forth several times, which
usually leads to recanalization. In addition, we usually also
perform local lysis via the catheter (e.g. 20mg Actilyse).

Angiology 575
Tip for everyday practice, if there is a contraindication for
systemic lysis in case of massive pulmonary embolism
or if you simply do not dare to go high with systemic lysis
(e.g. because the patient only had a major surgery the
day before): A 7F sheath is inserted into the internal ju-
gular vein. Puncture is also possible if systemic lysis has
already taken place shortly before and is usually very
simple anyway in the case of a fulminant pulmonary em-
bolism, since the internal jugular vein is massively dilated
here. The sonographically controlled puncture, however,
is obligatory. Then a pulmonary artery catheter is inser-
ted at the patient's bed via the sheath under control of the
pressure curve on the monitor and under echocardiogra-
phy. Echocardiographically one can see the main stem of
the pulmonary artery and possibly even the embolus in
the parasternal short axis at the level of the aortic valve.
For better visualization, echo contrast medium (easiest
and cheapest: 20ml shaken up saline solution) can be
applied intravenously. In case of poor ultrasound condi-
tions in the transthoracic echo, TEE, which can also be
performed on the bed side, is also very helpful. If the
catheter is then located in the pulmonary artery (verified
by the typical pressure curve and echocardiography),
Actilyse (10-20mg; local lysis) is performed via the ly-
ing pulmonary catheter (via the lumen "PA- distal ") and,
if necessary, thrombus fragmentation is performed by
pushing forward and pulling back the inflated balloon (tip:
Block balloon with water instead of air!). In the meantime
there are also pulmonary catheters with a Y-shaped end
for the bifurcation of the pulmonary artery, so that local
lysis can be applied selectively to the lefr oder right pul-
monal artery. The great advantage of this procedure is
that no fluoroscopy and thus no transport of the already
massively unstable patient is necessary, but that all this
can be carried out on the bed side in the intensive care
unit or in the emergency room. Alternatively, the C-arm
can be attached to the intensive care bed and a right
heart catheter with appropriate thrombus fragmentation
can be performed. In my opinion, the recommendation
for the surgical embolectomy in the case of a contrain-
dication for lysis with massive pulmonary embolism is
far away from clinical everyday life: Who has a cardi-
ac surgery in the clinic? As a rule, the patient has to be
transferred, which is completely utopian for a massively
unstable patient or under resuscitation conditions: The
patient usually does not even survive the transfer from
the box in ICU to the corridor!
Surgical embolectomy
• Trendelenburg operation
-- named after the German surgeon Friedrich Trende-
lenburg (1844-1924), who first performed the ope-
ration in 1872 (note: none of the operated patients
survived the operation at the time.)
-- with heart-lung machine
-- in patients in shock and resuscitation
• „no more room for surgery in acute pulmonary embo-
lism“ (Oakley 1989)
• today modified Trendelenburg operation:
-- median sternotomy
-- access not from central, but from peripheral (with
aspirators)
576 Angiology
-- without cardioplegic cardiac arrest and without clam-
ping of the aorta
-- technically relatively simple (at least according to the
ESC guidelines 2014)
-- if necessary perioperative va-ECMO for stabilization
-- today embolectomy also possible down to the sub-
segment level
• surgical lethality:
-- formerly: 31% (with resuscitation even 60%)
-- today: 6%
• ESC guidelines 2014 + 2019: class IC recommen-
dation for contraindications against lysis or for unsuc-
cessful lysis
• pulmonary endarterectomy (PEA) in chronic pulmona-
ry hypertension (CTEPH: chronic thromboembolic pul-
monary hypertension)
Chronic thromboembolic pulmonary hy-
pertension (CTEPH)
Definition
• WHO class IV of pulmonary hypertension
• Only in 1.5% (formerly in 3.8% [Pengo et al, N Engl
2004; Becattini et al, Chest 2006]) pulmonary hyper-
tension remains after pulmonary embolism (however,
according to recent data [Guerin et al, Thromb Hae-
most 2014] allerdings in 5.4%).
• 1-year survival rate: only 30% (→ surgery [PEA: pul-
monary endarterectomy]!)
• risk factors: i.a. endovascular foreign material (e.g.
pacemaker leads, ventriculo-atrial shunt), splenecto-
my, chronic inflammation, hypothyroidism
Epidemiology
• m=w
• mean age: 63 years
• mean time (latency) to diagnosis: 1.5 years
• incidence: 5/1000000
Diagnostics
• Echokardiographie
-- echocardiography: Routine echocardiographic fol-
low-up after pulmonary embolism in asymptomatic
patients is not recommended.
-- Clinical monitoring 3-6 months after pulmonary em-
bolism is now routinely recommended in the ESC
guidelines (class I). If the patients suffers from dys-
pnoea, echocardiography should be performed.
• ventilation-perfusion scintigraphy:
-- diagnostic of choice (sensitivity 97%, specificity
95% [Tunariu et al, N Engl J 2007])
-- evidence of a mismatch
• chest CT:
-- A normal chest CT does not exclude CTEPH!
-- i.a. mosaic pattern (post-embolic changes) in HR-CT
(HR: high-resolution)
◦◦ pattern:
▪▪ bright: still healthy (perfused)
▪▪ dark (sick; no longer perfused due to emboli)
 ◦◦ Often the bright areas are misinterpreted as
ground glass opacities and the false diagnosis of
an alveolitis is made.
◦◦ but unspecific because it occurs also in other
forms of pulmonary arterial hypertension
• spiroergometry
• right heart catheter
-- a precapillary pulmonary hypertension:
◦◦ mPAP (mean pulmonary artery pressure) > 25
mmHg
◦◦ PCWP (pulmonary capillary wedge pressure) < 15
mmHg
-- no vasoreactivity testing necessary here
• annotation to the procedure: After the diagnosis has
been made, oral anticoagulation is first carried out over
a period of three months in order to better differentiate
CTEPH from acute or subacute pulmonary embolism.
Then the right heart catheter examination takes place
again and only then the therapy is initiated.

Fig. 822  chest CT in CTEPH: The typical mosaic pattern

can be seen here. The bright areas (arrows) are often mi-
sinterpreted as ground glas opacities (as an indication of
alveolitis) on CT. Ultimately, this are only the areas of the
lungs that are still perfused. The dark areas are no longer
perfused due to the multiple emboli.

Therapy
• surgical: pulmonary endarterectomy (PEA)
-- first choice (even curable!)
-- relatively (to the spontaneous prognosis of the di-
sease) low surgical mortality (6%; more recent data
[Mayer et al, J Thorax Cardiovasc Surg 2011] even
only 4.7%)
-- under hypothermia and cardioplegic cardiac arrest
-- Not only an embolectomy, but also an endarterecto-
my (bilaterally) is performed, i.e. the intima with the
fibrous stenoses (transformed thrombus material) is
peeled out of the pulmonary arteries.
Fig. 821  ventilation-perfusion scintigraphy for CTEPH: It is -- good long-term prognosis
the first choice diagnostic tool here. Numerous perfusion -- prerequisite: especially for central (not peripheral)
defects can be seen. obstructions (ideally at the lobe to proximal segment
level)
-- postoperative often temporary use of va-ECMO
-- age up to 65 years (relative)
-- inoperable in 50% (technical [therefore pulmonary
angiography is important preoperatively] or medical)
-- The operation is not offered in all cardiac thoracic
surgery clinics, but only in appropriate centers.
• interventional: BPA (balloon pulmonary angioplasty)
-- only if inoperable
-- dilatation of obstructions

Angiology 577
 -- usually several sessions (5-10) necessary
-- high perinterventional complication rate (especially
pulmonary artery perforation and dissection), espe-
cially frequent bleeding (usually stop spontaneously;
if not: temporary insufflation of the balloon proximal
to the perforation, possibly embolization)
-- still relatively little common
• pharmacological (only if inoperable)
-- general: lifelong oral anticoagulation
◦◦ also after pulmonary endarterectomy
◦◦ VKA or alternatively NOAC
-- special:
◦◦ riociguat (stimulator of the soluble guanylate cy-
clase [sGC]; CHEST-1 study [approval study]; of-
ficially approved for this purpose since 2014 [as
the only drug for the treatment of pulmonary hy-
pertension here])
◦◦ possibly bosentan (BENEFIT study [Jais et al, J
Am Coll Cardiol 2008])

Prognosis
• mortality: 8% overall (massive pulmonary embolism
[high risk group]: 25-30%)
• The main lethality is on day 1, and here especially in
the first 3 hours: 80% of all deaths occur in the first
3 hours. Therefore monitoring for 24 hours is usually
sufficient.
• decisive prognostic parameter: detection of right ven-
tricular dysfunction → mortality: 10-15% (with additio-
nal arterial hypotension [shock]: 25-30%)
• prognosis estimation (i.a. low-risk group: PESI class I
or sPESI 0P.)
-- PESI score (the score best validated and therefore
recommended by the guidelines; according to Kore-
an et al, J Intern Med 2009; see infobox)
-- simplified PESI score: sPESI (s: simplified; only 5
parameters; according to Jimenez et al, Br J Haema-
tol 2010; see infobox

VTE (venous thromboembolism): It is

completely irrelevant where the clot is
located in the small circuit (in a leg
vein or pulmonary artery). The only
prognostically decisive factor is
whether there is a RV dysfunction!

578 Angiology

study
Pulmonary Embolism Hospitalization, Readmission and
Mortality Rates in US Older Adults
Bikdeli et al, JAMA 2019
• retrospective observational study
• 810,969 inpatients with discharge diagnosis "pulmonary
embolism" and age ≥ 65 years (mean age: 77.6 years)
• results: in the period 1999-2015
-- increase in the hospital first admission rate from
120/100000 insured persons to 187/100000 (peak
2010 with 198/100000)
-- decrease in hospital readmission rate (after 30 days)
from 15.5% to 13.6%
-- decrease in length of hospital stay from 7.7 to 5.5 days
-- decrease in mortality
◦◦ short-term mortality (hospital): from 8.7% to 4.0%
◦◦ long-term mortality (1 year): from 26.3% to 24.1%
Recurrence prophylaxis
Definition
• syn.: maintenance therapy
• recurrence rate: 4%/year (high!)
-- For idiopathic (i.e. without a known risk factor) ve-
nous thromboembolism, the risk of recurrence is
10% after 1 year, 25% after 5 years and 33% after
10 years! Therefore, unlimited anticoagulation ma-
kes sense here.
-- for malignancy: 20%/year
-- for men higher (by 60%) than for women
• The biggest risk factor for a renewed VTE is an already
suffered (idiopathic) VTE!
• The recurrence rate is independent of the type of first
event of venous thromboembolism, i.e. it is not higher
after pulmonary embolism than after deep vein throm-
bosis!
• Recurrence may also occur during anticoagulation (in
2% after 2 weeks, in 6% after 3 months, in 8% after 6
months).
• annotation on oral contraceptives ("pill"): After a (espe-
cially idiopathic) VTE, women should best discontinue
oral contraceptives (6-fold increased risk of VTE) and
consider other options for contraception. If oral contra-
ceptives are continued to be taken, one should switch
to a pure progestin preparation (i.e. monopreparation
without additional estrogen), as progestins are signi-
ficantly less thrombogenic than estrogens. Most oral
contraceptives today are mixed preparations made
from an estrogen and a progestin.
Cancer patients
Anticoagulation
In cancer patients, anticoagulation (after a VTE) should
be performed for the duration of the active disease, i.e.
in a palliative situation for the rest of their life. The risk of
recurrence in patients with malignancy is twice as high
as in patients without malignancy. Pulmonary embolism
is the second leading cause of death in these patients.
Anticoagulation should be performed with low molecular
weight heparins (LMWH). VKA (e.g. marcumar) should
not be used in cancer patients, as reliable INR adjust-
ment is usually problematic due to drug interactions, tu-
mor cachexia and liver insufficiency (e.g. in liver metas-
tases). LMWH are superior to oral anticoagulation with
VKA in secondary prophylaxis after venous thromboem-
bolic events in cancer patients (i.a. CLOT study [Lee et
al, N Engl J 2003; dosage here: dalteparin 200 IE/kg s.c.
1 x daily. s.c. over 4 weeks, then reduction to 75%, i.e.
150 IE/kg 1 x daily]; CATCH study [Lee et al, ASH 2014:
tinzaparin 125 IU/kg 1 x daily s.c. ober 85 days halved
the risk of recurrence of venous thromboembolism com-
pared to warfarin!], CANTANOX study [Meyer et al, Arch
Intern Med 2002] and ONCENOX study [Deitcher et al,
Clin Appl Thromb Hemost 2006] each for enoxaparin 1.5
mg/kg/d over 3 months with analogous advantages over
LMWH). Cancer patients often develop thrombopenia
(e.g. due to chemotherapy or bone marrow infiltration):
As long as the thrombocytes are > 50000/μl, the dose
of heparin is not reduced. With regard to the novel oral
anticoagulants (NOAC), there were no studies on secon-
dary prophylaxis after venous thromboembolic events
in tumor patients and therefore no recommendations
for a long time. In several studies (see boxes; Hokusai
VTE Cancer study for edoxaban, ADAM VTE study for
apixaban, SELECT-D study for rivaroxaban) NOAC were
found to be equivalent to LMWH. NOAC can definitely be
used in cancer patients (provided that the kidney function
is still normal). This is much more pleasant for the patient
than the s.c. application of LMWH. In the ESC guideli-
nes 2019, edoxaban and rivaroxaban are recommended
as alternatives to LMWH (IIa recommendation), only not
in patients with gastointestinal tumors (especially gast-
ric cancer), since the studies have shown a significantly
increased bleeding rate here. However, one should be
careful about the interactions with other drugs (especially
chemotherapeutic agents), so that the NOAC here (es-
Angiology 579
pecially during a chemotherapy cycle) should be swit-
ched to LMWH (in a fully therapeutic dose):
• increase in NOAC levels (cave: risk of bleeding ↑):
-- calcineurin inhibitors (cyclosporine, tacrolimus, siro-
limus)
-- tyrosine kinase inhibitors
◦◦ very high risk: sunitinib, vandetanib
◦◦ high risk: imatinib, nilotinib, crizotinib
-- macrolide antibiotics (especially clarithromycin)
-- azole antifungals (fluconazole, voriconazole)
• decrease in NOAC levels (cave: risk of thromboem-
bolism ↑):
-- dexamethasone (is often used for antiemesis as part
of chemotherapy)
-- doxorubicin
-- vinblastine
HOKUSAI VTE Cancer
study
Edoxaban for the Treatment of Cancer-Associated Venous
Thromboembolism
Raskob et al, N Engl J 2017
• open randomized non-inferiority study
• 1050 patients with venous thromboembolism (VTE) and
malignancy; for 6-12 months
-- LMWH (dalteparin 200 IU/kg for 1 month, then 150
IU/kg)
-- edoxaban 1 x 60mg
• result: primary endpoint (a combined endpoint of VTE
recurrence and severe bleeding) → no difference (equi-
valent; less VTE, but more bleeding with edoxaban [es-
pecially gastrointestinal bleeding, especially with gastro-
intestinal tumors such as gastric cancer])
ADAM VTE study
Apixaban versus Dalteparin in Active Cancer Associated
Venous Thromboembolism
McBane et al, ASH 2018
• open randomized non-inferiority study
• 300 patients with venous thromboembolism (VTE) and
malignancy; for 6 months
-- LMWH (dalteparin 200 IU/kg for 1 month, then 150
IU/kg)
-- apixaban (for 7 days 2 x 10mg, then 2 x 5mg)
• result: no difference in the bleeding rate (primary end-
point) with fewer VTE recurrences in the apixaban group
580 Angiology
SELECT-D study
Comparison of an Oral Factor Xa Inhibitor With Low Molec-
ular Weight Heparin in Patients With Cancer With Venous
Thromboembolism
Young et al, J Clin Oncol 2018
• open randomized non-inferiority study
• 203 patients with venous thromboembolism (VTE) and
malignancy; for 6 months
-- LMWH (dalteparin 200 IU/kg for 1 month, then 150
IU/kg)
-- rivaroxaban (for 21 days 2 x 15mg, then 1 x 20mg)
• result: lower VTE recurrence rate (primary endpoint)
with an increased bleeding rate in the rivaroxaban group
Tumor search
10% of all patients with malignancy develop a venous
thromboembolism. Particularly thrombogenic tumors are
pancreatic and gastric carcinoma. The paraneoplastic
occurrence of VTE is also known as Trousseau syndro-
me (named after the French internist Armand Trousseau
[1801-1867], who diagnosed himself due to an unclear
thrombophlebitis on his arm with gastric carcinoma, from
which he died a few months later). An idiopathic VTE is
often (3-15%) based on a previously occult malignancy.
More than half of all malignancies detected in VTE are
detected at a very early stage and can still be treated
curatively (Monreal et al, J Thromb Haemost 2004)! 10%
of all patients with idiopathic VTE develop a malignancy
within the next 5-10 years. In many places, after an idio-
pathic VTE a tumor search of varying extent (incl. gas-
troscopy, colonoscopy) is carried out. However, there is
definitely no clear evidence for this! In a study (Di Nisio
et al, J Thromb Haemost 2005), idiopathic VTE was in-
vestigated using CT (abdomen, pelvis), mammography
(in women) and sputum cytology. There was no benefit
in terms of mortality after 5 years. In its guidelines, the
German Society for Phlebology recommends the search
for tumors in idiopathic VTE (e.g. abdominal sonography,
hemoccult test). Also in the current guidelines "diag-
nostics and therapy of venous thrombosis and pulmo-
nary embolism" of the German Society for Angiology, a
tumor search is recommended for etiologically unexplai-
ned VTE (i.a. the updating of age- and gender-specific
statutory tumor early detection measures). The determi-
nation of tumor markers as a screening is explicitly not
recommended. With regard to the colonoscopy perfor-
med in many places to search for tumors after pulmonary
embolism, it should only be noted that the main cause
of death in colonoscopy is cardiovascular and the car-
diovascular risk is definitely increased immediately after
pulmonary embolism! The ESC guidelines only recom-
mend a physical examination, a basic laboratory and a
chest X-ray, which is not necessary in already performed
CT thorax anyway. Routine CT screening also has no
benefit (Carrier et al, N Engl J 2015). Nor is there any
evidence and therefore no recommendation to perform
a gastroscopy and colonoscopy before any planned oral
anticoagulation to exclude a source of bleeding. It cer-
tainly makes sense to perform colonoscopy from the age
of 55 (in the further cause [> 4 weeks], not immediately) PADIS-PE study
and to screen men for prostate cancer (PSA levels) and
women for breast and cervical cancer.

Duration Six months vs extended oral anticoagulation after first epi-

• with cause (provoked; transient risk factor; e.g. im- sode of pulmonary embolism
Couturaud et al, JAMA 2015
mobilization, surgery, trauma, acute internal disease,
pregnancy, estrogen therapy): limited • PADIS-PE: prolonged anticoagulation during eighteen
-- 3 months (not longer than 6 months! This does months vs placebo after initial six-month treatment for a
not only appliy to deep vein thrombosis, but also to first episode of idiopathic pulmonary embolism
pulmonary embolism!) • randomized placebo-controlled study
-- The risk of recurrence after anticoagulation over only • 371 patients with idiopathic pulmonary embolism (i.e.
3 months is not higher than after anticoagulation no risk factors), 6 months anticoagulation with warfarin
over 6 months or even 12 months (i.a. Schulmann (target INR 2-3)
et al, N Engl J 1997; Douketis et al, Ann Intern Med -- additional 18 months anticoagulation with warfarin
2007). -- placebo
• result: significant reduction of primary combined end-
• without cause (unprovoked; idiopathic): unlimited (pro-
point (symptomatic recurrence of venous thromboembo-
longed maintenance therapy lism and severe bleeding)
-- If no clear cause can be identified, unlimited antico-
agulation should be considered. Venous thromem-
bolism is a disease that will “catch” ist recurrence pro contra
sometimes! risk factor persisting passager
-- at least 3 months
genesis unclear triggered
-- depending also on the bleeding risk (e.g. HASBLED
score) recurrence yes no
-- regular reevaluation in the course bleeding risk low high
-- decision support (overview regarding support for de- previous quality of oral
cision making: see table): anticoagulation good poor
◦◦ D-dimer 1 month after discontinuation of oral an- D-dimers increased not increased
ticoagulation residual thrombus yes no
▪▪ D-dimer increased: increased risk of recurrence
sex man woman
(i.a. Fattorini et al, J Thromb Haemost 2002; Pa-
lareti et al, J Thromb Haemost 2002; Duoketis et thrombus extension long distance short distance
al, Ann Int Med 2010; RIETE study [Avnery et al, thrombus localization proximal distal
JIM 2019]) → continue anticoagulation severe thrombophilia yes no
▪▪ D-dimer normal: no longer increased risk of
patient preference for it against it
relapse → discontinue anticoagulation (cave:
relatively unreliable; also in case of second ne- Fig. 823  Criteria for or against prolonged maintenance the-
gative result after 1 month; especially unreliable rapy after venous thromboembolism (according to S2 gui-
delines "Diagnosis and Treatment of venous thrombosis
in men; only reliable in women who were under
and pulmonary embolism"); severe thrombophilia includes,
estrogen therapy [e.g. pill] and stopped it [Kea- for example, antiphospholipid syndrome, but not heterozy-
ron et al, Ann Int Med 2015]) gous factor V or heterozygous prothrombin mutation
◦◦ after deep vein thrombosis: ultrasound of the veins
(residual thrombosis present → continue antico-
agulation)
-- lifelong:
◦◦ second idiopathic VTE
◦◦ CTEPH
◦◦ thrombophilia

According to the ESC guideline 2019, a distinction is no

longer made between provoked and unprovoked, but the
risk factors are divided into 3 groups (see infobox)

Angiology 581
 Pharmacological recurrence prophylaxis
• oral anticoagulation
-- Vitamin K antagonists (VKA; e.g. marcumar, warfa-
rin)
-- NOAC (non-vitamin K antagonist / novel / new oral
anticoagulants; agent of choice [ESC 2019: class I
recommendation]): no overlap necessary here; can
also started immediately, i.e. without prior parenteral
anticoagulation
◦◦ applies only to rivaroxaban and apixaban, for dabi-
gatran (10 days) and edoxaban (5 days) parente-
ral anticoagulation must be performed
◦◦ does not apply to hemodynamically unstable pati-
ents (NOAC are only approved for hemodynami-
cally stable patients.)
• ASA

Marcumar
• overlapping for at least 5 days (otherwise increased
risk for cumarin-induced skin necrosis
• if applicable begin at the same time as parenteral an-
ticoagulation (e.g. 3-2-1-scheme: d1 3 pills d2 2 pills,
d3 1 pill)
• heparin is not terminated until INR has been in the tar-
get area for two days
• target INR: 2-3
• Marcumar reduces recurrence rate by 90% (not 100%!
NNT = 9)

NOAC
• rivaroxaban (Xarelto)
-- approved since 2012 for this purpose
-- study: EINSTEIN-PE (pulmonary embolism; rivaro-
xaban versus enoxaparin / marcumar in pulmona-
ry embolism → not inferior; fewer major bleedings
[Büller et al, N Engl J 2012])
-- dosage: 3 weeks 2 x 15mg, then 1 x 20mg (ap-
proved for extended maintenance therapy with 1 x
10mg [CHOICE study])
• dabigatran (Pradaxa)
-- approved since 2014 for this purpose
-- studies: RECOVER I/II, REMEDY, RESONATE
-- dosage: first 10 days parenteral anticoagulation,
then 2 x 150mg (if age > 80 years or verapamil: 2
x 110mg)
• apixaban (Eliquis)
-- approved since 2014 for this purpose
-- studies: AMPLIFY, AMPLIFY-EXT
-- dosage: for 7 days 2 x 10mg, dann 2 x 5mg (ap-
proved for extended maintenance therapy with 2 x
2.5mg [ADVANCE study])
• edoxaban (Lixiana)
Types
-- approved since 2015 for this purpose
• pharmacological
-- study: Hokusai-VTE
• interventionel (vena cava filter)
-- dosage: first 5 days parenteral anticoagulation, then
1 x 60mg p.o. (if GFR 30-50 ml/min or weight < 60kg:
1 x 30mg)

582 Angiology

NOAC: with rivaroxaban or apixaban
immediate (i.e. without prior admini-
stration of heparin) as well as pro-
longed maintenance at half the dose
therapy possible
ASA
• studies
-- WARFASA study (Becattini et al, N Engl J 2012):
ASA versus placebo for another 2 years after idiopa-
thic venous thromboembolism → reduction of recur-
rent venous thromboembolism
-- ASPIRE study (Brighton et al, N Engl J 2012): ASA
versus placebo for another 4 years after idiopathic
venous thromboembolism → no reduction of recur-
rent venous thromboembolism
-- INSPIRE study (analysis of data from WARFASA
and ASPIRE studiy; Simes et al, Circulation 2014):
ASA versus placebo (following cessation of oral anti-
coagulation) in idiopathic venous thromboembolism
→
◦◦ reduction of recurrent venous thromboembolic di-
sease by 32% (5.1% instead of 7.5% per year)
◦◦ reduction of major vascular events (recurrent
venous thromboembolism, myocardial infarc-
tion, stroke, cardiovascular death) by 34% (5.7%
instead of 8.7% per year)
◦◦ no significantly increased risk of bleeding
• recommendation: ESC 2014 + 2019 IIb
reduction in pulmonary embolisms, if patients with
deep leg vein thrombosis received a vena cava filter
in addition to oral anticoagulation (no difference in
mortality)
-- PREPIC-2 study (Mismetti et al, JAMA 2015): no
reduction in pulmonary embolisms, if patients with
deep leg vein thrombosis received a vena cava filter
in addition to oral anticoagulation (ineffective
-- ICOPER-Register (ICOPER: International Coope-
rative Pulmonary Embolism Registry; Kucher et al,
Circulation 2006): high efficacy
-- retrospective cohort study (Muriel et al, J Am Coll
Cardiol 2014): The vena cava filter could only redu-
ce pulmonary embolism associated mortality, but not
all-cause mortality. The vena cava filter group even
showed an increased risk of recurrence of venous
thromboembolism.
-- retrospective cohort study (Turner et al, JAMA 2018):
-- even excess mortality (increased mortality by 18%
after 30 days)
• evaluation: class IIa recommendation (ESC guidelines
2014 + 2019

ASA in idiopathic VTE not as an

alternative to oral anticoagulation
(only half as effective), but as an
option in contraindications or
rejection of oral anticoagulation (at
least better than placebo!)

Interventional recurrence prophylaxis:

vena cava filter
• indication:
-- recurrent pulmonary embolisms despite sufficient
anticoagulation
-- contraindication for anticoagulation Fig. 824  Cava filter (in the inferior vena cava)
-- after surgical thrombectomy (A vena cava filter is
usually implanted as standard.) Excursus: Pulmonary embolism in
• types:
pregnancy
-- permanent vena cava filter (high rate of late compli-
cations [especially fracture, dislocation, migration],
therefore worse)
-- temporary cava screen (removable; better; e.g. An-
gel catheter [company BiO2 Medical])
• placement: interventional (access usually via the fe-
moral vein; placement just below the renal veins; best
use of removable filters
• studies:
-- PREPIC study (Desousus et al, Circulation 2005:

Angiology 583
Introduction
• During pregnancy, the risk of pulmonary embolism is
increased per se (four times higher than outside preg-
nancy).
• Pulmonary embolism is the most common cause of
death in pregnancy (especially in the last trimester and
in the first 6 weeks postpartum)! In the first trimester,
the risk is increased if in vitro fertilization has taken
place.
• Pulmonary embolism is the "killer No.1" in pregnan-
cy. Therefore, it should be excluded very generously
(using a perfusion scintigraphy). One can only warn
against discharging patients back home with some
imaginary pseudodiagnosis without excluding pulmo-
nary embolism. If the patient has cardiovascular arrest
at home and dies, you must explain this to the husband
(widower) and father of the deceased baby and the pa-
rents of the deceased woman! You wont´s forget this
as a pysician for your whole life!
• incidence:
-- 10-15/100000 pregnancies
-- 1.7 / 1,000 deliveries (1 death / 100,000 deliveries)
• The radiation exposure for the still unborn child is the
main problem in diagnostics during pregnancy. The
threshold of radiation exposure, at which damage to
the fetus occurs, is 50 mSv. The radiation exposure for
CT thorax is 2-6 mSv, for scintigraphy only 1.1 mSv.
Diagnostics
• anamnesis / physical examination; i.a. LEFt rule (re-
garding thrombosis in pregnancy):
-- parameters:
◦◦ L: left leg
◦◦ E: edema (difference in calf circumference ≥ 2cm)
◦◦ Ft: first trimester
-- interpretation: If none of the three parameters is
met, no deep vein thrombosis is present in 100%
(very high negative predictive value; Chan et al, Ann
Int Med 2009; also confirmed by Righini et al, Ha-
ematologica 2013).
• laboratory: i.a. D-dimers:
-- mostly increased in pregnant women and only poor-
ly helpful (i.a. DiPEP study [Diagnosis of Pulmonary
Embolism in Pregnancy; Hunt et al, Br J Haematol
2018])
-- A negative D-dimer, however, excludes pulmonary
embolism to 95% in the same way as in non-preg-
nant women.
-- adaptation of the threshold value to gestational
age (higher specificity without reduction of sensitivity
[Morse et al, J Thromb Haemost 2004; Chan et al, J
Thromb Haemost 2010]):
◦◦ 16th WOP: 191 +/- 25 μg/l
◦◦ 26th WOP: 393 +/- 72 μg/l
◦◦ 34th WOP: 544 +/- 96 μg/l
• determination of the alveolar dead space fraction
(AVDSF; see page 550): An alveolar dead space
fraction < 0.1 in combination with an inconspicuous fin-
ding in sonography pf the leg veins makes pulmonary
embolism (very) unlikely.
584 Angiology
• ultrasound:
-- sonography leg veins
◦◦ An inconspicuous sonography of the leg vein ex-
cludes a pulmonary embolism in 90%.
◦◦ in pregnancy thrombosis mostly on the left leg
◦◦ always also assess the pelvic veins, which are
frequently affected by thrombosis during pregnan-
cy:
▪▪ pw-Doppler in the proximal superfemoral vein:
The flow has to cease with deep inspiration and
Valsalva. This rules out pelvic vein thrombosis
by 95%.
▪▪ Compression sonography (with the linear trans-
ducer) is often difficult in the pelvic area, but
usually works very well with the convex (= abdo-
men) transducer!
◦◦ If a thrombosis can be detected in the sonogra-
phy of the leg veins, the diagnosis of pulmonary
embolism is considered confirmed (with corres-
ponding symtoms [e.g. dyspnea]).
-- echocardiography
◦◦ A pulmonary embolism cannot be ruled out if there
is no right ventricular dysfunction. 80% of all pati-
ents with pulmonary embolism have no right ven-
tricular dysfunction at all.
◦◦ during pregnancy frequently physiologically dila-
ted right heart cavities (hypervolemia)
◦◦ possibly direct visualization of an embolus in the
pulmonary artery (main trunc) and in the area of​​
the bifurcation in the TTE (only works very rarely;
possibly also with contrast agent [shaken saline
solution])
-- lung sonography
◦◦ very good option with corresponding expertise
◦◦ can prove pulmonary embolism with a positive re-
sult, but cannot rule out pulmonary embolism with
a negative result
• chest CT
-- contraindicated due to radiation exposure for unborn
child (only relatively); furthermore also increased
risk for breast cancer (maternal breast), which, how-
ever, is negligible with modern CT devices
-- however feasible with vital indication from the third
trimester under appropriate protection (body-wrap-
ping lead covering of the abdomen, options for tech-
nical dose optimization)
-- possibly therapy as if it would be a pulmonary em-
bolism (e.g. LMWH s.c.) and chest CT immediately
after delivery
• scintigraphy
-- first choice for diagnosing pulmonary embolism du-
ring pregnancy (ESC guidelines 2014: IIb recom-
mendation)
-- Usually only a perfusion scintigraphy is performed.
Here the radiation exposure for the fetus is almost
negligible because he is not in the direct scan area.
At most, some scattered radiation reaches him. Per-
fusion scintigraphy is also relatively safe in early
pregnancy. The i.v. marker substance gets stuck in
the mother's pulmonary capillaries and does not get
 into the fetal circulation.
◦◦ If the perfusion scintigraphy is inconspicuous, pul-
monary embolism is ruled out and no further diag-
nostics are required
◦◦ If the perfusion scintigraphy is conspicuous (evi-
dence of a perfusion deficit), it can either be a pul-
monary embolism or a structural lung disease (va-
soconstriction due to the Euler-Liljestrand reflex;
e.g. COPD, pneumonia). For this differential dia-
gnosis, ventilation scintigraphy is then performed
as standard outside of pregnancy. This is incons-
picuous in pulmonary embolism (mismatch), and
conspicuous in structural lung disease (match).
However, an additional ventilation scintigraphy si-
gnificantly increases the radiation exposure. Since
pregnant women usually do not have any structu-
ral lung disease due to their young age, a chest x-
ray is completely sufficient instead of a ventilation
scintigraphy to rule out a structural lung disease.
A chest X-ray has only minimal radiation exposure
(< 0.01 mSv) and is allowed during pregnancy. The
chest X-ray can still be made after the perfusion
scintigraphy, if it was conspicuous (pathological).
-- Only with the combination of perfusion and ventilati-
on scintigraphy, which is extremely rarely necessary
in pregnancy, the radiation exposure for the uterus
would be higher than with CT (Schae­fer-Prokop et
al, Eur Radiol 2008).
• MRI (allowed in pregnancy, but limited in significance
and therefore not yet generally recommended)
to exclude pulmonary embolism in
pregnancy → perfusion scintigraphy
(only low radiation exposure): If it is
normal, pulmonary embolism is
excluded!
D-dimer
negative positive (mostly the case)
PE Echo
excluded (RV dysfunction? PPCM?)
positive PE proven
sonography leg veins
(thrombosis proven)
negative
lung sonography positive
negative
chest X-ray conspicuous, i.e. a finding that explains
the dyspnea (e.g. pneumothorax,
pneumonia)
inconspicuous
perfusion scintigraphy
Fig. 825  Algorithm for diagnosis of suspected pulmonary
embolism in pregnancy (PE: pulmonary embolism; PPCM:
peripartum cardiomyopathy); note: If you have no clinical
or laboratory evidence of pneumonia, chest x-ray is not ab-
solutely necessary.)
study
Pregnancy-Adapted YEARS Algorithm for Diagnosis of
Suspected Pulmonary Embolism
van der Pol et al, N Engl J 2019
• prospective observational study
• 498 pregnant women with suspected pulmonary embo-
lism were hospitalized; use of the YEARS algorithm for
rule-out (see page 555; YEARS algorithm was modified
in such a way that with clinical suspicion on a deep vein
thrombosis sonography of the leg veins was performed
and, if this was positive, a CT chest was waived and full
anticoagulation was initiated); otherwise (if no rule-out) a
chest CT was performed in all pregnant women
• results:
-- Venous thromboembolism only occurred in 0.21% af-
ter 3 months (primary endpoint).
-- avoidance of an unnecessary chest CT:
◦◦ in the first trimester: in 65%
◦◦ in the third trimester: in 32%
Therapy
• LMWH s.c.
-- Heparins (both UFH and LMWH) neither cross the
placenta nor the breast milk.
-- Pre-filled syringes should always be used and not
the multidose bottles, as these contain preservatives
that can damage the fetus.
-- The recommended dosages adapted to the body
weight relate to the current actual weight at the be-
ginning of the pregnancy. The child does not have
a VTE and therefore does not need any anticoagu-
lation.
-- The therapy with LMWH in pregnancy should always
be monitored by means of anti-factor Xa control, i.e.
even with normal creatinine and weight.
-- for 3 months (and not only for about 10-14 days) full-
therapeutic dosage, then switch to the semi-thera-
peutic dosage is possible
• fondaparinux: also possible during pregnancy (i.a. ac-
cording to the S2k guidelines 2015 "diagnostics and
therapy of venous thrombosis and pulmonary embo-
lism" fondaparinux can be used in case of contraindi-
cations against heparins [e.g. HIT II] during pregnancy
[based on numerous case reports and collection ca-
suistics]).
• oral anticoagulation:
-- VKA (e.g. marcumar): contraindicated in pregnancy
(reason: mainly fetal hemorrhages, fetal hepatopa-
thies, malformations), but allowed in lactation period
(However, since it passes into breast milk, the child's
physiological hypoprothrombinemia may be exacer-
bated, so that breastfed infants should receive vita-
min K [Konakion].)
-- NOAC: contraindicated in pregnancy (and also in
lactation period)
Angiology 585
• lysis (fibrinolytic therapy): Pregnancy is not a contra-
indication for lysis per se. Fibrinolytics don't cross the
placenta. If a pregnant woman is hemodynamically un-
stable in the context of pulmonary embolism or even
has to be resuscitated, lysis can and must be perfor-
med. A dead mother does not help the child a lot! Lysis
here is also relatively safe and effective: In a review
(Ahearn et al, Arch Intern Med 2002) of 200 cases of
massive pulmonary embolism (high risk group) during
pregnancy with successful lysis, a very low maternal
mortality rate of 1% was found. If there are contrain-
dications for lysis, an embolectomy should be perfor-
med.
• survival rates (Martillotti et al, J Thromb Haemost
2017) with massive pulmonary embolism (high risk
group) during pregnancy:
-- mother:
◦◦ with lysis: 94%
◦◦ with embolectomy: 86%
-- child:
◦◦ with lysis: 88%
◦◦ with embolectomy: 80%
• Anticoagulation after venous thromboembolism in
pregnancy should be carried out in therapeutic dosage
for at least 3 months and in total (e.g. then in semi-
therapeutic dosage) at least up to 6 weeks postpartum.
In case of a renewed pregnancy after having suffered
from VTE in a previous pregnancy, prophylactic antico-
agulation should be performed during the entire preg-
nancy up to 6 weeks postpartum.
• procedure peripartal:
-- VTE before 37th WOP → stop anticoagulation with
beginning labor; restart anticoagulation:
◦◦ after vaginal delivery: after 6-12h
◦◦ after cesarean section: after 12-24h
-- VTE after 37th WOP → switch to perfusor with un-
fractionated heparin (target PTT: 50-70s)
-- note: If an pepidural catheter is planned, no LMWH
(in therapeutic dosage) should be applied 24 hours
before installation until 4 hours after removal (also
no LMWH 12 hours before cesarean section and in
time before vaginal delivery).
Excursus: Bridging
586 Angiology
Definition
• interruption of an oral anticoagulation (VKA [vitamin
K antagonist, e.g. marcumar, warfarin]; not necessary
with NOAC) for surgical interventions and bridging with
heparin
• indications (oral anticoagulation)
-- atrial fibrillation (stroke risk on average only 4%/year
[risk per day 1:10000])
-- mechanical heart valves (stroke risk up to 20%/year)
-- status post venous thromboembolism (VTE; deep
vein thrombosis / pulmonary embolism)
-- Note: If a patient is admitted to the intensive care
unit, a pre-existing oral anticoagulation (VKA,
NOAK) should be switched to LMWH s.c. change,
because initially you never know exactly what will
happen and what will be necessary (e.g. installation
of large-volume accesses, emergency surgery ne-
cessary, massive decrease in platelets as part of a
sepsis-induced DIC). Exceptions are certainly pati-
ents with mechanical valves..
BRIDGE study
Perioperative bridging anticoagulation in patients with atrial
fibrillation
Duoketis et al, N Engl J 2015
• prospective randomized controlled double-blind study
• 1884 patients with atrial fibrillation + oral anticoagulation
(VKA [warfarin]), which was discontinued 5 days preope-
ratively (started again 24h postoperatively):
-- with bridging (dalteparin 100 IU/kg 2 x daily s.c. 3
days preoperatively up to 24 hours before surgey and
then up to 5-10 days postoperatively)
-- without bridging (only placebo)
• results:
-- no difference in the frequency of systemic arterial em-
bolisms (especially stroke, TIA; in total 0.4% after 30
days)
-- significantly more bleeding in the bridging group
• annotations:
-- predominantly only patients with a low cardioembolic
risk (average CHADS2 score only 2.3P.)
-- fully therapeutic (and not, as is usually the case, semi-
therapeutic) dose of dalteparin
-- exclusion criteria: i.a.
◦◦ mechanical heart valves
◦◦ stroke in the past 3 months
 Risk of bleeding - intervention
• interventions with low risk of bleeding (< 1.5%; see in-
fobox): no discontinuation of VKA (mandatory) neces-
PAUSE study sary (retain VKA; continuation if necessary with lower
target INR [1.8-2.0])
• interventions with a high risk of bleeding (> 1.5%): dis-
continuation of VKA (4-7 days before) necessary
Perioperative Management of Patients With Atrial Fibrilla-
-- bridging with heparin depending on the thromboem-
tion Receiving a Direct Oral Anticoagulant
Douketis et al, JAMA Int Med 2019
bolism risk (see infoxox)
-- types of heparin:
• retrospective observational study ◦◦ LMWH (mostly used for bridging, but off-label use
• PAUSE: Perioperative Anticoagulation Use for Surgery for mechanical heart valves)
Evaluation ◦◦ UFH
• 3007 patients with atrial fibrillation with NOAC who
▪▪ in renal insufficiency with GFR < 30 ml/min (al-
underwent elective surgery; NOAC was discontinued
preoperatively according to a simple scheme (PAUSE ternatively, however, tinzaparin [Innohep] also
scheme: 1 day before in case of low risk of bleeding, possible here: the only LMWH that does not
2 days before in case of high risk of bleeding) and re- accumulate in renal insufficiency and therefore
started postoperatively (after 1 day in case of low risk of also possible here [but only up to a GFR of 20
bleeding, after 2 days in case of high risk of bleeding); ml/min])
no bridging (such as with heparin) was performed ▪▪ either s.c. or i.v.
• results:
-- major bleeding up to day 30: < 2% (for procedures
with a high risk of bleeding: < 3%)
-- arterial embolism (especially ischemic strokes) up to
day 30: < 1%

The main perioperative risk is not the

risk of embolism, but the risk of
bleeding!

Horror haemorrhagicus instead of

Horror embolicus!

The approach depends on the one hand on the risk of

bleeding (both of the patient [HAS-BLED score; see page
436] and of the intervention) and on the other hand on
the risk of thromboembolism (see infobox).

Risk of bleeding

Risk of thromboembolism

Risk of bleeding - patient

• HAS-BLED score < 3P.: low
• HAS-BLED score ≥ 3P.: high

Angiology 587
 Special forms (pulmonary embo-
lism)
• fat embolism
• cholesterol embolism (siehe Seite 987)
• air embolism
• tumor embolism
• ammniotic fluid embolism
• foreign body embolism
• septic embolism
-- occurrence: e.g. in the context of tricuspid valve
endocarditis, lead infection of a pacemaker / AICD,
CVC infection, septic thrombophlebitis
Risk factors -- most common germ: S. aureus

Fat embolism

Definition
• obstruction of vessels (especially pulmonary and ce-
rebral) by fat droplets, especially by washout of bone
marrow components
• mostly only venous (in 25% also additionally arterial
[e.g. via a lung passage or a patent foramen ovale])
• mostly caused by trauma (In 90% fat embolisms occur
in polytrauma, but usually remain asymptomatic due to
the clearance capacity of the pulmonary vessels.)
• If corresponding symptoms occur, one speaks of fat
embolism syndrome (FES).
• mostly occurring with a latency period of 12-24h

588 Angiology
Occurrence physical examination (especially petechiae; inspiratory
• trauma (especially after pelvic fractures, fractures of crackles on both sides)
long tubular bones, serial rib fractures [e.g. after re- • BGA: paO2 ↓
suscitation]) • laboratory:
• orthopedic / trauma surgery (especially intramedullary -- thrombopenia (in 30%)
nailing, hip/knee TEP) -- anemia (in 60%)
• manipulation of the bone marrow: bone marrow biopsy, -- BSR > 70 mm/h
intraosseous injection, bone marrow transplantation -- increased blood fat values, fat macroglobulinemia
• others: liposuction, acute pancreatitis, hepatocellular (visible fat droplets in the blood [lipemia])
necrosis (e.g. in amanita poisoning), burns, electrical • urine: lipuria (visible fat droplets in the urine)
injury (especially in high-voltage accidents), high ex- • echocardiography (posiibly visualization of the fat dro-
ternal fat intake plets ["snow flurries"])
• chest X-ray: bilateral patchy infiltrates in the upper
fields (typical!)
• chest CT
• bronchoscopy: fatty macrophages in the BAL
• possibly cranial CT / MRI
• possibly inspection of the ocular fundus (fundoscopy:
"cotton-wool" foci)

unclear respiratory insufficiency,

disturbance of consciousness
and petechiae (Gurd´s triad)
12-24h after trauma: think of fat
embolism!

Fig. 826  Fractures of long tubular bones (such as a dislo-

cated femoral shaft fracture on the left) can trigger a fat
embolism.

Symptoms
• pulmonary: dyspnea, tachypnoea, hemoptysis
• dermatological: petechiae (especially trunk, neck, axil-
la, conjunctiva)
• cerebral: headache, disturbance of consciousness
(due to petechial bleeding into the white substance of
the brain), reduction of vigilance, hemisymptomatic

Complications
• pulmonary embolism
• ARDS
• stroke
• cardiac arrhythmia Therapy
• DIC • symptomatic
• acute kidney injury • mostly self-limiting
• possibly high doses of methylprednisolone (but no ge-
Diagnosis neral recommendation)
• anamnesis (trauma / surgery during the last days), • lysis (fibrinolytic therapy): not effective here

Angiology 589
Air embolism Diagnosis
• anamnesis, clinical examination (e.g. auscultation of
the heart: "mill wheel" murmur)
• ECG
• BGA
• echocardiography: detection of air bubbles in the
right system
• chest X-ray
• CT
Definition -- chest-CT: ventrally located round or mirror-like opa-
• syn.: vascular gas embolism cities
• penetration of air into the vascular system (mostly ve- -- CCT (cranial; detection of air bubbles in the brain)
nous) with consecutive obstruction of the pulmonary
arteries or the right ventricular outflow tract ("airlock")
in venous or obstruction of coronary or cerebral arte-
ries in arterial form
• also right-left shunt via a patent foramen ovale pos-
sible
• lethal dose:
-- venous: 50-100ml
-- arterial: already from 1ml potentially fatal (e.g. in the
coronary arteries)

Types
• arterial (arterial gas embolism [AGE]; less often; more
dangerous; e.g. air in the coronary arteries in case of
improper coronary angiography [conduit system not
free of air], diving accident with pulmonary barotrau-
ma)
• venous (venous gas embolism [VGE]; more often)

Etiology
• mostly iatrogenic
• occurrence:
-- CVC placement ( most common cause; espe-
cially if patient is exsiccated and the insertion is not Fig. 827  CCT: detection of air in the brain (see arrows; here
in the sinus veins)
performded in head-down position) or CVC removal
(e.g. while sitting instead of lying down)
-- improper manipulations of the dialysis or Port cathe-
ter
-- endoscopy with air insufflation (especially in case of
punctures; therefore better under CO2 atmosphere),
-- lung biopsy (bronchoscopic transbronchial or CT-
guided)
-- rupture of the balloon of the pulmonary artery ca-
theter (especially if further "attempts to inflate" were
made)
-- surgery: thoracic surgery, cardiac surgery (espe-
cially valve surgery), neurosurgery (especially when
surgery while sitting)
-- diving accident (arterial gas embolism)
-- helium intoxication (arterial gas embolism; e.g. inha-
lation of helium gas ["balloon" gas] for amusement
["Mickey Mouse" voice])

590 Angiology

Fig. 828  CCT: pronounced air in the brain ubiquitous (see
arrows)
Therapy
• positioning: In the past, lying on the left side with head-
down position (Durant maneuver) was recommended,
today a flat supine position is recommended.
• aspiration of the air via right heart catheter or only via
an CVC (tip: If the patient has a CVC anyway [espe-
cially if air embolism occured as a complication of the
CVC plasement, which is the most common cause], it
is only necessary to push the CVC as far as possible
into the patient and then simply suck off the air.)
• high-dose oxygen administration
• possibly hyperbaric oxygenation (HBO, pressure
chamber)
-- arterial gas embolism (AGE): obligatory
-- venous gas embolism (VGE): facultative (especially
if symptomatic [e.g. hemiparesis, seizure, visual im-
pairment])
• lidocaine:
-- especially in arterial gas embolism (e.g. diving ac-
cident)
-- rationale: Lidocaine is said to have membrane-sta-
bilizing effects and can thus prevent neurological
(cerebral) damage.
-- Although there are only animal data, lidocaine is
used by numerous HBO centers.
-- dosage: 1.5 mg/kg as a bolus i.v., then continuous
infusion over 24-48 hours in low doses (target level
< 20 μmol/l)
VGE (venous gas embolism): diagno-
sis by echocardiography (air in the
right heart); therapy: place CVC,
advance in completely + aspirate!
Amniotic fluid embolism (AFE)
Definition
• syn.:
-- Steiner-Lushbaugh syndrome
-- amniotic infusion syndrome
• 4th most frequent maternal cause of death
• mortality:
-- mother: 86% (catastrophic prognosis; of which
50% die in the first hour already)
-- child: 21% (permanent neurological damage in 61%)
• incidence: 2/100000 births
• always an exclusion diagnosis (most important DD:
pulmonary embolism, myocardial infarction, peripar-
tum cardiomyopathy, eclampsia, postpartum bleeding,
aspiration, sepsis, anaphylaxis), ultimately only detec-
table postmortem (autopsy)
• biphasic course: initial cardiorespiratory insufficiency,
then DIC
Occurrence
• peripartum (spontaneous delivery, Cesarean section):
2h before to 4h after birth
• during a premature placental separation
Pathophysiology
• There is a transfer of amniotic fluid via endocervical
veins, uterine lesions or the placental insertion site into
the maternal circulation.
• amniotic fluid components: meconium, lanugo hair, fe-
tal scales, vernix flakes
• less a mechanical (obstruction of the pulmonary tract)
than an inflammatory and allergic (anaphylactoid) re-
action to the components of the amniotic fluid (hence
the term "anaphylactoid syndrome of pregnancy")
• vasospasm of the pulmonary artery with right heart fai-
lure
Risk factors
• age of the mother > 35 years
• Cesarean section
Angiology 591
• plazenta praevia hysterectomy)
• multiple pregnancy (e.g. twins) • lysis (fibrinolytic therapy): ineffective and possibly
• intrauterine fetal death harmful here (cave: The main problem is usually mas-
sive bleeding!)
Symptoms
• dyspnoea, tachypnoea, cyanosis (due to pulmonary Foreign body embolism
obstruction; but also frequent pulmonary edema and • occurrence: e.g. dislocated Port catheter, dislocated
ARDS) CVC guidewire, broken catheter, dislocated vena cava
• restlessness, anxiety, agitation, panic, confusion, coma filter, cyanoacrylate (histoacryl; a rapidly curing plastic
• visual disturbance, photophobia for the sclerotherapy of fundus varices: As a complica-
• chest pain tion a pulmonary embolism can occur during sclerothe-
rapy due to the adhesive.)
• tachycardia, hypotension (possibly even cardiovascu-
lar arrest) • therapy: removal by right heart catheter (e.g. Goo-
seneck snare, LoopMaster-Sochman snare; see info-
• seizures
box)
• coagulopathy
-- DIC (caused by procoagulatory mediators in the am-
niotic fluid)
-- hyperfibrinolysis (frequent!)
-- The main problem is bleeding with hemorrhagic
shock (possibly death of bleeding; cave lysis [fibrino-
lytic therapy] with suspected pulmonary embolism)!
• suddenly unclear fetal hypoxia ("fetal distress"; recog-
nizable in CTG) during delivery

Triad hypoxia, hypotension and

coagulation disorders (especially
bleeding) peripartum: think of
amniotic fluid embolism!

Diagnostics
• laboratory (hemoglobin ↓, thrombocytopenia, Quick ↓ /
INR ↑, AT III ↓, fibrinogen ↓, D-dimers ↑)
• ECG (to exclude myocardial infarction)
• echocardiography (i.a. right ventricular dysfunction)
• chest X-ray (often pulmonary edema)
• chest CT (to exclude [conventional, i.e. caused by an
embolus] pulmonary embolism)

Therapy
• circulatory stabilization (often requiring resuscitation)
-- volume therapy
-- catecholamine therapy
-- if necessay va-ECMO
• administration of oxygen, if necessary intubation and
mechanical ventilation (almost always necessary)
• hemosthasiological therapy (e.g. RCC, platelet con-
centrates, FFP; in hyperfibrinolysis fibrinogen + tran-
examic acid; if necessary recombinant factor VII as
ultima ratio)
• steroids (high dose)
• immediate birth of the child (2/3 of the amniotic fluid
embolisms occur prepartum), if necessary emergency
Cesarean section
• postoperative uterotonics (e.g. oxytocin; note: Sul-
prostone [prostaglandin E2] is contraindicated here
due to potentiation of pulmonary vasoconstriction.) for
prophylaxis or therapy of uterine atonia (if necessary

592 Angiology
Fig. 829  Gooseneck snare

Angiology 593
 Gooseneck snare

port catheter
(distal end) guiding
catheter

opened Gooseneck
snare right next to
the distal end of the
port catheter

594 Angiology
 Fig. 831  A good alternative to the Gooseneck snare is the
so-called LoopMaster-Sochman snare (Andramed compa-
ny). In addition to the catching loop (diameter 25mm), a sa-
fety wire is also integrated here. This snare has the great
advantage that it can also be used to grasp foreign bodies
in the middle, so that it is not necessary to reach the end
of the foreign body with the guiding catheter. An 8F sheath
and an 8F guiding catheter are required. The disadvantage
is that it is more expensive (approx. 700 €).

Fig. 830  Foreign body embolism: A port catheter (tube) em-

bolized into the right ventricle and main trunk of the pul-
monary artery. In the first picture, no more catheter (tube)
is connected at the port chamber of the forearm. The most
frequent reason for this is that a port, that has been diffi-
cult to flush and aspirate, is flushed with a too high stamp
pressure (use of max. 10ml syringes, not smaller). The em-
bolized tube was captured under fluoroscopy and removed
transcutaneously, i.e. together with the sheath, after a 7F
sheath had been established in the femoral vein and a gui-
ding catheter with a so-called Gooseneck snare had been
inserted. The last picture shows the removed corpus de-
licti.

Angiology 595
 ACUTE AORTIC SYNDROME

Fig. 832  aortic dissection: schematic illustration of the in-

timal tear

Definition Pathophysiology
• acute chest pain (the 3 most important differential di- • first tear (entry) into the intima layer of the aortic wall
agnoses): (in 90% ventral)
-- acute coronary syndrome • Most dissections (65%) have their origin in the proxi-
-- acute pulmonary embolism mal ascending aorta immediately after the aortic valve
(mostly in the area of the ostium of the RCA), because
-- acute aortic syndrome this is where the load on the aortic wall is greatest due
• classification according to Svennson to the flow properties.
• guidelines: ESC guidelines on the diagnosis and treat- • intramural bleeding into the aortic wall (bleeding inside
ment of aortic diseases 2014 the media)
• splitting into an inner and outer layer of the vascular
wall (dissection)
• The blood flow opens up a new path, a false lumen
develops.
• spread of the dissection:
-- antegrade (towards distal; mostly)
-- retrograde (towards proximal; rarely)
• mostly second tear (reentry)

entry
Acute aortic dissection (Svennson blood flow
dissection
type I)

Definition reentry
tear in the
• rear of the intima layer of the aortic wall with dissection wall (intima)
• structure of the aortic wall:
dissection
-- intima (endothelium, basal membrane, connective
tissue)
-- media (elastic fibres, musculature)
-- adventitia: connective tissue, vessels, nerves
• mostly hypertensive blood pressure situation
• Contrary to frequent opinion, the aorta in aortic dissec- Fig. 833  aortic dissection: schematic illustration of the pa-
thophysiology
tion is not dilated previously (in 80%), i.e. there is no
pre-existing aortic aneurysm.

596 Angiology
Causes ◦◦ secondary (e.g. Bechterew´s disease, Behçet´s
disease, SLE, rheumatoid arthritis, IgG4-associa-
• cardiovascular: arterial hypertension (no.1)
ted aortitis)
• genetic: connective tissue diseases (genetic aortic
-- infective (mostly bacterial)
syndromes [GAS])
◦◦ in the context of aortic valve endocarditis (espe-
-- Marfan syndrome (named after the French pediatri-
cially in prosthetic valves)
cian Antoine-Bernard Marfan [1858-1942])
◦◦ syphilis (Treponema pallidum [mesaortitis luica]),
◦◦ prevalence 1:5000
tuberculosis
◦◦ inheritance: autosomal dominant
• iatrogenic (p.d. Svennson type V; see page 608)
◦◦ mutation in the fibrillin-1 gene (genetic analysis
• traumatic (p.d. Svennson type V; see page 608)
recommended)
◦◦ signs: especially tall stature, dolichostenomelia
(abnormally long and thin limbs), arachnodactyly
(abnormally long and thin fingers ["spider finger"]),
hyperextensible joints, chest deformity (sunken
[pectus excavatum] or protruding [pectus carina-
tum]), scoliosis, subluxation of the lens)
◦◦ 5% of all patients with aortic dissection (at age <
40 years even in 50%!)
◦◦ most common cause of death: aortic rupture (due
to aneurysm) or aortic dissection (mostly between
the ages of 20-30 years)
◦◦ β-blockers and lorsartan recommended to reduce
aortic dilatation (inhibition of the TGFβ signaling
pathway [central mechanism in Marfan syndro-
me])
-- Loeys-Dietz syndrome
◦◦ connective tissue disease similar to Marfan' syn-
drome (also autosomal dominant inheritance) Fig. 834  Takayasu´s disease: a rare cause of aortic dissec-
tion. The duplex of the carotid artery shows a remarkably
◦◦ in addition, hypertelorism, craniosynostosis, uvula thickened vascular wall.
bifida, cleft palate, aneurysms of the arteries
◦◦ mutation in the TBFGR-1/2 gen
Risk factors
-- Ehlers-Danlos syndrome
• arterial hypertension
◦◦ 6 different forms (involvement of the aorta, espe-
cially in the vascular type [type IV]) • nicotine abuse
◦◦ inheritance: mostly autosomal dominant • pregnancy
◦◦ disruption of collagen synthesis (mutations in vari- • aortic malformations:
ous collagen genes) -- bicuspid aortic valve (only two instead of 3 leaflets)
◦◦ signs: especially overstretchability (cutis hyper- ◦◦ Cause is a genetic mutation in the NOTCH-1
elastica) of the skin (thin, translucent), overstret- gene, resulting in a lack of fibrillin.
chable joints ("contortionist"), pronounced tenden- ◦◦ 1% of the population, in up to 10% aortic dissec-
cy to bleed tion (no harmless anomaly!)
-- cystic medial necrosis Erdheim-Gsell ◦◦ 6% of all patients with aortic dissection have a bi-
-- Ullrich-Turner syndrome (syn.: monosomy X, X0- cuspid aortic valve.
syndrome) -- aortic isthmus stenosis (in 50% also bicuspid aortic
-- aneurysm osteoarthritis syndrome [AOS]) valve)
• toxic: intoxication especially with • homocysteinuria
-- cocaine • polycystic kidney disease
-- amphetamines (drugs, methylphenidate [Ritalin; in-
dication: ADHD])
• pharmological: fluoroquinolones (twice the risk of aor-
tic aneurysm and aortic dissection [i.a. Pasternak et al,
BMJ 2018]; i.a. Red-Hand letter in Germany 10/2018;
in the follow-up studies [Dong et al, JAMA 2020; Gopa-
lakrishnan et al, JAMA Intern Med 2020] however not
confirmed)
• inflammatory (aortitis; rare)
-- autoimmune
◦◦ primary: vasculitis (e.g. Takayasu´s disease, poly-
myalgia rheumatica)

Angiology 597

Fig. 835  Bicuspid aortic valve: In the parasternal short axis
only two instead of three leaflets can be seen. In the aortic
M-mode (parasternal long axis) the typical eccentrically lo-
cated middle echo is visible.
Epidemiology
• incidence
-- 2-3/100000 (after a retrospective data analysis
in Berlin / Brandenburg in Germany [Kurz et al,
Int Journal Cardiol 2017] even four times as high:
11,9/100000)
-- increasing
• m:w = 3:1
• average age: 63 years
• often in the early morning hours (due to the sympa-
thetic adrenergic activation; similar to myocardial in-
farction)
• more frequent than the rupture of abdominal and tho-
racic aortic aneurysms together
Classification
• Stanford classification (named after the university in
the USA; see infobox)
• DeBakey classification (today abandoned; named af-
ter the American heart surgeon Michael Ellis deBakey
[1908-2008], who ironically suffered an aortic dissec-
tion himself)
-- type I: dissection of the entire aorta
-- type II: dissection of the ascending aorta
-- type III: dissection of the descending aorta
598 Angiology
Stanford
classification
Fig. 836  Stanford classification of aortic dissection: In
Stanford A dissection, dissection begins proximally at the
ascending aorta. In Stanford B dissection, dissection be-
gins distally to the left subclavian artery. Strictly speaking,
it is not the location of the tear (entry), but the part of the
aorta, which is affected by the dissection, that is decisive
for the classification. For example, a dissection with entry
distal to the left subclavian artery can spread retrograde
into the ascending aorta, so that it is Stanford A dissection.
Symptoms
• mostly hypertensive blood pressure derailment (p.d.
here hypertensive emergency)
• very severe pain:
-- localization (possibly also changing)
◦◦ chest (retrosternal excruciating pain)
◦◦ back (especially between the scapulae )
◦◦ possibly abdomen
-- character:
◦◦ stabbing ("as if piercing with a dagger"), tearing,
cutting
◦◦ abrupt beginning
• tips for emergency physicians:
-- If the chest pain is so severe in the context of an al-
leged ACS that morphine is no longer sufficient and
fentanyl has to be given, then one should always
assume an aortic dissection initially and then (espe-
cially if there are additional clinical hints [e.g. RR or
pulse difference between the two arms]) do not give
aspirin and heparin preclinically!!
-- As a target hospital, you should always go to a hos-
 pital with cardiac thorax surgery. Otherwise the loss
of time due to the interhospital transfer can be fatal!
Complications
• bleeding into the pericardial sac (This also includes
the proximal part of the ascending aorta.) → pericar-
dial tamponade
• malperfusion syndrome:
-- tearing of the coronary arteries (most frequent-
ly RCA) → „myocardial infarction“; possibly pro-
nounced reduction of ejection fraction as a result
of reduced coronary perfusion (in 20% cardiogenic
shock)
-- tearing of arteries supplying the brain → "stroke"
(cave lysis [fibrinolytic therapy]!)
-- tearing of spinal cord arteries (especially A. radicula-
ris magna [Adamkiewicz] → "paraplegia" (atrauma-
tic)
-- tearing of the mesenteric arteries (celiac trunk, supe-
rior mesenteric artery, inferior mesenteric artery) →
„acute abdomen“
-- tearing of the renal arteries → "acute kidney injury"
(oligo-/ anuria)
-- tearing of the iliac artery (for the leg) → "acute limb
ischaemia " (6P according to Pratt); if bilateral: Leri-
che syndrome
• rupture
• acute aortic valve insufficiency
• fistulae:
-- aorto-esophageal (massive hematemesis [upper
gastrointestinal bleeding])
-- aorto-pulmonary (massive hemoptysis, asphyxia)
-- aorto-caval (between abdominal aorta and inferior
vena cava; consequence: acute left-right shunt)
Acute aortic cissection: "chame-
leon of emergency and intensive
care medicine"!
least 16-line] necessary), with which the three most im-
portant differential diagnoses of acute chest pain can
be assessed in one session:
-- pulmonary artery (pulmonary embolism)
-- aorta (acute aortic dissection)
-- coronary arteries (acute myocardial infarction)
Physical examination
• blood pressure (BP) difference between both arms (>
20mmHg)
• pulse difference between both arms
• cold extremity (one-sided))
• aortic valve insufficiency
-- signs:
◦◦ Musset sign (pulse synchronous rhythmic nodding
or bobbing of the head)
◦◦ Corrigan sign (visible pulsations in the carotid ar-
tery; "water hammer" pulse)
◦◦ Quincke sign (visible capillary pulse under the fin-
gernails)
-- blood pressure measurement: high BP amplitude
(e.g. 180/30 mmHg)
-- diastolic murmur
Laboratory
• CRP (C-reactive protein)
-- vascular injury → proinflammatory cytokines ↑­
-- high sensitivity (normal CRP → aortic dissection un-
likely; note: in our clinic other experience! Since the
synthesis of CRP is induced by cytokines [esp. in-
terleukin 6], an increase in CRP usually only occurs
after 24-48 hours!)
• D-dimers
-- vascular injury → activation of the coagulation sys-
tem
-- high sensitivity (95% [Suzuki et al, Circulation 2009],
in the ADVISED study [Nazerian et al, Circulation
2018] even 96.7% [negative predictive value 99.2%])

Diagnosis D-dimers negative → in 95% no

• anamnesis, physical examination acute aortic dissection and no acute
• ECG (in 2/3 conspicious!) pulmonary embolism
• laboratory
• chest X-ray
-- findings:
◦◦ mediastinal widening
◦◦ pleural effusion (hemorrhagic; mostly left-sided)
◦◦ tracheal compression
-- in 75% pathological in aortic dissection
• imaging (TEE, CT)
• Routine preoperative coronary angiography, which
used to be practiced frequently, is no longer recom-
mended.
• Some clinics perform CT according to the TRO proto-
col ("triple rule out") in patients with acute chest pain
in the emergency department: This is a special CT
sequence (ECG-triggered; however, multi-line CT [at

Angiology 599
 Imaging
• computed tomography (CT)
• transesophageal echocardiography (TEE)

According to the IRAD register (IRAD: International Regi-

stry of Acute Aortic Dissection; Moore et al, Am J Cardiol
2002) a CT is performed in 2/3 of the cases, a TEE in 1/3
of the cases. In 75% of the cases the CT is followed by
the TEE.

Tip: In the suprasternal view of TTE

(acoustic window jugular fossa) the
ascending aorta, the aortic arch and
the initial part of the aorta descendens
are sometimes well recognizable!

Fig. 838  Transthoracic echocardiography (TTE) from su-

prasternal (placement of the transducer in the jugular fossa
and sounding from above): A dissection membrane (see ar-
row) can be seen in the aortic arch.

Computed tomography (CT)

• equivalent to TEE (like TEE but difficulties in the area
of the aortic arch)
• cave pulsation artefact (therefore always with ECG
triggering and diagnosis by an experienced radiolo-
gist!)

Fig. 837  Chest X-ray in an aortic dissection Stanford A: The

widened mediastinum is already visible.

600 Angiology
 Fig. 840  chest CT in aortic dissection Stanford A: In addi-
tion to the dissection membrane, the clearly dilated ascen-
ding aorta and a hematopericardium are visible.

Fig. 839  chest CT: aortic dissection Stanford A

Fig. 841  chest CT in aortic dissection Stanford A: Here,

rupture with bleeding into the mediastinum and a pleural
effusion on the left side have alerady occurred.

Angiology 601
 Fig. 844  detection of a dissection membrane in the thora-
cic descending aorta

Fig. 842  abdomen CT with aortic dissection Stanford B

Transesophageal echocardiography (TEE)

• sedation as deep as possible (cave hypertension!)
• difficulties in the area of the aortic arch ("blind spot":
interposition with left main bronchus; the aortic arch is
well visible in the suprasternal view of TTE!)
• detection of dissection membrane: thin, hypermobile
lamella
• localization of entry and reentry
• visualization of double lumen:
-- true lumen (smaller [true lumen collapse] and pul-
sating)
-- false lumen (larger and does not pulsate)
• aortic valve insufficiency
• pericardial effusion
-- often hyperechoic (due to the blood)
-- A lamella in a pericardial effusion is pathognomonic
for aortic dissection!

Fig. 843  TEE: detection of a dissection membrane in the

ascending aorta (Stanford A)
Fig. 845  TEE: representation of the true and the false lu-
men (Only the true lumen is perfused in the color duplex.)

602 Angiology

Fig. 846  TEE: representation of the entry (arrow)
Fig. 848  TEE: A membrane in the ascending aorta shows
up: This was only an artifact caused by the postrior wall of
the ascending aorta: The distance between the transducer
and the "membrane" is twice as large as the distance bet-
ween the transducer and the posterior wall of the ascen-
ding aorta (repetition artifact!). Furthermore, in the M-mode
you can see that the "membrane" moves synchronously
with other heart structures.

Fig. 847  sonography abdomen: An abdominal aortic aneu-

rysm (diameter 6 cm) with a dissection membrane can be
seen.

Differential diagnosis: dissection membrane

• artifact (near-field artifact)
-- caused by the posterior wall of the ascending aorta
-- repetition artifact: The distance between the transdu-
cer (probe) and the aortic wall is always exactly half
the distance between sound generator and artifact.
-- synchronous movement to other heart structures
-- horizontal course
-- validation by CT / MRI
• innominate vein (left brachiocephalic vein: However,
if you switch on the color duplex, you can see that it
is a vessel [venous flow profile] and not a dissection
membrane.)

Angiology 603
Fig. 849  Cardiac catheterization images of a 55 year ol man Stanford A
who was admitted by the emergency service with the dis-
gnosis of a STEMI (chest pain for 1 hour, in the ECG ST
• mortality: 50% (1% per hour in the first 48h) → imme-
elevations above the anterior wall) and was therefore ca- diate surgery
theterized immediately. On the one hand, it was difficult to • After 2 weeks the surgery shows no more benefit in
advance the Judkins catheter up in the aorta through the case of type A dissection.
inguinal artery (due to the narrowing of the true lumen by • cardiothoracic surgery:
the false lumen). On the other hand, the catheter was in a
completely unstable position, so that an aortography was -- use of the heart-lung machine in hypothermia
performed. On the one hand, this showed that the true lu- -- closure of the entry
men of the aorta is clearly narrowed (see arrows in the first -- replacement by plastic prosthesis (conduit)
picture). On the other hand, after administration of contrast
-- if necessary aortic valve replacement (Bentall ope-
agent with the pigtail catheter in the proximal ascending
aorta, after a few cycles the left ventricle was completely
ration: implantation of a tubular prosthesis with valve
filled as a sign of severe aortic valve insufficiency (second ["composite graft"])
picture). A TEE was immediately performed in the cath lab, • surgical mortality: 20-25% (in corresponding "high-
in which a dissection membrane appeared in the ascending volume" centers, however, only 7% today)
aorta. Ultimately, the cause was a Stanford A aortic dissec- • no stenting (endovascular [TEVAR]) in type A dissec-
tion including dissection of the LAD (left anterior descen-
tion; annotations:
ding artery).
-- If the descending aorta is also dissected, it is trea-
ted with an intraoperative antegrade stent. At least
Therapy the thoracic descending aorta should be completely
• conservative treated.
• surgical -- In individual cases (e.g. inoperable, multimorbid
elderly patients), endocasvular therapy (stenting;
Conservative therapy TEVAR) can also be performed exceptionally with
• immediate lowering of blood pressure (since patients a Stanford A dissection. For this purpose, however,
are mostly hypertensive) and lowering of the rate of special stents are required that have corresponding
pressure increase (dP/dtmax [pulse pressure]) recesses or own lumina for the branches of the aor-
-- means of choice: β-blocker (highly dosed! metop- tic arch (brachiocephalic artery, left common carotid
rolol up to 50 mg; alternatively esmolol [0,5mg/kg; artery and left subclavian artery).
advantage: only short-acting]; the ultra-short-acting
β-blocker landiolol is not suitable here, as it almost
does not lower blood pressure [only by 10%])
-- targets:
◦◦ SBP: 100-120 mmHg
◦◦ heart rate: 60/min
• analgesia (with opioids), sedation
• possibly antagonizing an anticoagulation (e.g. prota-
mine (1000E protamine antagonize 1000E heparin
[UFH]) in case of heparin [e.g. if UFH was previously
administered by the emergency physician, who admit-
ted the patient with the working diagnosis of ACS; note
ACS: only in 0.1% aortic dissection])
• pericardial effusion → puncture mostly pointless (only
in case of tamponade)

Fig. 850  heart lung machine (courtesy of Andrea Wenig-

Means of choice for the hypertensive hofer, Department of Medical, Therapeutic and Diagnostic
crisis in aortic dissection: β-blockers Health Professions, Medical University Campus, AKH Vien-
na [Austria])

Surgical therapy

604 Angiology
Fig. 851  In a Stanford A dissection, a classic open cardio-
thoracic surgery is performed. The dissected aorta is re-
placed by a plastic prosthesis.
Stanford B
• therapy
-- OP: Stanford B dissection is not treated surgi-
cally (worse results than conservative therapy [Nie-
naber et al, Circ 2003: higher mortality]).
-- – stenting (endovascular): domain (TEVAR: tho-
racic endovascular aortic repair)
-- studies:
◦◦ INSTEAD studs (Nienaber et al, Circulation 2009):
▪▪ TEVAR was not superior to conservative the-
rapy with uncomplicated Stanford B dissection.
However, this study showed an extremely high
1-year and 2-year mortality (97%!)
▪▪ In the extension study (INSTEAD-XL [Nienaber
et al, Circ Cardiovasc Interv 2013]), a reduced
progression of dissection as well as a reduced
mortality were observed after 5 years in the TE-
VAR group.
◦◦ ADSORB study (Brunkwall et al, Eur J Vasc Endo-
vasc Surg 2012; see box)
◦◦ In a retrospective cohort analysis (Qin et al, J Am
Coll Cardiol 2016) TEVAR showed a significantly
reduced overall mortality compared to conserva-
tive therapy with uncomplicated Stanford B diss-
ection.
• indication: intervention (i.e. TEVAR) with Stanford type
B dissection only in case of complications (so-called
complicated type B dissection):
-- progressive pain (symptomatic)
-- acute kidney failure
-- diameter of the aorta > 55mm
-- progression of dissection, increase of aortic diame-
ter
-- poorly adjustable arterial hypertension
Fig. 852  status post stent implantation after aortic dissec-
tion Stanford B
ADSORB study
A study on the efficacy of endovascular grafting in uncom-
plicated acute dissection of the descending aorta
Brunkwall et al, Eur J Vasc Endovasc Surg 2012
• multicenter randomized study
• 61 patients with uncomplicated Stanford-B dissection
-- conservative
-- interventional (endovascular; stenting)
• results: interventional
-- significantly larger free lumen
-- significantly fewer thromboses
• note: The study was not yet sufficient to induce a para-
digm shift (already with uncomplicated Stanford-B diss-
ection stenting).
aortic dissection:
Stanford A: surgery
Stanford B:
- uncomplicated: conservative
- complicated: interventional (TEVAR)
Prognosis
• Stanford A dissection:
-- mortality 50% in 48h
-- mortality 75% after 2 weeks (without surgery; with
surgery: 17% [Shiga et al, Arch Int Med 2006])
• Stanford B dissection:
-- better than type A dissection
-- Under conservative therapy 75% of all patients live
after 5 years and 60% after 10 years.
-- mortality (after 1 month):
◦◦ uncomplicated Stanford B dissection: 10%
◦◦ complicated Stanford B dissection: 30%
Angiology 605
Intramural hematoma (IMH; Svenn-
son type II)

Definition
• acute bleeding from the vasa vasorum of the media
• "apoplexy of the aorta"
• p.d. no communication with the true lumen
• frequent progression to dissection (Svennson type I;
dangerous!)
• spontaneous regression in 10%
• localization:
-- ascending aorta: 60%
-- descending aorta: 30%
-- aortic arch: 10%
Fig. 854  chest CT: intramural hematoma with a dissection
membrane (arrow)
Diagnosis
• echocardiography (TEE) Echocardiography
• chest CT (better) • sickle-shaped hypoechoic thickening in the aortic wall
(hematoma)
• p.d. no communication with the true lumen in the color
duplex

Differential diagnosis
An important differential diagnosis to an intramural he-
matoma is a mural thrombus (e.g. in the case of throm-
bosed dissection). The differential diagnosis can be
carried out using the intimal displacement sign (syn .:
luminal displacement of intimal calcium): The intima,
which is frequently atherosclerotically altered and thus
calcified, especially in older patients, so that it is often
easy to recognize, is displaced towards the lumen.
• intramural hematoma (less often, but dangerous): in-
timal displacement sign positive, i.e. the intima is dis-
placed (lies close to the lumen)
• thrombus (more often and mostly harmless): intimal
displacement sign negative, i.e. the intima is not dis-
placed (it lies far from the lumen)

Fig. 855  In the intramural hematoma (left), the intima

Fig. 853  chest CT: intramural hematoma (various examp- (shown here in black) is displaced (intimal displacement;
les) location: close to the lumen), in the mural thrombus (right)
the intima is not displaced (location: far from the lumen).

606 Angiology
 Therapy
• IMH in ascending aorta (type I): surgical
• IMH in descending aorta (type II): conservative (follow-
up)

Local dissection (Svennson type III)

• usually only discovered intraoperatively
• clinically minor significance

Penetrating aortic ulcer (PAU;

Svennson type IV)

Definition
• ulceration of aortic plaque
• a pseudoaneurysm (covered only by the adventitia of
the aorta)
• usually only in cases of pronounced atherosclerosis
(elderly patients)
• in the descending part of the thoracic aorta

Complications
• intramural hematoma (IMH; due to erosion of the vasa
vasorum)
• dissection
• rupture

Diagnosis
• echocardiography (TEE)
Fig. 856  chest CT: detection of intimal displacement (ar-
row) in intramural hematoma
-- usually pronounced atherosclerosis
-- possibly visualization of the ulcer
• chest CT (better)

Fig. 857  abdomen CT: no evidence of intimal displace-

ments (arrow), i.e. the intima is not displaced here. It is sim-
ply a harmless mural thrombus (here partially thrombosed
infrarenal abdominal aortic aneurysm).

Angiology 607
 • iatrogenic:
-- cardiac surgery (especially ascending aorta; fre-
quency: in 0.06%; e.g. CABG, aortic valve replace-
ment, intervention of aortic isthmus stenosis)
-- PCI (especially in dissection of a coronary artery [co-
ronary dissection] close to the main stem after PCI,
which spreads proximally over the main stem into
the ascending aorta)
-- IABP
-- ESWT (extracorporeal shockwave therapy; e.g. for
kidney stones)

Fig. 858  somography abdomen: ulcer (see arrow) of the

abdominal aorta

Fig. 859  abdomen CT: ulcus (see arrow) of the abdominal

aorta

Therapy
• indication: from diameter > 20mm + depth > 10mm
• types
-- interventional (endovascular)
-- surgical

IMH + PAU: usually progressive to

dissection → therapy such as dissec-
tion (type A: surgical, type B: conser-
vative); note: but only if symptomatic
(not if asymptomatic [e.g. incidental
finding in CT])

Iatrogenic / Traumatic dissection

(Svennson type V)
• traumatic (e.g. deceleration trauma, thoracic trauma):
-- The most common cause of death from a chest trau-
ma is a traumatic aortic dissection!
-- In 20% of all fatal traffic accidents, traumatic aortic
dissection is the cause of death..

608 Angiology
Fig. 860  As a complication of an acute PCI of ​​the RCA, a
coronary dissection oocured, which spread proximally to
a Stanford A aortic dissection. Contrast media can be seen
not only in the RCA, but also in the aortic wall.

Sinus valsalvae aneurysm (SVA)

Definition
• enlargement of the sinus valsalvae (= initial part of
the ascending aorta from which the coronary arteries
emerge; syn.: bulbus aortae) > 35mm
• mostly in right coronary sinus

Etiology Fig. 861  Sinus valsalvae aneurysm

• congenital (most common; in 50% combined with
ventricular septal defect; rupture mostly in the age bet-
ween 30-40 years)
• acquired
-- degenerative (atherosclerotic [e.g. in arterial hyper-
tension])
-- inflammatory (mesaortitis luica, Takayasu's disease,
infectious endocarditis, tuberculosis
-- traumatic

Complications
• aortic valve insufficiency
-- most common complication (25%)
-- due to geometric distortion of the aortic valve
• rupture
• obstruction of the RVOT (right ventricular outflow tract)
• compression of the left coronary artery

Rupture
• perforation
-- aneurysm of the right coronary sinus → into the right
atrium / ventricle → left-right shunt → acute right
heart failure
-- aneurysm of the left coronary sinus → in left atrium /
ventricle → acute left heart
• possibly pericardial effusion
• symptoms
-- sudden massive chest pain
-- dyspnea
-- shock
• diagnostics
-- auscultation: machine-like heart murmur (machi-
ne noise)
-- echocardiography (TTE, TEE)
-- chest CT
• therapy: immediate surgery

severe chest pain, shock, machi-

ne noise: think of a ruptured
sinus valsalvae aneurysm!

Angiology 609
Fig. 862  Sinus valsalvae aneurysm in the area of the right
coronary aortic valve leaflet with perforation into the right
atrium (recognizable by the turbulent color jet)

610 Angiology
Angiology 611
Pulmonology
 due to a severe acute mitral valve regurgitation often
ARDS is often very similar to ARDS!)
-- PiCCO: pulmonary vascular permeability index
(PVPI):
◦◦ PVPI < 3: cardiac (hydrostatic pulmonary edema)
◦◦ PVPI > 3: ARDS (permeability pulmonary edema)
-- pro-BNP (The cut-off value of 100 pg/ml has a rela-
tively high sensitivity of 95%, but only a relatively low
specificity of 27% [i.a Levitt et al, Crit Care 2008].)
◦◦ > 100 pg/ml: cardiac
◦◦ < 100 pg/ml: ARDS

Criticism of the old definition

• no consideration of PEEP and ventilation ("blood gas"
ARDS)
• increased PCWP also possible in septic cardiomyopa-
thy; ARDS may also be present in sepsis

Due to these criticisms, an ARDS Task Force developed

a new definition which was presented at the 2011 ESICM
(European Society of Intensive Care Medicine) congress
in Berlin as the ARDS "Berlin Definition" (published by
Ranieri et al, JAMA 2012).

Introduction Berlin-Definition (ARDS)

• "The fetal lung in the unborn child - pathology, therapy
and forensic medication" (Eduard Jörg, 1835) mild moderate severe
• first described by David Ashbaugh and Thomas Petty time acute onset (< 1 week)
in a case series of 12 patients (Lancet: "acute respira-
Horovitz quotient 200-300 100-200 < 100
tory distress in adults")
(mmHg)
• acute lung failure
• designations: PEEP (cmH2O) 5-10 5-10 > 10
-- IRDS: infant respiratory distress syndrome origin of edema respiratory insufficiency (not fully explai-
ned by heart failure or volume overload)
-- ARDS: adult (today better: acute) respiratory dist-
ress syndrome
• ARDS is the pulmonary manifestation of multiorgan radiological bilateral bilateral 3-4 quadrants
failure (MOF). changes (chest
X-ray, CT)
• ARDS is a syndrome and not a disease!
additional physio- - - VE corr > 10 l/min
logical disorder compliance <
Definition 40 ml/cmH2O
(according to AECC [American European Consensus
VE korr: corrected RMV (VE x pCO2 / 40); Criticism: Pati-
Conference] 1992; "old" definition)
ents with a Horovitz quotient < 100 mmHg and a PEEP
• acute occurrence
between 5-10 cmH2O are not considered.
• Horovitz quotient (paO2/FiO2; syn.: P/F ratio, oxygena-
tion index):
-- 200-300 mmHg: ALI (acute lung injury)
-- < 200 mmHg: ARDS
• bilateral infiltrates in the chest X-ray (a.p.); Note: Ac-
cording to more recent radiological recommendations
one no longer speaks of infiltrates but of consolida-
tions.
• pulmonary capillary wedge pressure (PCWP; Wedge-
Druck) < 18 mmHg or missing signs of left heart failure,
i.e. no cardiac pulmonary edema (p.d. a non-cardiac Innovations (Berlin-Definition)
pulmonary edema). Pulmonary capillary wedge pres-
sure is measured using a pulmonary catheter, which is • The term "acute" was determined at less than 1 week.
rarely used nowadays. Today one uses above all: • no more ALI (p.d. mild ARDS)
-- Echocardiography (Especially pulmonary edema • consideration of PEEP (Therefore the diagnosis of

614 Pulmonology
 ARDS is only possible with ventilation [invasive / non- Causes
invasive] and not with spontaneous breathing [e.g. HF-
NOT]!) • pulmonary (direct; pneumogenic; primary ARDS)
• no more PCWP and therefore no more pulmonary ca- • extrapulmonary (indirect; secondary ARDS)
theter necessary (echocardiography sufficient to exclu-
de cardiac pulmonary edema) Pulmonary causes
• pneumonia (→ parapneumonic ARDS): most fre-
quent cause of ARDS
• lung contusion (thoracic trauma)
• aspiration
-- aspiration - gastric juice (Mendelson's syndrome;
e.g. in an ileus; in 30% ARDS)
-- salt/fresh water (drowning accident)
-- note: Aspiration of blood (e.g. bleeding after tonsil-
lectomy, upper gastrointestinal bleeding) does not
usually lead to ARDS, since blood is usually sterile
and has a physiological pH!
• viral diseases, especially
-- influenza H1N1 (swine flu [see page 1145])
-- coronavirus infections:
◦◦ SARS (severe acute respiratory syndrome; espe-
cially COVID-19 by SARS-CoV-2 [see page 845])
◦◦ MERS (middle east respiratory syndrome; by
MERS-CoV)
• inhalation trauma (smoke gas)
• pulmonary vasculitis
• high oxygen partial pressures
• high altitude pulmonary edema (HAPE)
-- pathophysiology: excessive vasoconstriction of the
pulmonary arteries due to the hypoxia in high altitude
-- symptoms: dyspnea, tachypnea, fever, hemoptysis
-- prophylaxis: inhaled steroid
• re-expansion pulmonary edema (Therefore a maxi-
mum of 1.5 litres should be drained during a pleural
puncture. This applies particularly to patients with
pre-existing heart failure who have a significantly in-
creased risk of re-expansion pulmonary edema. In the
case of malignant effusions, more than 1.5 litres can
be discharged.)
• surfactan washout
Epidemiology -- occurence: e.g. after extensive BAL (bronchoal-
• incidence veolar lavage; therefore no BAL in severe ARDS;
BAL is contraindicated from a Horovitz quotient <
-- Europe: 3/100000
100mmHg!), after irrigation in the context of an en-
-- USA: 6/100000
dobronchial hemorrhage
• average age: 44 years
-- Thus ARDS is also induced in animal experiments
• m = w by irrigating the lung extensively with saline solution.
• 10% of all intensive care patients (LUNG-SAFE study -- Surfactant is washed out here.
2016)
• bronchial bleeding: The blood can cause surfactant
• 20% of all invasively ventilated intensive care patients inactivation.
• substances with preferred pulmonary distribution (pa-
raquat, bleomycin [BIP: bleomycin-induced pneumoni-
ARDS: frequently in ICU!
tis; see page 713])
- every 10th intensive care patient
- every 5th ventilated intensive care • inhalation of baby powder (contains talc; especially in-
patient fants; see page 1469)
• E-cigarettes (vaporizer)
-- EVALI: e-cigarette or vaping associated lung injury;
syn.: vaping-induced acute lung injury
-- especially when inhaling THC ("cannabis-liquids"

Pulmonology 615
 [87% of the cases]; less often when inhaling nicotine
[13% of the cases]; David et al, N Engl J 2020)
-- ARDS caused by the vitamin E acetate-containing
oil in the vaporizer liquid
• bronchoalveolar carcinoma (alveolar cell carcinoma;
rarely acute course)
• miliary tuberculosis (mortality: 60%)
• alveolar proteinosis (see page 712; rarely acute
course)
Extrapulmonary causes
• sepsis (severe sepsis → in 35% ARDS)
• shock (→ "shock lung; p.d. oly the non-cardiogenic
shock)
• polytrauma
• massive transfusion (p.d.: > 15 RCC in 24h) → TRALI
(transfusion-related ALI; more frequent after FFP than
after RCC administration; see page 1016)
• DIC
• pancreatitis (severe pancreatitis → in 45% ARDS)
• burns
• long cardiopulmonary bypass times
• malaria (especially tropical malaria)
• intoxications
-- e.g. heroin, cocaine, salicylates, organic phospha-
tes, petroleum
-- classic toxic pulmonary edema (also a permeability
pulmonary edema)
• iatrogenic (VALI [ventilatorassoziierte Lungenschädi-
gung]; unfortunately a common cause!)
most frequent causes of ARDS:
no.1: pneumonia
no.2: sepsis
no.3: polytrauma
616 Pulmonology
Fig. 863  Traffic accident with fall from scooter into river;
here two causes for ARDS: polytrauma and near-drowning
Pathophysiology
• acute inflammatory response to pulmonary or extrapul-
monary trauma
• non-specific inflammatory reaction of the lungs as an
immunologically highly potent organ to different trig-
gers
• infiltration of neutrophil granulocytes
• The lung is an extremely vulnerable organ, the alveoli
are very fragile.
• damage:
-- primary ARDS: directly (initial epithelial damage)
-- sekundary ARDS: indirectly (initial endothelial dama-
ge)
• increased pulmonary capillary permeability → perme-
ability pulmonary edema (intra-alveolar) → „wet lung“
(comparable to a sponge soaked in water), increased
lung weight; increased extravascular lung water index
[ELWI]) →
-- compliance (norm: > 50 ml/cmH2O) ↓ ("stiff lung";
ARDS is a restrictive ventilation disorder)
-- diffusion length ↑ → diffusion disorder
• obliteration of the lung capillaries by microthrombi →
perfusion disorder
• development of atelectasis due to:
-- destruction of type II pneumocytes (alveolar macro-
phages) → lack of surfactant (surface active agent)
-- the high weight of the lungs due to the fluid accumu-
lation: The lungs are like a wet sponge full of water
and therefore relatively heavy. The dorsal parts are
compressed due to gravity and therefore no longer
ventilated ("sponge effect").
• despite high FiO2 pronounced hypoxia as a result of
-- intrapulmonary right-to-left shunts
◦◦ due to atelectasis
◦◦ perfused but no longer ventilated alveoli
◦◦ the main pathomechanism of acute lung fai-
lure!
-- distribution disorder (disorder in perfusion/ventilation
ratio)
• histology: diffuse alveolar damage (DAD)
• increases airway pressure
• pulmonary hypertension (in 25% in ARDS); causes:
-- hypoxic vasoconstriction (Euler-Liljestrand reflex)
-- ventilation (especially with high pressures → right
ventricular afterload ↑)
-- obliteration of the lung capillaries by microthrombi
• The pathomorphological changes in the lung are regi-
onally very different, so that one speaks also of a "mul-
ticompartment lung" in ARDS.
sue, which currently does not participate in gas ex-
change, but which could be recovered (recruited) for
it.
-- zone H (healthy): Ventrally healthy lung tissue is lo-
cated.
• interpretation:
-- The aim is the transition from "R to H".
-- Zone H (healthy lung tissue) is reduced to 25% in
severe ARDS. Gattinoni (Intensive Care Med 2005)
coined the term "baby lung" for the remaining small
part of the healthy lung. Functionally, an ARDS pati-
ent only has the lung of a small child!

bronchioli

zone H

alveoli
zone R

zone D

fluid

normal ARDS
Fig. 865  3-zone model in ARDS
Fig. 864  In contrast to the normal lungs, in ARDS there is
not air, but water in the alveoli ("wet lung").
Diagnostics
Phases • laboratory
• exudative (within hours): • BGA
-- infiltration of neutrophil granulocytes • chest X-ray
-- perfusion disorder, hyperemia • chest CT
-- increased permeability of the capillaries: pulmonary • advanced hemodynamic monitoring (generous in
edema (high in protein; first interstitial, then alveolar) ARDS), e.g. PiCCO:
-- increase of the intrapulmonary fluid volume -- increased extravascular lung water index (ELWI >
• proliferative (within days [mostly 5-7 days]): 10 ml/kg)
-- destruction of type II pneumocytes (alveolar macro- -- increased pulmonary vascular permeability index
phages) → decreased surfactant production → ate- (PVPI > 3)
lectasis
-- formation of hyaline (Greek: glass) membranes (mi- Chest X-ray
croscopic eosinophilic, amorphous material that li-
nes the alveloar walls; therefore syn.: "hyaline mem- • p.d. bilateral alveolar opacities
brane syndrome") • diffuse lung infiltrates
-- microthrombi in the lung capillaries • heart size normal (in contrast to decompensated heart
-- beginning fibrosis (still reversible) failure
• fibrotic (within weeks; rarely occurs): • no pleural effusions (in contrast to decompensated
heart failure; in pleuropneumonia, however, as a cause
-- thickening of the alveolocapillary membrane (up to 5
of ARDS, pleural effusions are also possible)
times of the norm)
• extreme form: "white lung"
-- faulty regeneration of the lung tissue
-- completed fibrosis (scarring; pulmonary fibrosis; ir-
reversible)

3-zone model
• zones:
-- zone D (diseased): Dorsally there are atelectatic
areas in which there is no pulmonary gas exchange
and almost no therapy available.
-- zone R (recruitable): In the middle area is lung tis-

Pulmonology 617
 Fig. 866  Classic chest X-ray images in ARDS (various ex-
amples): bilateral alveolar opacities, heart not enlarged, no
pleural effusions (in contrast to chest X-ray in cardiac de-
compensation!)

Fig. 867  Pulmonary edema in acute mitral regurgitation of-

ten looks deceptively similar to ARDS ("butterfly-shaped").

Chest CT
• This is important for determining the treatment strate-
gy (especially the recruitment potential) and should be
performed generously (especially at the beginning) in
ARDS.
-- If the ARDS is only located dorsally, a high PEEP
is of little use (it only causes damage because it is
destroyes the healthy lung; to open these atelecta-
sis a PEEP of approx. 30 mbar would be necessary,
which is absolutely utopian), but the prone positio-
ning brings a lot.
-- If, on the other hand, the ARDS is diffusely (homoge-
neously) distributed, a high PEEP will bring a lot, but
prone positioning will have little effect.
• Such a decision cannot be made at all on the basis
of the X-ray image (bed image; only one-dimensional)
alone.

618 Pulmonology
• Areas with ground glass opacities (p.d. vessels still re- Fluid restriction
cognizable) are still easy to recruit, while areas with
• goal: negative fluid balance (in patients with circulatory
consolidations (p.d. vessels no longer recognizable)
stability)
are difficult (usually not at all) to recruit.
• means:
-- diuretics
ARDS: generous chest CT! -- RRT (renal replacement therapy: CVVH / intermit-
tent hemodialysis)
• „Keep the lung dry“
• control by clinic, chest X-ray, echocardiography and
advanced hemodynamic monitoring (e.g. PiCCO [tar-
get: ELWI < 10 ml/kg])
• no prospective randomized controlled studies showing
a reduction of mortality due to fluid restriction
• In practice this is usually the procedure: ARDS is usu-
ally associated with sepsis. Accordingly, the patient is
haemodynamically unstable, so that a negative balan-
ce is not possible. The stabilization of hemodynamics
is in the foreground, so that the patient has to be ba-
lanced positive initially by fluid administration. Further-
more, patients with ARDS usually benefit from a hig-
her PEEP, which also causes circulatory depression.
Therefore, fluid administration is necessary in the first
few days and negative balancing is not indicated. After
stabilization of the haemodynamics and improvement
of the gas exchange, the volume is then withdrawn la-
ter if necessary (e.g. by diuretics or CVVH).

FACT study

Fluid and catheters treatment trials - Comparison of two

fluid-management trials in acute lung injury
Wiedemann et al, ARDS Clinical Trials Network, N Engl J
2006

• FACTT: fluids and catheters treatment trial

• multicenter randomized prospective study
• 1000 patients with acute lung injury (ALI)
• restrictive versus liberal fluid management (cumulative
Fig. 868  Different variants of an ARDS (chest CT): The first fluid balance after 6 days: +/- 0 versus + 7 liter)
image shows a local (mainly dorsally localized) ARDS. Here • results: restrictive fluid management
a high PEEP is of little use, but prone positioning is of high
-- improvement of the oxygenation index
benefit. The second image shows a diffuse (homogeneous-
ly distributed) ARDS: Here a high PEEP brings much, but -- increased number of ventilation-free days
prone positioning little. -- shortening of ICU length of stay
-- less central nervous complications (brain edema ↓)
-- no influence on mortality (60 days)
Therapy • critical note:
-- Patients with renal failure were excluded.
• causal therapy: ARDS is a syndrome of different
-- mean age: only 50 years
causes, so that the therapy of the underlying disease
(e.g. pneumonia, pancreatitis etc.) is the first priority!
• fluid restriction (negative balance)
• kinetic therapy (positioning therapy)
• ventilation therapy
• drug therapy

Pulmonology 619
Kinetic therapy (positioning therapy)
Introduction
• 1955 Blair and Hickham: proof of a beneficial effect of
positioning drainage on lung function
• S2e guideline 2015 "positioning therapy and early mo-
bilisation for prophylaxis or therapy of pulmonary dys-
function" of the German Society for Anaesthesiology
and Intensive Care Medicine (DGAI)
Fig. 869  reverse-Trendelenburg positioning (RTP): obliga-
tory in every ventilated patient with obesity
Never ventilate obese patients flat in
supine position! always reverse
Trendelenburg positioning!
620 Pulmonology
Prone positioning
Definition
• dorsoventral change of position
• change from supine to prone position
• duration
-- change every 12h (if necessary 12-24h; S2e guide-
line 2015: prone position for at least 16h) or as long
as paO2 is higher than in the previous position
-- If there is no persistent improvement in oxygena-
tion after turning back into the supine position (i.e.
Horovitz quotient after 4h supine position still <
150mmHg), the patient should be turned back to
prone position. Here you must not make the mis-
take of speaking of a non-responder and therefore
not pronating the patient again. The patient does not
have to be pronated again if 4 hours after supination
the Horovitz quotient is > 150 mmHg for a PEEP <
10 cmH2O and a FiO2 < 0.6.
-- Numerous clinics usually leave patients with severe
ARDS in prone position for 20 hours and only turn
them back in the morning for care, before turning
them back into prone position again.
-- Tip (orientation to the shift times of the nursing staff):
prone position for 2 shifts, supine position for 1
shift (The turning should take place during the shift
change, so you have more staff.)
• non-responder: 10-20%
-- Definition Non-Responder: increase of the Horovitz
quotient (paO2/FiO2) by less than 20% from the initial
value (no improvement of oxygenation)
-- Especially patients with diffusely homogeneously
distributed ARDS often do not respond.
• possibly additional upper body elevation (upright prone
position; often difficulties because patients often slide
downwards on the anti-decubitus mattress
• The same principles apply to ventilation in the prone
position as in the supine position (including lung pro-
tection). For example, spontaneous breathing compo-
nents (e.g. CPAP-ASB) should already be integrated in
the prone position!
• particularly efficient:
-- early phase of ARDS (Here you still have water that
can be mobilized in contrast to the late phase, when
the lungs are already fibrosed.)
-- extrapulmonary induced ARDS
-- (dorsally) localized ARDS (less effective in homoge-
neously diffusely distributed ARDS)
• S2e guideline2015:
-- ARDS with Horovitz quotient < 150 mmHg (S2e
guideline 2008: < 100 mmHg)
-- for at least 16h (S2e guideline 2008: 12h)
-- contraindications for prone position → conti-
nuous lateral rotation therapy (CLRT)
• unfortunately only rarely implemented in severe ARDS
(although clearly recommended):
-- LUNG-SAFE study (Bellani et al, JAMA 2016): onlyin
16%
-- APRONET study (Guerin et al, Intensive Care Med
2018): only in 33%

Fig. 870  prone positioning
Effects
• homogenization of respiratory gas distribution
• improvement of pulmonary perfusion and increase of
ventilation-perfusion ratio
• decrease of pulmonary edema in the gravity-depen-
dent lung sections → recruitment of dorsal lung sec-
tions by prone position
• reduction of pleural pressure gradient
-- main effect
-- transpulmonary pressure = alveolar pressure - pleu-
ral pressure
-- In a patient in supine position the pleural pressure
increases from ventral to dorsal..
• increase of the functional residual capacity (FRC)
• reduction of the frequency of ventilator-associated
lung injury (VALI; prone positioning shows physiologi-
cal protection!)
• improvement of the respiratory mechanics (change of
the position of the diaphragm
• reduction of the intrapulmonary shunt: The atelectatic
dorsobasal parts of the lung are ventilated again by the
abdominal positioning, which leads to a reduction of
the shunt (already perfused alveoli are now ventilated
again).
• secretion mobilization (After turning back from the pro-
ne to the supine position, it is often necessary to suck
of the patient endobronchially [if necessary by bron-
choscopy].)
Fig. 871  Compared to the supine position on the left, the
dynamics of the diaphragm in the prone position on the
right are increased (increase in muscular dynamics in the
area of the spine). The respiratory gas distribution (arrows)
is homogenized and atelectasis (hatched) reduced.
Studies
• The studies on prone positioning (until 2013) showed
an improvement in oxygenation (in 75%), but no mor-
tality advantage (two earlier outcome studies on prone
positioning: Gattinoni et al, N Engl J Med 2001; Guerin
et al, JAMA 2004); points of criticism of the two out-
come studies:
-- no lung-protective ventilation performed there (VT 12
ml/kg instead of 6 ml/kg)
-- far too low PEEP
-- prone position far too short (only 7 hours)
• post-hoc analysis in subgroup with Horovitz quotient <
88 mmHg even significant survival advantage (Gattio-
nini et al, N Eng J 2001)
• The milestone study for the prone position finally was
the PROSEVA study (see box).
Pulmonology 621
 Prone-Supine II study meta-analysis

Prone Positioning in Patients With Acute Respiratory Dis- Effect of prone positioning during mechanical ventilation
tress Syndrome on mortality among patients with acute respiratory distress
Taccone et al, JAMA 2009 syndrome: a systematic review and meta-analysis
Sud et al, CMAJ 2014
• multicenter randomized controlled trial
• 342 patients with ARDS • meta-analysis (11 RCT)
-- prone-group (prone position by means of Rotoprone; • 2341 patients with ARDS with lung-protective ventilation
average 18h/d) -- prone-group
-- supine-group -- supine-group
• results (prone-group) • results: prone-group
-- mortality: no difference (only with severe ARDS [p.d. -- significant reduction of mortality (by 26%; NNT
Horovitz quotient < 100mmHg trend towards lower only 11)
mortality]) -- significant improvement of oxygenation (increase of
-- increased rate of complications (e.g. tube dislocation, Horovitz quotient
need for deeper sedation)

ARDS with Horovitz quotient < 150

mmHg → prone position (for at least
meta-analysis 16h; in case of contraindications:
CLRT)

An updated study-level meta-analysis of randomized trials Types

on proning in ARDS and acute lung injury • incomplete prone position (135°; "crawl swimming po-
Abroug et al, Crit Care Med 2011 sition")
• complete prone position (180°): The complete prone
• meta-analysis (7 RCT)
positioning is considerably more effective than the in-
• 1675 patients with ALI and ARDS
complete prone positioning in terms of improving oxy-
-- prone-group
genation (Bein et al, Anaesthesist 2004 [see box]) and
-- supine-group
should therefore be preferred.
• results: prone position
-- no reduction in mortality
-- only the 4 RCT with ARDS: significant reduction
in mortality study

PROSEVA study Comparison of incomplete (135°) and complete prone po-

sition (180°) in patients with acute respiratory distress syn-
drome. Results of a prospective, randomized trial
Bein et al, Anaesthesist 2004

Prone Positioning in Severe Acute Respiratory Distress • prospective randomized study

Syndrome • 59 patients with ARDS and prone position
Guerin et al, N Engl J 2013 -- incomplete (135°)
-- complete (180°)
• multicenter prospective randomized study
• result: complete prone position
• PROSEVA: Proning in Severe ARDS
-- significantly better oxygenation (increase of Horovitz
• 466 patients with severe ARDS (Horovitz quotient < quotient
150mmHg, FiO2 > 0.6, PEEP > 5 cm H2O)
-- no increased rate of complications
-- supine-group
-- prone position (for at least 16h; average 17h)
• result: prone position → significant reduction (hal-
ving!) of mortality (after 28d from 32.8% to 16%; NNT
only 6! milestone study!)

622 Pulmonology

The complete prone positioning (180°)
is more effective than the incomplete
prone positioning (135°)!
Contraindications
• acute phase of traumatic brain injury, increased int-
racranial pressure (but only relative: Prone position
can lead to an increase in intracranial pressure and
thus to a reduction in cerebral perfusion flow. But if
both the atlanto-occipital axis and the cervical spine
are positioned in a strictly neutral position, a critical
increase in intracranial pressure is unlikely. Futher-
more, prone positioning can improve oxygenation and
thus the cerebral oxygen supply. In individual cases,
after weighing up the individual risks and benefits, it is
possible to perform prone positioning in patients with
increased intracranial pressure. However, a measure-
ment of intracranial pressure is then obligatory.)
• unstable spine
• pelvic fracture with external fixator
• severe facial trauma
• pronounced cardiovascular instability (note: The use of
catecholamines alone is not a contraindication for pro-
ne position.), malignant cardiac arrhythmias; reason:
Sufficient chest compression is difficult in the prone po-
sition, but quite possible (i.a. recommendations ILCOR
and ERC for CPR in patients with COVID-19 2020):
-- pressure point: between the shoulder blades
-- Only if a DBP > 25 mmHg cannot be achieved, the
patient should be turned back in supine position.
-- defibrillation: anterior / posterior or bi-axillär
• open abdomen
• intraabdominal compartment syndrome (manifest)
• ECMO (but only relative: Many clinicians also perform
prone positioning in patients under ECMO). In a small
number of patients it could be shown that prone posi-
tioning is relatively safe even under ECMO [Kipping et
al, Int J Artif Organs 2013]. The risk of complications
is certainly lower with vv-ECMO than with va-ECMO.)
Fig. 872  prone positioning (with elevated upper body po-
sition [upright prone position]) in a patient with vv-ECMO
Complications
• accidental extubation, tube dislocation, dislocation of
catheters (e.g. CVC; above all when turning around;
therefore the physician always holds the tube when
turning around and secures the CVC
• positional damage, pressure ulcers (especially chin,
nose, forehead, thorax, pelvis, knee; therefore only in
one bed with anti-decubitus mattress, especially in pa-
tients with an increased risk of decubitus [especially
cachexia, obesity, higher doses of catecholamine the-
rapy, steroid therapy]), edema (especially in the face)
• increase in intra-abdominal pressure (IAP)
-- possibly aspiration: This is why the enteral nutrition
must be reduced (tube feeding up to a maximum of
20 ml/h; here the gastric residual volume [GRV] has
to be measured always).
-- Caution should be exercised especially in patients
with (abdominal) obesity in whom the intraabdo-
minal pressure is already elevated and a manifest
intraabdominal compartment syndrome (IACS) with
corresponding organ failure may occur due to prone
positioning. In a study (Weig et al, J Crit Care 2014)
it was shown that patients with abdominal obesity
with prone positioning due to ARDS were significant-
ly more likely to suffer from acute kidney injury and
ischemic hepatitis. The longer the prone positioning
was performed in these patients, the higher the mor-
tality was. If prone positioning has to be performed
in the context of ARDS in patients with abdominal
obesity, the intraabdominal pressure (IAP) should
be measured generously! A good alternative to the
complete prone position, however, is the incomplete
(135°) prone positioning: Here one has the advan-
tage that a large part of the fat mass is simply placed
sideways without increasing the intraabdominal
pressure.
• increase in intracranial pressure (ICP)
• increase in intraocular pressure (IOP)
• intolerance of the patient, need for deeper sedation
• hypotension, tachycardia, cardiac arrhythmia
Fig. 873  positioning damage (arrows) after multiple prone
positioning on the chin and forehead; furthermore facial
edema with swollen lips
cave IACS in prone positioning
for obesity: generous measure-
ment of IAP!
Pulmonology 623
Fig. 874  Especially in patients with abdominal obesity, we
like to use the 135° lateral position instead of the (com-
plete) prone position (incomplete prone position; "crawl
swimming position"), because the lateral displacement of
the abdomen causes the intraabdominal pressure (IAP) to
increase less than under the strict prone position..
Fig. 875  CLRT: continuous lateral rotation therapy (here
Triadyne) [21]
Procedure (turning maneuver)
• Turning should (only if possible) be performed during
shift change, because there you have more personnel.
• A physician and 2-3 nurses are needed.
• Before turning around, a possibly running enteral nut-
rition is stopped and the stomach is sucked off via the
gastric tube.
• set FiO2 to 1.0
• secure and fix tube, catheter, drainages (extension
cord if necessary)
• The physician holds the tube and secures the CVC
against dislocation.
• switch on the systole tone
• deepening of analgosedation for the turning maneuver
Fig. 876  CLRT: continuous lateral rotation therapy (here:
Rotorest) [21]
Continuous lateral rotation therapy (CLRT)
Definition
• continuous rotation of the patient about his longitudinal
axis in a motor-driven special bed ("swing bed")
• originally developed for decubitus prophylaxis in im-
mobilized patients
• according to the company (KCI) only approved up to a
body weight of 160kg
• duration: 18-20h/day
• The pressure transducer for invasive RR measure-
ment must be attached to the bed system at median
axis level to avoid incorrect measurements..
• very rarely used in our clinic (e.g. polytrauma with ex-
ternal fixator)
• can also be safely performed with ECMO (i.a. Knedel
et al, Perfusion 2014)

Types (according to the swivel angle)

• TriaDyne (up to 45°)
• RotoRest (62°/ 62°)
• RotaProne (360°; no longer rented by the KCI compa-
ny in Europe)

Fig. 877  CLRT: continuous lateral rotation therapy (here:

Rotorest)

624 Pulmonology
 • protective ventilation
• recruitment maneuvers
• rescue measures
study

Continuous lateral rotation therapy to prevent ventilator-
associated pneumonia: The neglected effects of gravity on
pathogenesis of ventilator-associated pneumonia
Staudinger et al, Crit Care Med 2010
• prospective randomized clinical study
• 150 patients with invasive ventilation > 48h (without
pneumonia)
-- with CLRT (90º)
-- without CLRT
• results: CLRT
-- significant reduction of VAP
-- significant reduction of duration of ventilation and
length of ICU stay
Indication
• therapeutic: ARDS with Horovitz quotient < 150mmHg
and contraindications to prone position (only optional;
can be considered)
• prophylactic: CLRT is, however, less for the therapy
of ARDS than more for the prophylaxis of a VAP (i.a.
Staudinger et al, Crit Care Med 2010 [siehe box]; Si-
monis et al, Clin Res Cardiol 2012)! However, it is cer-
tainly not possible to place every ventilated patient in
a RotoRest bed just to avoid VAP! CLRT is also not
recommended in PEG or KRINKO guidelines for VAP
prophylaxis..
Protective ventilation
Introduction
• syn.: LPV (lung protective ventilation)
• Protective ventilation aims to protect the lung from
ventilator associated lung injury (VALI).
• The term "protective" is actually misleading: Ventilation
is always destructive and never protective! The term
"as little destructive ventilation as possible” would be
better.
• Ventilation per se is completely unphysiological: It is
performed with positive pressure. Physiologically, on
the other hand, spontaneous breathing occurs with ne-
gative pressure. It is no causal therapy at all. It´s just a
bridging measure until the lung is healed for example
from the pneumonia with antibiotics or by itselfs (enor-
mous self-healing tendency of the lung!)
VALI
• ventilator associated lung injury
• syn.: VILI (ventilator induced lung injury), "respirator
lung"
VALI
ventilator associated lung injury

CLRT: only in case of contraindicati-

ons for prone position! significantly
worse oxygenation than prone
position (i.a. Staudinger et al, Crit
Care 2001)!

Ventilation Therapy

Pulmonology 625

Fig. 878  barotrauma: right-sided pneumothorax
Fig. 879  shear stress (arrows) between collapsed infiltra-
ted alveolus (red) and healthy alveolus (blue) with good
compliance
Concept
• low tidal volumes (6 ml/kg)
• limited inspiratory pressures (< 30 cmH2O): The ins-
piratory pressure should not exceed 30 cmH2O. The
higher the inspiratory pressure, the higher the mortality
(meta-analysis Brower et al, AJRCCM 2002).
• high PEEP (10-15 cm H2O)
• pressure gradient ("driving pressure") Δp from inspira-
tion pressure and PEEP < 15 cmH2O
• FiO2: With the adjustment of the FiO2 one orients
oneself more at the saturation SpO2 (target > 90%)
and less at the paO2. Three-digit paO2 values (i.e. >
100mmHg) are not necessary (no "luxury oxygenati-
on"). In the ANZICS study (Panwar et al, Am J Respir
Crit Med 2015), a liberal (SpO2 ≥ 96%) and a restrictive
(SpO2 88-92%) oxygenation group showed no differen-
ces with respect to new organ failure or mortality. In the
subgroup with an initial Horovitz quotient < 300mmHg
(ARDS) the restrictive oxygenation group even show-
ed a tendentially lower mortality. According to the S3
guideline "Invasive ventilation" 2017, an SpO2 > 90%
or a paO2 > 60 mmHg is completely sufficient.
• possibly inversed ratio ventilation (IRV; abandoned to-
day)
626 Pulmonology
• permissive hypercapnia
• pressure-controlled ventilation
• early spontaneous breathing
Tidal volume VT
• reduction of tidal volume (VT) from 10 ml/kg (ventilation
of an undamaged lung) to 6 ml/kg bodyweight (This is
our physiological tidal volume!)
• ARDS network study (see box)
• based on the ideal (standard weight; PBW: predicted
body weight; non-real) body weight (no ventilation of
fat! also applies to underweight [e.g. cachectic] pati-
ents)
• exact: ideal weight + ¼ (real weight - ideal weight)
• SepNet (Brunkhorst et al, Crit Care 2008): Only in
4% a low-tidal-ventilation is carried out, although 92%
would know it.
• The low-tidal-ventilation is recommended today not
only for lung-damaged (e.g. ARDS), but also for lung-
healthy patients (i.a. S3 guideline 2017 "Invasive ven-
tilation and use of extracorporeal procedures for acute
respiratory failure" of the DGAI). In the IMPROVE stu-
dy (Futier et al, N Engl J 2013), postoperative respira-
tory insufficiency was significantly less common in pati-
ents ventilated during surgery (2-3h during anesthesia)
if ventilation was performed with a tidal volume of 6-8
ml/kg instead of 10-12 ml/kg. However, the IMPROVE
study did not only include lung healthy patients. A me-
ta-analysis (Gu et al, CMAJ 2014) also showed advan-
tages. In a retrospective analysis of general surgical
patients ventilated in the operating theatre without lung
failure, an increased 30d mortality was observed when
they were ventilated with a tidal volume of 6-8 ml/kg
instead of 8-10 ml/kg (Levin et al; Br J Anaest 2014).
In a retrospective analysis (Ladha et al, BMJ 2015),
fewer respiratory complications were observed post-
operatively. In the PReVENT study (see box), howe-
ver, in which ventilated patients without ARDS were
examined, there were no advantages due to low-tidal
ventilation.
• Of course, volume-controlled ventilation would be opti-
mal to maintain the limited tidal volumes (as it was also
carried out in the ARDS Network study). In Europe,
however, pressure-controlled ventilation is standard.
• The tidal volume depends on the compliance of the
lung, which cannot be greatly influenced, and the pres-
sure difference: the higher the pressure difference bet-
ween inspiration pressure and PEEP (pressure ampli-
tude [= driving pressure] Δp = IPAP - PEEP), the higher
the tidal volume! ! In order to achieve low tidal volu-
mes, a low pressure amplitude must therefore be set,
i.e. a low inspiration pressure (IPAP) and a high PEEP!
The pressure difference should be less than 15mbar.
In order to achieve a sufficient respiratory minute volu-
me (RMV = respiratory rate x VT), the respiratory rate
(16-30/min) must be increased consecutively.
 ARDS-Network study study

Ventilation with Lower Tidal Volumes as Compared with Driving Pressure and Survival in the Acute Respiratory Dis-
Traditional Tidal Volumes for Acute Lung Injury and the tress Syndrome
Acute Respiratory Distress Syndrome Amato et al, N Engl J 2015
ARDS-Network, N Engl J 2000
• etrospective study (data analysis; no prospective rando-
• multicenter randomized trial mized controlled study)
• 861 patients with ALI / ARDS (permature stop of the stu- • 3562 patients with ARDS
dy); volume controlled ventilation with a tidal volume of: • The lower the pressure difference between IPAP and
-- 12 ml/kg PBW PEEP, the lower the mortality.
-- 6 ml/kg PBW • The prognostic significance of a low pressure diffe-
• results: 6 ml/kg PBW rence is even higher than that of a low tidal volume or a
-- reduction of mortality from 40% to 31% high PEEP.
-- more ventilator-free days
-- The most important result and the central mes-
sage of the study is that on the one hand there was
worse oxygenation (BGA ["worse gases"], Horovitz
quotient]), but on the other hand a better survival (a
PReVENT study
milestone study)!
• further parameters of the study:
-- PEEP 9.4 cmH2O
-- pCO2 40 mmHg Effect of a Low vs Intermediate Tidal Volume Strategy on
-- RR 29/min (high respiratory rate!) Ventilator-Free Days in Intensive Care Unit Patients
-- A volume-controlled ventilation was performed! Simonis et al, JAMA 2018

• multicenter randomized trial

• PReVENT: Protective Ventilation in Patients Without
ARDS
study • 961 ventilated intensive care patients without ARDS
with an expected ventilation duration > 24h; tidal volume:
-- low (4 ml/kg)
-- intermediate (10 ml/kg)
• results: no difference
Lung protective mechanical ventilation and two year sur-
-- primary endpoint: number of ventilation-free days
vival in patients with acute lung injury: prospective cohort
study -- secondary endpoints (length of ICU / hospital stay,
Needham et al, BMJ 2012 mortality, occurrence of ARDS, pneumonia, atelecta-
sis, pneumothorax)
• prospective cohort study
• 485 ventilated patients with ARDS Standard body weight
• protective ventilation → absolute reduction in mor-
• formula
tality by 7.8%
-- men: BW = 50 + 0.91 x (height in cm - 152.4)
-- women: BW = 45.5 + 0.91 x (height in cm - 152.4)
• It is easier and much more practical for everyday
clinical use to measure body height (size) with a tape
measure (belongs in the coat pocket of an intensive
care physician!). Lung size correlates extremely well
with body size in humans. The ideal body weight is
then calculated quite simply: height in cm - 100 (for
women: -10%).
• Chumlea method (according to Bojmehrani et al, Resp
Care 2014)
-- determination of body height (size) by measuring the
length of the lower leg from the patella to the heel
-- formula: body height (in cm)
◦◦ men: 64.19 - (0.04 x age) + (2.02 x lower leg
length in cm)

Pulmonology 627
 ◦◦ women: 84.88 - (0.24 x age) + (1.83 x lower leg
length in cm)
ARDS: tidal volume: 6 ml/kg (not 10
ml/kg)
Fig. 880  A tape measure should be placed in the intensive
care physician's coat pocket!
Fig. 881  Chest CT in a patient with morbid obesity: It is
easy to see how small the lungs actually are in obese pa-
tients. The lungs don't grow when people get heavier. For
this reason, the tidal volume is based on the ideal weight
rather than the real weight. Fat does not have to be venti-
lated!
PEEP
Definition
• PEEP (positive end expiratory pressure) prevents the
alveoli from collapsing and therefore protects against
the development of atelectasis with consecutive shunt.
• for the recruitment of atelectatic districts and for kee-
ping it open („open the lung and keep it open“)
• for the prevention of cyclic alveolar collapse (alveolar
cycling)
• This also includes reducing the bronchial toilet to a mi-
nimum, as this leads again and again to a reduction
and even to a loss of PEEP. Suction should only beper-
formed if mucus is obstructing the tube (no standard
suction). ). If possible, closed sucstion systems should
be used. Disconnections should be avoided. If they are
necessary, PEEP clamps should be used.
628 Pulmonology
• A too high PEEP leads to capillary compression and
thus to increased dead space ventilation (dead space:
alveolus still ventilated, but no longer perfused). By in-
creasing the dead space ventilation, the alveolar (i.e.
effective) ventilation decreases consecutively, so that
pCO2 increases.
• A too low PEEP leads to the formation of atelectasis
(derecruitment).
• Usually a higher PEEP is necessary in the initial phase
of ARDS. Due to the resulting circulatory depression,
sufficient fluid administration is necessary in the first
few days. If the gas exchange improves in the course
of the treatment, PEEP should be reduced again (no
permanent dwelling at high PEEP pressures!) accor-
ding to the following rulel: PEEP reduction by 1mbar
-- FiO2 > 0.5: every 12h
-- FiO2 < 0.5: every 8h
Static PV curve
• lower inflection point (LIP): point above which a slight
increase in pressure is followed by a greater increase
in volume; < LIP: atelectasis (atelectrauma; "stress"
[tension])
• upper inflection point (UIP): point beyond which the
elastic properties of the lung tissue are overstrained
and the lung becomes overstretched (start of over-
stretching); > UIP: overstretching (volutrauma; "strain")
volume
upper inflection point
tidal
volume
lower inflection point
PEEP inspiratory pressure
pressure
Fig. 882  Static PV curve (simplified representation; actu-
ally a hysteresis curve)
Strategies (titration methods "best PEEP";
"PEEP show")
• LIP measurement
• PEEP trial: upward titration of PEEP until pCO2 rises
(PEEP → overstretching of the alveoli → compression
of the vessels → dead space ventilation ↑ ) or down
titration (In the PEEP trial it is best to titrate the PEEP
from top to bottom!)
• after a successful recruitment maneuver back titration
until pO2 suddenly drops
• ARDS network table (Roy et al, N Engl J 2004):
-- syn.: NIH protocol (National Institutes of Health)
-- the simplest and most practicable for clinical eve-
ryday life (also recommended in the S3 guideline
2017 "Invasive ventilation" of the German Society
 for Anaesthesiology and Intensive Care Medicine)!
• computer tomography (disadvantage: elaborate trans-
port)
-- local (e.g. dorsal): lower PEEP
-- diffuse (homogeneous): higher PEEP
• pleural pressure s
• tress index
• determination of FRC (functional residual capacity)
• EIT (electrical impedance tomography)
-- The PEEP is usually set above the LIP anyway. The
question in everyday clinical life is rather, how high
one can go with the PEEP, so that there is no over-
inflation.
-- Furthermore the static PV curve considers inspirati-
on, but PEEP is a parameter of expiration!

Fig. 884  derivation of the PV curve (pressure-volume cur-

Fig. 883  The search for the "best PEEP" sometimes resem-
bles the search for the Holy Grail!
ve) on the ventilator - here using the LowFlow PV loop
measurement maneuver on the Evita XL: The lung is filled
here with a very low flow (usually only 4-10 l/min) cons-
tantly slowly (volume-controlled ventilation). ). This makes
the breathing cycle extremely long (20-30s). Complications
include circulatory depression and pneumothorax. The lo-
wer (LIP) and the upper (UIP) inflection points can be deter-
mined by a cursor line that can be adjusted with the rotary
knob-

LIP measurement ARDS-network table (NIH protocol)

• determination of the LIP (lower inflection point) in the Coupling ("Tandem" setting) of PEEP to the set FiO2
individual static PV curve (set FiO2 so, that SpO2 > 90% or paO2 > 60 mmHg); two
• A pressure e.g. 2 cmH2O above the LIP is then selec- tables proposed by the ARDS network: low-PEEP (most
ted as PEEP. common) and high-PEEP table
• measurement
-- static (Supersyringe method: The lung is filled step
Low-PEEP table
by step with a large syringe and emptied. To do this,
FiO2 PEEP (cmH2O)
the patient must be disconnected from the ventila-
tor.) 0.3 5
-- dynamic; settings: 0.4 5-8
◦◦ volume-controlled ventilation (The measurement 0.5 8-10
is only possible with volume-controlled ventilation 0.6 10
and not with pressure-controlled ventilation!)
0.7 10-14
◦◦ flow 60l/min (constant flow), Plateau 1-2s
◦◦ low respiratory rate (e.g. 5/min) 0.8 14
◦◦ long expiratory time (e.g. set I:E to 1:8) 0.9 14-18
◦◦ PEEP 0 mbar (ZEEP [zero PEEP]) 1.0 20-24
◦◦ Deep analgosedation (if necessary relaxation; pa-
High-PEEP table
tient must not breathe spontaneously)
• Almost all ventilators meanwhile have automatic FiO2 PEEP (cmH2O)
measuring maneuvers (e.g. LowFlow PVLoop at EVI-
0.3 5-14
TA XL from Dräger as part of the Lung Protection Pa-
ckage) to derive the points. 0.4 14-16
• The LIP measurement has numerous weaknesses 0.5 16-18
with considerable limitations and is therefore of minor 0.6 20
importance in clinical everyday life:
0.7 20
-- The measurement is relatively complex and risky
(including increased pneumothorax risk, circulatory 0.8 22
instability [measurement only possible if the patient 0.9 22
is circulatory stable]). 1.0 24
-- In ARDS, often no inflection points can be deduced.

Pulmonology 629
Pleural pressure
• The decisive factor for oxygenation is the transpulmo-
nary pressure. This is determined by the difference
between the alveolar pressure and the pleural pres-
sure.
• transpulmonary pressure = alveolar pressure - pleural
pressure
-- alveolar pressure: pressure in the alveolus ("internal atelectasis

pressure")
-- pleural pressure: pressure around the alveolus ("ex-
ternal pressure")
• The surrogate parameter for the alveolar pressure is
the ventilation pressure, the surrogate parameter for
the pleural pressure is the esophageal pressure.
• measurement of the pleural pressure via esophageal
Fig. 885  In both cases a PEEP of 15 mbar is set: On the
catheter, measurement of the esophageal pressure as left this is sufficient, on the right not. Here the high pleural
a surrogate parameter for the pleural pressure pressure leads to a negative transpulmonary pressure and
• esophageal catheter: consecutive to atelectases. Here the PEEP must be incre-
-- balloon catheter in the middle esophagus ased (courtesy of PD Dr. G.-C. Funk, Medical University of
Vienna [Austria]).
-- The balloon is blocked with air.
-- commercially available nasogastric feeding tube
with integrated esophageal balloon
-- verification of the correct position by x-ray and evi-
dence of cardiac synchronous fluctuations of the
pressure curve
-- currently only available for a few ventilators (e.g.
Engström Carestation, Hamilton) pleura esophagus
• The higher the pleural pressure, the higher the PEEP
should be set (i.a. Talmor et al, N Engl J 2008).
• studies:
-- EPVent-1 study (Talmor et al, N Engl J 2008; EP-
Vent: esophageal-pressure guided mechanical ven-
tilation): significantly better oxygenation if PEEP is
controlled by esophageal pressure instead of ARDS-
network table
Fig. 886  The CT shows the anatomical proximity between
-- EPVent-2 study (Beitler et al, JAMA 2019): no reduc-
the esophagus and the pleural space. Therefore the pleural
tion in mortality or duration of ventilation if PEEP is pressure can be determined indirectly via the pressure in
controlled by esophageal pressure instead of ARDS- the esophagus.
network table
• The possibility of pleural pressure measurement will
(probably) become routine in the new ventilators.
• This can be used to differentiate between pulmonary
and extrapulmonary restrictions. An extrapulmonary
restriction may be:
-- abdominal (e.g. increased intraabdominal pressure,
ascites, obesity)
-- thoracic (e.g. pleural fibrosis, thoracic wall edema,
thoracic deformities [e.g. kyphoscoliosis], large heart
[e.g. DCM, pericardial effusion])
• It should be noted that, on the one hand, the measu-
rements are relatively susceptible to interference and,
on the other hand, that lung damage in ARDS is often
distributed inhomogeneously.

630 Pulmonology
 Fig. 889  measurement of esophageal pressure (as a surro-
gate parameter for pleural pressure): The pleural pressure
curve is shown here. The typical pulse-synchronous pres-
sure fluctuations can be clearly seen.

Fig. 887  measurement of esophageal pressure (as a surro-
gate parameter for pleural pressure) using a balloon inte-
grated into a special gastric tube (courtesy of PD Dr. G.-C.
Funk, Medical University of Vienna [Austria])
Stress index
• form of the pressure curve in volume-controlled venti-
lation (i.e. ventilation must switch from pressure-cont-
rolled to volume-controlled ventilation)
• ΔP = a x Δtb + c (Ranieri formula: The stress index is
the exponent b.)
• target: 0.9-1.1
• Grasso et al, Am J Resp Crit Care Med 2007
• only possible in volume-controlled ventilation (A cons-
tant [not decelerating ] flow must be set.)

curve: convex curve: linear curve: concave

stress index < 1 stress index = 1 stress index > 1
PEEP too hogh PEEP optimal PEEP too low
overstretching atelectasis
Fig. 890  stress index: shape of pressure curve with volu-
me-controlled (It should neither be convex nor concave,
but linear!)

FRC determination
• FRC: functional residual capacity
• syn.: EELV (endexspiratory lung volume)
• definition: volume remaining in the lung after normal
expiration
• methods:
-- CT (less practicable)
-- gas dilution method
◦◦ helium
◦◦ nitrogen (COVX module on the Engström Caresta-
tion ventilator from GE Healthcare; measurement
Fig. 888  measurement of pleural pressure (here on the of the FRC takes about 20 minutes)
Engström Carestation ventilator from GE Healthcare) • principle:
-- The higher the measured FRC, the higher the PEEP
should be set.

Pulmonology 631
 -- The tidal volume should not be larger than the FRC,
otherwise overstretching (strain) will occur (target:
VT < FRC; strain = VT / FRC, target < 1).

VC
TLC

FRC

RV
Fig. 891  representation of the lung volumes: TLC (total
lung capacity), VC (vital capacity), RV (residual volume),
FRC (functional residual capacity): The functional residual
capacity is the volume that remains in the lung at the end of
a normal expiration.
Fig. 892  FRC measurement (here on the Engström Caresta-
tion ventilator from GE Healthcare)
Electrical impedance tomography (EIT)
• measurement of thoracic bio-impedance via an elect-
rode belt (16 electrodes) attached to the thorax of the
ventilated patient
• Changes in lung volume are associated with a change
in impedance. Tomographic images (analogous to CT,
but without X-rays) are reconstructed from the mea-
sured impedances according to a specific algorithm.
On the basis of these images, the regional distribution
of ventilation volumes in the lung can be continuously
displayed ("ventilation is made visible") and monitored
on the bed side, and possible pathologies (atelecta-
ses, overstretching) can be detected. Ultimately, venti-
lation can be optimized in this way (i.a. Putensen et al,
Crit Care 2007: electric impedance tomography guided
ventilation therapy).
• EIT can also be used to adjust the PEEP: An optimal
PEEP is present if the EELI (end expiratory lung impe-
dance) curve is horizontal.
• This procedure is currently only possible with the Pul-
moVista 500 from Dräger (an electrical impedance to-
mograph).

Fig. 893  electrode belt

632 Pulmonology
 meta-analysis

Higher vs Lower Positive End-Expiratory Pressure in Pa-

tients with ALI and ARDS
Briel et al, JAMA 2010

• meta-analysis from the 3 large PEEP studies:

-- ALVEOLI (2004)
-- LOVS (2008)
-- EXPRESS (2008)
• 2299 patients with ALI and ARDS
-- low PEEP (< 10 mbar)
-- high PEEP (> 10 mbar)
Fig. 894  electrical impedance tomography (EIT): derivation • results: high PEEP
of tomography images -- no difference in mortality (subgroup: only ARDS → si-
gnificantly lower mortality)
-- no difference in frequency of pneumothorax or vaso-
pressor administration
EXPRESS study

ARDS: PEEP: 10-20 cmH2O!

best use ARDS-network table (PEEP
Positive End-Expiratory Pressure Setting in Adults with ALI
and ARDS according to the set FiO2)!
Mercat et al, JAMA 2008

• multicenter randomized controlled trial It would certainly make sense to adapt ventilation not to
• 767 patients with ALI (protective ventilation) the gas exchange, but to the individual breathing mecha-
-- low PEEP (7 mbar) nics of the patient (e.g. by measuring esophageal pres-
-- high PEEP (14 mbar) sure). If you have nothing else to do but to take care of
• results: high PEEP the optimal PEEP of a single patient all day long, this is
-- no difference in mortality (hospital) certainly the best procedure. In clinical everyday life, ho-
-- significant improvement in oxygenation (Horovitz quo- wever, at least in our small clinic, the internist still has to
tient) take care of the daily activities (e.g. endoscopy program,
emergency room), so that we orientate ourselves on the
ARDS network table not least because of the practicabili-
ty of the PEEP setting. This way you are able to cope with
90% of ARDS patients. The ARDS network table is also
meta-analysis recommended in the S3 guideline "Invasive ventilation"
of the German Society for Anaesthesiology and Intensive
Care Medicine for the orientation PEEP setting, since it is
the best documented and simplest method at the same
Does a higher PEEP decrease mortality in acute respira- time. It should be noted, however, that for some patients
tory distress syndrome? (10%) a more differentiated PEEP setting is necessary.
Phoenix et al, Anesthesiology 2009

• meta-analysis (6 studies)
• 2484 patients with ARDS: With the PEEP setting, however, you
-- low PEEP (< 10 mbar)
should not only focus on gas ex-
-- high PEEP (> 10 mbar)
change, but also on compliance,
respiratory mechanics and, above all,
• result: high PEEP (> 10 mbar) → significant reduction
of mortality on the patient's hemodynamics!

Pulmonology 633
Inverse ratio ventilation (IRV)
Definition
• I:E ratio normal 1:2
• inverse ratio ventilation: I:E 1:1 to 3:1
• indication (previous): SpO2 < 90% in spite of PEEP > 5
cmH2O, IPAP > 35 cmH2O and FiO2 > 0.5
• largely abandoned (no longer recommended)
Effects
• With ARDS, the lungs are sick and the elasticity (com-
pliance) is significantly reduced. To avoid barotrauma
(especially pneumothorax), the inspiration time must
be extended. The longer the inspiration time, the more
protective the ventilation.
• extension of the contact time between alveolar gas
and capillary blood
• increase of the median respiratory pressure
• extension of the inspiration time → also compartments
with large time constants fill up
• By the shortened expiration time an intrinsic PEEP is
generated intentionally, which helps to reopen atelec-
tatic districts with low compliance and high resistance
(alveolar collapse ↓) → improvement of oxygenation
• increase of FRC (functional residual capacity: volume
remaining in the lung after normal expiration)
• reduction of the right-to-left shunt
Disadvantages
• arterial hypotension, decrease of preload (→ catecho-
lamine requirement ↑ )
• deeper analgosedation necessary because intrinsic
PEEP is poorly tolerated (overinflation)
• The intrinsic PEEP is difficult to control. To improve
oxygenation, it is therefore better to work with the ex-
trinsic PEEP, which can be adjusted normally on the
ventilator.
Permissive hypercapnia (PHC)
Definition
• Ventilation should be carried out as protectively as
possible, whereby increased pCO2 values (up to pH of
7.2) are tolerated
• In a study (Hickling et al, Intensive Care Med 1990),
permissive hypercapnia (pCO2 on average 62 mmHg)
showed a significantly reduced mortality in patients
with severe ARDS.
• limit values
-- pCO2 < 70 mmHg
-- pH > 7.20 (Too low pH values are particularly harm-
ful for the kidney!)
• too high pCO2 values / increasing respiratory acido-
sis → classic indication for extracorporeal CO2 elimina-
tion (e.g. pECLA [iLA] or low-flow vv-ECMO)
• However, an uncontrolled permissive hypercapnia can
even increase mortality (Tiruvoipati et al, Crit Care
Med 2017; Nin et al, Intensive Care Med 2017).
634 Pulmonology
permissive hypercapnia: simply
tolerate increased pCO2 values as
long as the pH value is > 7.2!
Contraindications
• pulmonary hypertension (e.g. fulminant pulmonary
embolism)
-- Hypercapnia leads to an increase in PVR (pulmo-
nary vascular resistance) via vasoconstriction of the
pulmonary arteries and can even trigger acute right
heart failure in the pre-existing of pulmonary hyper-
tension!
-- Alveolar hypoventilation causes vasoconstriction of
the pulmonary arteries via the Euler-Liljestrand re-
flex!
-- Hyperpapnia leads systemically (including cereb-
rally) to vasodilation, but pulmonarily to a vasocon-
striction.
• heart failure requiring catecholamines (vasodilatation,
contractility ↓)
• TBI with increased intracranial pressure (The higher
the pCO2, the higher the ICP!)
• cerebral seizures (hypercapnic seizures)
If there are contraindications to permissive hypercapnia,
extracorporeal CO2 elimination (decarboxylation) may
also be performed (if available).
Extracorporeal decarboxylation
• types
-- with pump (av-ECCO2-R [arterio-venous extracorpo-
real carbon dioxide removal]): pECLA (iLA)
-- without pump (vv-ECCO2-R [veno-venous extracor-
poreal carbon dioxide removal])
◦◦ Hemolung (Alung)
◦◦ Decap (Hemodec; no longer on the market)
◦◦ ila activve (Novalung)
◦◦ Prismalung (Gambro)
◦◦ vv-ECMO (low-flow)
• see especially page 700
Grocott (N Engl J 2009) investigated mountaineers on
Mount Everest (arterial BGA, SO2). The mean pO2 was
24.6 mmHg and the mean SO2 was between 34-69%
with­out causing serious damage to the mountaineers.
This underlines that the BGA and the SO2 are comple-
tely overrated in clinical everyday life and unfortunately
therefore the invasiveness of ventilation is often unne-
cessarily increased, which only leads to the described
lung damage (VALI)! There is almost no ARDS without
a doctor! As an illustration the following example should
be mentioned: A patient with known COPD presents him-
self to a pulmonologist on an outpatient basis with the
question of whether long-term oxygen therapy should be
initiated at home. A arterial BGA is taken, which shows a
paO2 of 49 mmHg, so that the indication for the initiation
of a long-term oxygen therapy (indicated at paO2 < 55
mmHg) is given. The patient is sent home with the infor-
mation that the oxygen device with tank will be delivered
in three weeks. If a patient in intensive care in the BGA
has a paO2 of 49 mmHg, it is not uncommon for panic
to break out (not that code blue alarm is almost trigge-
red) and ventilation is forced to such an extent that VALI
is unfortunately often generated. The Italian anesthetist
Antonio Pesenti described ventilation as "a life saving
procedure that can kill the lung". Actually one should
prohibit BGAs in the ARDS (exaggeratedly formulated)!
The most important thing about ventilation in ARDS is the
motto: "Keep cool man!"

Fig. 896  The warning "Ventilation can be fatal" should be

affixed to the ventilators in the intensive care unit (espe-
cially with ARDS) analogously to the inscription on the ci-
garette packs!

Fig. 895  To ventilate a damaged lung is similar to running a

400m run with a broken leg: You only have to go around the
stadium round once here, so you have to do it slowly and
don't want to set a world record with a super time, otherwise
everything will break completely and you won't get 5 feet!

SpO2 > 90%, paO2 > 60 mmHg and

paCO2 < 70 mmHg completely
sufficient! Most important: no damage
to the lungs due to forced ventilation!

no BGA cosmetics at the ARDS! no Recruitment maneuver

atmo-centric therapy (not the BGA
values are in the foreground, paO2 is
not the target parameter)! Improve-
ment of oxygenation ≠ Improvement
of survival!
Patients in ARDS rarely die of hypoxe-
mia, but unfortunately often of the
consequences of VALI!
Definition
• maneuver to reopen closed (atelectatic) lung areas
that are no longer participating in the gas exchange
• The clinically most common recruitment manoeuvre is
(better: was) the Lachmann maneuver.
• effective especially in the early phase of an extrapul-
monary ARDS
Types
• intermittent sighs (respiratory form in which several in-
termittent breaths with high inspiratory pressure and
PEEP are applied at a set frequency per hour, resulting
in hyperinflation of the lung and recruitment of atelec-
tatic areas)
• airway-pressure-release-Ventilation (APRV):

Pulmonology 635
 -- spontaneous breathing with high CPAP-level (20-30
mbar) and short (1-2sec) decrease at a lower pres-
sure level
-- corresponds to BIPAP with IRV LOV study
-- low significance (i.a. excessive rapid shallow brea-
thing, severe hypercapnia → not feasible)
-- option to implement spontaneous breathing portions
early in patients with ARDS (BiRDS study 2019 [see Ventilation Strategy Using Low Tidal Volumes, Recruit-
page 638]: no decrease in mortality) ment Maneuvers, and High Positive End-Expiratory Pres-
sure for Acute Lung Injury and Acute Respiratory Distress
-- see also page 116 Syndrome
• automatic recruitment maneuver with EVITA XL Meade et al, JAMA 2008
• recruitment maneuver according to Lachmann (Lach-
mann maneuver) • randomized controlled trial
• 983 patients with acute lung failure with a Horovitz quo-
tient < 250 mmHg
Lachmann maneuver
-- without recruitment + low PEEP (9.8 mbar)
Definition -- with recruitment (here plateau pressure of 40 mbar
after each disconnection from ventilator) + high-PEEP
• open lung concept (1992; named after the German (14.8 mbar)
anesthetist Burkhard Lachmann): „Open the lung and • results: with recruitment + high-PEEP
keep it open!“ -- significantly better oxygenation
• principle: -- no difference in mortality
-- opening of atelectatic lung compartments with tem-
porary high pressure levels
-- keeping the lung open by application of high PEEP
(above the occlusion pressure)
meta-analysis
• indication: poor oxygenation in case of ARDS despite
protective ventilation and kinetic therapy
• side effects:
-- cardiac output ↓, blood pressure ↓
Effects of alveolar recruitment maneuvers on clinical out-
-- risk of barotrauma (e.g. pneumothorax) comes in patients with acute respiratory distress syndrome
-- ICP­ ↑ (therefore be careful in patients with TBI) Suzumura et al, Intensive Care Med 2014

Execution • 10 RCT
• FiO2 100%, RR 40/min, I:E to 1:1 / 2:1 • 1594 ventilated patients with ARDS
• set alarm limits to maximum (pmax and AMV) -- with recruitment
-- without recruitment
• increase inspiratory pressure together with PEEP in
• results: recruitment
5mbar steps (Δp 12 mbar), until paO2 (Paratrend [no
-- significant reduction in mortality (hospital)
longer on the market]) and SpO2 rises abruptly (= ope-
-- no increased rate of barotrauma
ning pressure; usually at 45-60 mbar)
-- no difference in the need to use rescue measures
• return until tidal volume suddenly drops (= closing (e.g. NO inhalation, ECMO), ventilation duration, ICU
pressure), then select PEEP 2-3 mbar above; adjust / hospital stay
inspiratory pressure

Assessment
• no study that would have proven a decrease in morta-
lity by recruitment maneuvers (i.a. meta-analysis Fan
et al, Am J Respir Crit Care Med 2008; on the contrary:
even increased mortality in the ART study [see box])
• no longer recommended today
• Short recruitment maneuvers (< 10s) can be carried
out and are sometimes very helpful. However, it is
known that atelectasis that does not open after 3s no
longer open after 60s, so that the classic protracted
recruitment maneuvers (e.g. Lachmann maneuvers),
should no longer be performed especially due to the
adverse effect on hemodynamics.

636 Pulmonology

ART study
Effect of Lung Recruitment and Titrated Positive End-Ex-
piratory Pressure (PEEP) vs Low PEEP on Mortality in Pa-
tients With Acute Respiratory Distress Syndrome
The ART-Investigators, JAMA 2017
• ART: Alveolar Recruitment for ARDS-Trial
• multicenter (120 intensive care units, 9 countries) pros-
pectively randomized controlled trial
• largest study on this topic
• 1010 ventilated patients with moderate or severe ARDS
(Horovitz quotient < 200mmHg)
-- with recruitment (by gradually increasing PEEP [up to
max. 35 cmH2O], Δp 15 cmH2O)
-- without recruitment (low PEEP)
• results: recruitment
-- primary endpoint (mortality after 28d): significantly in-
creased (absolute by 6%)
-- secondary endpoints: i.a.
◦◦ increased pneumothoraces
◦◦ fewer ventilator-free days
PHARLAP study
Maximal Recruitment Open Lung Ventilation in Acute Res-
piratory Distress Syndrome
Hodgson et al, AJRCCM 2019
• PHARLAP: Permissive Hypercapnia, Alveolar Recruit-
ment and Low Airway Pressure
• multicenter (35 intensive care units, 5 countries [espe-
cially Australia and New Zealand]) prospectively rando-
mized controlled study (phase II study)
• 115 ventilated patients with moderate or severe ARDS
(Horovitz quotient < 200mmHg)
-- with recruitment (by gradually increasing PEEP [up to
max. 40 cmH2O])
-- without recruitment
• results: recruitment
-- primary endpoint (ventilator-free days on day 28): no
difference
-- secondary endpoints: i.a.
◦◦ mortality: no difference
◦◦ duration of ventilation: no difference
◦◦ barotrauma (pneumothorax): no difference
◦◦ ICU / hospital stay: no difference
◦◦ reduction of the need for measures such as prone
positioning, ECMO or NO inhalation
recruitment maneuver: no (longer)
recommended
Spontaneous breathing
• objectives (of early spontaneous breathing in ARDS):
-- avoidance of inactivity atrophy of the diaphragm,
which occurs already after 48 hours of ventilation
-- reduction of intrapulmonary shunt: Spontaneous
breathing recruits the dorsobasal parts of the lung,
which are usually not ventilated during mechanical
ventilation, resulting in a reduction of the shunt (al-
ready perfused alveoli are now ventilated again).
• The implementation of early spontaneous breathing is
not always easy in everyday clinical practice. In any
case, desynchronization and false triggering should
be avoided, because this increases both the work of
breathing and the pressure differences in the lungs
(phenomenon of swinging air) with the result that the
shear forces (shear stress) and thus the lung damage
increase even further! Furthermore, negative pressure
pulmonary edema can occur in certain areas due to
asynchrony.
• cave SILI (self-inflicted lung injury): Excessive sponta-
neous breathing (e.g. in CPAP-ASB mode; increased
breathing drive) can lead to an increase in the tran-
spulmonary pressure and thus to an increase in the ti-
dal volume due to the increase in negative intrapleural
pressure, which also can damage the lungs! The ven-
tilator does not limit the tidal volume during spontane-
ous breathing. Lung damage is not only possible with
positive pressure ventilation (PPV), but also with nega-
tive pressure ventilation (NPV; i.e. spontaneous brea-
thing)! This applies especially to an already severely
damaged lung as is the case of a severe ARDS, so that
SILI is another counter argument against spontaneous
breathing in severe ARDS. One can try to lower an in-
creased breathing drive with the resulting increased
tidal volumes by medication (e.g. by the administration
of morphine).
• In the first 48 hours, spontaneous breathing should be
avoided in severe ARDS with a Horovitz quotient < 150
mmHg and the patient should even relaxed (muscle re-
laxation) if necessary (Spontaneous breathing activity
in acute lung injury and acute respiratory distress syn-
drome; Gama et al, Curr Opin Anaesthesiol 2012). In
severe ARDS, the diaphragm is sacrificed to the lung
parenchyma in the early phase. This is because (pro-
bably) one does not recover from severe lung damage
as quickly as from severe diaphragmatic damage. The
diaphragmatic damage is almost always reversible
• studies:
-- BiRDS (see box)
-- PReSPON (current ongoing multicenter randomized
controlled study on the benefit of early spontaneous
breathing [using APRV]; planned 1000 patients)
Pulmonology 637
 -- only casuistics (e.g. Bein, Crit Care Med 2006 [see
box]), no controlled studies yet
-- today only of minor importance (largely replaced by
BiRDS study pump-driven systems [especially low-flow-vv-EC-
MO])

Early Spontaneous Breathing in Acute Respiratory Dist-

ress Syndrome
Richard et al, congress presentation DGIIN 2019

• multicenter prospective randomized controlled trial

• 700 ventilated patients with moderate or severe ARDS
(Horovitz quotient < 200mmHg)
-- with early spontaneous breathing (i.e. after 3h APRV
[airway pressure release ventilation])
-- without early spontaneous breathing
• results: early spontaneous breathing
-- primary endpoint (hospital mortality) → no difference
-- secondary endpoints: i.a.
◦◦ duration of ventilation: no difference
◦◦ rate of complications (especially pneumothorax, hy- Fig. 897  pECLA in a patient in prone position
poxemia, organ failure): no difference
◦◦ less sedation and muscle relaxation Construction
• extracorporeal capsule with heparin-coated membrane
-- gas exchange surface 1.3m2 of polymethylpentene
Rescue measures (for therapy-re- (PMP)
-- very low flow resistance → vlood flow of 1.0-1.5 l/min
fractory hypoxemia) sufficient (no pump necessary)
• extracorporeal procedures • supply of oxygen via wall connection (gas flow): The
• high frequency ventilation higher the gas flow, the higher the CO2 elimination.
• inhalation of selective pulmonary vasodilators One starts with an oxygen flow of 1 l/min: Then one in-
creases successively up to max. 10 l/min and reduces
• liquid ventilation
the respiratory minute volume in ventilated patients at
the same time.
Extracorporeal procedures • It should be over 800 ml/min, because only from a
• without pump: pECLA blood flow of 800 ml/min an effective CO2 elimination
• with pump: ECMO occurs.
• without pump (pumpless)
pECLA -- advantage: less foreign material and complete he-
parin coating of all components → only low antico-
Definition agulation necessary (heparin dose for thrombosis
• percutaneous extracorporeal lung assist prophylaxis sufficient)
• syn.: iLA (interventional lung assist) -- disadvantage: only possible with stable circulation
• pumpless (arterio-venous ["heart as pump]"; pressure (prerequisite: MAP > 70 mmHg)
gradient = MAP - CVP])
• first successful application 1997 (Philipp, Kardiotech-
nik 1997)
• effect:
-- very effective for CO2 elimination (decarboxylation;
especially in permissive hypercapnia and respiratory
acidosis)
-- only slightly effective for oxygenation (only marginal
effect on oxygenation [The blood is drawn arterially,
where the oxygen saturation is higher than venous,
so that further saturation with oxygen is only possi-
ble to a much lesser extent than if the blood is with- Fig. 898  iLA [25]
drawn venously.])
• If resuscitation occurs during pECLA, it must be dis-
connected due to the arteriovenous shunt.
• assessment:

638 Pulmonology
 Fig. 901  cannulas [25]

study

A new pumpless extracorporeal interventional lung assist

in critical hypoxemia/hypercapnia
Bein et al, Crit Care Med 2006

• retrospective analysis at the University Hospital Regens-

burg / Germany (1996-2004)
• iLA (interventional lung assist) in 90 patients with severe
ARDS
Fig. 899  iLA : construction [25] • causes:
-- pneumonia (30)
-- polytrauma (15)
-- sepsis (11)
-- pancreatitis (11)
-- other (23)
• results:
-- significant decrease in pCO2 and increase in pH (main
effect)
-- significant increase in Horovitz quotient (paO2/FiO2)
-- possibility of reducing the invasiveness of ventilation
(FiO2, IPAP, VT)
-- 37 patients (41.1%) survived.
• mean length of stay of the iLA: 5 days
• complication rate: 24% (especially leg ischemia)

study

Fig. 900  iLA (Novalung)

Extracorporeal pumpless interventional lung assist in clini-
cal practice: determinants of efficacy
Accesses
Müller et al, ERJ 2009
• 2 accesses:
-- femoral artery (15 F) • cohort study
-- femoral vein (17 F) • iLA (interventional lung assist) in 96 patients with severe
ARDS
• beforehand sonographic measurement (prerequisite:
• results:
diameter of femoral artery > 6mm)
-- significant decrease in pCO2 and increase in pH
• implantation in Seldinger technique
-- significant increase in Horovitz quotient (paO2/FiO2)
• no implantation in: -- possibility of reducing the invasiveness of ventilation
-- PAD (peripheral artery disease) (FiO2, IPAP, VT)
-- too small vessels

Pulmonology 639
Indications
pECLA: today only of minor impor-
• mainly for CO2 elimination (decarboxylation) tance
• improvement of respiratory acidosis
• reduction of the invasiveness of ventilation (enabling
protective ventilation, possibly even ultraprotective
ventilation with VT 3ml/kg , i.a. Xtravent study [see
ECMO
box]; current ongoing studies for ultraprotective ven-
tilation: SUPERNOVA II (In the SUPERNOVA I study
[Combes et al, Intensive Care Med 2019] as a phase
II study, the feasibility with pump-driven systems [vv-
ECCO2-R: veno-venous extracorporeal carbon dioxide
removal] has already been proven.), REST (largest
study ever on extracorporeal procedures)
• special indication: traumatic brain injury (pCO2 ↓ →
intracranial pressure ↓)

Xtravent study

Lower tidal volume strategy (3 ml/kg) combined with ex- Definition

tracorporeal CO2 removal versus ‘conventional’ protective • extracorporeal membrane oxygenation
ventilation (6 ml/kg) in severe ARDS : The prospective ran-
domized Xtravent study • the great development in intensive care medicine in
Bein et al, ICM 2013 the last 15 years
• Each of us has been involved in an extracorporeal gas
• prospective randomized study exchange: Just think of the prenatal period (placenta)!
• 97 patients with ARDS • first described in 1972 by Hill in the New England Jour-
-- VT 6 ml/kg nal of Medicine as part of the treatment of a young
-- VT 3 ml/kg ("ultraprotective") + extracorporeal CO2 eli- polytraumatized accident victim
mination (using pECLA)
• with pump (pump-driven)
• results
-- ventilator-free days → no difference (in subgroup with
• construction:
Horovitz quotient < 150 mmHg: VT 3 ml/kg + pECLA -- oxygenator ("lung replacement")
→ significant increase) -- pump ("heart replacement")
-- mortality: no difference • anticoagulation with heparin-perfusor (UFH; PTT con-
trol [target: 1.5-2 times the norm] or ACT [target: 180-
Prerequisites 200s])
• disadvantages:
• normal ejection fraction or cardiac output (CO) > 6 l/
min -- hemolysis
• MAP > 70 mmHg -- stronger anticoagulation necessary → bleeding risk
­↑
• femoral artery diameter > 6 mm (cannula diameter ma-
ximum 2/3 of the artery diameter) -- not ubiquitously available (only in corresponding
centres)
• especially for oxygenation (in contrast to pECLA)
before pECLA: echocardiography • But also decarboxylation (CO2 removal) by means of
(TTE) + duplex of femoral arteries! ECMO is possible. The CO2 removal is controlled by
the gas flow ("sweep gas", "purge gas"[oxygen via the
wall connection]): The higher you set it, the more CO2
Contraindications is removed.
• heart failure (left / right) • ECMO per se is not a therapy of the ARDS! It only pro-
• shock (i.a. cardiogenic, septic) cures time to correct the lung failure (e.g. by antibiotic
• PAD (peripheral artery disease; especially Fontaine treatment for severe pneumonia).
stage III/IV) • ECMO is increasingly being used and has certainly
• too small femoral arteries (not uncommon in obese lost the myth of a highly elitist therapy in recent years,
women) which may an can only be carried out at centres. Espe-
• severe hypoxemia (Horovitz quotient < 80 mmHg) cially the vv-ECMO (especially the low-flow vv-ECMO
for decarboxylation) is increasingly used outside cen-
• HIT II
tres. The invasiveness (especially with a double lumen

640 Pulmonology
 cannula) is not much higher than with a Shaldon ca-
theter for CVVH. However, va-ECMO (especially for
circulatory support) is certainly not suitable for every
hospital and should in my opinion be reserved for the
corresponding centres (currently 36 ECMO centres in
Germany [as of May 2020]). In order to have sufficient
expertise, at least 10 ECMO's should be carried out
annually. The S3 guideline 2017 "Invasive ventilation
and use of extracorporeal procedures for acute res-
piratory failure" of the German Society for Anaesthe-
siology and Intensive Care Medicine recommends that
ECMOs are only performed at centers with at least 20
ECMOs annualy. The required structural prerequisites
include the presence of vascular and thoracic surgery
and a care key of 1:1 per ECMO patient.
Goals
• bridge to recovery (bridging the time until the lung has
recovered [e.g. by antibiotic treatment in case of seve-
re pneumonia])
• bridge to therapy (bridging the time until the circulation
is restored, e.g. by lysis in pulmonary embolism, e.g.
by PCI in myocardial infarction)
• bridge to bridge (bridging the time until a longer-term
bridging system [e.g. LVAD, artificial heart] is implan-
ted)
• bridge to plantation
-- bridge to transplantation (bridging the time until
transplantation in terminal lung disease; mainly by
awake ECMO, i.e. without intubation and invasive
ventilation; significantly better survival [i.a. Fühner
et al, Am J Respir Crit Care 2012])
-- bridge to explantation (syn.: bridge to candidacy; in
France for example, ECMO implantation is perfor-
med in cases of cardiovascular arrest with the aim of
generating organs for explantation when the patient
dies [note: questionable ethics].)
-- Cardiohelp (Maquet): 1.8 m2
-- PLS (permanent life support; Maquet): 1.8 m2
-- Hilite LT (Medos): 1.9 m2
• plasma resistant
• coating: with heparin (called at Maquet Bioline, at Me-
dos Rheoparin), exception: ECO 0.5 from Sorin: here
coated with phosphorylcholine
• mostly hollow diffusion oxygenators
• The oxygenator (membrane; "artificial lung") consists
of about 20000 capillaries (hollow fibers; plastic tubes).
These are microporous. In the capillaries (intraluminal)
the gas (oxygen) flows, between the capillaries (in the
channels; extraluminal) the blood flows. The blood
flows countercurrent past the hollow fibres filled with
oxygen.
• The oxygen concentration in the hollow fibres is adjus-
ted by a gas mixer ("blender").
• The gas exchange takes place by diffusion.
• After the blood has passed through the membrane, it
enters a heat exchanger immediately before being re-
turned to the body in order to compensate for a loss
of heat.
• positioning of the oxygenator always below the heart
leve
• In the process, fibrin precipitates, so that the gas ex-
change surface decreases and the gas exchange be-
comes insufficient and ultimately the oxygenator no
longer operates. Mostly it has to be replaced after 8-9
days.
• An increasing transmembrane pressure gradient indi-
cates thrombus formation in the oxygenator (the most
frequent complication with 30%).

ECMO: but don´t bridge to "nowhere"!

Components
• oxygenator
• pump
• cannulas
• hose system
• heat exchanger

Oxygenators
• bubble oxygenator
• membran oxygenator (today standard)

Membrane oxygenator
• membrane made of polymethylpentene (PMP; former-
ly of polypropylene)
• membrane surface: depending on the representative
-- ECO 0.5 (extracorporeal oxygenation; Sorin): 1.2 m2
-- iLA (interventional lung assist; Novalung): 1.3 m2

Pulmonology 641
 Cannulation

Definition

oxygen
blood blood
Fig. 902  scanning electron microscopy of a membrane
(oxygenator): It consists of numerous capillaries in which
oxygen flows. The blood flows between the capillaries in
tcountercurrent principle (courtesy of Mr. Alois Philipp, car-
diotechnician at the Clinic for Cardiac, Thoracic and Cardi-
ac Vascular Surgery of the University Hospital Regensburg
[Germany]).
Pumps
• roller pump
-- mostly double bow roller pump
-- occlusive
-- disadvantage: increased hemolysis (very cell trau-
matic)
-- today obsolete
• centrifugal pump
-- impeller-driven pump (Impella)
-- today most frequently used
-- significantly less cell traumatic than roller pumps and
thus significantly less hemolysis
-- non-occlusive (If the rotor is stops, the blood can
flow in both directions. Therefore, the arterial line
must be disconnected when the rotor is stopped!)
-- blood flow rate: 3.0-4.5 l/min (in weaning reduction
to 1.0-1.5 l/min; note: The pump in a renal replace-
ment procedure [e.g. Prismaflex] achieves a maxi-
mum of 500 ml/min, i.e. 0.5 l/min.)
-- measurement of the pump flow (electromagnetic or
sonographic [Doppler])
-- rotational speed: up to 10000 rpm (rpm: revolutions
per minute)
-- filling volume: 35-80ml
-- examples:
◦◦ Centrimag (Levitronix)
◦◦ Rotaflow (Maquet)
◦◦ Capiox (Terumo)
◦◦ Delphin (Sarns)
• axial pump
-- advantage: very small
-- disadvantage: increased hemolysis (very cell trau-
matic due to the high rotational speed)
• diagonal pump (e.g. Deltastream pump)
• Cannulation of the femoral vessels (vein and artery) is
performed percutaneously according to the Seldinger
technique and preferably under sonographic control.
Cannulation of the subclavian artery is performed by
open surgery using a vascular prosthesis.
• It should always be done in pairs: One punctures, the
other takes care of the wire so that it always runs freely.
• A skin incision (e.g. stab incision with a scalpel before
advancing the dilator) should be avoided as it can bleed
during the course of the procedure. Under ECMO the-
re is frequent bleeding anyway (e.g. frequent throm-
bocytopenia and thrombocytopathy, heparin perfusor).
• Two red blood cell concentrates should be available
before cannulation.
• For cannulation (after successful placement of the gui-
de wires) 5000 IU of heparin (UFH) are administered
as i.v. bolus.
• Finally, the cannulas must be secured to avoid dislo-
cation.
• As a rule, mobilization during ECMO therapy does not
occur. However, kinetic therapy such as prone posi-
tioning (e.g. Kipping et al, Int J Artif Organs 2013) or
CLRT (e.g. Knedel et al, Perfusion 2014) is possible
with ECMO.
• Depending on the indication, cannulation (connection
technique) is carried out veno-venously or veno-arte-
rially. The blood is always withdrawn from a vein and
then returned depending on the indication either to a
artery (va-ECMO) or a vein (vv-ECMO) The machine
is always the same.
Types
• according to location (exactly: according to the type of
vessel into which the blood is returned)
-- veno-venous (vv-ECMO)
-- veno-arterial (va-ECMO)
• according to invasiveness (technique)
-- interventional (percutaneous)
-- surgical (open)
Fig. 903  ECMO veno-venous (vv-ECMO [23])

642 Pulmonology

Fig. 904  ECMO veno-arterial (va-ECMO [23])
vv-ECMO
• more often than va-ECMO
• Orte: The blood is usually withdrawn from the femoral
vein (21-23 F) and returned to the internal jugular vein
(15-19 F). The blood should always be withdrawn in-
ferior and returned superior, since the saturation in the
inferior vena cava is lower (in critically ill patiens) than
in the superior vena cava and therefore the ECMO is
much more effective!
• femoro-jugular cannulation: Blood withdrawal from the
area of the inferior vena cava (mostly right femoral
vein; long [38cm] cannula [drainage cannula]) and re-
turn to the area of the superior vena cava (mostly right
internal jugular vein; short [15-23cm] cannula [reperfu-
sion cannula])
• technical: series connection
• for lung replacement (pulmonary support ["pulmo-
nary" ECMO]; in acute lung failure [ARDS]; ventila-
tion is continued, but the invasiveness of ventilation
can then be significantly reduced in the sense of [very]
lung-protective ventilation; settings / goals: FiO2 < 0.6,
inspiratory pressure < 28 cmH2O, PEEP mostly un-
changed, tidal volume < 4 ml/kg, respiratory rate 12/
min, I:E 2:1)
• classification according to blood flow:
-- < 2.5 l/min: low-flow vv-ECMO (especially for hyper-
capnic respiratory failure [e.g. exacerbated COPD
and NIV failure]; good for decarboxylation; for low-
flow ECMO see also page 700)
-- > 2.5 l/min: high-flow vv-ECMO (especially for hypo-
xemic respiratory failure [especially ARDS])
• procedure:
-- low-low (blood flow < 2.5 l/min: If only decarboxyla-
tion (e.g. exacerbated COPD) is required, low blood
flows are sufficient. A relevant decarboxylation is
already possible from a blood flow of approx. 800
ml/min. Intubation can already be avoided from a
blood flow of 1 l/min. This is because carbon dioxide
is much more soluble than oxygen. A double lumen
cannula (only a venous puncture) is then sufficient.
With a double lumen cannula a maximum blood flow
of about 1.5 l/min is possible.
-- high-flow (blood flow > 2.5 l/min): If, on the other
hand, oxygenation (e.g. severe ARDS) is desired,
higher blood flows are necessary. Sufficient oxyge-
nation only begins at a blood flow of approx. 3 l/min.
A double lumen cannula is no longer sufficient for
this: Two cannulas must be placed here (e.g. drai-
nage via femoral vein and return via internal jugular
vein).
• control:
-- oxygenation: Oxygenation is controlled via the blood
flow. This is set by means of the rotary wheel (num-
ber of revolutions of the centrifugal pump per minute
[rpm]) on the control panel.
-- Decarboxylation:
◦◦ Decarboxylation is controlled both via the blood
flow (however, the maximum of decarboxylation is
reached at 2 l/min) and via the gas flow, i.e. via
the oxygen supply (dry oxygen [100% and not just
21%; oxygen and not compressed air]) of the wall
connection.
◦◦ The oxygen hose is plugged onto the oxygen con-
nection of the membrane. This presses the car-
bon dioxide out of the capillaries of the membrane
("sweep gas", "purge gas").
◦◦ By default, one starts with a gas flow of 1 l/min:
Then after approx. 20 minutes a BGA is taken and
the respiratory minute volume at the respirator is
accordingly reduced the stepwise by 10% (respi-
ratory rate and tidal volume [by reduction of the
pressure difference from inspiratory pressure and
PEEP). This is then repeated every 20 minutes.
In small steps the gas flow can be increased up
to max. 10 l/min. Gas flow is increased until tidal
volume < 4 ml/kg and respiratory rate < 10/min
(lung-protective ventilation). The gas flow should
only be increased slowly so that no hypocapnia
and possibly even cerebral ischemia occurs. A
flush maneuver should be performed once per
shift (i.e. every 8 hours) so that no condensed wa-
ter collects. To do this, the gas flow is increased to
15 l / min for 15 seconds.
◦◦ After connecting to the ECMO, the enttidal CO2
(ETCO2) suddenly drops. This is completely nor-
mal (and no sign of a sudden circulatory instabili-
ty), since the carbon dioxide is no longer elimina-
ted via the lungs, but via the oxygenator.
• The blood flow is measured by a flow sensor (ultra-
sound; Doppler principle) and depends on:
-- Size of the cannulas: The larger the cannulas, the
higher the possible blood flow.
◦◦ Double lumen cannula: This allows a maximum
blood flow of approx. 1.5 l/min. Therefore, a dou-
ble lumen cannula can only be used for decar-
boxylation and not for oxygenation, which is only
possible from a blood flow of 3 l/min.
◦◦ singular cannulas: femoro-jugular cannulation (fe-
moral vein and internal jugular vein):
▪▪ 21F / 17F: attainable blood flow approx. 3 l/min
▪▪ 23F / 19F: attainable blood flow approx. 4 l/min
▪▪ 25F / 21F: attainable blood flow approx. 4.5 l/
min
-- membrane; e.g. with iLA activve (Novalung):
◦◦ MiniLung petit membrane ventilator (blood flows
up to 0.8 l/min possible)
Pulmonology 643
 ◦◦ MiniLung membrane ventilator (blood flows up to
2.4 l/min possible)
◦◦ iLA membrane ventilator (blood flows up to 4.0 l/
min possible)
◦◦ XLung membrane ventilator (blood flows up to 6.5
l/min possible)
-- cardiac output
◦◦ high-output (e.g. hyperdynamic circulation in sep-
sis): higher blood flow (e.g. 5 l/min) necessary
(The higher the HZV, the less efficient the ECMO!)
◦◦ low-output (e.g. heart failure): lower blood flow ne-
cessary
• A blood flow of at least 0.5 l/min is obligatory, other-
wise clotting of the membrane will occur. One usually
starts with a blood flow of 1 l/min and then observes
how the patient tolerates this hemodynamically. Then
the desired blood flow is set on the rotary wheel of the
control panel.
• The flow sensor is installed after the pressure gauge
p3 and not only measures the blood flow, but also de-
tects air bubbles in the system: As soon as air bubbles
are detected, the alarm signal sounds and the system
is automatically stopped. The corresponding alarm
function ("zero flow with air bubble") should always be
activated.
• During the vv-ECMO you can typically see color diffe-
rences between the two hoses:
-- drainage hose (leading away from the patient): dark Fig. 905  drainage cannula: It is mostly located in the femo-
(deoxygenated) ral vein. Here the blood (deoxygenated) is withdrawn from
the body. The blood in the cannula is dark red.
-- reperfusion hose (leading to the patient): bright (oxy-
genated)
• If a patient suddenly has to be resuscitated on a vv-
ECMO, the system should simply be allowed to con-
tinue running at the same speed (only switch off the
alarms). This ensures at least oxygenation.
• renal replacement therapy: If the patient additionally
develops renal failure requiring dialysis at the vv-EC-
MO, a renal replacement therapy can be performed via
certain membranes (with the iLA activve, only the iLA
membrane ventilator membrane is equipped with the
corresponding Luer-Lock connections) via the lying
cannulas. For the duration of the renal replacement
therapy, however, the ECMO must be paused (i.e. gas
flow to 0 l/min). ). However, most patients do not to-
lerate this, so that it is almost always better to place
an additional Shaldon catheter and then run the renal
replacement therapy over it.

Fig. 906  reperfusion cannula: It is mostly located in the in-

ternal jugular vein. Here the blood (oxygenated) is returned
to the body. The blood in the cannula is bright red.

644 Pulmonology
 control of
- oxygenation: only via blood flow
- decarboxylation: via blood flow
and gas flow
increase in blood flow → oxygenati-
on ↑ (pO2 ↑) + decarboxylation ↑
(pCO2 ↓ [limit: 2 l/min])
increase in gas flow → decarboxyla-
tion ↑ (pCO2 ↓)

Fig. 907  chest X-ray: You can see the tip of the drainage
cannula (thick arrow) that was inserted over the right femo-
ral vein. Above is the tip of the CVC (thin arrow), which was
inserted through the left internal jugular vein.

Fig. 910  The oxygen hose is plugged onto the oxygen con-
Fig. 908  vv-ECMO (drainage cannula in the femoral vein, nection of the membrane. The flow is regulated (as usual
reperfusion cannula in the internal jugular vein) when you apply oxygen) simply through the wall connec-
tion. Due to the oxygen flow, the CO2 is pressed out of the
capillaries of the membrane ("sweep gas", "purge gas")
clinical hypercapnia hypoxemia and thus washed out. The higher the oxygen flow is set, the
problem more CO2 is removed.
effect of va-ECMO
oxygenation
• rarer than vv-ECMO (note: At ECMO centers, howe-
effect of ver, va-ECMO is more common than vv-ECMO.)
decarboxylation • location:
-- venous: femoral vein (21-23 F; standard: 21 F)
blood flow
-- arterial (15-17 F; standard: 15 F) - Here one distin-
0.8 l/min 3.0 l/min guishes between two connections in principle:
Fig. 909  Effective decarboxylation (CO2 removal) is already ◦◦ peripheral: femoral artery (most frequent connec-
possible from a blood flow of 0.8 l/min, since carbon dioxi- tion; percutaneous cannulation)
de is much more soluble than oxygen. However, effective ◦◦ central: subclavian artery (cannulation via open
oxygenation is only possible from a blood flow of approx.
surgery [mostly via a vascular prosthesis])
3 l/min. At a blood flow of 2 l/min, however, the maximum
of decarboxylation is reached. Further decarboxylation is • technical: parallel connection
then only possible here by increasing the gas flow. From a • The blood is drained from the right atrium and then
blood flow > 2 l/min, decarboxylation only depends on the gets to a pump (centrifugal pump) and then to an
gas flow. oxygenator. It is then returned to the body via an ar-
tery (usually the femoral artery; retrograde perfusion).
This leads to a non-pulsatile flow with largely constant
mean arterial pressure.

Pulmonology 645
• for heart replacement (cardiac support ["cardiac" ventricle and connection with the venous cannula of
ECMO]; in acute circulatory failure [especially car- the ECMO
diogenic shock]; e.g. in the context of resuscitation -- additional implantation of an Impella ( the most
[ECLS: extracorporeal life support]) common venting strategy): The impella pumps the
• e.g. also with ARDS and additional circulatory failure blood out of the left ventricle and thus relieves it. The
(septic cardiomyopathy) afterload decreases. The combination of va-ECMO
• most frequent indication: previous postcardiotomy fai- and Impella is called ECmella.
lure, today cardiovascular arrest (va-ECMO can res-
tore circulation and one can perform parallel coronary
angiography with PCI in myocardial infarction or lysis
in pulmonary embolism). The va-ECMO is already
being used preclinically today.
• By attaching a Y-connector to the arterial cannula (in
the groin) one immediately has a lying sheath for co-
ronary angiography and does not have to puncture
again.
• BGA-acquisitions as well as saturation measure-
ments always only on the right arm (radial artery): The
flow of va-ECMO is retrograde, the flow of the heart
antegrade. Both flows compete with each other. The
location of the highest mixed blood percentage is the
right arm.
• With decreasing contractility (ejection fraction) of the
left ventricle, the flow becomes less pulsatile and more
laminar. It is therefore often no longer possible to de-
rive saturation with pulse oximetry: This measures the
difference between the minimum absorption in the sys-
tole and the maximum absorption in the diastole. With
a laminar flow, however, you no longer have systole
and diastole.
• flow: 2-4 l/min (The flow is more important than the
pressure: The organs are also dependent on the flow
and less on pressure!)
• Especially in cardiogenic shock the afterload should
not be too high. A low blood pressure (target MAP 50-
60mmHg) is aimed for. More important than the pres-
sure is the perfusion (flow)!
• After 7 days at the latest, a decision should be made
on the further procedure (weaning or further therapy
options such as LVAD or heart transplantation).
• for the va-ECMO in resuscitation (ECLS [extracorpore-
al life support]) see page 311
• However, it should be noted that the stroke work (syn.:
pressure-volume-work) and thus the total oxygen con-
sumption of the left ventricle is higher under va-ECMO
than, for example, under an Impella or even without
any mechanical circulatory support (see working dia-
grams of the left ventricle on page 413). With a va-
ECMO, the retrograde flow in the aorta increases the
afterload for the left ventricle. Left ventricular dilatation
can be a complication. Then you have to relieve the
left ventricle again (venting, LV unloading) by reducing
the afterload again. There are several venting options
(strategies):
-- additional implantation of an IABP (also reduces the
afterload [deflation of the balloon]; only rarely used
today)
-- atrial septostomy with drainage of the left atrium with
a catheter and connection with the venous cannula
of the ECMO
-- transaortal venting with a pigtail catheter in the left

646 Pulmonology
 Anticoagulation
• means: unfractionated heparin (UFH); after the im-
plantation of the cannulas, a bolus of 50 IU / kg un-
fractionated heparin is admistered, then the guiding
is performed by (best always use both parameters for
control):
-- PTT (standard)
◦◦ should be determined at least once a day
◦◦ A positive lupus anticoagulant as a spontaneous
cause of PTT prolongation should be excluded.
◦◦ target (At a fibrinogen level > 400 mg/dl the target
PTT is increased by 10s.)
▪▪ low-flow-vv-ECMO (blood flow < 2.5 l/min): tar-
get PTT approx. 40-50s
▪▪ high-flow-vv-ECMO (blood flow > 2.5 l/min) and
va-ECMO: target PTT approx. 50-60s
-- ACT (activated clotting time; target: 180-200s)
-- anti-factor-Xa activity (despite unfractionated hepa-
rin; target: 0.2-0.3 U/ml)
• For heparin to be effective, the AT III level should be >
70%, so that antithrombin III (Kybernin) may have to
be substituted.
• If clotting occurs again and again despite normal AT
III level, epoprostenol (Flolan; dosage: 2-4 ng/kg/min)
can be added locally before of the membrane.
• With thrombocytopenia < 20000/µl, anticoagulation
should completely be avoided due to the of the high
risk of bleeding.

Parameter
• recommendations of ELSO (extracorporeal life support
organization)
• sufficient support (best parameter for this: central ve-
nous oxygen saturation > 70%):
-- newborns: 100 ml/kg/min
-- children: 80 ml/kg/min
-- adults: 60 ml/kg/min
• maximum perfusion pump pressure: 400 mmHg
• maximum suction: 300 mmHg
• pump performance (centrifugal pump): 3.0-6.5 l/min
(blood flow rate; sufficient in everyday clinical practice)

Complications
• rheological
-- bleeding (common; especially retroperitoneal, int-
racranial), vascular rupture
-- thrombosis (in 15%), possibly pulmonary embolism
(main complication of venous cannulation; therefore
always leg vein duplex after decannulation [in 75%
thrombosis!])
-- leg ischemia, compartment (main complication of ar-
terial cannulation)
◦◦ The cannula diameter should be a maximum of
2/3 of the artery diameter.
◦◦ To avoid leg ischemia, in addition to the retrogra-
Fig. 911  va-ECMO: various examples (courtesy of Mr. Alois de inserted ECMO cannula (proximal cannula) an
Philipp, cardiac technician at the Department of Cardiac, additional (antegrade) perfusion cannula (distal
Thoracic and Cardiac Surgery, University Hospital Regens- cannula; 6-8 F) is implanted into the femoral artery
burg [Germany])

Pulmonology 647
 (distal perfusion procedure; example: CureSave
system for femoral perfusion [Freelife Medical,
Germany]). In stable patients, puncture and in-
sertion of the guide wire should be performed first
for the distal cannula before the proximal cannula,
otherwise the pulse is no more palpable. In unsta-
ble patients (e.g. cardiovascular arrest), the proxi-
mal cannula is inserted first and the distal cannula
only inserted at intervals.
◦◦ efficient monitoring of tissue oxygen saturation on
the lower leg of the arterially cannulated groin by
means of adhesive electrodes placed on the lo-
wer leg (medially; best on both sides as there is a
good side comparison) via the NIRS system (near
infrared spectroscopy; is actually used for neuro-
monitoring [see page 1317]; with this the tissue
oxygen saturation can be measured without a pul-
satile flow being necessary)
-- perforation of the right ventricle, possibly pericar-
dial tamponade (especially through the guide wire:
Therefore, cannulation should always be performed
in pairs: One punctures, the other one takes care of
the wire so that it always runs freely.)
-- retroperitoneal hematoma (complication by the gui-
de wire)
-- misalignment, dislocation
-- clotting (thrombus in the cannula; often not visible
from the outside; consequence: insufficient ECMO)
-- Harlequin syndrome (syn.: watershed phenomenon,
phenomenon of differential hypoxia; "blue head &
red legs", "north-south" syndrome): This syndrome
occurs when a va-ECMO has been implemented
during a cardiovascular arrest and ROSC (return of
spontaneous circulation) has suddenly occurred with
reestablished cardiac function: This leads to a com-
peting blood flow from the retrograde flow of the va-
ECMO and the antegrade flow of the own heart. The
water sheath ("blood sheath") then usually forms in
the area of the distal aortic arch. The consequence
is that the legs are well supplied with blood ("red
legs"), but the coronaries and the head ("blue head")
are not. Myocardial ischemia and hypoxemic brain
damage may occur.
• mechanical (oxygenator failure)
-- plasma leakage (rare today)
-- clotting
◦◦ thrombi in the system (oxygenator thrombosis)
◦◦ with 30% the most common complication in
ECMO
◦◦ signs:
▪▪ hemolysis
▪▪ increase in transmembrane pressure gradient
▪▪ LDH ↑
▪▪ Increased D dimers indicate clotting in the oxy-
genator, increased (free) hemoglobin (as a re-
sult of hemolysis) indicates clotting in the pump
head. The system must be replaced if the free
hemoglobin is > 1000 mg/l.
◦◦ therefore control twice a day (e.g. inspection,
transmembranous pressure gradient) obligatory
648 Pulmonology
-- air in the system, possibly air embolism
-- infection of the oxygenator
-- disconnection, cannula dislocation, cannula fracture
-- pump defect (rare today)
-- hose rupture (rare today)
• hematologica
-- thrombocytopenia and thrombocytopathy (in 80%
acquired von Willebrand-Jürgens syndrome [The
von Willebrand factor is destroyed by the excessive
shear stress.])
◦◦ Up to 40% drop in thrombocytes in the first days
under ECMO is normal.
◦◦ Under ECMO the platelets should always be >
50000/μl (if necessary administration of platelet
concentrates).
◦◦ pronounced increased risk of bleeding
▪▪ All invasive measures (including thoracic drai-
nage) should therefore be avoided as far as
possible. Surgery should only performed in ca-
ses of absolutely vital indication.
▪▪ cave above all intracranial bleeding (in 4% [ac-
cording to Luyt et al, ICM 2016 even in 7,5%];
unfortunately mostly then with infaust prognosis,
so that the therapy is usually stopped then)
▪▪ In thrombopenia < 20000/µl no more anticoagu-
lation should be admistered.
◦◦ If the patient requires a dual platelet aggregation
(e.g. after PCI + stent in myocardial infarction with
cardiogenic shock), the ADP antagonist is omitted
from a platelet count < 50000/μl and only ASA is
admistered.
-- hemolysis (especially with a suction pressure p1
above 80mmHg)
-- hyperfibrinolysis (e.g. as a result of an oxygenator
thrombosis)
-- deficiency of factor XIII (in 88% under ECMO [Kalb-
henn et al, Perfusion 2015])
-- HIT II:
◦◦ in 30% positive HIT antibodies, but only in 3% then
additionally also positive HIPA test (i.e. confirmed
HIT)
◦◦ If a HIT occurs during ECMO, the anticoagulation
is changed from heparin to argatroban. The sys-
tem, which is also coated with heparin, is usually
left as it is. Due to the biofilm, there is usually no
longer any contact. Alternatively, you can switch (if
available) to a heparin-free system (EOS ECMO
system from Sorin: not coated with heparin, but
with phosphorylcholine).
• infectiological: Under ECMO the risk of nosocomial in-
fections is increased, so that in many places - although
not evidence-based - antibiotic prophylaxis is carried
out
• thermical: hypothermia (Due to the high blood flow, the
patient can cool off, so that heating (heat exchanger;
target temperature 37°C) is always necessary.)

Monitoring
• monitoring of the patient
• monitoring of the system
Monitoring (patient)
• ECG
• invasive blood pressure measurement
• urine production (diuresis)
• pulse oximetry (in va-ECMO always on the right arm)
• arterial BGA (in va-ECMO always on the right arm)
• laboratory: i.a. blood count, hemolysis parameters, D-
dimers, fibrinogen, ACT or PTT (anticoagulation), CRP
• central venous oxygen saturation (target: > 70%)
• arterial cannulation:
-- femoral artery: NIRS (near infrared spectroscopy)
with adhesive electrodes on the lower leg
-- subclavian artery: measurement of the extent of the
ipsilateral arm (An increase indicates hyperperfusi-
on. The blood flow can be reduced by pulling on a
loop distal to the prosthesis anastomosis that was
put on during the surgical cannulation.)
• temperature (cave: the heat exchanger automatically
regulates the temperature and keeps it constant so
that fever is masked under ECMO!)
• chest X-ray
• neuro-monitoring (cerebral) with NIRS (with adhesive
electrodes on the forehead; for va-ECMO)
Monitoring (system)
• Pressure measurements: In the system 3 pressures
are measured by default. The pressures must be ze-
roed once per shift (by opening the three-way valve to
the atmosphere.
-- p1: pressure before the pump (suction pressure; is
always negative; standard: - 50mmHg)
◦◦ If the negative pressure exceeds 80mmHg, the
risk of hemolysis increases.
◦◦ procedure if the suction pressure is exceeded:
▪▪ reduction of the rotational speed (The cannula
often sucks itself into the vessel wall when the
blood flow is too high.)
▪▪ retraction of the cannula (Possibly it lies against
the vessel wall.)
▪▪ intravascular fluid administration
-- p2: pressure between pump and membrane (mem-
brane pressure; the highest value in the entire sys-
tem; usually < 250mmHg; membranes are approved
up to approx. 450mmHg; an increasing membrane
pressure is an indication of a clotting of the mem-
brane)
-- p3: pressure after the membrane (reperfusion pres-
sure)
◦◦ The difference between p2 and p3 is referred to as
transmembrane pressure gradient. An increase of
the transmembrane pressure gradient is an indica-
tion for a clotting of the membrane.
◦◦ The pressure p3 should always be lower than the
pressure p2.
• blood flow, pump rotational speed
• gas flow
• temperature
• inspection pump head, oxygenator
Weaning
Weaning from vv-ECMO
• If the gas exchange has improved (i.a. FiO2 < 0.4; pO2
> 80mmHg, pCO2 < 45mmHg), the blood flow at the
ECMO is reduced to 1.5 l/min and the gas flow to 1.0
l/min.
• If the patient is then stable (circulatory, respiratory
[blood gases]), the gas flow is switched off for one hour
Then the device is no longer effective. However, this
may only be done with vv-ECMO and never with va-
ECMO, as deoxygenated blood would then be pumped
into the arterial system! The ECMO continues to run,
cannot thrombose and is no longer effective.
• If the patient then remains stable, the heparin is swit-
ched off after two hours and the cannulas are removed
after one hour. The PTT should be normal before the
cannula is pulled out.
• An extubation under still running ECMO is the excepti-
on. First decanulation, then extubation!
• After withdrawing the cannulas, compression is carried
Pulmonology 649
 out for 60 minutes to prevent bleeding. Then the punc-
ture points can be taped with a pressure patch (e.g.
SafeGuard).
• The blood flow is reduced up to 1.5 l/min (not 1.0 l /
• For patients who do not succeed in weaning from va-
• decannulation: The arterial cannula is also pulled wi-
Status
• neonatology: long established, especially in the field
• adult medicine:
Fig. 912  After removal of the cannulas (decannulation) and
longer comperssion, the cannulation sites (mostly right
vein femoralis and right vein jugularis) are provided with a
pressure patch (here SafeGuard) to prevent bleeding. The
balloon is blocked with a total of 40 ml of air and then defla-
ted every hours by 5 ml.
Weaning from va-ECMO
• In weaning, the blood flow is gradually reduced stepwi-
se by 0.5 l/min. The blood flow is reduced by 0.5 l/min
for approx. 2 minutes (ECMO reduction test) and the
following parameters are observed. If they are fulfilled,
the attempt is considered successful:
-- blood pressure (target: SBB > 90mmHg or MAP >
60mmHg with only minimal pharmacological circula-
tory support [dobutamine < 3-6 μg/kg/min, noradre-
nalin < 0.15 μg/kg/min)
-- central venous oxygen saturation (best measured
continuously) > 50%
-- pulsatile instead of laminar flow as a sign of cardi-
ac ejection (note: not absolutely necessary, since a
pulsatile flow might me masked by a too high ECMO
flow)
-- echocardiography (The reduction in blood flow
should always be done under echo control!):
◦◦ function:
▪▪ left heart: EF (ejection fraction) > 25%, VTI (ve-
locity time integral) > 12cm
650 Pulmonology
▪▪ right heart: TAPSE (tricuspid annular plane sys-
tolic excursion) > 15mm
◦◦ diameter: There should be no dilation of the left
(LVEDD> 56mm) or right ventricle (RVEDD>
42mm)
min). Then the ECMO explantation is performed.
ECMO, the implantation of an LVAD (left ventricular
assist device) is a good option
thout a vascular surgeon. After removal cannulation
site is compressed (for 60-90 minutes) to prevent blee-
ding, then a pressure bandage is applied for 24h.
of:
-- meconium aspiration syndrome (MAS)
-- congenital diaphragmatic hernia
-- neonatal persistent pulmonary hypertension
-- neonatal sepsis
-- neonatal respiratory distress syndrome (NRDS)
-- especially since the H1N1 pandemic in 2009), al-
ready firmly established in many places (in 2013
approx. 1000 ECMO procedures in Germany; trend
clearly increasing; 2019 approx. 9000 procedures in
Germany)
-- Worldwide, most ECMOs are installed in Germany
(with the worst outcome!).
-- In the randomized prospective studies (published
until 2008; on the vv-ECMO) there was never a sur-
vival advantage. In the CAESAR study (see box) the
significance could unfortunately only be achieved
by manipulation at the primary endpoint: This was
only achieved by adding "severe disability", mortality
alone showed no difference. Also in a meta-analysis
(Zampieri et al, J Crit Care 2013) no benefit in mor-
tality could be shown. A reliable evidence for ECMO
(vv-ECMO) in adult medicine is therefore currently
limited at best. Finally, the EOLIA study (see box)
from France brought great disappointment, as it
could no showa decrease in mortality.
-- For va-ECMO in cardiogenic shock or cardiovascu-
lar arrest, there is no prospective randomized study
at all and therefore no scientific evidence, so this is a
purely experimental procedure.
 CESAR study EOLIA study

Efficacy and economic assessment of conventional venti-
latory support versus extracorporeal membrane oxygena-
tion for severe adult respiratory failure (CESAR)
Peek et al, Lancet 2009
• multicenter randomized controlled trial
• CESAR: Conventional ventilatory support vs Extracor-
poreal membrane oxygenation for Severe Adult Respi-
ratory failure
• 180 patients with ARDS (Lung Injury Score > 3 or hyper-
capnia with pH < 7.2)
-- without ECMO (conventional)
-- with ECMO
• result: ECMO → significant reduction in primary end-
point (death, severe disability)
-- conventional ventilation: 53%
-- ECMO: 37%
• critical remarks:
-- Significance was achieved only by adding "severe
disability", the mortality alone showed no difference.
-- treatment of all patients in a single highly specialized
center (were flown there with rescue helicopter [bias!])
-- only insufficient (in 70% only) lung protective ventilati-
on in the control group
-- A crossover was not permitted.
-- no standardized ventilation protocols
Extracorporeal Membrane Oxygenation for Severe Acute
Respiratory Distress Syndrome
Combes et al, N Engl J 2018
• multicenter randomized controlled trial
• EOLIA: ECMO to Rescue Lung Injury
• 249 patients with severe ARDS
-- conventional (including ECMO as rescu therapy)
-- ECMO
• inclusion criteria (one of the 3 criteria)
-- Horovitz quotient (paO2/FiO2)
◦◦ < 50 mmHg > 3h or
◦◦ < 80 mmHg > 6h
-- pH < 7.25 + paCO2 > 60 mmHg > 6h
• results: ECMO
-- primary endpoint (mortality after 60 days: no dif-
ference
-- secondary endpoints:
◦◦ significantly better gas exchange (pO2 ↑, pCO2 ↓)
◦◦ significantly shorter duration of ventilation
◦◦ complication rate: no difference (except more blee-
ding requiring transfusion and less ischemic stro-
kes in the ECMO group)
◦◦ significantly less acute kidney injury
• annotations:
-- Overall, the study was very well done (without the cri-
tical remarks and mistakes of the CESAR study).
-- The level of significance was just not reached with p
= 0.07
-- The mortality rate was relatively low at 35% compared
to the real-life data (58%).
-- In the study, a crossover was (ethically correctly)
permitted (in contrast to the CESAR study), i.e. pa-
tients with a therapy-refractory ARDS were allowed
to switch from the conventional group into the ECMO
group. In fact, this was very often the case (in 28%)!
If you now compare all patients who received ECMO
(i.e. including the crossover group) with the conventi-
onal group, the ECMO showed a significant reduction
in mortality! Nevertheless, according to strict scientific
criteria, it is clearly a negative study!

Indications
According to the ELSO (extracorporeal life support or-
ganization), ECMO is indicated from a mortality risk of
80%. Meanwhile there is the S3 guideline 2017 "Invasive
ventilation and use of extracorporeal procedures for acu-
te respiratory failure" of the DGAI (German Society for
Anaesthesiology and Intensive Care Medicine) with the
corresponding recommendations. Here the vv-ECMO is
only recommended for severe therapy-refractory ARDS
and only as a rescue measure after all conservative
measures have been exhausted. It is clearly spoken out
against liberal use. For the va-ECMO there is also a posi-
tion paper from the Austrian Cardiological Society on the
use of extracorporeal membrane oxygenation (ECMO)

Pulmonology 651
in adult cardiological patients 2015 and, especially for
cardiovascular arrest, a German consensus paper 2018
"Recommendations for extracorporeal cardiopulmonary
resuscitation (eCPR)" from various German Societies
(DGIIN, DGK, DGTHG, DGfK, DGAI, DIVI, GRC).
The following indications apply to ECMO:
• lung support (vv-ECMO):
-- Horovitz quotient (paO2/FiO2) < 65 mmHg (IPAP >
35 cmH2, PEEP > 20 cmH2O, pH < 7.25); note: ac-
cording to the S3-guideline 2017 of the DGAI from a
Horovitz quotient <80 mmHg (possibly even from <
60mmHg), according to the ELSO recommendation,
2013 alerady from a Horovitz quotient <100 mmHg
(FiO2 > 0.9)
-- sufficient gas exchange only possible with no longer
lung-protective ventilation
-- exclusion of potentially remediable causes (espe-
cially pneumothorax [especially the respirator-asso-
ciated pneumothorax is not so rare!])
• cardiac support (va-ECMO):
-- cardiac index < 2.0 l/min/m2
-- cardiac arrest (resuscitation)
ARDS with a Horovitz quotient <
65mmHg → ECMO
The indication for ECMO should be
read less on the BGA paper than on
the ventilator! The goal is protective
ventilation!
652 Pulmonology
Always exclude a RAP (respirator-
associated pneumothorax) before
initiating an ECMO!
average running times:
vv-ECMO: 8 days
va-ECMO: 3 days
Contraindications
• rejection by the patient (documented in writing or
presumed will) [note: But this happens almost never in
everyday clinical practice, that in advance healthcare
directive like a living it is written down that no ECMO
is desired.])
• ventilation with high invasiveness (e.g. inspiratory
pressure > 30 mbar, FiO2 > 0.9) > 7 days
• malignancies in palliative situation
• contraindication for effective anticoagulation (e.g. re-
cent intracranial bleeding [the only absolute contrain-
dication!])
• terminal lung disease (e.g. pulmonary fibrosis; i.a.
long-term oxygen therapy) with no prospect of soon
transplantation
• immunosuppression (especially neutropenia)
• severe aortic valve regurgitation, aortic dissection (va-
ECMO)
• liver cirrhosis Child B/C (relative)
• end stage renal disease (relative)
• age > 75 years (relative)
Prognosis
• The hospital mortality of patients under ongoing ECMO
therapy in Germany (Karagiannidis et al, ICM 2016) is:
-- va-ECMO: 66%
-- vv-ECMO: 58% (mortality in the EOILA study:
nonly 35%)
• The mortality of patients under ECMO can be estima-
ted with the following scores:
 -- va-ECMO: SAFE score (SAFE: Survival After Veno- ◦◦ advantage: easier mobilization of the patient
arterial ECMO; according to Schmidt et al, Eur Heart • miniaturized systems (e.g. Cardio Help)
J 2015; www.save-score.com) • high-performance membrane oxygenators
-- vv-ECMO: • iLA-activve (Novalung)
◦◦ PRESERVE score (PRESERVE: Predicting death
for Severe ARDS on vv-ECMO; according to
Schmidt et al, ICM 2013; see infobox)
◦◦ RESP score (RESP: Respiratory Extracorporeal
membrane oxygenation Survival Prediction; ac-
cording toSchmidt et al, Am J Respir Crit Care
Med 2014; www.respscore.com)

Fig. 913  double lumen cannulas [25]

Further developments
• double lumen cannula (bicaval) for veno-venous
ECMO
-- examples:
◦◦ Avalon Elite (for internal jugular vein; through Fig. 914  Double lumen cannula
the right heart into the inferior vena cava; length
30cm; sizes: 19-23F)
◦◦ Novalung Twinport (for internal jugular vein [15F] Maybe in the future only cannula
and femoral vein [24F]) instead of tube?
-- insertion always under control using fluoroscopy or
echocardiography (cave perforation of the right ven-
tricle! Double lumen cannulas have the highest risk Miniaturized heart-lung machines (va-
of complications during cannulation!), followed by x-
ray control ECMO)
-- assessment: • syn.:
◦◦ well suitable for low-flow vv-ECMO (e.g. for de- -- mini-ECC (extracorporeal circulation)
carboxylation in exacerbated COPD; a maximum -- MECC (minimal extracorporeal circulation)
blood flow of approx. 1.5 l/min is possible via a -- ELS (emergency life support)
double lumen cannula) -- ECLS (extracorporeal life support)
◦◦ not suitable for oxygenation disorders (Oxygenati- • combination of ECMO and heart pump
on is only possible from a blood flow of 3 l/min, i.e. • indications:
2 cannulas must be placed here.)

Pulmonology 653
 -- resuscitation (main indication; also preclinical): This -- XLung membrane ventilator (blood flows up to 6.5
allows the circulation to be restored and, in paral- l/min [well suited for severe oxygenation disorders
lel, e.g. coronary angiography with PCI or lysis for such as ARDS])
pulmonary embolism (see also chapter resuscitation • Novatherm:
page 311). -- heating to compensate the heat loss by the ECMO
-- combined heart and lung failure (especially severe at higher blood flows (always necessary e.g. with the
ARDS and septic cardiomyopathy [EF ↓↓]) XLung membrane)
• transportable -- But also an active cooling e.g. after resuscitation is
• examples: see page 311 possible.
-- adjustable temperature: 15-39°C
-- The water tank is filled with approx. 900ml still water
procedures (e.g. conventional mineral water [no AquaDest])
extracorporeal -- The device is connected to the membrane (not pos-
sible with iLA membrane ventilator).
• incl. surrogate pump (no hand crank included) and two
batteries (one battery lasts 30min at maximum power
[rotational speed 10000 rpm], approx. 3 hours at nor-
mal power)
• connection for CVVH (CRT connector): only available
with the iLA membrane, not with the MiniLung petit, Mi-
niLung or XLung membranes (Here an additional Shal-
don catheter must be inserted if a renal replacement
procedure is indicated at the same time.)
• financing:
iLA activve
-- offered by the company as a "support" solution, i.e.
• innovation (Novalung company [in course: Xenios; me- you do not buy the machine, but get it when needed
anwhile Fresenius Medical Care]) (24h hotline) and only pay for the set of membrane
• centrifugal pump (mini-pump) with diagonal flow (Im- and hoses (incl. experienced colleague for on-site
pella; max. rotational speed: 10000 rpm) care in the intensive care unit)
• veno-venous: -- reimbursement via OPS code 8-852.0 ECMO (ad-
-- double lumen cannula (With this max. blood flow ditional fee; to be negotiated beforehand with the
of approx. 1.5 l/min is possible, i.e. as a rule only health insurance companies)
decarboxylation [e.g. in the case of exacerbated
COPD] can be carried out.)
-- two single cannulas (single): femoro-jugular (for oxy-
genation; e.g. for ARDS)
◦◦ drainage cannula in the femoral vein
◦◦ reperfusion cannula in the internal jugular vein
• for decarboxylation and oxygenation (depending on
blood flow)
• objective: Reduction or replacement of mechanical
ventilation
• indications (according to the iLA activve-registry):
-- ARDS (main indication; 81%; average duration: 15
days)
-- COPD (29%; average duration: 10 days)
• also suitable for awake (active) patients
• Membranes: Depending on whether only decarboxyla-
tion (only low blood flows necessary) or oxygenation
(higher blood flows necessary) is desired, the desired
membrane is inserted into the system.
-- MiniLung petit membrane ventilator (blood flows up
to 0.8 l/min; mainly in pediatrics)
-- MiniLung membrane ventilator (blood flows up to 2.4
l/min)
-- iLA membrane ventilator (blood flows up to 4.0 l/min;
here no connection for heat exchanger [Novatherm]
possible, but CRT connector [i.e. connection for re-
nal replacement procedures, i.e. no extra Shaldon
catheter required])

654 Pulmonology
Fig. 915  iLA activve [25]

Fig. 918  iLA activve: The distinct color difference between

Fig. 916  iLA activve: pump drive and pump head [25] the dark red blood (still deoxygenated) in the drainage can-
nula (femoral vein) and the light red blood (already oxyge-
nated) in the reperfusion cannula (internal jugular vein) can
also be seen here.

MiniLung petite
MiniLung

XLung
Fig. 919  different membranes

Fig. 917  iLA activve

Pulmonology 655
Fig. 920  iLA membrane ventilator (filling volume 420ml, ex-
change surface 1.3m2): With this membrane, blood flows of
up to 4 l/min are possible. Filling ("priming") is done with
500ml NaCl 0.9% (without heparin addition). It has no con-
nection for the heat exchanger (Novatherm).
656 Pulmonology
Fig. 921  XLung (filling volume 550ml, exchange surface
1.9m2): It is placed over a mandrel on the console. With this
membrane, blood flows of up to 6.5 l/min are possible. Fil-
ling ("priming") is done with 1000ml NaCl 0.9% (with hepa-
rin addition: 2000IU heparin in 1000ml NaCl 0.9%). It has
two connections for the heat exchanger (Novatherm).
Fig. 922  Novatherm (heat exchanger)

Fig. 923  The iLA membrane (iLA membrane ventilator) has
extra connectors for the CVVH. This has the big advantage
that you don't have to insert an additional Shaldon catheter
if the patient requires renal replacement therapy. However,
this is not possible with the other three membranes (Mini-
Lung petit, MiniLung, XLung).
Fig. 924  For transport journeys (e.g. CT) battery operation
is used.
High frequency ventilation (HFV)
Definition
• syn.: jet-ventilation
• type of ventilation with a respiratory frequency (respi-
ratory rate [RR]) > 60/min
• regarding mortality not superior to conventional
ventilation in (previous) randomized controlled trials
Types
• high frequency positive pressure ventilation (HFPPV):
RR 60-120/min
• high frequency jet ventilation (HFJV): RR 120-190/min
• high frequency oscillation ventilation (HFOV): RR 600-
3000/min
High frequency oscillation ventilation
(HFOV)
Definition
• ventilation at a frequency of 600-3000/min (5-15 Hz)
• established in preterm / neonatal infants
• supply of oscillations into a CPAP ventilation system,
the pressure of which is determined by the amount of
respiratory gas flow and the degree of opening of the
outlet valve
• The coupled oscillator sets the gas stream in high-fre-
quency vibrations.
• The level of adjustable mean respiratory pressure
(CPAP) and FiO2 determine oxygenation.
• The physical processes through which the gas ex-
change takes place have not yet been fully clarifiedt.
• generation of "quasi tidal volumes" corresponding to
almost apneic ventilation in the lung periphery
• S3 guideline 2017 "Invasive ventilation and use of ex-
tracorporeal procedures for acute respiratory failure"
(DGAI): not recommended
Pulmonology 657
Assessment
• advantage: only small tidal volumes necessary (VT
2.0-2.5 ml/kg bw; very lung-protective [ultraprotective
ventilation possible])
• disadvantages:
-- only available at centres
-- deep sedation necessary
-- increased risk of barotrauma (pneumothorax; due to
the relatively high mean airway pressure)
-- hypercapnia (possibly combination with extracorpo-
real decarboxylation [pECLA or low-flow vv-ECMO])
-- no mortality advantage proven in studies so far
(even excess mortality!)

Devices (HFOV ventilators)

• SensorMedics 3100b
• NovaLung Vision α

Fig. 926  high-frequency oscillation ventilator NovaLung

Vision α [25]
Studies
• David et al, Intensive Care Med 2003
• Mehta et al, Chest 2004
• Bollen et al, Crit Care 2005 (discontinued; no mortality
advantage)
• MOAT study (Derdak et al, Am J Resp Crit Care Med
2002; see box): no mortality advantage
• OSCAR study (Young et al, N Engl J 2013; see box):
no mortality advantage
• OSCILLATE study (Ferguson et al, N Engl J 2013; see
box): even increased mortality

MOAT study

Fig. 925  high-frequency oscillation ventilator SensorMe-

dics 3100b [9]
High-Frequency Oscillatory Ventilation for Acute Respira-
tory Distress Syndrome in Adults
Derdak et al, Am J Resp Crit Care Med 2002

• multicenter randomized controlled study

• 148 patients with moderate or severe ARDS (Horovitz
quotient < 200 mmHg + PEEP > 10 cmH2O):
-- conventional ventilation
-- HFOV
• HFOV: no difference in mortality

658 Pulmonology

OSCAR study
High-Frequency oscillation for Acute Respiratory Distress
Syndrome
Young et al, N Engl J 2013
• multicenter randomized controlled study
• 398 patients with moderate or severe ARDS (Horovitz
quotient < 200 mmHg):
-- conventional ventilation
-- HFOV
• HFOV: no difference in mortality
OSCILLATE study
High-Frequency oscillation in Early Acute Respiratory Dis-
tress Syndrome
Ferguson et al, N Engl J 2013
• multicenter randomized controlled study
• 1200 patients (planned) with moderate or severe ARDS
(Horovitz quotient < 200 mmHg)
-- conventional ventilation
-- HFOV
•
premature termination of the study after 548 patients
because even increased mortality in the HFOV group
High frequency oscillation ventilation
in ARDS (adult): not (any longer)
recommended!
Inhalation of selective pulmonary va-
sodilators
• NO
• prostaglandins (prostanoids): prostacyclin (epoproste-
nol), iloprost
25% of patients with ARDS suffer from pulmonary hyper-
tension. The causes for this are the hypoxic vasocon-
striction (Euler-Liljestrand reflex), ventilation (especially
with high pressures → right ventricular afterload ↑) and
the obliteration of the lung capillaries by microthrombi.
Pulmonary hypertension is p.d. not postcapillary (Berlin
definition: no cardiac pulmonary edema). These subs-
tances (NO, prostaglandines) cause vasodilation of the
pulmonary vessels. The pulmonary vascular resistance
decreases, which leads to a decrease in pulmonary hy-
pertension. The diagnosis and therapy should only be
carried out using pulmonary catheter.
It is crucial to apply the substances inhalatively and not
systemically (i.v.): Due to the inhalative application, the
substances only enter the still ventilated alveoli and
cause vasodilation only selectively of the capillaries the-
re. This leads to a redistribution of blood from the non-
ventilated alveoli to the ventilated alveoli. The perfusion
of the ventilated alveoli increases (consequence: dead
space ↓) and the perfusion of the non-ventilated alveoli
decreases (consequence: shunt ↓). This leads to a re-
duction in the shunt, the main pathomechanism of the
ARDS, and thus to an improvement in the disturbed ven-
tilation / perfusion ratio, since both dead space and shunt
decrease. This is the big difference to the systemic (i.v.)
application: Here there is also an increase in perfusion
especially of the non-ventilated alveoli, so that the shunt
would even increase here!
NO inhalation (iNO [inhaled NO])
Physiology
• L-arginine is converted to citrulline and NO by NO syn-
thetase; NO activates intracellular guanylate cyclase
→ cGMP ↑ , calcium concentration ↑ → Relaxation of
vascular muscles
• NO is a pulmonary vasodilator.
Application
• NO-Domo as attachment for Evita
• INOvent (Linde company):
-- therapy system for inhalative application of NO
(INOmax)
-- can be combined with all common ventilators
-- approved for peri- and postoperative pulmonary hy-
pertension after cardiosurgical operations (all age
groups)
• Pulmonox device (Messer company)
• continuous NO supply
NO application very complex and
cumbersome!
Assessment
• 60% responder, 40% non-responder
• studies (Dellinger et al, Crit Care Med 1998; Lundin et
al, Intensive Care Med 1999; Taylor et al, JAMA 2004):
improvement of oxygenation, but no mortality advan-
tage
• meta-analyses (Afshari et al, Cochrane 2010; Adhikari
et al, Crit Care Med 2014; Gebistorf et al, Cochrane
2016): no mortality advantage
• rebound phenomenon possible after discontinuation
• increased rate in acute kidney injury
• expensive
• no approved drug (restriction of use to controlled stu-
dies or curative trials)
• previous indications (according to British experts):
-- severe ARDS (Horovitz quotient < 84 mmHg) to im-
prove oxygenation; low NO concentration necessary
(5-15 ppm)
-- severe right heart failure: high NO concentration ne-
Pulmonology 659
 cessary (20-40 ppm)
• According to a European panel of experts, NO inhala-
tion is no longer even indicated as a rescue measure
in severe ARDS (Germann et al, Intensiv Care Med
2005).
• guidelines:
-- sepsis guidelines 2010 + 2018 (German Sepsis So-
ciety): no longer recommended
-- S3 guideline "Invasive ventilation and use of extra-
corporeal procedures for acute respiratory failure"
2017 (DGAI): no longer recommended
Prostacyclin
• prostacyclin (PG I2) → activation of adenylate cyclase
→ intracellular cAMP ↑ → pulmonary vasodilatation
• prostacyclin analogue: iloprost
• 5-15 ng/kg/min via nebulizer ( relatively simple!)
• stronger reduction of pulmonary arterial pressure than
NO
• side effects:
-- blood pressure ↓ (partly systemic resorption)
-- inhibition of thrombocyte function (possibly bleeding)
meta-analysis
The use of inhaled prostaglandins in patients with ARDS
Fuller et al, Chest 2015
• 25 studies (including 2 RCT)
• 1362 ventilated patients with ARDS
-- inhalative prostaglandin
-- placebo
• result: inhalative prostaglandin
-- significantly better oxygenation (increase in Horovitz
quotient [paO2/FiO2])
-- significant decrease in mean pulmonary arterial pres-
sure
-- increased hypotension and thrombopenia (including
bleeding and need for transfusion)
Liquid ventilation
Historical
• 1966 Clark and Gollan: Mouse 1h spontaneous brea-
thing in PFC (Perfluorocarbon)
• 1976 Shaffer: total liquid ventilation in lambs
• 1990 first clinical application
Perfluorocarbon (PFC; LiquiVent)
• colorless and odorless fluid
• high physical solubility for O2 (2.5 times higher than
that of blood) and CO2
• high specific gravity (twice as heavy as water [H2O]) →
enrichment especially in the dorsal lung sections
• improvement of compliance by surfactant-like effect
660 Pulmonology
with reduction of surface tension
• no chest X-ray possible (high density)
• also used as a coolant in the RhinoChill intranasal coo-
ling system
Types
• total liquid ventilation (TLV):
-- The lung is completely filled with perfluorocarbon.
-- Ventilation is performed with a special ventilator (li-
quid ventilator).
• partial liquid ventilation (PLV):
-- The lung is only filled with perfluorocarbon to the ex-
tent of the FRC (30 ml/kg).
-- Ventilation is performed with a conventional ventila-
tor.
Studies
• randomized controlled trials (Kacmarek et al, Am J Re-
spir Crit Care Med 2000; Hirschl et al, Am J Respir Crit
Care Med 2002): no survival advantage
• meta-analyses: no survival advantage
-- adults (Galvin et al, Cochrane Database Syst Rev
2013)
-- children (Kaushal et al, Cochrane Database Syst
Rev 2013)
liquid ventilation: no significance at
all!
Pharmacological therapy
• steroids
• ketoconazole
-- older azole antifungal
-- inhibition of thromboxane synthase → vasodilatation
-- no effect
• surfactant application
-- indicated for IRDS (newborns)
-- nit indicated for ARDS (adults; i.a. Spragg et al, N
Engl J 2004: recombinant surfactant protein C → no
survival advantage; meta-analysis Meng et al, J Car-
diothorac Vasc Anesth 2012: no survival advantage;
meta-analysis Zhang et al, Exper Ther Med 2013: no
survival advantage)
• lisofylline: no effect
• incyclinides (modified tetracyclines; anti-inflammatory
effect; animal experimental data only)
• N-ACC (acetylcysteine)
-- N-ACC as glutathion substitute: acts as antioxidant
(radical scavenger)
-- high dose: 150 mg/kg loading-dose, then 12.5 mg/h
-- positive effects on ARDS described in small studies
(i.a. Domenighetti et al, J Crit Care 1997)
-- no general recommendation
• ambroxol
-- increase in synthesis and release of surfactant
-- application:
◦◦ perfusor 125 mg/h (3g/d) oder
◦◦ 3 x 1g/d i.v.
-- shortening the duration of ARDS, but no survival be-
nefit
-- no general recommendation
-- cheap
• Adrenomedullin (peptide); Müller et al, DGIIN (meeting
of German Society of Internal Medicine and Emergen-
cy Medicine) 2009 (animal model):
-- pulmonary vascular permeability ↓
-- PVR ↓
-- inflammation ↓
• omega-3 fatty acids (have an anti-inflammatory effect)
-- immunonutrition: OxEPA (omega-3 fatty acids + anti-
oxidants) recommendation grade C (SSC guidelines
2012; S2k guideline 2010: not mentioned)
-- In the omega study (Rice et al, JAMA 2011; see
box) the administration of omega-3 fatty acids did
not lead to a reduction of mortality on the one hand,
and on the other hand even to less ventilator-free
and therapy-free days, so that there was a rather
harmful effect!
-- SSC guidelines (Surviving Sepsis Campaign) 2016:
no longer recommended
• GM-CSF (granulocyte-macrophage colony stimulating
factor)
-- GM-CSF is important for the formation of the alveo-
lar epithelium and surfactant. .
-- In the study of Paine et al (Crit Care Med 2011) the
administration of recombinant GM-CSF showed no
effect at all (neither reduction of mortality nor of ven-
tilator-free days.
-- GM-CSF can induce leukocyte aggregation and thus
even lead to a deterioration in pulmonary function up
to ARDS (especially in patients with sepsis).
• statins
-- effect: Inhibition of HMG-CoA reductase
-- rationale: Statins also have an anti-inflammatory ef-
fect (pleiotropic effects) and should reduce inflam-
mation.
-- studies:
◦◦ HARP I study (Thelma et al, Am J Resp Crit Care
Med 2011): improvement of oxygenation
◦◦ HARP II study (Daniel et al, N Engl J 2014): no
effect; also studies Truwit et al, N Engl J 2014 und
McAuley et al, N Engl J 2014: no effect
-- evaluation: no recommendation
• human albumin
-- rationale: Hypalbuminemia increases mortality in
ARDS (i.a. Mangialardi et al, Crit Care 2000). The
oncotic pressure is reduced, so that more fluid es-
capes from the capillaries into the alveoli and thus
aggravates the ARDS
-- evaluation: no recommendation (i.a. Finfer et al, N
Engl Med 2004: no reduction of mortality)
• heparin inhalation
-- rationale: to reduce the formation of microthrombi in
the capillaries and the fibrin deposition in the alveoli
-- evaluation: In a small study (Nebulized heparin is as-
sociated with fewer days of mechanical ventilation in
critically ill patients: a randomized controlled trial; Di-
xon et al, Crit Care 2010) the duration of ventilation
could be reduced by inhaling heparin. In this respect,
however, larger studies are necessary, so that he-
parin inhalation cannot be generally recommended.
• β2-agonists
-- effect: stimulation cAMP-dependend protein kinases
-- rationale:
◦◦ reduced release of proinflammatory cytokines
◦◦ reduced accumulation of neutrophil granulocytes
◦◦ increased reabsorption of alveolar fluid
-- application: i.v. oder inhalative (Mattayh et al, Am J
Resp Crit Care Med 2011: also no benefit)
-- studies:
◦◦ BALTI-1 study (Perkins et al, Am J Respir Crit
Care Med 2006): positive effects described by Sal-
butamol i.v. (e.g. reduction of extravascular lung
water, reduction of plateau pressure in the respi-
ratory tract)
◦◦ BALTI-2 study (Smith et al, Lancet 2012; see box):
even excess mortality with salbutamol i.v.!
• interferon-β-1a
-- rationale: Interferon-β-1a activates CD73 and there-
fore increases the release of adenosine. This has
an anti-inflammatory effect and reduces thecapillary
permeability.
-- study (Ranieri et al, JAMA 2020): no reduction in
primary composite endpoint (death, ventilator-free
days) by IFN-β-1a 10 μg i.v. over 6 days compared
placebo
• vitamin C (ascorbic acid)
-- CITRIS-ALI studie 2019 (only a phase II-study; see
page Seite 860):
◦◦ high dose vitamin C infusion (50 mg/kg 4 x daily
over 4 days) versus placebo in patients with ARDS
and sepsis
◦◦ The 28d mortality as a secondary endpoint was
positive. However, the study had 49 endpoints, 46
of which were negative (including all primary end-
points)!
-- no general recommendation
• possibly muscle relaxants in the first 48h
Pulmonology 661
 EDEN-Omega study
ARDS network
• Omega-Trial (Rice et al, JAMA 2011): Omega-3 fatty
acids in ARDS → no mortality advantage (even more
ventilation days!)
• EDEN-Trial (Rice et al, JAMA 2012): trophic versus full
enteral nutrition → no advantage
Omega study
Enteral Omega-3 Fatty Acid, γ-Linolenic Acid, and Antioxi-
dant Supplementation in Acute Lung Injury
Rice et al, JAMA 2011
• multicenter randomized controlled study (phase III)
• 272 ventilated patients with acute lung injury (ALI)
-- omega-3 fatty acids
-- placebo
• results: omega-3 fatty acids
-- no difference in mortality
-- significantly fewer ventilator-free days
-- significantly fewer intensive therapy-free days
EDEN study
Initial trophic vs full enteral feeding in patients with acute
lung injury: the EDEN randomized trial
Rice et al, JAMA 2012
• multicenter randomized controlled study
• 1000 ventilated patients with acute lung injury (ALI): diet
in the first 6 days
-- only trophic diet (minimal-enteral-feeding; 400 kcal/
day)
-- "full" enteral nutrition (1300 kcal/day)
• results:
-- no difference in ventilator-free days
-- no reduction in mortality
-- increased gastric residual volume and more vomiting
with a fully enteral diet
662 Pulmonology
BALTI-2 study
Effect of intravenous β-2 agonist treatment on clinical out-
comes in acute respiratory distress syndrome: a multicent-
er, randomized controlled trial
Smith et al, Lancet 2012
• multicenter randomized controlled study
• 326 ventilated patients with ARDS
-- salbutamol 15 μg/kg/h i.v. over 7 days
-- placebo
• premature termination due to excess mortality (main-
ly caudes by arrhythmia) in the salbutamol group
Steroids
• The effect and significance of steroids in ARDS has
long been discussed controversial, so that there is no
general, consistent recommendation in the guidelines
of the large societies ( the Surviving Sepsis Campaign).
• possibly option for ARDS due to pneumonia or sepsis
(especially in septic shock)
• evaluation (studies)
-- steroids in the late phase (to reduce fibroblastic ac-
tivity in the proliferative phase) of the ARDS: not ef-
fective (Steinberg et al, N Engl J 2006 [see box])
-- steroids in the early phase of ARDS: effective
◦◦ Meduri et al, Chest 2007 (see box)
◦◦ DEXA-ARDS study (Villar et al, Lancet Resp Medi-
cine 2020 [see box])
• meta-analyses (Tang et al, Crit Care Med 2008; Meduri
et al, Journal of Intensive Care 2018 [see box]): survi-
val advantage
• SCCM/ESICM guidelines 2017 (Guidelines for the
Diagnosis and Management of Critical Illness-Rela-
ted Corticosteroid Insufficiency [CIRCI] in Critically Ill
Patients; SCCM: Society of Critical Care Medicine;
ESICM: European Society of Intensive Care Medicine;
Annane et al, Crit Care Med):
-- remcommended (IIB-recommendation) for a a least
moderate ARDS (Horovitz quotient < 200 mmHg
+ PEEP > 5 cmH2O) within 14 days after onset of
ARDS
-- Methylprednisolone (Urbason) is recommended as
the steroid because it best penetrates the lung tissue
and has a long biological half-life. Furthermore it is
a pure glucocorticoid with no mineralocorticoide side
effects.
-- dosage: methylprednisolone
◦◦ early (< 7 days): 1 mg/kg for 14 days, then tape-
ring:
▪▪ d15-21: 0.5 mg/kg
▪▪ d22-25: 0.25 mg/kg
▪▪ d26-28: 0.125 mg/kg
◦◦ late (> 7 days [but < 14 days]): 2 mg/kg for 7 days,
then tapering:
 ▪▪ d15-21: 1 mg/kg
▪▪ d22-25: 0.5 mg/kg
▪▪ d26-28: 0.25 mg/kg
▪▪ d28-30: 0.125 mg/kg
• In the case of a SARS-CoV-2 (COVID-19) induced
ARDS, steroids are clearly recommended as a result
of the RECOVERY study 2020 (Hobry et al, N Engl J
2020 [see page 934]), namely dexamethasone 6 mg
once daily i.v. for 10 days.
study
Efficacy and Safety of Corticosteroids for Persistent Acute
Respiratory Distress Syndrome
Steinberg et al, N Engl J 2006
• multicenter randomized controlled study
• 180 patients with ARDS > 7 days
-- methylprednisolone: Bolus 2 mg/kg, then 0.5 mg/kg
every 6h for 14d, then 0.5 mg/kg every 12h for 7 days,
then tapering
-- placebo
• results: methylprednisolone
-- primary endpoint (mortality after 60 and 180 days): no
reduction (in subgroup with ARDS > 14 days even in-
creased mortality!)
-- secundary endpoints: i.a.
◦◦ lower number of ventilator and shock-free days
◦◦ more frequent neuromuscular problems (CIP, CIM)
study
Methylprednisolone Infusion in Early Severe ARDS
Meduri et al, Chest 2007
• multicenter randomized controlled study
• 91 patients with severe ARDS (note: in 66% caused ba
sepsis); within 72h:
-- methylprednisolone: 1 mg/kg i.v.
-- placebo
• results: methylprednisolone
-- primary endpoint (reduction of the Lung Injury Score
by 1 point or successful extubation up to day 7): signi-
ficant improvement
-- secundary endpoints: i.a.
◦◦ mortality: significantly reduced
◦◦ duration of ventilation: significantly reduced
◦◦ length of ICU stay: significantly reduced
◦◦ even lower infection rate in the steroid group
meta-analysis
Prolonged low-dose methylprednisolone treatment is high-
ly effective in reducing duration of mechanical ventilation
and mortality in patients with ARDS
Meduri et al, Journal of Intensive Care 2018
• 9 RCT
• 816 patients mit with at least moderate ARDS
-- methylprednisolone
-- placebo
• results: methylprednisolone
-- significant reduction in mortality (NNT only 7)
-- significant reduction in duration of ventilation
-- significant reduction in ICU and hospital stay
-- side effects (i.a. hyperglycemia, infections, neuromu-
scular problems [CIP, CIM], gastrointestinal bleeding):
no difference
DEXA-ARDS study
Dexamethasone treatment for the acute respiratory dis-
tress syndrome
Villar et al, Lancet Resp Med 2020
• multicenter (17 ICU´s in Spain) randomized controlled
study
• 277 patients with at least moderate ARDS (Horovitz quo-
tient < 200 mmHg, PEEP > 10 cmH2O, FiO2 > 0.50; note:
in 77% caused by pneumonia or sepsis)
-- methylprednisolone: d1-5 20mg i.v., d6-10 10mg i.v.
daily
-- placebo
• results: methylprednisolone
-- primary endpoint (number of ventilator-free days): si-
gnificantly increased (reduction of duration of ventila-
tion by 4.8 days)
-- secundary endpoints: i.a.
◦◦ mortality (after 60 days): significantly reduced (21%
versus 36%)
◦◦ side effects (i.a. hyperglycemia, infections, neuro-
muscular problems [CIP, CIM]): no difference
Steroids in ARDS: currently not
generally recommended!
Pulmonology 663
 in case of ARDS due to SARS-CoV-2
(COVID): steroids clearly recommen-
ded (dexamethasone 6mg 1 x daily study
i.v. for 10 days)

Muscle relaxants Effect of neuromuscular blocking agents on gas exchange

in patients presenting with acute respiratory distress syn-
• studies: The ACURASYS study (see box) showed fa- drome
vorable effects of muscle relaxation in the early phase Gainnier et al, Crit Care Med 2004
of ARDS. The study by Gainnier et al (see box) show-
ed a significantly better oxygenation. However, the • multicenter randomized controlled study
ROSE study (see box), which was structured in exactly • 56 patients with severe ADRS (Horovitz quotient < 150
the same way as the ACURASYS study and was only mmHg)
three times larger, could show no advantages at all. -- with muscle relaxation
• The SSC guidelines 2012 and 2016 recommend -- without muscle relaxation
muscle relaxants for ARDS with a pO2/FiO2 < 150 • results: Muscle relaxation led to a significant improve-
mmHg in the first 48h (IIC recommendation). This ment in oxygenation (increase in the Horovitz quotient)
is not uncontroversial as it mainly counteracts early
spontaneous breathing. In severe ARDS, however, the
diaphragm is sacrificed to the lung parenchyma in the
early phase. This is because (probably) one does not
recover from severe lung damage as quickly as from
severe diaphragmatic damage.
• Muscle relaxation can also be performed in ARDS if
the patient repeatedly presses against the ventilator
despite extensive analgosedation and as a result ade-
quate ventilation is no longer possible.
• Muscle relaxation in ARDS only makes sense if there
is an asynchrony between the patient and the ventilati-
on machine ("fight the ventilator").
• If muscle relaxants are used for a longer period of time,
the monitoring of the effect (relaxometry; usually by
means of TOF [see page 51]) is obligatory.

ROSE study
ACURASYS study

Early Neuromuscular Blockade in the Acute Respiratory

Neuromuscular blockers in early acute respiratory distress
syndrome
Papazian et al, N Engl J 2010
• multicenter randomized controlled study
• 340 patients with severe ADRS (Horovitz quotient < 150
mmHg)
-- with muscle relaxation (cisatracurium: bolus 15 mg,
then 37.5 mg/h)
-- without muscle relaxation
• results: muscle relaxation
-- primary endpoint (mortality after 90 days): signifi-
cantly reduced (note: Only the adjusted mortality dif-
fered, not the real mortality!)
-- secundary endpoints: i.a.
◦◦ ventilator-free days: significantly reduced
◦◦ rate of neuromuscular problems (CIP, CIM): not in-
creased
Distress Syndrome
PETAL Clinical Trials Network, N Engl J 2019
• multicenter randomized controlled study
• ROSE: reevaluation of systemic early neuromuscular
blockade
• 1006 patients with severe ADRS (Horovitz quotient <
150 mmHg)
-- with muscle relaxation (Cisatracurium) for 48h
-- without muscle relaxation
• results: with muscle relaxation
-- primary endpoint (mortality after 90 days): no diffe-
rence
-- secundary endpoints: i.a.
◦◦ rate of neuromuscular problems (CIP, CIM): incre-
ased
◦◦ ventilator-free days: no difference
◦◦ length of hospital stay: no difference

664 Pulmonology
 pharmacological therapy of ARDS:
disappointing
ALIEN study

There are only 2 measures that reduce

mortality in ARDS (basic measures):
- lung-protective ventilation Incidence and outcome of acute respiratory distress syn-
(VT < 6 ml/kg, Δp < 15 mbar) drome in the era of lung protective ventilation
Villar et al, Int Care Med 2011
- prone positioning (if paO2 / FiO2
< 150mmHg) • prospective multicenter observational study in Spain
over 1 year
• 255 patients with ARDS (still the old definition)
• incidence: 7.2/100000
Prognosis • most common causes
-- pneumonia (No.1)
• Since ARDS is a syndrome, mortality is primarily deter-
-- sepsis (No.2)
mined by the underlying disease.
-- trauma (No.3)
• mortality -- aspiration (No.4))
-- ALIVE study (Brun-Buisson et al, Intensive Care • parameters
Med 2004) -- mean Horovitz quotient: 114 mmHg
◦◦ ALI: 23% -- mean tidal volume: 7.2 ml/kg
◦◦ ARDS: 35% -- mean plateau pressure: 26 cmH2O
-- Rubenfeld et al, Chest 2007 -- mean PEEP: 9.3 cmH2O
◦◦ ALI: 50% • mortality
◦◦ ARDS: 58% -- ICU mortality: 42.7%
-- hospital mortality: 47.8%
-- ALIEN study 2011 (see box): 47.8% (hospital mor-
tality of ARDS)
-- Villar et al, Crit Care Med 2015: hospital mortality:
◦◦ group I (paO2/FiO2 > 150 mmHg, PEEP < 10
mbar): 23% LUNG-SAFE study
◦◦ group II (paO2/FiO2 > 150 mmHg, PEEP > 10
mbar): 32%
◦◦ group III (paO2/FiO2 < 150 mmHg, PEEP < 10
mbar): 44% Epidemiology, Patterns of Care and Mortality for Patients
◦◦ group IV (paO2/FiO2 < 150 mmHg, PEEP > 10 With Acute Respiratory Distress Syndrome in Intensive
mbar): 60% Care Units in 50 Countries
Bellani et al, JAMA 2016
• The main cause of death in ARDS is not therapy
refractory hypoxemia, but sepsis / multi-organ failure! • multicenter international prospective cohort study (459
ARDS is usually only an organ failure (namely that of intensive care units, 50 countries; observation study
the lungs) in the context of septic multi-organ failure! over 4 weeks)
• duration of ventilation: on average 8 days • LUNG-SAFE: Large Observational Study to Understand
• increased rate of neurocognitive disorders in the long- the Global Impact of Severe Acute Respiratory Failure
term course (The main risk factor therefore is hypoxe- • 29144 ventilated patients (invasive / non-invasive)
mia during therapy!) • results:
-- prevalence of ARDS (fulfilled ARDS criteria according
• Every third patient has muscle weakness when di-
to the Berlin definition): 10.4% (in invasively ventilated
scharged from hospital (Dinglas et al, Crit Care Med patients: 23.4%)
2017)!
-- ARDS not detected at all in 60%
• DACAPO study (see box)
-- no lung protective ventilation in 33% (VT > 6 ml/kg)
• follow-up care useful (e.g. telephone contact, family
-- prone positioning in severe ARDS only in 16%
doctor, aftercare outpatient clinics)
-- in 83% PEEP < 12 mbar
-- hospital mortality: 40% (on average)
◦◦ mild ARDS: 34.9%
◦◦ moderate ARDS: 40.3%
◦◦ severe ARDS: 46.1%

Pulmonology 665
 Mortality of ARDS: 40% (for years
already!)
DACAPO study

study Surviving ARDS: The Influence of Quality of Care and Indi-

vidual Patient Characteristics on Quality of Life (DACAPO)
Brandstetter et al, congress presentation DGIIN 2018

Functional Disability 5 Years after Acute Respiratory Dis- • prospective multicenter (63 intensive care units in Ger-
tress Syndrome many) observational study (cohort)
Herridge et al, N Engl J 2011 • study on the influence of quality of care and individual
patient characteristics on the health-related quality of life
• follow-up (5 years) of 109 patients after surviving ARDS in survivors of ARDS
(mean age: 44 years) • 1125 patients with ARDS included in intensive care, 877
• results: of whom could be discharged from the hospital (hospital
-- normal lung function in almost all patients mortality: 30%), 396 patients after 12 months
-- 6min walking test: 76% of the age norm • mean age: 56 years
-- major depressive episode in 51% • results after 12 months:
-- 20% of the patients discharged from the hospital
died within 1 year!
-- signifinat cognitive and mental limitations
-- risk factors cognitive limitations:
study ◦◦ permissive hypercapnia
◦◦ longer (> 5 minutes) phases with hypoxemia (SpO2
< 85%)
-- only 50% able to work again
The adult respiratory distress syndrome cognitive out- -- in 43% post-traumatic stress disorder
comes study: long-term neuropsychological function in -- in 24% depression
survivors of acute lung injury -- no significant association between the quality of care
Mikkelsen et al, Am J Respir Crit Care Med 2012 in the intensive care unit and the outcome or quality
of life after 12 months (i.e. regardless of whether the
• follow-up (after 1 year) of 122 patients after surviving treatment took place at a university center or in a dis-
ARDS results trict hospital)
• results:
-- memory disorder: in 13%
-- cognitive impairment: in 55%
-- depression: in 36%
-- post-traumatic stress disorder: in 39%
-- anxiety disorder: in 62%

666 Pulmonology
 Guidelines
PULMONARY ESC/ERS-Guidelines for the diagnosis and treatment of
HYPERTENSIon pulmonary hypertension 2015

Consensus Conferences (World Sympo-

sia)
• 1993 Geneva
• 1998 Evian
• 2003 Venice
• 2008 Dana Point (California / USA)
• 2013 and 2018 Nice (i.a. proposal to lower the treshold
of the mPAP for pulmonary hypertension from 25 to 20
mmHg)
• 2016 Cologne: Cologne Consensus Conference (CCC;
only national [Germany])

Causes
• primary pulmonary hypertension (unknown)
Definition • secondary pulmonary hypertension
-- COPD (most common cause of cor pulmonale; in
• pulmonary vasculopathy (a disease of the blood ves-
50%; in 50%; usually only mild pulmonary hyperten-
sels in the lungs)
sion), pulmonary emphysema
• prevalence: 1% (at age > 65 years: 10%)
-- pulmonary fibrosis (pulmonary hypertension in 11%)
• Pulmonary hypertension is defined hemodynamically
-- recurrent pulmonary embolisms (M. embolicus);
(invasive measurements with right heart catheterizati-
syn.: CTEPH (chronic thromboembolic pulmonary
on) by the following criteria:
hypertension; see page 576)
-- mean pulmonary arterial pressure (mPAP; PAmean) >
-- collagenosis (e.g. scleroderma [new term: systemic
25 mmHg
sclerosis])
-- pulmonary vascular resistance (PVR) > 240 dyn x
-- appetite suppressants
sec x cm-5 (> 3 Wood; 1 Wood = 80 dyn x sec x cm-5);
-- kyphoscoliosis
PVR = 80 x (mPAP - PCWP) / HZV
-- obesity
• classification: mean pulmonary arterial pressure
(mPAP) > 25 mmHg -- sleep apnea syndrome
-- precapillary pulmonary hypertension: PCWP (pul-
monary capillary wedge pressure) < 15 mmHg
(group I, III, IV)
Classifications
-- postcapillary pulmonary hypertension: PCWP (pul-
monary capillary wedge pressure) > 15 mmHg
(group II, V)
• mean pulmonary arterial pressure (mPAP): thresholds
-- upper limit of normal pressure: 20 mmHg
-- latent pulmonary hypertension: 20-25 mmHg
-- manifest pulmonary hypertension: > 25 mmHg
• Cor pulmonale: dilatation or hypertrophy of the right
heart due to a lung disorder
• note: High pressures in the large circuit (MAP) auto-
matically lead to high pressures in the small circuit.
In a hypertensive crisis with a MAP of 130mmHg, the
mean pulmonary arterial pressure is of course also in-
creased (e.g. mPAP 40mmHg). However, it would be
misleading here to speak of pulmonary hypertension.
Therefore the following rules apply:
-- mPAP < MAP / 3 (The mean pulmonary arterial pres-
sure should not exceed a third of the MAP.)
-- PVR < SVR / 5 (The pulmonary vascular resistance
should not exceed a fifth of the systemic vascular
resistance.)

Pulmonology 667
 The most common cause of pulmonary
hypertension is disease of the left
heart!

Pulmonary hypertension group 1 (pulmo-

nary arterial hypertension [PAH])
• idiopathic pulmonary arterial hypertension (IPAH;
No.1; formerly: primary pulmonary hypertension)
• familial pulmonary arterial hypertension (FPAH)
-- syn.: hereditary (HPAP)
-- numerous genetic mutations: BMPR2 (bone morpho-
genetic protein receptor 2; most common mutation),
ALK-1, ENG, Smad9, CAV1, KCNK3 (i.a. channelo-
pathy [reduced potassium channel current]: defect in
the KCNK3 gene [Ma et al, N Engl J 2013])
• PAH associated (APAH; No.2) with:
-- drugs (DPAH: drug-induced PAH; i.a. appetite sup-
pressants [e.g. aminorex, fenfluramine, dexfenflura-
mine], SSRI, interferon, chemotherapeutics [espe-
cially cyclophosphamide], dasatinib, pergolide, St.
John's wort), drug abuse (i.a. amphetamines, cocai-
ne), toxins (e.g. canola oil, rapeseed oil)
-- HIV (1000 times increased risk of pulmonary hyper-
tension; frequency of pulmonary hypertension in HIV
infected persons: 0.5%)
-- collagenosis (especially scleroderma [new term:
systemic sclerosis])
-- portal hypertension (porto-pulmonary hypertension
[POPH])
-- congenital heart diseases (CHD-PAH):
◦◦ left-right shunt (ASD [atrial septal defect; mostly
only mild pulmonary hypertension], VSD (ventricu-
lar defect), PDA [persistent ductus arteriosus])
◦◦ Eisenmenger syndrome (shunt reversal; named
after the Austrian physician Viktor Eisenmenger
[1864-1932])
-- schistosomiasis
• PAH in venous or capillary lung diseases
-- pulmonal-venoocclusive disease (PVOD)
◦◦ diagnosis: HR-CT
◦◦ therapy: Lungentransplantation (lung transplanta-
tion; cave: Specific PAH drugs would worsen the
situation here!)
-- pulmonary capillary hemangiomatosis (PCH)
• persistent pulmonary hypertension of the newborn
(PPHN)

668 Pulmonology

Fig. 927  ASD - the most common congenital heart disease
classically discovered in adulthood; typical cause of pul-
monary hypertension
Fig. 928  scleroderma (here tobacco pouch mouth): 15%
develop pulmonary hypertension.
IPAH (idiopathic pulmonary arterial hyperten-
sion)
• most common form of pulmonary arterial hypertensi-
on(63%)
• mostly women
• average age: 50 years
• incidence ↑ (5-10/1000000)
• etiology: unclear
• incurable
• median survival time: 2.5 years
Prognosis of IPAH: like a malig-
nancy!
Porto-pulmonary hypertension (POPH)
• definition:
-- the thid most common type of pulmonary arterial hy-
pertension (a subform of APAH)
-- pulmonary hypertension in portal hypertension (por-
tal vein hypertension); mainly occurring in liver cir-
rhosis
-- occurring in 2-3% of all patients with liver cirrhosis
• pathophysiology:
-- irritation of the endothelium of the pulmonary arte-
ries due to the hyperdynamic circulation in liver cir-
rhosis → increased endothelin production
-- liver cirrhosis → reduced production of protein C, S
and antithrombin III → increased small pulmonary
embolisms
• severity (according to ERS Tasc Force on PHD [Pul-
monary-Hepatic vascular Disorders]): according to
mean pulmonary arterial pressure (mPAP)
-- mild POPH: mPAP < 35 mmHg
-- moderate POPH: mPAP 35-45 mmHg
-- severe POPH: mPAP > 45 mmHg
• diagnosis: invasive measurement (tip: You can mea-
sure both in one session with a balloon catheter [pul-
monary artery catheter]! In everyday clinical practice,
however, the portosystemic pressure gradient is usu-
ally not measured.)
-- pulmonary hypertension: mean pulmonary arterial
pressure (mPAP) > 25mmHg), PCWP (pulmonary
capillary wedge pressure) < 15mmHg (POPH is pre-
capillary pulmonary hypertension.)
-- portal hypertension: portosystemic pressure gradi-
ent (PSPG) > 12 mmHg
• prognosis: 1-year mortality 60%
• therapy:
-- therapy of the underlying disease (causal)
-- PAH specific drugs improves hemodynamics and
resilience (Faisal et al, Pulm Med 2014). All 3 subs-
tance classes (PDE-5 inhibitors, endothelin receptor
antagonists, prostacyclin analogs) are possible.
-- The following therapies are contraindicated in POPH:
◦◦ TIPS (By bypassing the liver, the short-circuit con-
nection between the portal vein and the liver veins
leads to an increased influx into the right atrium,
which can lead to a decompensation of the pulmo-
nary hypertension.)
◦◦ oral anticoagulation with VKA (e.g. marcumar; due
to increased risk of bleeding)
◦◦ β-blocker (such as non-selective β-blockers such
as propranolol, since tachycardia is an important
compensation mechanism for maintaining an ade-
quate cardiac output)
-- lung transplantation: only an option for mild POPH
(i.e. mPAP < 35 mmHg), because otherwise the pe-
rioperative mortality of lung transplantation is too
high. The higher the pulmonary artery pressure, the
higher the surgical mortality! In severe pulmonary
hypertension with a mPAP of 50mmHg, the periope-
rative mortality is 100% [Krowka et al, Liver Transpl
2000].)
Pulmonary hypertension group 2
• definition:
-- pulmonary hypertension due to left heart disease
-- hemodynamics (postcapillary pulmonary hyperten-
sion):
◦◦ mean pulmonary arterial pressure (mPAP) > 25
mmHg
◦◦ pulmonary capillary wedge pressure (PCWP) >
15mmHg
◦◦ isolated postcapillary pulmonary hypertension
▪▪ PVR < 240 dyn x sec x cm-5 (< 3 Wood)
▪▪ diastolic pressure difference: DPD = PAdiast -
PCWP) < 10mmHg
◦◦ mbined pre- and postcapillary pulmonary hy-
pertension (Over time, postcapillary pulmonary
hypertension may develop pulmonary vessel re-
modeling processes, resulting in additional preca-
pillary pulmonary hypertension.)
▪▪ PVR > 240 dyn x sec x cm-5 (> 3 Wood)
Pulmonology 669
 ▪▪ diastolic pressure difference: DPD = PAdiast -
PCWP) > 10mmHg
• most common cause of pulmonary hypertension
• representatives:
-- dysfunction
◦◦ systolisc (HFREF [heart failure with reduced ejec-
tion fraction]; note: 83% of all patients with systolic
heart failure have pulmonary hypertension. The
higher the PAP, the worse the prognosis [Lam et
al, JACC 2009].)
◦◦ diastolic (HFPEF [heart failure with preserved
ejection fraction])
-- valvular heart disease (left-sided)
◦◦ frequent especially in mitral valve insufficiency
◦◦ The highest PAP values at all are found in mitral
valve stenosis (above all here often additional in-
dependent precapillary pulmonary hypertension
due to the remodeling process of the pulmonary
vessels).
-- congenital cardiomyopathy / congenital disease of
the left ventricular inflow / outflow tract
• PAH specific drugs are not indicated here (ESC 2015:
IIIC). All studies were negative:
-- HFREF:
◦◦ LEPHT study (riociguat)
◦◦ Sil-HF study (sildenafil)
◦◦ PITCH-HF study (tadalafil)
-- HFPEF:
◦◦ RELAX study (sildenafil)
◦◦ DILATE study (riociguat)
◦◦ MELODY-1 study (macitentan)
◦◦ PASSION study (Tadalafil; currently still ongoing)
Pulmonary hypertension group 3
• definition: pulmonary hypertension due to disease of
the lungs or hypoxia
• second most common cause of pulmonary hyperten-
sion
• representatives:
-- COPD (most common; usually only mild pulmona-
ry hypertension [mPAP rarely > 40 mmHg]; COPD
GOLD IV: in 90% low pulmonary hypertension
[mPAP 20-30mmHg; only in 3% mPAP > 35mmHg)],
pulmonary emphysema
-- interstitial lung disease
-- CPFE (combined pulmonary fibrosis and emphyse-
ma; mixture of restriction and obstruction; frequent
[in 68%] pulmonary hypertension)
-- sleep-disordered breathing, alveolar hypoventilation
-- ARDS (in 25% pulmonale Hypertonie; see page
659)
-- chronic exposure to high altitude
-- disturbance of lung development (congenital dia-
phragmatic hernia, bronchopulmonary or alveolo-
capillary dysplasia, surfactant disorder, pulmonary
hypoplasia, pulmonary interstitial glycogenosis, al-
veolar proteinosis, lymphangiectasia)
• pathophysiology:
-- hypoxic vasoconstriction of the pulmonary arteries
670 Pulmonology
(Euler-Liljestrand reflex)
-- hypercapnia (especially with COPD) → pulmonary
arterial pressure ↑ (Increased pCO2 values ​​lead to
systemic vasodilation, but pulmonary vasoconstric-
tion.)
• therapy: The aim is to treat the underlying lung disease
(causal therapy). According to the current ESC/ERS
guidelines, PAH specific drugs is clearly not indicated
(IIIC-Empfehlung). By the way, theses drugs are not
approved for this purpose. The guiding principle here
is: "Treat the lung and not the pressure" (Peacock, BMJ
1990). Vasodilatation occurs as a result of the mecha-
nism of action of the PAH specific drugs. But the lung
remains ill. This results in an increased perfusion of not
or only insufficiently ventilated alveoli, so that a shunt
and a consecutive oxygenation disorder develops or
a pre-existing oxygenation disorder worsens further.
PAH specific drugs in COPD can be considered if 2 of
the 3 criteria are met:
-- mean pulmonary artery pressure > 35 mmHg
-- mean pulmonary artery pressure > 25 mmHg + car-
diac index < 2 l/min/m2
-- pulmonary vascular resistance (PVR) > 480 dyn x
sec x cm-5 (> 6 Wood)
• differential diagnosis: Even if a lung disease is present
at the same time, a pulmonary arterial hypertension
(group 1) can still be present, so that PAH specific
drugs are indicated. The following points are indicative
of the presence of PAH in the case of simultaneous
lung disease:
-- pulmonary function test (spirometry):
◦◦ FEV1 > 60% (for COPD)
◦◦ VC > 70% (for interstitial lung disease)
-- chest CT (preferably HR-CT [HR: high resolution]):
only slight parenchymal changes (for interstitial lung
disease)
-- spiroergometry: signs of exhausted circulatory re-
serve (preserved respiratory reserve, reduced O2
pulse, low mixed venous saturation, no increase in
pCO2 under stress) instead of exhausted ventilato-
ry reserve (reduced respiratory reserve, normal O2
pulse, normal mixed venous saturation, increase in
pCO2 under stress)
Symptoms
• discrete, often very late (if symptoms occur, the mean
pulmonary arterial pressure is usually already > 60
mmHg; mean PA pressure at diagnosis: 64 mmHg!)
• angina pectoris
• dyspnea on exertion
• syncope (together with angina pectoris and dyspnea
on exertion triad as with aortic valve stenosis!)
• rapid exhaustion
• tachycardia
• leg edema
• dizziness (especially at change of position; misdiagno-
sis: "orthostatic dysregulation")
• Raynaud's symptoms
• cyanosis
Diagnostics ECG
• anamnesis, physical examination • in 50% inconspicuous
• chest X-ray • P-pulmonale (prominent P-wave; P wave > 0.25 mV)
• chest CT • right bundle branch block
-- exclusion of pulmonary embolism (more suitable to • electrical axis (location type): vertical type, sagittal
exclude CTEPH: perfusion scintigraphy!) type, SI QIII type
-- i.a. HR-CT (interstitial lung disease, PVOD) • early R/S transition right precordial
-- ratio diameter pulmonary artery : aorta > 1 • negative T-waves
• laboratory: i.a. -- in V1-V4
-- pro-BNP -- in II, III, aVF
-- autoimmune serology, scleroderma markers (anti- • right ventricular Sokolow-Lyon index: RV1 + SV5 > 1.05
centromere-AB, scl-70 mV
-- HIV • sinus tachycardia
-- possibly drug screening urine (in unclear cases in
younger patients)
-- BGA (mostly hypoxemia and hypocapnia due to
compensatory hyperventilation)
• abdominal ultrasound (e.g. liver cirrhosis)
• ECG
• echocardiography
-- TTE
-- TEE (for the exclusion of ASD [Especially the sinus
venosus defect is almost only visible in the TEE.])
• spirometry, DLCO (diffusing capacity of the lungs for
carbon monoxide)
-- especially on the question of an obstructive or re-
strictive ventilation disorder
-- PAH: classically severe diffusion disorder with no
evidence of an obstructive or restrictive ventilation
disorder
• perfusion scintigraphy to exclude CTEPH
• screening for sleep apnea syndrome (e.g. Epworth-
Sleep scale, nocturnal pulse oximetry with nocturnal
desaturation [SpO2 < 90%]), if necessary polysomno-
graphy; clarification of obesity hypoventilation syndro-
me (former name: "Pickwick" syndrome; BMI > 30 kg/
m2, daily hypercapnia [pCO2 > 45mmHg] without ex-
planatory pulmonary or neuromuscular disease)
• 6-min walking test Fig. 929  ECG in pulmonary hypertension
• spiroergometry
• right heart catheterization (obligatory)

Physical examination
• signs of right heart decompensation:
-- congested jugular veins
-- edema
-- congested liver
• auscultation:
-- loud + split 2nd heart tone
-- systolic murmur p.m. 4th ICS right parasternal (tri-
cuspid valve insufficiency); typically increase in ins-
piration [Carvallo sign])
-- Graham Steell noise (diastolic: relative pulmonary
valve insufficiency)
Fig. 930  P-pulmonale

Pulmonology 671
 the right ventricle
-- parasternal short axis at the level of the papillary
muscles
-- measurement: end-diastolic
-- Because of the compression by the right ventricle,
the left ventricle no longer has an "O" shape, but a
"D" shape.
• reduced TAPSE (tricuspid annular plane systolic ex-
cursion)
• possibly pericardial effusion (due to reduced reabsorp-
tion of pericardial fluid due to increased venous pres-
Fig. 931  R/S transition to early right precordial
sure; note: Diagnosis of a tamponade is more difficult
here because the right ventricle collapses very late
Echocardiography due to high pressure.)
• measurement of pulmonary arterial pressure (PAP)
-- measurement PAsys + addition of CVP
-- CVP estimation using inferior vena cava (VCI) or
CVP measurement with lying CVC
◦◦ inspiratory collapsed VCI: 5 mmHg
◦◦ moderately dilated VCI (p.d. > 2cm), moderate re-
spiratory modulation: 10 mmHg
◦◦ clearly dilated VCI, missing respiratory modulati-
on, dilated central hepatic veins (p.d. > 10mm at
the confluence): 15 mmHg
-- total PAP (measured PAsys + CVP):
◦◦ normal < 30 mmHg
◦◦ 30-40 mmHg: mild pulmonary hypertension
◦◦ 40-60 mmHg: moderate pulmonary hypertension
◦◦ > 60 mmHg: severe pulmonary hypertension
-- tricuspidal regurgitation velocity (TRV):
◦◦ < 2.8 m/s: mild pulmonary hypertension
Fig. 932  Echocardiography in pulmonary hypertension: si-
◦◦ 2.8-3.4 m/s: moderate pulmonary hypertension
gnificantly enlarged right atrium and right ventricle
◦◦ > 3.4 m/s: severe pulmonary hypertension
-- Normal PAP (analogous normal TRV) does not rule
out pulmonary hypertension at all! For example, in
the DETECT study (Coghlan et al, Ann Rheum Dis
2014) in scleroderma patients (high-risk patients for
pulmonary hypertension) 39% of patients with pul-
monary hypertension detected in the right heart ca-
theter showed a normal PAP or normal TRV, i.e. 39%
would not have been diagnosed with pulmonary hy-
pertension if only the PAP in the echocardiography
had been relied upon. Furthermore, the PAP values​​
measured in the echocardiography show deviations
of more than 10 mmHg in approx. 50% from the PAP
values measured
​​ in the right heart catheter (i.a. Fis-
her et al, Am J Resp Crit Care Med 2009; Rudski et
al, J Am Soc Echo 2010). The PAP is also neither
a prognosis nor a control parameter in the further
course! Reasons:
◦◦ The right ventricular ejection fraction is often redu-
ced so that no increased PAP can be generated
any more.
◦◦ Often a higher degree of tricuspid valve insuffici-
ency is found, so that pressure equalization oc-
curs and an increased PAP is no longer possible.
• enlarged right ventricle (usually larger than the left
ventricle) and right atrium
• LV eccentricity index (LVEI; = Ryan index) < 1
-- right ventricular load → compression of the left by

672 Pulmonology
Fig. 933  Right ventricular load in the M-mode: right ventric- Fig. 935  Measurement of PAP using cw-Doppler: here: se-
le dilated, paradoxical septal motion (i.e. during systole not vere pulmonary hypertension
dorsal- but ventralwards)

Fig. 936  Measurement of PAP using cw Doppler: PAP here

massively increased with 82mmHg above CVP!
Fig. 934  Tricuspid valve insufficiency (vena contracta
6mm; moderate)
A normal PAP does not exclude
pulmonary hypertension! PAP is also
neither a prognosis nor a control
parameter!

Chest X-ray
• abnormalities only in 40%
• prominent pulmonary arch
• dilatation of the right main pulmonary artery > 4.5 cm
• caliber jump ("amputated hilus")
• right heart enlargement (lateral image: reduction of the
retrosternal space, increased sternal contact area)

Pulmonology 673
Fig. 937  Chest X-ray in pulmonary hypertension (bilateral
"amputated hilus")
Fig. 938  Chest X-ray in pulmonary hypertension: The pro-
minent pulmonary arch can be seen on the right.
Fig. 939  Chest CT in pulmonary hypertension: The distinct
enlargement of the pulmonary artery can be seen.
674 Pulmonology
Fig. 940  Scintigraphy: first image ventilation scintigraphy
(inconspicuous), second image perfusion scintigraphy:
Here, pronounced perfusion loss can be seen segmentally
and subsegmentally after recurrent pulmonary embolisms.
CTEPH (chronic thromboembolic pulmonary hypertension)
is present. To exclude recurrent pulmonary embolisms,
scintigraphy is much better than CT! (courtesy of Dr. Neu-
maier, Medical Care Centre Regensburg [Germany])
Right heart catheterization
• obligatory
• measurement of pulmonary arterial pressure (PAP)
and pulmonary capillary wedge pressure (PCWP) and
calculation of pulmonary vascular resistance (PVR;
PVR = 80 x [mPAP - PCWP] / CO)
• Typical for pulmonary arterial hypertension (precapilla-
ry) is that the diastolic PA pressure is greater than the
pulmonary capillary wedge pressure (PAdiast > PCWP;
„PC-jump“). For the diagnosis of precapillary pulmona-
ry hypertension it is required that the diastolic pressure
difference DPD (diastolic pressure difference: DPD =
PAdiast - PCWP) is more than 10mmHg.
• PCWP should be measured at the end of normal ex-
piration.
• vasoreactivity testing
 -- previously administration of oxygen up to SpO2 > Adenosine (Adrekar)
93% • agonist at A1- and A2-receptor
-- types -- A1-receptor:
◦◦ inhalative (NO, ilomedine [Iloprost; standard; 1 ◦◦ occurrence: sinus and AV node
amp. = 20 μg with 5ml NaCl 0.9% via ultrasound
◦◦ effect: Activation leads to negative chronotropy
nebuliser])
and dromotropy.
◦◦ i.v. (adenosine, prostacyclin); note:
-- A2-receptor:
◦◦ Testing with inhalative substances should be pre-
◦◦ occurrence: smooth musculature
ferred.
◦◦ effect: Activation leads to vasodilation.
-- "20-20 criterion": vasoreactivity is positive if PAP and
PVR decrease by 20% or (current recommendation) • perfusor: 20 amp. adenosine (1 amp. = 2ml = 6mg
decrease of the mean PAP below 40 mmHg and > [note: new ampouls 1 amp. = 2ml = 10mg]) + 60 ml
10 mmHg compared to the initial value (baseline) NaCl 0.9% → 1.2 mg/ml (2 perfusor syringes a 50ml),
infusion rate (in ml/h): see table
-- The test is only positive in 10%. If this is the case,
however, the patients can be treated very effectively • dose levels I-IV (increase every 3min; see table)
(and inexpensively) with calcium channel blockers. • 50-200 μg/kg/min
These patients have a good prognosis! • previously vasoreactivity test with 100% oxygen respi-
-- Testing only makes sense with IPAH, HPAH and ration for 3min
DPAH (drug-induced). • side effects: i.a.
• Three months after the start of therapy (or also after a -- bradycardia, higher degree AV block
change in therapy) a right heart catheterization should -- intracoronary steal phenomena (cave CHD)
be performed again.
50kg 60kg 70kg 80kg 90kg 100kg
I 125 150 175 200 225 250
II 250 300 350 400 450 500
III 375 450 525 600 675 750
IV 500 600 700 800 900 1000
Fig. 943  Adenosine perfusor: 1.2 mg/ml, infusion rate indi-
cated in ml/h; dose levels I-IV (increase every 3min)

Fig. 941  Right heart catheterization: here in the right ven-
tricle clearly increased pressure values (RVsys = 52 mmHg)
Fig. 942  Right heart catheterization: massively increased
PA pressure (yellow curve)
Therapy
• general measures
• causal therapy (therapy of the underlying disease: e.g.
connective tissue disease, HIV, ASD [e.g. interventio-
nal closure])
• anticoagulation
• initiation of long-term oxygen therapy (LTOT) if paO2 <
60mmHg
• diuretics (e.g. furosemide i.v., possibly spironolactone)
in case of hydropic decompensation
• An iron deficiency leads to a significantly increased
morbidity. Therefore, a corresponding diagnosis / cla-
rification and, if necessary, iron administration (i.v.)
should be carried out.
• atrial fibrillation: generous indication for cardioversion
(rhythm control)
• pharmacological PA pressure reduction (specific drug
therapy)
• surgery
-- balloon atrial septostomy (interventional)
◦◦ generation of a right-left shunt ("overpressure val-
ve")
◦◦ as a palliative measure (no importance in Europe
today)
-- pulmonary endarterectomy (PEA) in case of recur-
rent pulmonary embolism (CTEPH; see page 576)
-- possibly denervation of the pulmonary arteries: In

Pulmonology 675
 the PADN-1 study (Chen et al, J Am Coll Cardiol
2013) and PADN-2 study (Chen et al, ACC 2015),
the ablation of sympathetic nerve fibers and baro-
receptors at the bifurcation of the main pulmonary study
artery in patients with IPAH resulted in a reduction
of the pulmonary arterial mean pressure and an im-
provement in exercise capacity (6min walking test). .
• ultima ratio: lung Anticoagulation and survival in pulmonary arterial hyper-
-- bilateral tension: results from the Comparative, Prospective Reg-
istry of Newly Initiated Therapies for Pulmonary Hyperten-
-- possibly combined heart-lung transplantion (rarely
sion (COMPERA).
required) Olsson et al, Circulation 2014
-- urgent listing due to the very poor prognosis for pul-
monary venoocclusive disease (PVOD) and pulmo- • analysis of data from the COMPERA registry (European
nary capillary hemangiomatosis (PCH) PH registry; COMPERA: Comparative Prospective Re-
gistry of Newly Initiated Therapies for Pulmonary Hyper-
tension)
General measures • 1283 patients with pulmonary hypertension (66% of
• physical training (best under supervision; no complete which IPAH)
physical rest, but heavy physical strain should be avo- -- without anticoagulation
ided [no overexertion]) -- with anticoagulation
• no air travel without oxygen application (hypoxic vaso- • result: IPAH with anticoagulation → significant reduc-
constriction; only ondicated of paO2 < 60mmHg) tion in mortality (increased 3-year survival)
• no extended stay at altitudes > 1500m
• vaccinations (influenza, pneumococcus)
• β-blockers contraindicated (RV compensation me- Specific drug therapy
chanisms ↓: Via the tachycardia a sufficient cardiac
output should be generated if the stroke volume is re-
duced.)
• connection of the patient to a PAH center (p.d. at least
50 patients with PAH or CTEPH per year)
• for elective surgery if possible better epidural anest-
hesia instead of general anesthesia due to the signifi-
cantly increased risk of anesthesia
• psychosocial support

Anticoagulation • calcium antagonists (calcium channel blockers)

• PDE-5 inhibitors
• oral anticoagulation
• guanylate cyclase stimulator (riociguat)
-- PH group 4 (CTEPH)
• endothelin receptor antagonists (ERA)
◦◦ VKA (e.g. marcumar; target Quick: 20-30%, target
INR 2-3), alternatively also novel oral anticoagu- • prostacyclin analogues
lants [e.g. rivaroxaban, apixaban]; however not
approved for this purpose) Calcium antagonists
◦◦ lifelong (even if pulmonary endarterectomy has al- • only indicated with positive vasoreagibility test (10% of
ready been performed) all patients)
-- PH group 1 (PAH) • but then very efficient
◦◦ all patients with PAH (nnot recommended, howe- • high dose administration
ver for APAH [here even excess mortality!]) • representatives: use depending on the patient's heart
◦◦ target Quick: 30-40%, target INR 1.5-2 rate
◦◦ ESC guidelines 2015: IIb recommendation (was -- tachycardia → diltiazem (up to 720 mg/d)
downgraded from IIa) -- bradycardia →
• no anticoagulation in ◦◦ amlodipine (up to 20 mg/d)
-- PH group 2 (left ventricular failure) ◦◦ nifedipine (up to 240mg)
-- PH group 3 (COPD, pulmonary emphysema, pulmo-
nary fibrosis) PDE-5 inhibitors
• inhibition of the phosphodiesterase-5: degradation of
cGMP ↓ → vasodilatation
• representatives
-- sildenafil
-- tadalafil (Cialis, Adcirca; 1 x 40mg p.o. daily; PHIRST

676 Pulmonology
 study)
-- vardenafil (Levitra; 10-20mg p.o. daily; EVALUATI-
ON study)
• no concomitant ingestion of substances that also act
via inhibition of cGMP (cave effect enhancement with
pronounced drop in blood pressure):
-- nitrats
-- Rriociguat
Sildenafil (Revatio)
• dosage
-- 3 x 20mg to 3 x 80mg daily (also i.v. possible: 3 x
10mg; 10mg i.v. correspond to 20mg p.o.)
-- Health insurances in Germany actually reimburse
only 3 x 20mg.
• only approved for IPAH and APAH with collagenoses,
i.d. off-label-use i.a. in PH group 3 (COPD, pulmonary
emphysema, pulmonary fibrosis) or PH group 4 (pul-
monary embolism)
• side effects:
-- epistaxis, nasal mucosal swelling
-- flush
-- headache
-- diarrhea
-- temporary disorder of color vision
SUPER 1 study
Sildenafil Citrate Therapy for Pulmonary Arterial Hyperten-
sion
Galie et al, N Engl J 2005
• multicenter randomized controlled study
• 278 patients with pulmonary arterial hypertension (PAH;
idiopathic, collagenosis, shunts)
-- sildenafil (20/40/80 mg 3 x daily) for 12 weeks
-- placebo
• results: sildenafil
-- improvement of the walking distance achieved in the
6min walking test
-- improvement in NYHA class
-- decrease of PVR
-- high dosage (3 x 80mg): regarding walking distance
no further improvement, but even stronger decrease
of PVR
-- long-term extension study: survival benefit (SUPER 2
study [Rubin et al, Chest 2011]): survival benefit
Riociguat (Adempas)
• stimulator of the soluble guanylate cyclase (sGC) →
NO ↑
• dual mechanism of action (NO-independent and NO-
synergistic)
• indication: approved since 2014 for
-- inoperable patients with CTEPH (chronic thrombo-
embolic pulmonary hypertension) or persistent or
recurrent CTEPH after surgery (the only PH specific
drug that is not only approved for PH group 1, but
also group 4)
-- pulmonary arterial hypertension (PAH)
• dosage: start with 3 x 1mg p.o. daily, then titrate up
under BP control to max. 3 x 2.5mg
• no combination with PDE-5 inhibitors (contraindicated)
• studies:
-- CHEST-1 (Phase III pivotal study: Ghofrani et al, N
Engl J 2013): riociguat in patients with inoperable
CTEPH (chronic thromboembolic pulmonary hyper-
tension) or recurrence after pulmonary endarterec-
tomy
◦◦ primary endpoint: walking distance (6min walking
test): significant increase
◦◦ secondary endpoints
▪▪ proBNP: significant reduction
▪▪ PVR: significant reduction
▪▪ WHO functional class: significant improvement
-- PATENT-1 (Ghofrani et al, N Engl J 2013): riociguat
in patients with PAH
◦◦ walking distance (6min walking test): significant
increase
◦◦ secondary endpoints
▪▪ proBNP: significant reduction
▪▪ PVR: significant reduction
▪▪ WHO functional class: significant improvement
-- RESPITE: ongoing study on riociguat in patients
with PAH who did not respond adequately to mono-
therapy with PDE-5 inhibitors or combination thera-
py of PDE-5 inhibitors with endothelin receptor ant-
agonists
• side effects:
-- collapse / syncope
-- nausea, vomiting, diarrhea
-- dysphagia
-- edema
-- hemoptysis, possibly hemoptosis
• contraindicated in pulmonary hypertension due to in-
terstitial lung disease (i.a. excess mortality in the RI-
SE-IIP study, also not approved in this case
Endothelin receptor antagonists (ERA)
Representatives
• non-selective (ET-A and ET-B receptor ["dual"])
-- bosentan (Tracleer)
-- macitentan (Opsumit)
• selective (ET-A receptor only)
-- sitaxentan (Thelin)
-- ambrisentan (Volibris)
Bosentan (Tracleer)
• unselective endothelin receptor antagonist (ET-A and
ET-B)
• studies: BREATHE 1-3 (significant improvement in
NYHA class and 6-min walking test)
• early start (already in NYHA II [EARLY studiy])
Pulmonology 677
• dosage: start with 2 x 62.5 mg, then 2 x 125-250 mg/d • extension study STRIDE-2X (Seibold et al, Chest
• warfarin level ↓ → dose increase necessary 2008): survival rate after 12 months (posthoc analysis)
• reduced or lost effectiveness of oral contraceptives -- bosentan: 88%
• no longer the first choice drug due to the side effects -- sitaxentan: 96%
(especially hepatotoxicity) and interactions • withdrawn from market since 2010 (due to increased
cases of liver failure)
Macitentan (Opsumit)
• unselective endothelin receptor antagonist (ET-A and Ambrisentan (Volibris)
ET-B) • selective endothelin A receptor antagonist (ET-A)
• dosage: 1 x 10mg p.o. • studies: ARIES-I/II
• SERAPHIN study (see box) • dosage: start with 1 x 5mg, then 1 x 10mg/d
• approved since 2014 for long-term treatment of pulmo- • no effect on warfarin level
nary hypertension (both monotherapy and combinati-
on therapy) Side effects (ERA)
• no effect on warfarin level • hepatotoxicity: transaminases ­↑ (monthly control obli-
• no interaction with oral contraceptives gatory; initially already elevated transaminases repre-
sent a contraindication for ERA!)
• flush
• edema
SERAPHIN study • anemia, cytopenia
• teratogen → strict contraception

Prostacyclin analogues (prostanoids)

Macitentan and Morbidity and Mortality in Pulmonary Arte-
rial Hypertension
Pulido et al, N Engl J 2013
• multicenter randomized controlled study
• 742 patients with pulmonary arterial hypertension (PAH)
-- macitentan
-- placebo
• observation period: 115 weeks (first long-term study!)
• results: macitentan
-- primary endpoint (combined endpoint of death, PAH
worsening, start with i.v. prostanoids, atrial septo-
stomy, lung transplantation): significantly reduced
(relative decrease by 45%, absolute by 15%; even in
patients pretreated with PDE5 inhibitors [relative risk
reduction here by 38%])
-- secondary endpoints:
◦◦ PAH-related mortality and hospitalization risk: signi-
ficantly reduced (by 50%)
◦◦ hemodynamics:
▪▪ cardiac index: significantly increased
▪▪ pulmonary vascular resistance (PVR): signifi-
cantly reduced
◦◦ significant improvement in NYHA class
◦◦ compared to placebo no increased incidence of
edema, elevation of LFT (liver function tests) or
anaemia
Representatives
• epoprostenol (Flolan) i.v. (2-24 ng/kg/min, increase to
100 ng/kg/min)
• treprostinil (Remodulin)
-- s.c.
-- i.v. (i.a. continuous infusion via a subcutaneously im-
planted pump [e.g. Lenus Pro pump]; start with 0.5
ng/kg/min, taregt: 10 ng/kg/min)
-- inhalative
• iloprost
-- inhalative (Ventavis): 2.5-5 mg 6-9x/d
-- i.v. (Ilomedin): 2 ng/kg/min
• beraprost (Dorner): p.o. (3 x 2 tabl.)
• selexipag (Uptravi): p.o.
-- a prostacyclin IP receptor agonist
-- 2 x 200μg up to max. 2 x 800μg
-- approved in Germany since 2016 (approved in the
USA since 2015)
-- GRIPHON study 2014 (see box)

Sitaxentan (Thelin)
• selective endothelin A receptor antagonist (ET-A)
• approved since 2006 for pulmonary arterial hypertensi-
on (PAH) from NYHA III
• dosage: 1 x 100 mg/d
• warfarin level­ ↑ → dose reduction necessary
• STRIDE-2 study (Barst et al, JACC 2006):
-- Sitaxentan To Relieve Impaired Exercise
-- as effective as bosentan (6min walking test) Fig. 944  Treprostinil (Remodulin): 20ml a 100mg (5 mg/ml),
mostly applied as continuous infusion i.v. via a subcutane-
-- less frequent increase in LFT, more frequent edema
ously implanted pump

678 Pulmonology
Side effects
• headache, jaw pain
• flush
meta-analysis
• nausea, vomiting, diarrhea
• bleeding (Prostacyclin is the strongest endogenous in-
hibitor of platelet aggregation!)
• arterial hypotension Efficacy and Safety of Pulmonary Arterial Hypertension-
specific Therapy in Pulmonary Arterial Hypertension
Liu et al, Chest 2016

GRIPHON study • meta-analysis (35 RCT, 6702 patients with pulmonary

arterial hypertension [PAH])
• pharmacological therapy with PAH-specific drugs:
-- significant reduction in mortality by 29%
Selexipag for the Treatment of Pulmonary Arterial Hyper- -- significant improvement in resilience (NYHA class ↓,
tension distance in the 6min walk test ↑)
Sitbon et al, N Engl J 2015 -- significant improvement in hemodynamics (cardiac
index ↑, PVR ↑)
• multicenter randomized controlled study
• 1156 patients with pulmonary arterial hypertension (lar-
gest randomized study to date on PAH)
-- selexipag PH specific drugs: no randomized
-- placebo trials for direct comparison
• result (selexipag): significant reduction in the com- approval only for pulmonary arterial
bined primary endpoint of death or PAH-related compli- hypertension (group 1 [note:
cations riociguat also for group 4])

Combination therapy
• low and medium risk (according to the risk stratification
meta-analysis ["traffic light system"] for estimation of the prognosis
[risk assessment] of the ESC guidelines 2015 [see
page 675]):
-- typical PAH: combination therapy (2 drugs [esp.
A meta-analysis of randomized controlled trials in pulmo- PDE-5 inhibitor + ERA])
nary arterial hypertension
-- atypical PAH: monotherapy; note: The Cologne Con-
Galie et al, Eur Heart J 2009
sensus Conference differentiates between typical
• meta-analysis (21 RCT, 3140 patients with pulmonary and atypical forms of PAH. Atypical PAH is defined
arterial hypertension [PAH]) as: esp.
• pharmacological therapy with PAH-specific drugs ◦◦ age > 65 years
(phosphodiesterase-5 inhibitor, endothelin receptor an- ◦◦ cardiovascular risk factors: arterial hypertension,
tagonists, prostacyclin analogues) → significant reduc- diabetes mellitus, obesity (BMI > 30 kg/m2)
tion in mortality by 43%
◦◦ CHD, atrial fibrillation, enlarged left atrium
• high risk: combination therapy (3 drugs)

meta-analysis

Targeted therapy of pulmonary arterial hypertension (PAH)

Klose et al, Deusch Med Wochenschr 2014

• meta-analysis (23 RCT)

• patients with pulmonary arterial hypertension (PAH);
pharmacological therapy with PAH-specific drugs
-- reduction in mortality by 43%
-- reduction of hospitalization rate by 61%

Pulmonology 679

AMBITION study
Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arte-
rial Hypertension
Galie et al, N Engl J 2015
• multicenter randomized controlled study
• 500 patients with pulmonary arterial hypertension (PAH)
-- monotherapy (ambrisentan or tadalafil)
-- combination therapy (ambrisentan and tadalafil)
• results: combination therapy
-- primary endpoint (combined death, hospitalization,
clinical worsening): significant reduction (by 50%)
-- secondary endpoints (e.g. pro-BNP, walking distance,
WHO functional class, dyspnea): significant reduction
meta-analysis
Combination therapy versus monotherapy for pulmonary
arterial hypertension
Lajoie et al, Lancet Respir Med 2016
• meta-analysis (15 RCT, 4095 patients with pulmonary
arterial hypertension [PAH])
-- monotherapy
-- combination therapy
• results: combination therapy
-- significant improvement in WHO functional class
-- significant improvement in walking distance
-- significantly fewer PAH-related hospitalizations
-- significantly longer time to clinical deterioration
PAH: early combination therapy
(especially in patients < 40 years of
age)
Second opinion regulation
• §73d of the social code V in Germany
• was valid since 2009 (resolution of the joint federal
committee)
• obligation that the PAH specific drug (relatively expen-
sive drugs) is approved by a second physician
• A similar regulation existed previosly already in the on-
cology.
• repealed in 2010 as part of the AMNOG (drug market
reorganization law)
680 Pulmonology
PAH and pregnancy
• Women with PAH should be strongly advised against
pregnancy. PAH is a relative contraindication to be-
coming pregnant. The mortality of pregnant women
is massively increased (up to 50%; especially due to
acute right heart failure and sudden cardiac death).
• If a pregnancy has nevertheless occurred, the preg-
nant woman should be closely linked to a PAH center.
• Endothelin receptor antagonists (ERA) have a tera-
togenic effect and are therefore contraindicated in
pregnancy. Calcium antagonists, PDE-5 inhibitors and
prostacyclin analogs are allowed during pregnancy
• Two methods should be combined to prevent pregnan-
cy. Because of the lower risk of thromboembolism, a
pure progestogen preparation (i.e. monopreparation
without additional estrogen) should be used as an oral
contraceptive.
• Bosentan can lead to a loss of effectiveness of oral
contraception and thus to unwanted pregnancy.
Prognosis
• median survival in PAH: 2.5 years
• mean pulmonary arterial pressure > 50 mmHg →
5-year survival rate 10%
• pulmonary hypertension due to recurrent pulmonary
embolism (CTEPH): 1-year survival rate 30% (→ sur-
gery [pulmonary endarterectomy]!)
Prognostic parameters (unfavorable
prognosis)
• clinical:
-- decrease in performance status
-- increasing dyspnea
-- syncope
• laborchemical:
-- BNP, NT-pro BNP ↑
-- uric acid ↑
◦◦ in 80% hyperuricemia
◦◦ uric acid → NO formation ↓ → pulmonary vasodi-
latation ↓
◦◦ allopurinol → pulmonary vasodilatation ­↑
• functional:
-- 6min walking test (< 300m)
-- VO2max (spiroergometry) < 11 ml/min/kg
• echocardiographic:
-- LV eccentricity index (LVEI, Ryan index, D-shape)
< 0,5
-- pericardial effusion
 -- TAPSE (tricuspid annular plane systolic excursion)
< 15mm
-- Tei index (RIMP [right ventricular myocardial perfor-
mance]) > 0,88 (pw-Doppler)
-- increasing tricuspidal valve regurgitation
-- enlarged right atrium (RA > 26 cm2; very sensitive!)
-- note: PAP is neither a prognostic nor a control para-
meter! If the RV function (RV-EF) continues to dete-
riorate, the pressure gradient automatically decrea-
ses. Furthermore, a higher degree of tricuspid valve
insufficiency often develops, resulting in a pressure
equalization and thus a reduction of the pressure
gradient! A recent retrospective analysis (Echocar-
diographic assessment of estimated right atrial pres-
sure and size predicts mortality in pulmonary arterial
hypertension; Austin et al, Chest 2015), however, Fig. 947  reduced TAPSE (6mm only)
showed a good correlation between the level of
(echocardiographically estimated) PAP and mortality Risk low moderate high
(PAP as an independent prognostic parameter). 1-year mortality (< 5%) (5-10%) (> 10%)
• hemodynamic: symptoms of right no no yes
-- CVP (RA pressure) > 14 mmHg heart failure
-- cardiac index < 2 l/min/m2 NYHA class I / II III IV
-- SVO2 (mixed-venous [from pulmonary artery]) < 60% progression no slow rapid
-- negative vasoreactivity test (non-responder)
syncope no rarely frequent
6min walking test > 440m 165-440m < 165m
spiroergometry: > 15 11-15 < 11
VO2max
(ml/min/kg)
spiroergometry: < 36 36-45 > 45
VE/VCO2 slope
BNP (ng/l) < 50 50-300 > 300
NT-proBNP (ng/l) < 300 300-1400 > 1400
echocardiography: < 18 18-26 > 26
RA area (cm2)
echocardiography: no minimal clear
pericardial effusion
hemodynamic: <8 8-14 > 8-14
RA pressure (mmHg)
Fig. 945  reduced LV eccentricity index (LVEI, Ryan index,
D-shape) hemodynamic: > 2,5 2,0-2,5 < 2,0
cardiac index
(l/min/m2)
hemodynamic: > 65% 60-65% < 60%
SgvO2

Risk assessment ("traffic light system" for the estima-

tion of the prognosis; according to the ESC guidelines
2015)

Fig. 946  M-mode through the lateral tricuspid valve ring;

simple and good parameter for RV function; normal value >
15mm; RV-EF = TAPSE x 3.2

Pulmonology 681

ACUTE RIGHT HEART
FAILURE
Definitions
• right heart insufficiency (right ventricular insufficiency)
-- right ventricular filling pressure > 9 mmHg
-- cardiac index < 2.5 l/min/m2
• right heart failure
-- low-output syndrome (cardiac index < 1.5 l/min/m2
despite sufficient fluid administration) with cardioge-
nic shock
-- right atrial pressure > 18 mmHg
Guidelines
ESC guidelines 2016 Contemporary management of
acute rightventricular failure: a statement from the Heart-
Failure Association and the Working Group on Pulmona-
ry Circulation and Right Ventricular Function (Harjola et
al, Eur Heart J)
Etiology
• acute pulmonary embolism (No.1; PAP rarely > 50
mmHg)
• acute right ventricular myocardial infarction (in every
third inferior myocardial infarction)
• decompensated pulmonary hypertension; frequent
(especially in ICU) reasons for acute decompensation
of a pre-existing pulmonary hypertension:
-- hypoxia of different genesis (e.g. pneumonia) via the
Euler-Liljestrand reflex (hypoxia → vasoconstriction
of the pulmonary arteries → pulmonary arterial pres-
sure ↑)
-- ventilation with high PEEP (too high PEEP → over-
inflation → compression of the pulmonary capillaries
→ right ventricular afterload ↑)
-- hypercapnia (e.g. in the context of an exacerbated
COPD or permissive hypercapnia): Hypercapnia in-
creases the pulmonary arterial pressure! Hyperpap-
nia (high pCO2) leads to vasodilation systemically
(including cerebral), but to a pulmonary vasocons-
triction.
-- noradrenaline (e.g. in the context of sepsis; nor-
adrenaline massively increases the pulmonary arte-
rial pressure!)
-- cardiac arrhythmia (e.g. tachyarrhythmia absoluta
[no more active atrial filling → CO ↓])
-- anemia
-- infections (strongest mortality factor [Sztrymf et al,
Eur Resp J 2010]!)
-- incompliance
• septic cardiomyopathy
• mechanical ventilation
-- with high pressures (increased right ventricular af-
682 Pulmonology
terload)
-- permissive hypercapnia (pCO2­↑ → PVR↑­)
• acute tricuspid valve endocarditis (i.v.-drug abuse)
• perforated sinus-valsalva aneurysm (e.g. in endocar-
ditis)
• ventricular septal rupture (VSR)
• congenital heart diseases in adulthood (e.g. ASD, pul-
monary stenosis, Ebstein anomaly)
• decompensated arrhythmogenic right ventricular dys-
plasia (ARVD)
• amniotic fluid embolism (peripartal only)
• after thoracic surgery (e.g. lobectomy, pneumectomy)
• after implantation of a left ventricular assist device
(LVAD; in 20%; caused on the one hand by septal dis-
placement in the context of volume relief [venting] of
the left ventricle, on the other hand by increased right
ventricular preload)
Symptoms
• dyspnea
• cyanosis
• congested jugular veins, prominent jugular vein pulse
• possibly pulmonary edema (also possible in right heart
failure due to a disturbed lymphatic drainage from the
lung and thus a congestion in the thoracic duct)
• centralization (cold acres, mottled skin)
• pronounced 2nd heart tone
• angina pectoris
• leg edema, ascites
• pain in the right upper abdomen (tension of the liver
capsule due to congestion of the liver); cave pitfall:
Usually the LFT are also increased and the gall bladder
wall is sonographically triple-layered (consequence of
right heart failure, has nothing to do with cholecystitis!),
no wrong indication for a cholecystectomy!
• bowel congestion → translocation → sepsis
Monitoring
• basic monitoring (i.a. central venous oxygen saturati-
on)
• extended (advanced) hemodynamic monitoring with
pulmonary artery catheter (PAC)
-- The pulmonary artery catheter is clearly superior to
the PiCCO system in acute right heart failure!
-- Acute right heart failure is the domain of the pul-
monary artery catheter!
-- cave: If the cardiac output is determined here by
thermodilution (PAC / PiCCO [especially here this
applies to all higher-grade valve insufficiencies,
i.e. for also for mitral or aortic valve insufficiency]),
it is measured incorrectly too low. Due to pulmona-
ry hypertension, there is almost always a relevant
tricuspid valve insufficiency (secondary). Due to tri-
cuspid valve insufficiency, the applied cold injection
solution is repeatedly thrown back into the right at-
rium so that it ultimately has more time to warm up:
The result is a larger temperature increase, so that a
 lower cardiac output is measured. Here the cardiac
output should be determined by echocardiography
or according to Fick (Fick's method: very simple and
elegant; see page 209).
-- mixed venous oxygen saturation
• cardiac power index: CPI = mPAP x CI x 0,0022
• echocardiography
Acute right heart failure: very often
overlooked! Echocardiography
essential for diagnosis! Monitoring:
Domain of the pulmonary artery
catheter!
Therapy
• causal (most important)
• symptomatic
Causal therapy
• pulmonary embolism → lysis (fibrinolytic therapy)
• right ventricular myocardial infarction → acute PCI
• tricuspid valve endocarditis with severe tricuspid val-
ve regurgitation → Antibiose, antibiosis, if necessary
surgery (tricuspid valve reconstruction [mostly annu-
loplasty] or tricuspid valve replacement [biological val-
ve])
• septic cardiomyopathy → sepsis therapy
• perforated sinus-valsalva aneurysm → surgery
• ventricular septal rupture (VSR) → surgery
Symptomatic therapy
• administration of oxygen (hypoxic vasoconstriction ↓)
• diuretics (if hydropically decompensated; e.g. furose-
mide / torasemide perfusor)
• fluid administration
-- Patients with right heart failure (e.g. pulmonary em-
bolism, right ventricular myocardial infarction) often
benefit from volume administration. The right ven-
tricle itself is hardly dependent on the preload (vo-
lume) at all, there is no Frank-Starling mechanism
on the right as there is on the left ventricle. The right
ventricle is mainly dependent on the afterload (PA
pressure). In the case of right heart failure, the right
ventricle only insufficiently pumps the blood towards
the left heart, so that the left ventricular preload de-
creases. Furthermore, the filling of the left ventricle
is impaired by the septum shift (displacement of the
septum to the left due to the high pressure in the
right ventricle [Bonnheim effect]), so that the left ven-
tricular filling and thus the left ventricular preload de-
crease even further. This can be increased by fluid
administration, so that the cardiac output increases.
In right heart failure, the volume is given to increase
the left ventricular preload.
-- target CVP: 12-15 mmHg (optional only, earlier re-
commendation; for estimation of volume response
see page 227)
• TAA → cardioversion (mainly electrical; no digitalis the-
rapy for acute right heart failure [hypoxemia → toxicity
↑, if necessary only for frequency control in TAA])
• anemia → RCC administration (possibly already from
Hb < 10 g/dl [no general recommendation however])
• cave ketamine: pulmonary arterial pressure (PAP) ↑,
pulmonary vascular resistance (PVR) ↑ (i.a. Strum-
pher et al, J Cardiothorac Vasc Anesth 2011)
• hypotension → vasopressor (especially if the syste-
mic-vascular resistance [SVR] is reduced):
-- noradrenaline (cave: Noradrenaline leads to a mas-
sive increase of the pulmonary vascular resistance
[PVR], so that in this situation noradrenaline should
possibly be combined with a right ventricular after-
load-lowering drug [e.g. ilomedin via perfusor].)
-- possibly vasopressin; effects:
◦◦ MAP (mean arterial pressure) ↑, SVR (systemic
vascular resistance) ↑
◦◦ PAP (pulmonary artery pressure) ↓, PVR (pulmo-
nary vascular resistance) ↓
• cardiac index < 2,5 l/min/m2 → inotropic
-- dobutamine (Dobutamine decreases the pulmo-
nary artery pressure [PAP] and the pulmonary-vas-
cular resistance [PVR]!)
-- possibly levosimendan:
◦◦ combines the benefits of RV inotropy and pulmo-
nary vasodilation (PAP ↓, PVR ↓ [Russ et al, Crit
Care Med 2009]), cave: also systemic vasodilation
with a consecutive decrease in blood pressure
◦◦ dosage: 0.1-0.2 μg/kg/min, possibly initial bolus
(6-12 μg/kg over 10min, but not if SBP < 90mmHg)
◦◦ ESC guidelines 2016 for right heart failure: re-
commended!
• In NYHA IV, none of the right ventricular afterload-lo-
wering drugs (PH specific drugs) is officially approved
→ off-lable-use
-- ilomedin (Iloprost; most common)
◦◦ i.v.:
▪▪ start with 2 ng/kg/min (titrate carefully, cave sys-
temic hypotension!)
▪▪ perfusor: 5 amp. ilomedin a 1ml a 20μg + 45 ml
NaCl 0.9% → 2 μg/ml
▪▪ for resuscitation: 10-20 μg
◦◦ inhalative: 2.5-5 μg, repeated every 1-3 hours
-- sildenafil i.v. 3 x 10mg daily
-- treprostinil (Remodulin) s.c. 18-54 μg every 6 hours
-- epoprostenol (Flolan) i.v.:
◦◦ 2-24 ng/kg/min (increase up to 100 ng/kg/min)
◦◦ the only right ventricular afterload-lowering
drug with a proven survival benefit in NYHA IV
(McLaughlin et al, Circulation 2002)
-- NO inhalation; e.g. INOvent (Linde company):
◦◦ therapy system for the inhalative application of NO
(INOmax)
◦◦ can be combined with all common ventilators
◦◦ approved for peri- and postoperative pulmonary
hypertension after cardiac surgery (all age groups
• invasive mechanical ventilation
-- If possible, select the lowest possible ventilation
Pulmonology 683
 pressures (high ventilation pressures → right ventri-
cular preload ↓, right ventricular afterload ↑­)
-- set the lowest possible PEEP
◦◦ PEEP improves the left ventricular, but worsens
the right ventricular function!) !
◦◦ A too high a PEEP leads to overstretching (hyper-
inflation) of the alveoli and thus to a compression
of the neighboring lung capillaries. The right ven-
tricular afterload increases (PAP ↑, PVR ↑).
◦◦ On the other hand, even in acute right heart failu-
re, the PEEP must not be too low: Otherwise ate-
lectasis occurs with the result that the shunt incre-
ases and oxygenation deteriorates. As a result of
the hypoxic induced vasocontraction (Euler-Liljes-
trand reflex), the PAP and PVR can even increase.
-- no permissive hypercapnia (here contraindicated;
hypercapnia increases pulmonary arterial pressure!)
• if necessary extracorporeal procedures:
-- minimally invasive heart pumps (e.g. Impella RP,
Tandem Heart [right ventricle])
-- ECMO (if possible still awake in the patient not yet
ventilated ["awake-ECMO"] to avoid complications
of ventilation and sedation: For a patient with pulmo-
nary hypertension in particular, mechanical ventilati-
on represents an extreme trauma with a massive ne-
gative effect on haemodynamics! Positive pressure
ventilation increases the right ventricular afterload!)
-- cardiac thoracic surgical implantation of a right ven-
tricular assist device (RVAD
◦◦ Here an inlet cannula is inserted into the right ven-
tricle. This leads to a pump which then directs the
blood through an outlet cannula into the pulmona-
ry artery
◦◦ examples: PVAD (Paracorporeal Ventricular As-
sist Device; Thoratec), CentriMag (Levitronix)
Fig. 948  Ilomedin (1 amp. = 1ml = 20μg)
pulmonary hypertension: One does
not die from the high PAP, but from
the low cardiac output!
in order to PA pressure ↓ + PVR ↓:
- vasopressor: vasopressin
- inotropics: dobutamine, levosimen- ge disk"], bagpipe) and function of the right ventricle
dan!
684 Pulmonology
Case
• 64 year old woman, previously known pulmonary hy-
pertension (COPD, OHS, status post pulmonary em-
bolism 2 years before)
• admission diagnosis: pneumonia, COPD exacerbated
by infection
• increasing dyspnea in the course, sinus tachycardia,
still stable circulation: Therefore chest CT was perfor-
med, in which a renewed pulmonary embolism was
excluded.
• then hemodynamic deterioration and finally resuscitati-
on in EMD (ROSC after 2min)
• transfer to intensive care unit; catecholamine-depen-
dent (noradrenaline 2mg/h, dobutamine 50mg/h), BP
70/40mmHg
• echocardiography: pronounced right ventricular load,
moderate tricuspid valve regurgitation, right ventricular
hypertrophy
• insertion of a pulmonary artery catheter (PAC); mea-
sured values:
-- PCWP (pulmonary capillary wedge pressure):
10mmHg (not increased)
-- PAsys 70mmHg (massively increased), PAdias 30mmHg
(significant jump to PCWP!), PAmean 48mmHg, RVsys
68mmHg, RVdias 14mmHg, RVmean 32mmHg
-- BGA from pulmonary artery (mixed venous oxygen
saturation): 45% (reduced [norm: 65-80%])
-- cardiac index: according to thermodilution 1.4 l/min/
m2 (slightly underestimated cardiac output due to a
relevant tricuspid valve regurgitation), according to
Fick 1.7 l/min/m2 (significantly decreased [norm: 2,5-
4,5 l/min/m2]; cardiogenic shock!)
-- PVR (pulmonary vascular resistance): 1036 dyn x
sec x cm-5 (significantly increased [norm: < 240 dyn
x sec x cm-5])
• therapy with ilomedin 50 μg/h i.v. (via perfusor)
• pulmonary artery catheter (PAC): measured values un-
der iomedin:
-- PAsys: 40mmHg (significantly decreased)
-- PVR: 280 dyn x sec x cm-5 (significantly decreased)
-- mixed venous oxygen saturation: 75% (significantly
increased)
-- cardiac index: 3,4 l/min/m2 (significantly increased)
Excursus: Echocardiography of the
right heart
Introduction
• stepchild in the echocardiography
• animal experiment (Starr et al, Am Heart J 1943): com-
plete destruction of the free wall of the right ventricle →
no relevant effect on hemodynamics
Anatomy
• complex geometry (semilunar; cartinoid ["curved oran-
• sits on the left ventricle crescent-shaped like a cap
• thin wall (approx. 50% of the thickness of the myocar-
 dium of the left ventricle), muscle-poor Normal values
• more pronounced trabecularization than the left ven-
tricle
• parts of the right ventricle
-- RVIT (right ventricular inflow tract)
-- RVOT (right ventricular outflow tract; infundibulum)
-- apex
-- free (lateral) wall
-- interventricular septum
• (still) no segmentation
• determination of right ventricular function (still) no cli-
nical routine

Physiology
• main contraction especially via the septum
• main contraction of the free wall especially longitudi-
nally (in the longitudinal direction [TAPSE therefore so
informative!])
• peristaltic contraction (RVIT → apex → RVOT)
• mutual influence of both ventricles via the septum
(interventricular dependence; syn.: RV-LV-crosstalk):
dilatation of the right ventricle → functional disorder
(especially filling disorder, typical restriction!) of the left
ventricle (Bonnheim effect)
• same stroke volume as left ventricle
• lower myocardial oxygen consumption than the left
ventricle
• The right ventricle is very sensitive to pressure (right
ventricular afterload; PAP ↑ → right ventricular EF ↓)
and is relatively insensitive to volume (right ventricular
preload; almost no Frank-Starling mechanism on the
right!), i.e. the stroke volume of the right ventricle de-
pends mainly on the afterload (PAP) and only very little
on the preload (volume).
• coronary perfusion
-- via RCA (right coronary artery)
-- partially nourishes itself directly from the blood in the
ventricle
-- continuous (in contrast to the left ventricle also in
systole due to the low myocardial wall tension)
-- better pronounced collaterals than left ventricle
-- longer ischemia tolerance than the left ventricle

Guidelines
• Guidelines for the echocardiographic assessment of
the right heart in adults - a report from the American
Society of Echocardiography 2010
• Recommendations for Cardiac Chamber Quantifica-
tion by Echocardiography in Adults: An Update from
the American Society of Echocardiography and the
European Association of Cardiovascular Imaging 2015

Fig. 949  Determination of the right ventricular myocardial

thickness via the subcostal view (here clear RV hypertro-
phy)

Pulmonology 685
Function (right ventricular function)

Fig. 950  Determination of the right ventricular pressure

increase rate dp/dtmax: derivation of the cw-Doppler spect-
rum of tricuspid valve insufficiency in the apical 4-chamber
view: The time is measured until the velocity has increased
from 100 to 200 cm/s (here 36ms). From this a pressure in-
crease rate is calculated: dp/dtmax = 12mmHg/0,036s = 333
mmHg/s (reduced)

TAPSE
• tricuspid annular plane systolic excursion
• syn.: TAM (tricuspid annular motion)
• baso-apical excursion of the tricuspid valve annulus
(systolic
• distance between tricuspid valve annulus in diastole
Ellipsoidal shell model and systole
• determination of right ventricular ejection fraction: EF = • The main contraction of the free wall occurs mainly
(EDV - ESV) / EDV longitudinally, i.e. in longitudinal direction.
• volume V = 2/3 x RV area x d • M-Mode measurement (lateral tricuspid valve annulus)
-- RV area: planimetry of the end systolic and end dia- • norm: > 20 mm (pathological < 15 mm; new guidelines:
stolic area of the right ventricle in apical 4-chamber < 16 mm)
view • The right ventricular ejection fraction (RV-EF) can easi-
-- d: RV-diameter anterior-posterior (parasternal short ly be calculated from the TAPSE: RV-EF = TAPSE
axis at the level of the aortic valve x 3.2
• inaccurate (no general recommendation) • limitations:
Fractional area change (FAC) -- incorrectly high TAPSE despite poor RV function
with volume overload of the right ventricle (e.g. high-
• FAC = (area end-diastolic - area end-systolic) / area er degree tricuspid insufficiency, ASD)
end-diastolic
-- considers only the longitudinal, not the circumferen-
• pathological: < 35% tial RV function, i.e. TAPSE may still be normal even
Right ventricular pressure increase rate though RV function is already reduced
• dp/dtmax
• spectrum of the cw-Doppler of the transtricuspid regur-
gitation flow in tricuspid valve insufficiency: increase of
pressure per time
• Spectrum represents the pressure difference between
right ventricle and right atrium (does not depend on the
severity of tricuspid insufficiency).
• The steeper the pressure increase, the better the glo-
bal pump function.
• calculation:
-- time t to increase of velocity from 1 to 2 m/s → dp/
dtmax = 12 mmHg/t or
-- time t to increase of velocity from 0.5 to 2 m/ → dp/
dtmax = 15 mmHg/t
• norm: > 400 mmHg/s
Fig. 951  normal TAPSE

686 Pulmonology
Fig. 952  reduced TAPSE
TAPSE: best and simplest parameter
for assessing right ventricular function!
TASV
• tricuspidal annular systolic velocity
• syn.: S´ (systole)
• measurement with tissue doppler imaging (TDI)
• norm > 10 cm/s
Fig. 953  TASV: normal (17 cm/s)
Fig. 954  TASV: pathological (5 cm/s)
Fig. 955  TASV: pathological (7 cm/s)
Tei index
• combined systolic and diastolic parameters (evaluati-
on of isovolumetric contraction and relaxation time)
• syn.: RIMP (right ventricular index of myocardial per-
formance)
• Tei index = (ICT + IRT) / ET
-- ICT: isovolumetric contraction time
-- IRT: isovolumetric relaxation time
-- ET: ejection time
• parameters to be measured:
-- a: time span of CD path (= time between end and
start of transtricuspid inflow profile)
-- b: time of systolic transpulmonary outflow (ejection
time; ET)
• Tei index = (a - b) / b
• in contrast to measurement on the left heart here 2
settings necessary (cannot be mapped in one setting)
→ best tissue Doppler in tricuspid valve for Tei index
determination on the right heart (in this way only 1
measurement is necessary)
• norm:
-- < 0.40 (pw Doppler)
-- < 0.55 (tissue Doppler)
Pulmonology 687
Fig. 956  Determination of the right ventricular Tei-index:
In contrast to the determination of the left ventricular Tei- Fig. 957  Example for the determination of pulmonary va-
index, two derivatives are necessary here: in the first image scular resistance PVR by echocardiography: 1. derivation
trans-tricuspid inflow profile in the apical 4-chamber view, of the maximum systolic velocity vmax of tricuspid valve
in the second image derivative of the ejection time ET of the insufficiency (TRV) by means of cw-Doppler in the apical
transpulmonary outflow in the parasternal short axis. A Tei- 4-chamber view (here 3.18 m/s = 318 cm/s); 2. derivation of
index is calculated: (409ms - 295ms) / 295ms = 0.38 the pw-Doppler signal in the RVOT in the parasternal short
axis: The velocity time integral (VTI; here 17 cm) is obtai-
Echocardiographic determination of pul- ned by tracing the envelope curve of the spectrum with the
trackball. PVR = (vmax / VTI) / 10 + 0.16 = (318 cm/s / 17 cm) /
monary vascular resistance (PVR) 10 + 0.16 = 2.03 Wood = 162.4 dyn x sec x cm-5 (conversion:
• norm: 1 Wood = 80 dyn x sec x cm-5)
-- < 240 dyn x sec x cm-5 bzw.
-- < 3 Wood (1 Wood = 80 dyn x sec x cm-5)
• determination (2 options): :
-- PVR = 80 x (PAmean – PCWP) / CO
◦◦ PAmean: determination via the derivative of the en-
velope of the transtricuspid cw Doppler signal
◦◦ PCWP: determination via the derivative of the fil-
ling index E/E´
◦◦ CO (cardiac output): see chapter hemodynamics
(see page 233)
-- PVR = (vmax / VTIRVOT) / 10 + 0.16 (unit: Wood; 1
Wood = 80 dyn x sec x cm-5)
◦◦ vmax: maximum velocity of tricuspid valve insuf-
ficiency (cw Doppler) in cm/s (syn.: TRV: tricuspid
regurgitation peak velocity)
◦◦ VTIRVOT: velocity time integral in RVOT (pw Dopp-
ler; pulmonary valve) in cm

688 Pulmonology
 Guidelines (bronchial asthma)
OBSTRUCTIVE PULMONA- • international: GINA 2020 (Global Initiative for Asthma)
RY DISEASES • national (German): S2k guideline for diagnosis and
therapy of patients with asthma 2017 (German Socie-
ty for Pneumology and Respiratory Medicine, German
Respiratory League)

Symptoms
• dyspnea
• tachypnoea (respiratory rate > 20/min; if > 30/min: im-
pending exhaustion)
• cough (The asthmatic traditionally coughs himself into
his asthma attack!)
• use of respiratory auxiliary muscles
• congested jugular veins
• cyanosis
• expiratory wheezing (possibly distance wheezing;
cave: silent lung)
• restlessness, anxiety
• tachycardia (cave: bradycardia), decrease in blood
pressure (Endogenous catecholamines are no longer
effective due to [respiratory] acidosis.)
Status asthmaticus • disorientation (CO2 anesthesia)
• pulsus paradoxus
Definition
• severe asthma attack (including PEF [peak expiratory Diagnostics
flow; patient self-measurement] < 50% of the best va- • anamnesis, physical examination (i.a. expiratory
lue or < 100 l/min), persistent (refractory to the patient's wheezing in the auscultation)
medication) with respiratory insufficiency • chest x-ray
• mostly known bronchial asthma • laboratory
• especially children and adolescent (m > w) • BGA
• nowadays only rarely seen in adult medicine in the in- • possibly spirometry
tensive care unit
• common triggers: exposure to the allergen (in extrinsic
bronchial asthma; e.g. animal hair, pollen), infections,
Differential diagnoses
drugs (especially β-blockers [contraindicated in bron- • exacerbated COPD
chial asthma], ASA, NSAIDs, metamizol, cholinergics • Asthma cardiale (decompensated heart failure)
[e.g. neostigmine], distraneurin), inhalative irritants • pneumothorax
(e.g. cigarette smoke), incompliance, cold air, exertion • pulmonary embolism
(exercise-induced asthma) • anatomical obstruction:
-- tumor (lung cancer)
-- foreign body (e.g. in children [especially peanut; for
foreign body aspiration in children see page 293])
-- granuloma (e.g. Wegener´s disease [granulomato-
sis with polyangiitis])
• vocal cord dysfunction (VCD; see infobox): This harm-
less differential diagnosis should be known as an
emergency / intensive care physician in order to avoid
unnecessary escalation of therapy (including steroids)
in an allegedly therapy-refractory bronchial asthma,
including in an emergency completely unnecessary
intubation or even conio- / tracheotomy.
Fig. 958  The three pathomechanisms of bronchial obstruc-
tion (right; left normal bronchus) in bronchial asthma are:
bronchospasm (smooth muscles), mucosal edema due to
inflammation and hypersecretion of viscous mucus (dys-
crinia).

Pulmonology 689

Therapy
• oxygen administration (no false restraint! Patients with
obstructive pulmonary diseases are often adapted
to increased pCO2 values, so that hypercapnia is no
longer a respiratory drive, but only hypoxemia. If the
hypoxemia is remedied by the administration of oxy-
gen, there is always the fear that there will be no more
respiratory drive at all. Therefore, a cautious use of
oxygen was postulated earlier. However, a hypoxemic
patient should always achieve oxygen. Should the res-
piratory drive cease to exist with a consecutive further
increase in the pCO2, the patient must be ventilated.)
• position: seated
• mucolytics (ACC, ambroxol)
• fluid administration (e.g. Ringer's solution)
• β2-mimetics
• sedation
• prednisolone
• theophylline (obsolete)
• magnesium sulfate 2g i.v. over 20min
690 Pulmonology
-- acts relaxing to smooth muscles
-- Silvermann et al, Chest 2002: significant increase in
FEV1
-- possible in severe bronchial obstruction (e.g. life-
threatening status asthmaticus)
-- good option: also inhalative (e.g. nebulization 1g [1
vial] 4 times a day; advantage: lowers the already
increased heart rate!)
• ketamine
• antibiosis in case of infectious exacerbation
• possibly inhalation of heliox:
-- a mixed gas of helium and oxygen (80% helium +
20% oxygen)
-- lower physical density and therefore also lower flow
resistance than room air, so that the work of brea-
thing is reduced
-- In practical everyday life it is practically irrelevant as
it is usually not available anyway and no effectiven-
ess could be shown in the studies (i.a. Leatherman
et al, Respir Care 2017).
• if necessary intubation and mechanical ventilation
• annotations:
-- Inhaled steroids are the basic therapy for bronchial
asthma, but they are of no value in severe asthma
attacks / status asthmaticus.
-- no buffering of respiratory acidosis (e.g. with NaBic
8.4%); respiratory acidosis must be ventilated!
β2-mimetics
• inhalative
• parenteral
β2-mimetics:
cave hypokalemia!
Inhalative β2-mimetics
• salbutamol: 2-4 puffs (1 puff: 0.1mg)
• fenoterol (Berotec): 2-4 puffs (1 puff: 0.2mg)
• Vernebelung mit Berodual (Fenoterol + Ipratropium-
bromid) 1ml + 3ml NaCl 0,9% 4-6 x tägl.
• nebulization with Berodual (fenoterol + ipratropium
bromide) 1ml + 3ml NaCl 0.9% 4-6 times per day
• formoterol (long-acting [Oxis, Foradil]; allowed
• if possible via spacer / pariboy
• flow: min. 5 l/min
• often no longer effective
Tip for nebulization in acute obstruc-
tion: put 10 gtt of Berodual solution
into the nebulizer together with 1 vial
of magnesium (1g) + NaCl 0.9% 5gtt
Parenteral β2-mimetics Inhalation narcotics
• terbutaline (Bricanyl) • (halothane), isoflurane, deflurane, sevoflurane, enflu-
-- 1 amp. = 1ml = 0.5mg rane
-- 4 x ½-1 amp. s.c. • (low) bronchodilatory effect
• salbutamol (Salbulair) • disadvantages
-- 0.25-0.50 mg i.v. -- only very little effect
-- perfusor: 1 amp. = 5mg in 50ml NaCl 0.9% → infusi- -- very laborious and costly (e.g. device to bind / suck
on rate: 2-10ml/h off anesthetic gases necessary to protect the medi-
• fenoterol (Partusisten) i.v. (officially not approved) cal staff)
• reproterol (Bronchospasmin) • little significance in status asthmaticus (no significance
-- 1 amp. = 0.09 mg at all for COPD)
-- 1 amp. diluted with NaCl 0.9% to 10ml slowly i.v. • There are, however, special application systems (Ana-
ConDa [Anaesthetic Conserving Device], MIRUS),
-- perfusor: 5 amp. (0.45mg) + 45ml NaCl 0.9% → 0.01
with which application is relatively easy: The device is
mg/ml, infusion rate: 2-10 ml/h
attached to the end of the tube, serves as a miniature
-- contraindications: evaporator and storage medium for the anesthetic ga-
◦◦ acute myocardial infarction (cautious but also in ses; only possible, however, for intubated and invasi-
chronic CHD [30% of all COPD patients!]) vely ventilated patients, not possible for spontaneous
◦◦ tachycardic cardiac arrhythmias or non-invasive ventilation; see also page 179).
◦◦ severe hyperthyroidism
◦◦ HOCM
◦◦ pheochromocytoma
◦◦ Tako-Tsubo cardiomyopathy
◦◦ note: In pregnancy and lactation the administrati-
on of reproterol is possible.

Prednisolone (Solu-Decortin H)
• 100-250 mg i.v., then 4 x 50-100 mg daily (in status
asthmaticus significantly higher doses than with exa-
cerbated COPD!)
• latency until onset of action
• β-permissive effect
• duration: 5-7 days (no tapering required)
Sedation
• morphine 2.5-5mg repetitively s.c./i.v.
• possibly promethazine (Atosil) 25-50mg i.v.
• no benzodiazepines (due to muscle relaxant and respi-
ratory depressive effect)
Sedation of choice in status asthmati-
cus: morphine
Ketamine (Ketanest)
• dosage: 3 mg/kg
• perfusor: 30 mg/ml = 1500 mg/50ml → infusion rate:
2-10 ml/h
• in combination with midazolam or propofol
• side effects: i.a.
-- hypersalivation, hypersecretion
-- seizure threshold ↓
-- heart rate ↑­, myocardial oxygen consumption ­↑
-- pulmonary arterial pressure ­↑, pulmonal-vaskulärer
Widerstand ↑ (i.a. Strumpher et al, J Cardiothorac
Vasc Anesth 2011)
-- distorted pupils
Fig. 959  Inhalation narcotics [6]
Intubation and ventilation (status asthma-
ticus)
Indications
• therapy refractoriness
• muscular exhaustion (i.a. respiratory rate > 30/min)
• clouding of consciousness
• irregular respiration
• bradycardia
• severe hypoxemia (paO2 < 40 mmHg; Horovitz quoti-
ent paO2/FiO2 < 100mmHg)
• severe respiratory acidosis (pH < 7.20)
Types
• non-invasive ventilation: in the status asthmaticus (al-
most) not (or only significantly more difficult) possible
due to the mostly existing bronchial hypersecretion
(note: In one study, however [Gupta et al, Respir Care
2010], NIV was able to shorten both ICU and hospital
stays and to reduce the use of bronchodilators compa-
red to standard therapy for severe asthma.)
• invasive ventilation
Anesthesia
• induction of anesthesia
-- S-ketanest 1.5 mg/kg and midazolam (Dormicum)

Pulmonology 691
 5-10mg
-- cave decrease in blood pressure (lack of volume,
maximum stimulated endogenous catecholamines,
vasodilation by β2-mimetics) → fluid administration
and noradrenaline perfusor (alternatively "thin" nor-
adrenaline: 1 amp. a 1mg in 100ml NaCl 0.9%, of
which apply milliliter-wise; further alternative: Akrinor
[1 amp. = 2ml = 10mg theodrenalin + 200 cafedrin];
dose: 1-2ml i.v.; also i.m. application possible)
• maintenance of anesthesia: sufentanil + propofol (
ketanest rather reserved because is causes bronchial
hypersecretion and propofol is also bronchodilatory!)
• often muscle relaxation necessary, e.g. rocuronium
(Esmeron; antagonizable by sugammadex [Bridion])
• as large a tube as possible (airway resistance ↓, e.g.
8.5)

Ventilation
• pressure-controlled ventilation
• low respiratory frequency: 10-12/min
• extended expiration duration (I:E = 1:2/1:3)
• permissive hypercapnia (pH is decisive)
• very helpful: manual ventilation ("take by the hand"
[Kuhn system])
• for invasive ventilation in obstruction see especially
page 696
• if necessary extracorporeal decarboxylation (ECCO2-
R; good option! see page 700)
Fig. 960  Mediastinal emphysema (pneumomediastinum): a
rare complication of status asthmaticus (usually caused by
spontaneous rupture; remember if a patient suddenly de-
velops severe chest pain during status asthmaticus; then
a chest X-ray [typical line at the edge of the heart] should
be performed and exploration should be made for classical
skin emphysema in the area of the neck muscles [see first
picture; palpable crepitation!])
Prophylaxis
After the status asthmaticus has been overcome, the pa-
tients should be adjusted according to the guidelines for
their bronchial asthma (step therapy [see infobox])

692 Pulmonology
Exacerbated COPD
Definition
• syn.: AECOPD (acute exacerbation of chronic obstruc-
tive pulmonary disease)
• acute worsening that goes beyond the extent of the
usual daily fluctuations and necessitates a change in
therapy
• Anthonisen criteria:
-- increase in dyspnea
-- increase in sputum
◦◦ amount
◦◦ purulence
• In my opinion, a very important criterion (especially
to distingusih other differential diagnoses of dyspnea)
for the definition of the exacerbation is the expirato-
ry wheezing, which unfortunately is not taken into ac-
count in the official definitions.
• Obstruction leads to over-inflation and thus to flatte-
ning of the diaphragm (main respiratory muscle), which
reduces its contraction force due to the changed initial
position. This leads to hypercapnic lung failure. This is
the main problem in the acute exacerbation!
Degrees of severity (classifications)
• BODE score
• TORCH classification (TORCH: towards a resolution
in COPD health)
-- mild: worsening with need for intensified treatment
-- moderate: need for systemic steroids
-- severe: cecessity of hospitalization
• Stockley classification
-- type I: clear sputum
-- type II: putrid sputum
• GOLD classification (GOLD: Global Initiative for chro-
nic obstructive lung diseases)
-- old GOLD classification (only oriented towards lung
function)
-- new GOLD classification (since 2012; in addition to
lung function also oriented towards symptoms and
number of exacerbations [≥ 2/year])
BODE score
• B: BMI
• O: Obstruktion (FEV1)
• D: Dyspnea
• E: Exercise capacity (6-min walking test)

Guidelines (COPD) 0 1 2 3
• international: GOLD 2019 (Global Global Initiative for FEV1 (%) > 65 50-65 35-50 < 35
Chronic Obstructive Lung Disease)
6min walking
• national (German-Austrian): S2k guideline for the dia-
distance (m) > 350 240-350 150-250 < 150
gnosis and treatment of patients with chronic obstructi-
ve bronchitis and pulmonary emphysema 2018 dyspnoea
scale 0-1 2 3 4

Epidemiology BMI (kg/m ) > 21 < 21

2

• in Germany 8% of the population (widespread di- MMRC: modified MRC score (MRC: medical research
sease), 13% population over 40 years of age (every council; 0: no dyspnea, 1: dyspnea with heavy exertion,
8th!) 2: dyspnea with light exertion, 3: too short of breath to
• in Germany 6.8 million patients with COPD leave home; 4: short of breath even when putting on and
• incidence ­↑ taking off); according to Celli et al, N Engl J 2004
• m:w = 2:1
GOLD classification (old)
• cause of death No.5 (2030: No.3; the only one of the
ten most frequent fatal diseases whose prevalence is
I FEV1 > 80%
increasing!)
• 4% of all deaths in Germany II FEV1 50-80%
• increasing morbidity and mortality III FEV1 30-50%
IV FEV1 < 30% or FEV1 < 50% and: cor pulmonale, chro-
COPD as a systemic disease ("extrapul- nic respiratory insufficiency (pO2 < 60 mmHg; LTOT)
monary manifestations") entrance: FEV1/VC < 70%
• CHD (30%)
• left heart failure (30%)
GOLD classification (new)
• cor pulmonale (50% [COPD is the most common
• lung function (spirometry): FEV1 ≥ / < 50%
cause of cor pulmonale!])
• symptoms: CAT (COPD Assessment Test; 8 questions
• osteoporosis (physical inactivity, systemic steroid the-
[at www.catestonline.de])
rapy)
• number of exacerbations per year: < / ≥ 2
• muscular atrophy
• cachexia (BMI < 20 kg/m2 → very poor prognosis; "pink
puffer" significantly worse prognosis than "blue bloa-
ter")
• depression

Pulmonology 693
FEV1 < 50% C D ≥2

exacerbations / year
1
FEV1 ≥ 50% A B 0

CAT < 10 CAT ≥ 10

Fig. 961  new GOLD classification: It considers not only

lung function, but also symptoms and the number of annu-
al exacerbations.

Therapy recommendation
• group A:
-- short-acting anticholinergic or
-- short-acting β2-mimetic
• group B:
-- long-acting anticholinergic or
-- long-acting β2-mimetic
• group C: in addition to group B inhaled corticosteroid
• group D: in addition to group C roflumilast Causes
• infections (No.1) → infective exacerbation of COPD
Asthma COPD -- bacteria (memo: other germ spectrum than in com-
munity auqired pneumonia!):
ICS LAMA ◦◦ Haemophilus influenzae (No.1)
◦◦ Pneumococci
◦◦ Moraxella catarrhalis
◦◦ GOLD III/IV or C/D:
LABA LABA ▪▪ Pseudomonas aeruginosa
▪▪ Klebsiella pneumoniae
-- viruses (in 40-50%!): especially rhinoviruses (No.1)),
influenza viruses, adenoviruses, RS virus
LAMA ICS • inhaled noxae
• non-compliance (independent withdrawal of the
Fig. 962  the different (contrary) valency ​​of inhalants in the sprays)
two various obstructive pulmonary diseases: While ICS are • in 30% unknown
the basic therapy for asthma, they are only rarely indicated
for COPD (especially in frequent exacerbations). Converse-
ly, LAMAs are only rarely indicated in asthma. Only tiotro- Diagnostics
pium bromide (Spiriva) is permitted here as LAMA (LAMA: • anamnesis (i.a. dyspnea, sputum, number of exacer-
long acting muscarinergic antagonist, LABA: long acting bations / year), physical examination (i.a. expiratory
beta agonist, ICS: inhaled corticosteroids).
wheezing)
• chest X-ray
• laboratory, if necessary PCT (ProCOLD study: PCT <
0.1 ng/ ml → no antibiotics necessary)
• BGA
• lung function, possibly spirometry
• microbiological examination of sputum (only recom-
mended for > 3 exacerbations / year, suspected multi-
resistant germs, therapy failure or purulent sputum)

694 Pulmonology
 Fig. 964  HR-CT: severe pulmonary emphysema (panlobu-
lar) with COPD in a patient with α1-antitrypsin deficiency
(Laurell-Eriksson syndrome)

Differential diagnoses
• decompensated heart failure (heart failure in 30% of all
COPD patients)
-- anamnesis (orthopnea), physical examination (coar-
se crackles, asthma cardiale, leg edema, 3rd heart
tone)
-- echokardiography
-- thoracic sonography
◦◦ increased evidence of B-lines (running vertically;
"comet tail" artifacts, "flashlight" phenomena): car-
diac induced dyspnea (here also pleural effusion
Fig. 963  COPD and pulmonary emphysema: low standing,
flattened diaphragms, horizontal ribs, hyper-transparency [mostly on the right])
of the lung ◦◦ increased evidence of A-lines (A: "air"; running
horizontally; reverberations): pulmonary induced
dyspnea
-- laboratory; i.a. proBNP
◦◦ if increased: cardiac induced dyspnea
◦◦ if not increased: pulmonary induced dyspnea
-- chest X-ray (signs of pulmonary venous congestion:
These are often not visible in COPD patients due to
peripheral vascular reattachment!)
• pulmonary embolism
-- 25% of all patients admitted to hospital with "ex-
acerbated COPD" (Rizkallah et al, Chest 2007; ac-

Pulmonology 695
 cording to a meta-analysis [Aleva et al, Chest 2017;
see box] 16%).
-- Just because the patient is known to have COPD
(e.g. from previous documents) and he now suffers
from dyspnea again, the diagnosis of exacerbated
COPD must not be made automatically. An expirato-
ry wheezing must be present in auscultation! A pul-
monary embolism, on the other hand, never causes
an expiratory wheezing!
-- BGA
◦◦ exacerbated COPD: pCO2 ↑
◦◦ pulmonary embolism: Here, pCO2 can be both de-
creased (due to hyperventilation) and increased
(increased dead space ventilation with reduced
effective ventilation).
• pneumonia
-- COPD is the most common co-morbidity in commu-
nity acquired pneumonia.
-- DD to infective exacerbation of COPD: Fig. 965  infective exacerbation of COPD with right-sided
pneumonia
◦◦ clinical: sudden deterioration of performance sta-
tus, fever, chills, pleuritic complaints
◦◦ laboratory: significantly elevated CRP, PCT ↑
◦◦ radiological (easiest: An infiltrate [consolidation]
can be seen in pneumonia.)
• pneumothorax
-- There is no one-sided "silent lung"!
-- cave: Do not confuse large bullous emphysema in
pulmonary emphysema with a pneumothorax (in
case of doubt perform native chest CT)!
• anatomical obstruction:
-- tumor (lung cancer)
-- foreign bodies (e.g. in elderly patients tooth or tooth
crown [for bronchoscopy image see page 1081])
-- granuloma (e.g. Wegener´s disease [granulomato-
sis with polyangiitis])
• panic disorder (often additional depression in COPD
patients)

meta-analysis

Prevalence and Localization of Pulmonary Embolism in

Unexplained Acute Exacerbations of COPD 
Aleva et al, Chest 2017

• 880 patients with exacerbated COPD of unknown cause

• in 16% pulmonary embolism in the chest CT (in eve-
ry 6th patient!)
• note: It is only unclear how the exacerbation was defined
in this meta-analysis, i.e. only as an increase in dyspnea
in a patient with known COPD or additionally with an
expiratory wheezing in the auscultation.

Fig. 966  Large bullous emphysema (as here [different ex-

amples]) can easily be confused with a pneumothorax. In
case of doubt, a chest CT (native sufficient) should be per-
formed before stitching.

696 Pulmonology

Fig. 967  In the chest CT (native sufficient) one can see that
it is only a large bullae and not a pneumothorax.
Fig. 968  A bronchoscopy should always be performed in
patients with "therapy-resistant" obstruction: Here, a ste-
nosing lung carcinoma was found to be the cause of the
obstruction.
Especially in the case of "therapy-re-
sistant" obstruction, bronchoscopy
should be performed to exclude an
anatomical obstruction (lung carci-
noma, foreign body)!
Therapy
• pharmacological therapy
• non-pharmacological therapy
Pharmacological therapy
• oxygen administration
-- target: SpO2: 88-92% (i.a. Austin et al, BMJ 2010)
-- after 20min perform BGA to detect CO2 retention
(Before the patient e.g. leaves the emergency de-
partment and comes to the normal ward, a new BGA
must be performed to exclude CO2 retention!)
• anti-obstructive therapy (inhalatives; as in status asth-
maticus)
• mucolysis
-- ACC 600mg 1-1-1
◦◦ effectiveness controversial
◦◦ In bronchoscopy for mucus aspiration, ACC can
also be given endobronchially via the working
channel!
◦◦ In the PANTHEON study (Zheng et al, COPD
2013) the exacerbation rate in patients with mode-
rate and severe COPD could be reduced by high-
dose administration of ACC (2 x 600mg) daily over
one year.
-- ambroxol 15mg i.v. 1-1-1 (advantage: fewer interac-
tions with drugs other than ACC; max. dose: 30mg
i.v. 1-1-1)
• Steroide (systemisch)
• steroids (systemic)
• β-blocker:
-- β-Blockers are only contraindicated in bronchial
asthma, not in COPD.
-- Even during exacerbation of COPD, β- blocker
should not be discontinued (reduction of cardiovas-
cular events)!
• nutrition: If patients are artificially nourished (e.g. be-
cause they are mechanically ventilated), one should
make sure that the carbohydrate intake is reduced and
the fat intake increased. The reason for this is that the
metabolism of carbohydrates (respiratory quotient RQ
1.0) produces significantly more CO2 than fats (respi-
ratory quotient RQ only 0.7). The fat content should be
increased from normally only 30-35% to approx. 50%.
This can be achieved for example with energy tube
feeding preparations (1.5 kcal/ml): Here the carbohyd-
rate content is reduced and the fat content increased.
Inhalatives (sprays)
Types
• β2-mimetics
-- short-acting: fenoterol (Berotec)
-- long-acting (LABA: long acting beta agonist)
◦◦ salmeterol (Serevent)
◦◦ formoterol (Oxis 12 μg 1-0-1, Foradil P 1-0-1)
◦◦ indacaterol (Onbrez Breezhaler) 150 μg 1 x daily
(new; an ultra-long acting bronchodilator [effective
for 24 hours; Donohue et al, Crit Care Med 2010],
rapid onset of action)
◦◦ vilanterol 25 μg 1 x daily ((new; an ultra-long ac-
ting bronchodilator [effective for 24 hours]; appro-
ved since 2013 as a fixed combination with flutica-
sone [Relvar] and since 2014 with umeclidinium
[Ellipta])
• anticholinergics
-- short-acting: ipratropium bromide (Atrovent) 250μg
2-2-2-2
-- long-acting (LAMA: long acting muscarinic antago-
nist)
◦◦ tiotropium bromide (Spiriva) 18 μg 1 x daily; note:
In a meta-analysis (Singh et al, BMJ 2011) there
was evidence for an increased rate of cardiovas-
Pulmonology 697
 cular events, some of which were fatal, especially
in a special dosage form (SMI [soft mist inhaler;
Respimat]). However, this could not be confirmed
in the large TIOSPIR study (Wiese et al, N Engl J
2013).
◦◦ aclidinium bromide (Bretaris) 322μg 2 x daily
◦◦ glycopyrronium bromide (Seebri) 44 μg 1 x daily
◦◦ umeclidinium (Incruse): 55 μg 1 x daily (approved
since 2014 as a fixed combination with vilanterol
[Ellipta])
• inhaled cotricosteroids (for prophylaxis only, not for Fig. 970  ultrasonic nebulizer [11, 24]
therapy with exacerbated COPD)

Application
• dry powder inhalation (not for exacerbation)
• nebulization (also via respirator)
• metered dose aerosol (also via respirator)

Nebulization
• types
-- jet nebulizer (out)
-- ultrasonic nebulizer (standard)
-- oscillation nebulizer (new)
• example: Berodual solution 10gtt + 5ml NaCl 0.9%
4-6x daily

Fig. 971  Ultrasonic nebulizer (changed every 7 days)

Metered dose aerosol

• significantly more effective than nebulization
• always via spacer (dead space)
• examples
-- β2-mimetic
◦◦ formoterol 2 puffs every 12h
◦◦ salbutamol 4 puffs every 4h
◦◦ fenoterol 4 puffs every 4h
-- anticholinergic (ipratropium bromide 4 puffs every
6h)
-- fenoterol/ ipratropium bromide (Berodual) 100/20
μg 4 puffs every 6h

Practical tips (for inhalation)

• During ventilation usually an active humidification is
performed, as passive humidification (HME filter) in-
creases the dead space ventilation, which reduces
the effective ventilation, so that the pCO2 increases.
During the inhalation, however, the active humidifica-
tion should be switched off, otherwise the dose will be
reduced by 50%!
• long inspiration (e.g. change I:E ratio at the ventilator
from 1:3 to 1:1 or 2:1 for a short period of time)
• NIV: if possible pause briefly for inhalation (is most ef-
Fig. 969  nebulizer mask (an oxygen mask with a nebulizer fective under spontaneous breathing)
pot): a good option for non-ventilated patients

698 Pulmonology
Theophylline (Euphylong, Bronchoparat)
• a non-selective phosphodiesterase inhibitor
• 200 mg as loading-dose in 15min as short infusion (in
glucose 5%), then 0.5 mg/kg/h over 24h (e.g. 600mg
in 24h)
• perfusor:
-- 4 amp. a 200mg a 10ml + 10ml NaCl 0.9% → 16
mg/ml or
-- pure (4 amp. = 40ml without 10ml NaCl 0.9%): 1ml
= 12 mg → 2 ml/h
• up to max. 15 mg/kg per day; max. 800mg per day (if
not yet pretreated)
• no bolus application, only as (short) infusion
• cave combination with fluoroquinolones (gyrase inhibi-
tor) → therapy-resistant VT
• increase in theophylline level by:
-- verapamil (by 20%)
-- macrolides (by 30%)
-- allopurinol
-- propranolol (by 10%)
• no longer recommended (i.a. Duffy et al, Thorax
2005: theophylline compared to placebo no improve-
ment in FEV1, but significantly more side effects)
• However, if the patient had theophylline in the preme-
dication, it should be continued in the hospital during
the exacerbation to avoid withdrawal.
Theophylline is no bronchodilator (no
longer recommended)!
Roflumilast (Daxas)
• a selective phosphodiesterase 4 inhibitor
• dosage: 500 μg 1 x daily p.o.
• effects:
-- bronchodilatory
-- antiinflammatory
• side effects (Due to the numerous side effects the drug
is often not tolerated!):
-- nausea, vomiting
-- diarrhea
-- abdominal pain
-- headache
-- weight loss (cave therefore especially in cachectic
COPD patients)
-- insomnia
-- increased suicide risk (therefore contraindicated in
depression)
• officially approved since 2010
• indication: exacerbation prophylaxis (from GOLD III
or group D)
study
Roflumilast - an oral anti-inflammatory treatment for chro­
nic obstructive pulmonary disease
Rabe et al, Lancet 2005
• double-blind prospective randomized multicenter study
(phase III)
• 1411 patients with COPD
-- roflumilast 250 / 500μg p.o. 1 x daily for 24 weeks
-- placebo
• results: roflumilast
-- significant increase in FEV1
-- significant reduction in exacerbations
REACT study
Effect of roflumilast on exacerbations in patients with se-
vere obstructive pulmonary disease uncontrolled by com-
bination therapy - a multicentre randomised controlled trial
Martinez et al, Lancet 2015
• double-blind prospective randomized multicenter study
• 1945 patients with severe COPD and already existing
combination therapy of a long-acting β2-mimetic and an
inhalative corticosteroid; additional:
-- roflumilast 500μg p.o. 1 x daily
-- placebo
• results: roflumilast
-- significant reduction of exacerbations (by 23%)
-- significant reduction of hospitalizations
Steroids
• prednisolone (Decortin H) 40mg once in the morning
(sufficient; in the case of p.o. administration, no divi-
sion is necessary due to the half-life, e.g. 20-20-0mg
[only necessary for i.v. administration]); in contrast to
status asthmaticus here low doses sufficient
• p.o. just as effective as i.v. (De Jong, ERJ 2004)
• The high dosed i.v. compared to low-dose p.o. admi-
nistration shows no advantages on the one hand, and
even an increased rate of therapy failure on the other
hand (pharmaco-epidemiological cohort study by Lin-
denauer et al, JAMA 2010).
• duration: Previously, steroids were recommended
systemically for at least 10 days to a maximum of 14
days. In the REDUCE study (see box), however, sys-
temic steroid therapy over only 5 days was shown to
be equivalent to therapy over 14 days. In the GOLD
guideline 2017 there is accordingly the recommenda-
tion for 5 to a maximum of 7 days. The standard today
is the administration of 40 mg prednisolone once a day
Pulmonology 699
 for a total of 5 days.
• no gradual dose reduction (no tapering): no increased
risk of adrenocortical insufficiency with abrupt discon-
tinuation!
• no systemic long-term therapy (mainly due to side ef-
fects such as muscular atrophy and osteoporosis)
REDUCE study
Short-term vs Conventional Glucocorticoid Therapy in
Acute Exacerbations of Chronic Obstructive Pulmonary
Disease - The REDUCE Randomized Clinical Trial
Leuppi et al, JAMA 2013
• multicenter randomized controlled study (Switzerland)
• REDUCE: Reduction in the Use of Corticosteroids in Ex-
acerbated COPD
• 311 patients with exacerbated COPD + systemic steroid
therapy (prednisolone 40mg daily)
-- 14 days
-- only 5 days
• results: non-inferiority
-- no difference in re-exacerbation rate (after 6 months
-- no difference in mortality
-- no difference in lung function (spirometry)
study
Prednisone in COPD exacerbation requiring ventilatory
support: an open-label randomised evaluation
Abroug et al, Eur Resp J 2013
• 217 patients with exacerbated COPD requiring ventila-
tion
-- with systemic steroid therapy (prednisolone 1 mg/kg
p.o. daily over 10d)
-- without systemic steroid therapy
• results: systemic steroid therapy
-- no difference in ICU mortality
-- no difference in duration of ventilation and duration of
ICU stay
-- increased rate of hyperglycemia
700 Pulmonology
study
Outcomes associated with corticosteroid dosage in critical-
ly ill patients with acute exacerbations of chronic obstruc-
tive pulmonary disease
Kiser et al, Am J Resp Care 2014
• retrospective cohort study
• 17239 intensive care patients with exacerbated COPD
-- 1/3: low-dose steroids (methylprednisolone < 240
mg/d)
-- 2/3: high-dose steroids (methylprednisolone > 240
mg/d)
• results: high-dose steroids
-- significantly longer duration of ventilation
-- significantly longer ICU and hospital stay
-- significantly more fungal infections
-- significantly more frequent insulin therapy
-- significantly higher costs
-- no mortality benefit
no high-dose steroids for exacerba-
ted COPD (in contrast to exacerbated
bronchial asthma)!
Antibiotics
Indications
• fulfilled Anthonisen criteria
• Stockley type II (purulent sputum; high predictive va-
lue [95%] for the presence of bacteria in the sputum
[Stockley et al, Chest 2000])
• exacerbation with respiratory insufficiency
• ventilated patients (non-invasive / invasive; note: How-
ever, if CRP is normal on two consecutive days, we
discontinue antibiotics despite NIV.)
• exacerbations with a tendency to relapse (> 4/year)
• exacerbations with relevant cardiac comorbidity
• elevated procalcitonin levels
• annotaions:
-- CRP is often elevated in COPD patients without in-
fection (systemic inflammation).
-- In contrast to pneumonia, patients with infective ex-
acerbation of COPD are not primarily threatened by
sepsis, but by ventilation failure.
Substances
• amoxicillin / clavulanic acid (Augmentan) 2.2g 1-1-1
i.v.
• fluorchinolones
-- moxifloxacin (Avalox) 400mg 1 x daily (gap in effec-
tiveness: pseudomonas)
-- levofloxacin (Tavanic) 500mg 2 x daily (also effective
against pseudomonas! cave red hand letter [warning
 of risks] in Germany 2012: QT interval prolongation
→ prior to administration an ECG with determination
of QT interval obligatory!)
• higher GOLD stages (from GOLD III also cover pseu-
domonas!):
-- levofloxacin (Tavanic)
-- piperacillin + tazobactam
-- carbapenems (imipenem, meropenem)
-- cefepim (Maxipime)
• annotations:
-- Completely contrary to community acquired pneu-
monia no combination therapy is recommended in
AECOPD! The germ spectrum is completely diffe-
rent here. The atypical germs do not have to be co-
vered here.
-- In the case of recurrent exacerbations of infections
one should not always use the same antibiotic, but
change to another class ("cycling").
Risk factors
for pseudomonas
Ventilation
• non-invasive ventilation (can prevent intubation in
80%) → chapter NIV; very effective (Ram et al, Cochra-
ne Database Syst Rev 2004):
-- avoidance of intubation: NNT 5
-- avoidance of death: NNT 8
• invasive ventilation (mortality 30%)
Invasive Ventilation (in case of obstruc-
tion)
• pressure-controlled (peak pressure < 35 cmH2O)
• PEEP
-- In earlier textbooks it was often stated that in asthma
or COPD you may not adjust PEEP. This is comple-
tely obsolete today!
-- In the case of obstruction (especially with COPD),
positive end expiratory pressure (PEEP) is abso-
lutely essential, as it leads to end expiratory splin-
ting, especially of the small respiratory tracts, and
thus makes it possible for the air to be completely
exhaled and no over-inflation to occur. PEEP fulfils
here exactly the function of pursed-lip breathing!
-- Mostly low PEEP is sufficient (best measure intrinsic
PEEP, then set 80% of the measured intrinsic PEEP
as PEEP on the ventilator) .
• ATC (automatic tube compensation [see also page
116]; auf 100% set to 100%): As soon as the patient
breathes spontaneously through the tube (e.g. CPAP-
ASB in weaning), the ATC should be switched on. In
case of an obstruction, however, the tube compensa-
tion should be limited to the inspiration. The expiratory
tube compensation should be switched off, since the
desired effect of "pursed-lip breathing" would be can-
celled by lowering the PEEP during expiration (how
to switch off the expiratory ATC on the EVITA XL, see
page 117).
• low respiratory rate (e.g. respiratory rate 10-12/min;
high respiratory rate → overinflation!)
• tidal volumes: 8-10 ml/kg bw (Aufgrund der niedrigen
Atemfrequenz muß zum Erreichen eines für die Venti-
lation und damit CO2-Entfernung ausreichenden Atem-
minutenvolumens das Atemzugvolumen erhöht wer-
den. In COPD (especially in the acute exacerbation),
it is not the lung itself that is affected, but the muscles
[especially the diaphragm], so that low tidal volumes of
6 ml/kg are not necessary by all means, as is the case
with ARDS. Therefore, ventilation is performed with
higher pressure differences. The risk for pneumotho-
rax is increased here (especially in pulmonary emphy-
sema with bullae). However, if ARDS is also present,
lung protection should be provided with a tidal volume
of 6 ml/kg and extracorporeal decarboxylation should
be carried out.)
• I:E 1:3 (long expiration time: The disturbance lies
in the expiration! A healthy person needs about 1 se-
cond for the expiration, here 2-3 seconds are usually
necessary.)
• short pressure rise time (i.e. set steep ramp: 0.1s):
This increases the inspiratory tidal volume. The shorter
the pressure rise time, the less the work of breathing.
Therefore, one should above all set a short pressure
rise time in weaning and under NIV.
• possibly decompression manoeuver: An extremely
long expiration time is set (under sufficient sedation)
for some cycles. If the tidal volume increases, it was
successful.
• possibly manual decompression after disconnection
from the tube: The patient is briefly disconnected from
the tube and then the lung is manually decompressed.
• Trigger (if the patient is spontaneously breathing du-
ring weaning [CPAP-ASB] or under NIV):
-- inspiratory trigger: set low (0.25-0.5 l/min; note: The
patient's respiratory muscles are usually too weak
for higher triggers, the attempts are not triggered
(flow-ineffective breath work; "missed efforts".)
-- expiratory trigger ("cycling off"; inspiratory terminati-
on): changing the expiration trigger (see page 106)
on the ventilator from 25% to 60% to shorten the ins-
piration period; Normally it is set to 25%, i.e. the ven-
tilator does not stop inspiration until the inspiration
flow has fallen below 25% of the maximum flow. In
the case of obstruction, this takes a very long time,
which increases the overall inspiration time, and you
don't want that (The goal is a long expiration time!).
Therefore, the "cycling off" should be set to 60% in
the case of an obstruction, i.e. the ventilator switches
from inspiration to expiration as soon as the flow falls
Pulmonology 701
 below 60% of the maximum flow. The setting of the
expiration trigger (as well as the inspiration trigger)
only makes sense for procedures of pressure-sup-
ported spontaneous breathing (e.g. CPAP-ASB).
• optional:
-- NAVA (see page 115)
-- extracorporeal decarboxylation
• In the weaning of COPD patients, one should ge-
nerously use energy-rich tube feeding preparations
(1.5 kcal/ml) for enteral nutrition. Here the carbohyd-
rate content is reduced and the fat content increased.
The reduced carbohydrate content reduces the work
of breathing.
the patient must first reduce the intrinsic PEEP before
there is a pressure drop in the alveoli and thus trig-
gering by the ventilator. The instrinsic-PEEP increases
the inspiratory trigger work. This leads to a massively
increased work of breathing due to the non-flow-effec-
tive attempts (to be recognized as "missed efforts" [=
untriggered inspiration efforts] at the flow curve). Dem
kann ein entsprechend hoch am Beatmungsgerät ap-
plizierter extrinsischer PEEP entgegenwirken.
end of expiration

Intrinsic-PEEP (iPEEP)
• syn.: auto-PEEP
• cause: dynamic overinflation (syn.: hyperinflation, "air bronchial system
trapping", volumen pulmonum auctum)
• The resting breathing position becomes higher and the alveolus
inspiratory load increases.
Fig. 972  Intrinsic PEEP: Not all the air can be exhaled, air
• Overinflation causes compression of the adjacent ca- remains trapped in the alveoli ("trapped air"), resulting in
pillaries: This increases the dead space (areas that are dynamic overinflation. The pressure that is created thereby
still ventilated but no longer perfused) and the redu- in the alveoli is called intrinsic PEEP (syn.: auto-PEEP).
ced alveolar ventilation leads to an increase in pCO2
(hypercapnia). Intrinsic PEEP is harmful and should
inspiration
therefore be reduced.
• reduction of the iPEEP by extending the expiration time
-- I:E 1:3
-- reduction of the respiration rate to 10-12/min (no
flow

"down-ventilating" of an increased pCO2 by increa- time

sing the respiration rate!)
trapped air
-- possible decompression manoeuvers: An extremely
long expiration time is set (under sufficient sedation) expiration
for some cycles. If the tidal volume increases, it was
successful. Fig. 973  Intrinsic PEEP: This shows that the air cannot be
• measurement of the intrinsic PEEP fully exhaled (air-trapping). If now in the BGA the pCO2 va-
lue is increased, very often the mistake is made that one
-- end-expiratory closure maneuver: By closing the
increases the respiratory rate at the ventilator in order to
expiration cycle for 10-30s at the end of the expi- "down-ventilate" the pCO2: However, this is exactly contra-
ration (e.g. Evita: expiration hold) there is pressure indicated in this case. Here you have to increase the expira-
equalization between the alveolar space and the ex- tion time and decrease the respiration rate!
piration hose. Then the intrinsic PEEP is measured
automatically. After opening the expiration valve, the
trapped air is released in an extended expiration and
measured.
-- One should then set 80% or 2/3 of the measured
intrinsic PEEP as PEEP on the ventilator. This ap-
plies to both controlled (mandatory) ventilation and
supported spontaneous breathing (CPAP-ASB). The
PEEP that is set on the ventilator is also called ext-
rinsic PEEP.
-- For a reliable measurement the patient should be
deeply analgosedated or sometimes even relaxed,
so that he does not change independently again to Fig. 974  Air-trapping: typical remaining stage at the end of
expiration (The expiratory flow does not return to baseline.)
the inspiration!
-- only measurable with invasive, not with non-invasive
ventilation (NIV)
• The flow curve should always be observed on the ven-
tilator: The flow should be zero at the end of the expi-
ratory cycle in order to avoid overinflation.
• With assisted spontaneous breathing (CPAP-ASB),

702 Pulmonology
 measurement inspiration
of the trapped

flow (l/min)
intrinsic volume
PEEP due to
trapped air extrinsic
PEEP
extension of
interruption of expiration
0
expiration
time (s)
Fig. 975  Measurement of the intrinsic PEEP on the venti-
lator: At the end of expiration, the valve is closed and the
breathing cycle interrupted ("expiration hold").

expiration
inspiration

flow (l/min)

0
time (s)

Fig. 976  The intrinsic PEEP (PEEPi) can be measured on

the EVITA XL under "Special Functions" - "Diagnostic
Functions".

expiration
Fig. 978  Significance of PEEP (set at the ventilator [extrin-
sic PEEP]) in obstruction (various flow curves): In the first
picture, shortly after the onset of expiration, the respiratory
compression of the
capillaries
tract collapses (e.g. COPD with severe pulmonary emphy-
over-
alveolus
capillaries
infaltion sema) followed by a very flat curve: Despite the very long
expiration time, complete expiration is not possible and
capillaries
over-
overinflation occurs. This leads to capillary compression
alveolus infaltion
with the result that the dead space ventilation increases
low standing diaphragma and the alveolar (= effective) ventilation decreases conse-
cutively, so that pCO2 increases. Here the set PEEP is too
low. In the second picture the PEEP at the ventilator was in-
normal lung overinflation creased: The area under the curve (yellow) is clearly larger.
Fig. 977  Overinflation of the alveoli (due to the high intrin- Due to the splinting of the unstable bronchial tubes (effect
sic PEEP due to air-trapping) results in compression of the of pursed-lip breathing), there is no more collapse of the
lung capillaries, resulting in dead space: The alveolus is respiratory tract, so that considerably more and above all
still ventilated, but no longer perfused. The increase of the complete expiration is possible. There is no overinflation,
dead space increases the dead space ventilation, whereby dead space ventilation decreases, the alveolar (effective)
the effective ventilation decreases. Due to the decrease in ventilation increases and pCO2 decreases.
effective ventilation, the pCO2 increases.

Pulmonology 703
 Fig. 981  "missed efforts" during NIV with CPAP-ASB

Fig. 979  Severe emphysema: shortly after the start of expi-

ration, the airways collapse. The PEEP is set too low here
and must be increased.
inspiration
flow (l/min)

0
time (s)

expiration
inspiration
flow (l/min)

0
time (s)

expiration
Fig. 980  "missed efforts" under spontaneous breathing
(e.g. under NIV with CPAP-ASB) in case of obstruction: The
inspiration efforts (black) are all below the intrinsic PEEP, Fig. 982  Changing the "cycling off" (expiratory trigger, in-
so that they are not answered by the ventilator with a me- spiratory termination) from 20% to 60%: This allows the ex-
chanical breath (no triggering, flow ineffective work of brea- piration time to be extended even further.
thing). Only the last inspiratory effort has a sufficient flow
so that the trigger threshold is exceeded and a mechanical
breath is delivered. Here the inspiratory trigger (flow trig-
ger) is set too high (1-2l/min): Patients with an exacerbated
COPD are often so exhausted that they no longer even have
the strength to apply this flow to trigger a mandatory me-
chanical breath. The inspiration trigger must be set lower
here (0.25-0.5 l/min).

704 Pulmonology

Extracorporeal decarboxylation (ECCO2-R)
Types
• without pump (pumpless; av-ECCO2-R [arterio-venous
extracorporeal carbon dioxide removal]): pECLA (iLA;
i.a. Kluge et al, Intensive Care Med 2013: iLA in NIV
failure → 90% intubation avoided, but no effect on mor-
tality [see infobox])
• with pump (pump driven; vv-ECCO2-R [veno-venous
extracorporeal carbon dioxide removal])
-- PALP (pump assisted lung protection; Maquet)
-- Hemolung (Alung)
-- Decap (Hemodec): a hemofiltration device in whose
circuit a membrane for gas exchange is built in (only
a Shaldon catheter needs to be installed; very low
flow ECMO; i.a. Forster et al, Crit Care 2013; mean-
while no longer on the market)
-- ila activve (Novalung)
-- Prismalung (Gambro)
◦◦ membrane, which is built into the circuit of a con-
ventional CVVH machine (Prismaflex; only a Shal-
don catheter needs to be installed)
◦◦ also possible without additional hemofilter
◦◦ mode: CVVHF
◦◦ anticoagulation with heparin (citrate anticoagulati-
on not possible
◦◦ maximum flow: 500 ml/min (note: Blood flow rates
in renal replacement procedures are usually indi-
cated in ml/h and not in ml/min.)
◦◦ CO2 elimination possible by 17%
-- vv-ECMO (low-flow, i.e. only with a blood flow from
0.8-2.0 l/min instead of the otherwise usual blood
flow from 3.0-4.5 l/min)
Fig. 983  Prismalung: The membrane is built into the circuit
of a conventional CVVH and enables (moderate) CO2 elimi-
nation.
Fig. 984  extracorporeal CO2 elimination with a pump-driven
procedure (vv-ECCO2-R [veno-venous extracorporeal car-
bon dioxide removal) in a patient with spontaneous brea-
thing. Intubation could be avoided in this way (according to
the motto "cannula instead of tube").
Assessment
• No prospective randomized trials on this subject have
been conducted to date, so this is still considered ex-
perimental.
• currently ongoing studies: VENT-AVOID, CORAIL,
ORION, Cologne-X-COPD
• meta-analyses (Fitzgerald et al, Crit Care 2014; Sklar
et al, Intensive Care Med 2015): significant reduction
in paCO2, but no reduction in mortality
Pulmonology 705
• either in addition to mechanical ventilation or even wit-
hout mechanical ventilation in spontaneous breathing:
In some centers, patients with severe hypercapnia
and respiratory acidosis are no longer intubated at all,
but only treated while breathing spontaneously with
an extracorporeal procedure (according to the motto:
"cannula instead of tube")! If one considers how long
intubated patients with exacerbated COPD are ulti-
mately attached to the ventilator, one must certainly
ask oneself in the future whether patients with NIV
failure should not be treated with an extracorporeal
procedure instead of intubation, especially in view of
the extremely increasing number of COPD patients
(almost an epidemic). vvECMO procedures are best
suited for this purpose: These procedures are now
only slightly invasive. Finally, a large lumen venous
access (double lumen cannula) is needed, so that this
is not much more invasive than a Shaldon catheter for
CVVH. Pumpless systems (e.g. pECLA) are often con-
traindicated in COPD patients, who usually also have
PAD and heart failure (in 30%). In addition, pumpless
systems require arterial cannulation, which significant-
ly hinders the patient's mobilization. In addition, pump-
less systems require arterial cannulation, which signifi-
cantly hinders the patient's mobilization. Furthermore,
CO2 elimination via a vv-ECMO (veno-venous) is much
more effective than via pECLA procedure (arterio-ve-
nous), since the CO2 content of the venous system is
higher than that of the arterial system.
• To preceed in case of NIV failure according to mot-
to "cannula instead of tube" certainly requires a lot of
experience and, due to the time-critical situation, only
makes sense if the corresponding extracorporeal sys-
tem is already on site and is not delivered "on de-
mand" so that the extracorporeal decarboxylation in
nIV failure is actually only rarely used. It is used much
more often in patients who are already intubated and
invasively ventilated if, despite optimization of the ven-
tilation, sufficient decarboxylation does not succeed.
study
Avoiding invasive mechanical ventilation by extracorporeal
carbon dioxide removal in patients failing noninvasive ven-
tilation
Kluge et al, Intensive Care Med 2012
• multicenter retrospective study
• 42 patients with an acute exacerbation of COPD and
NIV failure
-- intubation
-- extracorporeal procedure (without pump [pumpless]:
av-ECCO2-R [pECLA, iLA])
• results: av-ECCO2-R
-- In 90% intubation could be avoided.
-- significantly better values in the BGA (pCO2, pH)
-- no difference in mortality
706 Pulmonology
study
Extracorporeal CO2 removal in hypercapnic patients at risk
of noninvasive ventilation failure: a matched cohort study
with historical control
Del Sorbo et al, Crit Care Med 2015
• cohort study with historical control group
• 25 patients with acute hypercapnic lung failure and NIV
-- without extracorporeal CO2 removal
-- with extracorporeal CO2 removal
• results: The additional extracorporeal CO2 removal led
to a significant reduction in intubation rate and hospital
mortality.
ECLAIR study
The feasibility and safety of extracorporeal carbon dioxide
removal to avoid intubation in patients with COPD unre-
sponsive to noninvasive ventilation for acute hypercapnic
respiratory failure
Braune et al, Intensive Care Med 2016
• multicenter case-control study
• 50 patients with an acute exacerbation of COPD and
NIV failure
-- intubation
-- extracorporeal procedure (with pump [pump driven]:
vv-ECCO2-R [iLA-activve])
• results: vv-ECCO2-R
-- In 56% intubation could be avoided.
-- significantly better values in the BGA (pCO2, pH)
-- no difference in mortality
Non-pharmacological therapy
• physiotherapy (z.B. VRP1 flutter, RC-Cornet, Acapella
choice, PEP mask)
• initiation of long-term oxygen therapy (LTOT); indica-
tion (guidelines for oxygen therapy of the German So-
ciety for Pneumology and Respiratory Medicine):
-- paO2 < 55 mmHg under rest conditions in stable di-
sease phase, i.e. in the exacerbation-free interval
-- in case of additional cor pulmonale or polyglobulia
(p.d. hemoglobin > 17 g/dl in men or > 16 g/dl in
women) paO2 < 60 mmHg
-- arterial BGA necessary (alternatively also capillary
BGA, i.e. from hyperaemized [arterialized] earlobe,
possible)
-- Determining saturation by means of pulse oximetry
alone is not sufficient.
-- The paO2 must increase to > 60 mmHg when oxygen
is administered.
 -- for at least 16h per day (especially at night)
-- A continued nicotine abuse is a clear contraindica-
tion (beware of the risk of explosion).
• schooling
• rehabilitation (great benefit! [ NNT only 4]; i.a. me-
ta-analysis Puhan et al, Cochrane Database Syst Rev
2016; preferably immediately after the exacerbation)
• adjuvant therapy (possibly antidepressants, therapy
for osteoporosis)
• physical activity (training therapy)
-- as effective as pharmacological therapy
-- recommended for all degrees of severity
-- possibly participation in lung sports groups
• surgical therapy
-- lung volume reduction (LVR)
-- lung transplantation (LTX)
• intermittent self ventilation (ISV)
• implantation of a peripheral AV fistula
on): bronchoscopic placement of one-way valves (e.g.
VENT study)
-- Zephyr (Pulmonx)
-- Spiration (Olympus)
• non-blocking techniques (independent of collateral
ventilation):
-- implantation of coils (e.g. PneumRx; 2 studies [see
box])
-- polymeric lung volume reduction (PLVR; Aeris The-
rapeutics): injection of a hydrogel foam (AeriSeal)
into the over-inflated areas (The inflammatory stimu-
lus initiated by this leads to a shrinkage of the lung
tissue.)
-- bronchoscopic thermal vapor ablation (BTVA; Up-
take Medical): application of hot water vapor (125°C)
to the over-inflated areas (The inflammatory stimulus
initiated by this leads to shrinkage of the lung tissue.)

Fig. 985  chest HR-CT: severe pulmonary emphysema with

barrel chest

Lung volume reduction

• surgical (emphysema surgery)
• endoscopic

Surgical lung volume reduction

• indication (at least in the past):
-- upper lobe emphasized
-- low resilience (ergometry with 2l O2/ min < 40 Watt)
-- DLCO (diffusion capacity) > 20%
-- BMI > 20 kg/m2 Fig. 986  endoscopic lung volume reduction with one-way
valves (here example Zephyr from company Pulmonx [40])
-- no respiratory global (pCO2 > 50 mmHg: contrain-
dication)
-- no pulmonary hypertension
-- no bronchiectasss
• assessment: In the NETT study (NETT: National
Emphysema Treatment Trial; Fishman et al, N Engl J
2003) showed an increased mortality in the interventi-
on group, so that the surgical lung volume reduction ist
largely abandoned today.

Endoscopic lung volume reduction

• blocking techniques (dependent on collateral ventilati-

Pulmonology 707
 VENT study
A Randomized Study of Endobronchial Valves for Ad-
vanced Emphysema
Sciurba et al, N Engl J 2010
• multicenter randomized controlled study
• 321 patients with severe pulmonary emphysema (hete-
rogeneous)
-- 220 patients: with bronchoscopic valve implantation
-- 101 patients: without bronchoscopic valve implanta-
tion
• results: bronchoscopic valve implantation
-- positive:
◦◦ significantly higher FEV1
◦◦ significantly longer 6min walking distance
-- negative:
◦◦ significantly more exacerbations
◦◦ significantly more pneumonia
◦◦ significantly more hemoptysis
◦◦ no difference in mortality
study
Lung volume reduction coil treatment for patients with se-
vere emphysema: a European multicentre trial
Deslee et al, Thorax 2014
• multicenter prospective cohort study
• 60 patients with severe pulmonary emphysema
-- with bronchoscopic coil implantation (bilateral; Pne-
umRx; average 10 coils per lobe)
-- without bronchoscopic coil implantation
• results: bronchoscopic coil implantation
-- primary endpoint (clinical improvement based on St.
George's Respiratory Questionnaire [SGRQ]): signi-
ficant improvement
-- secondary endpoints: i.a.
◦◦ significantly higher FEV1 and higher residual volu-
me
◦◦ significantly longer 6min walking distance
708 Pulmonology
RENEW study
Effect of Endobronchial Coils vs Usual Care on Exercise
Tolerance in Patients With Severe Emphysema
Sciurba et al, JAMA 2016
• multicenter randomized controlled study
• 315 patients with severe pulmonary emphysema
-- with bronchoscopic coil implantation (bilateral; ave-
rage 12 coils per lobe)
-- without bronchoscopic coil implantation
• results: bronchoscopic coil implantation
-- primary endpoint: significantly longer 6min walking
distance
-- secondary endpoints: i.a.
◦◦ clinical improvement based on St. George's Res-
piratory Questionnaire" (SGRQ): significant impro-
vement
◦◦ significantly higher FEV1
Intermittent self ventilation (ISV)
• syn.: nocturnal non-invasive ventilation
• indication:
-- severe COPD
-- increased pCO2 (in exacerbation-free interval) [Ac-
cording to the DIGAB guidelines for out-of-hospital
ventilation, a corresponding BGA should not be re-
moved until 14 days after the end of acute treatment
at the earliest.]; note: with pulmonary fibrosis already
from pCO2 > 45 mmHg)
◦◦ nocturnal pCO2 > 55 mmHg or
◦◦ daytime pCO2 > 50 mmHg
-- base excess (BE) > 6 mmol/l (An increased base
excess in normal pCO2 in normal renal function in-
dicates chronic insufficiency of the respiratory pump
[compensatory renal counter regulation].)
-- symptoms of hypercapnia (e.g. daytime tiredness,
fatigue, poor concentration, morning headaches,
personality changes)
-- recurrent exacerbations
-- simultaneously other diseases (e.g. oSAS)
• For a long time there was no study which could show
a mortality advantage for ISV in COPD patients (al­
though only low ventilation pressures [12-14 mbar]
were used); for the first time in 2014 in a milestone
study (Köhnlein et al, Lancet Respir Med 2014 [see
box]) mortality advantage proven
 constriction ↓
• already appoved (e.g. in Germany) therapy measure
(at present however only in the context of studies used)
study
Prognosis
• mortality of an exacerbation: 10% (with invasive me-
chanical ventilation: 30%)
Non-invasive positive pressure ventilation for the treatment
of severe stable chronic obstructive pulmonary disease: a • after the first exacerbation
prospective, multicentre, randomised, controlled clinical -- after 2 years: 72% of patients are still alive
trial -- after 5 years: only 28% of patients are still alive
Koehnlein et al, Lancet Respir Med 2014
• After an exacerbation requiring intubation and invasive
• multicenter prospective randomized controlled study ventilation after 6 months only 57% are alive.
• 195 patients with COPD GOLD stage IV with hypercap- • GOLD IV → 5-year survival rate 30%
nia (pCO2 > 52 mmHg and pH < 7.35) • therefore aim for early EOL decision (end of life; at best
-- 102 patients: with intermittent self ventilation (NIV; before intubation and before admission to ICU if pos-
pressure-assisted, mean inspiratory pressure: 21.6 sible)
cmH2O; at least 6 hours daily; objective: reduction of
pCO2 by 20% or < 48 mmHg)
-- 93 patients: without intermittent self ventilation Prognosis of a patient with COPD
• results: intermittent self ventilation (ISV) requiring intubation: like a
malignancy
-- primary endpoint: mortality (after 1 year) → signifi-
cantly reduced (12% versus 33%)
-- secondary endpoints: i.a.
◦◦ BGA: significant decrease in pCO2 and bicarbonate
and increase in pH
◦◦ lung function (spirometry): significant increase in
CAOS study
FEV1
◦◦ quality of life: significant improvement

Survival and quality of life for patients with COPD or asth-

ma admitted to intensive care in a UK multicentre cohort:
the COPD and Asthma Outcome Study
meta-analysis Wildman et al, Thorax 2009

• prospective cohort study

• 832 patients with acute respiratory insufficiency in
COPD/asthma and need for admission to intensive care
Association of Home Noninvasive Positive Pressure Ven- unit
tilation With Clinical Outcomes in Chronic Obstructive Pul-
• results
monary Disease
Wilson et al, JAMA 2020 -- survival rate after 180 days: 62%
-- satisfaction with quality of life: 73% (96% would like to
• meta-analysis (21 RCT) have it that way again)
• 51085 COPD patients with hypercapnia
-- with intermittent self ventilation
-- without intermittent self ventilation
• results: intermittent self ventilation (ISV)
study
-- significant reduction in mortality
-- significantly fewer hospitalizations
-- significantly lower frequency of intubation
-- no difference in quality of life
Risk Trajectories of Readmission and Death in the First
Year after Hospitalization for Chronic Obstructive Pulmo-
Implantation of a peripheral AV fistula nary Disease
Lindenauer et al, Am J Respir Crit Care Med 2018
• implantation of a shunt (silicone tube [trade name ROX
AC2]) in the groin between the iliac artery and vein un- • retrospective analysis
der local anesthesia • examination of 2.3 million hospitalized COPD patients (>
• shunt flow: 0.8 l/min 65 years) 1 year after discharge from hospital:
• principle: -- re-hospitalization: in 64%
-- 20% of the cardiac output flows directly back into the -- mortality: 26% (if non-invasively ventilated: 42%, if in-
vasively ventilated: 46%)
lung, increasing the blood oxygen content.
-- increase of the oxygen saturation in the veins and
thus in the pulmonary circulation → hypoxic vaso-

Pulmonology 709
Prophylaxis
• vaccinations
• Impfungen
• aerosols (sprays; note: It is important not just to give
the patient the sprays, but also to explain how to use
them!):
-- LABA (long-acting beta-2 agonists)
-- LAMA (long-acting muscarinic antagonists)
-- inhaled corticosteroids (ICS; from GOLD III or group
C: significantly fewer exacerbations due to triple the-
rapy )
• roflumilast (from GOLD III or group D)
• possibly azithromycin
• possibly β-blocker: In a retrospective cohort study
(Bhatt et al, Thorax 2015) COPD patients showed sig-
nificantly fewer exacerbations under β-blockers. How-
ever, this is not yet a general recommendation.
POET study
Tiotropiumbromid versus salmeterol for the prevention of
exacerbations of COPD
Vogelmeier et al, N Engl J 2011
• multicenter double-blind randomized controlled study
• 7376 patients with COPD (after exacerbation)
-- tiotropium bromide
-- salmeterol
• results: tiotropium bromide
-- significant reduction in exacerbation frequency (by
17%)
-- significant reduction in hospital admissions (by 27%)
Smoking cessation
• S3 guideline 2014 Smoking Cessation in Chronic Obs-
tructive Pulmonary Disease of the German Society for
Pneumology and Respiratory Medicine
• nicotine replacement therapy (patch as base, chewing
gum on demand)
• drugs:
-- bupropion (Zyban)
◦◦ atypical antidepressant
◦◦ only indicated in clear depression and strong ad-
diction
◦◦ contraindications: i.a. epilepsy, alcohol abuse
◦◦ abstinence rate after 1 year: 27%
-- varenicline (Champix)
◦◦ nicotine receptor agonist
◦◦ contraindication: especially depression (because
of an increased suicide rate)
◦◦ EVITA study (Eisenberg et al, Circulation 2015):
after an acute coronay syndrome (ACS) reduction
of the number of smokers by 15% after 24 weeks
compared to placebo
◦◦ abstinence rate after 1 year: 31%
710 Pulmonology
• electric cigarette (e-cigarette):
-- simulation of the sensory experience of a real ciga-
rette
-- abstinence rate as bad as in nicotine replacement
therapy (In a more recent study, however, the ab-
stinence rate was twice as high [18% versus 9%]
than with nicotine replacement therapy [Hajek et al,
N Engl J 2019].)
-- carrier liquid: propylene glycol (side effect: irritation
of the respiratory tract), possibly COP [cryptogenic
organizing pneumonia])
-- meta-analysis (Mc Robbie et al, Cochrane Database
Sys Rev 2014):
◦◦ only 9% abstinent after 6 months
◦◦ cigarette consumption halved in 36%
◦◦ no indication of health risks (after 2 years)
-- risk of explosion and burns
-- no long-term data yet, therefore no general recom-
mendation (explicitly not recommended in the posi-
tion paper of the German Society for Pneumology
and Respiratory Medicine 2015; the European So-
ciety for Pneumology even explicitly warned against
this in 2019)
Vaccinations
• influenza: annual
• pneumococcus
-- once (STIKO recommendation since 2009: no more
booster vaccinations recommended [due to pro-
nounced local reactions and relatively low immuno-
genicity; only recommended for immunodeficiencies
and chronic kidney disease])
-- vaccines:
◦◦ 23-valent polysaccharide vaccine (PPSV23:
23-valent pneumococcal polysaccharide vaccine;
Pneumovax 23)
◦◦ 13-valent conjugate vaccine (PCV13: 13-valent
pneumococcal conjugate vaccine; Prevenar 13;
since 2015 also approved for the prevention of
pneumococcal pneumonia in adults [approval stu-
dy: CAPiTA])
Inhaled corticosteroids (ICS)
• representatives: beclomethasone, fluticasone, bude-
sonide
• as monotherapy in COPD (in contrast to bronchial
asthma [here the basic therapy]) no value (also not ap-
proved; only in combination therapy)
• indication: for exacerbation prophylaxis from GOLD III
or C (ICS are especially indicated for frequent exacer-
bations and for patients with an asthma component!)
• studies:
-- ISOLDE study (Lipworth et al, BMJ 2000), TRISTAN
study (Carverley et al, Lancet 2003: significant de-
crease in exacerbation frequency (by 25%)
-- WISDOM study (Magnussen et al, N Engl J 2014): A
tapering and discontinuation of the ICS did not lead
to an increase in exacerbation frequency.
-- FLAME study (Wedziche et al, N Engl J 2016 [see
box])
 -- TRILOGY study (Singh et al, Lancet 2016), TRINITY
study (Singh et al, Lancet 2017): significant decrea-
se in exacerbation frequency with the triple therapy
in COPD patients from GOLD C (at least one exa-
cerbation in the last year, FEV1 < 50%, CAT ≥ 10P.)
-- TRIBUTE study (Papi et al, Lancet 2018): significant
decrease in exacerbation frequency with the triple
therapy compared with the dual therapy (LABA +
LAMA) in COPD patients with at least one exacerba-
tion in the last year and FEV1 < 50%
-- IMPACT study (Lipson et al, N Engl J 2018 [see box])
-- note: COPD patients with eosinophilia (differential
blood count)
◦◦ A study (Pascoe et al, Lancet Resp 2015) showed
that COPD patients with eosinophils (differential
blood count) > 6% benefit from an inhaled corti-
costeroid.
◦◦ This was also shown in a subgroup analysis of the
WISDOM study (eosinophils > 400/μl).
• side effects: oropharyngeal candidiasis, increased risk
of pneumonias (however only secured for fluticasone),
cataract, hyperglycemia, fractures
• triple preparations (from LABA, LAMA and ICS); ex-
amples:
-- Trelegy Ellipta (GSK company; vilanterol 25μg, vme-
clidinium 62.5μg, fluticasone 100μg) 1 x daily (i.a.
IMPACT study)
-- Elebrato Ellipta (Berlin-Chemie company; vilanterol
22μg, umeclidinium 55μg, fluticasone 92μg) 1 x daily
(i.a. IMPACT study)
-- Trimbow (Chiesi company; formoterol 5μg, glycopyr-
ronium 9μg, beclometasone 87μg) 2-0-2 (studies i.a.
TRILOGY, TRINITY, TRIBUTE)
FLAME study
Indacaterol-Glycopyrronium versus Salmeterol-Flutica-
sone for COPD
Wedzicha et al, N Engl J 2016
• multicenter double-blind randomized controlled non-
inferiority study
• 3,362 patients with severe COPD (in 75% GOLD D) and
at least one exacerbation last year; over 52 weeks com-
bination of:
-- LABA + LAMA: indacaterol + glycopyrronium (Ultibro)
-- LABA + ICS: salmeterol + fluticasone
• results: LABA + LAMA
-- primary endpoint (exacerbation frequency): significant
reduction (note: independent of presence of eosino-
philia in differential blood count)
-- secondary endpoints: i.a.
◦◦ significantly less pneumonia
◦◦ significantly less use of emergency medications
IMPACT study
Once-Daily Single-Inhaler Triple versus Dual Therapy in
Patients with COPD
Lipson et al, N Engl J 2018
• multicenter randomized controlled study
• 10,355 patients with COPD and at least one exacerbati-
on in the last year; over 52 weeks:
-- triple therapy (ICS [fluticasone] + LABA [vilanterol] +
LAMA [umeclidinium])
-- dual therapy (either LABA + LAMA or LABA + ICS)
• results: triple therapy
-- significant decrease in exacerbation frequency (pri-
mary endpoint)
-- significant improvement in lung function
-- significant improvement in quality of life
-- significant decrease in mortality (only applies to com-
parison with the dual therapy LABA + ICS)
-- significantly more pneumonia with ICS
Azithromycin
• a macrolide antibiotic
• Here the antibiotic effect is less important than the anti-
inflammatory effect (inhibition of the transcription factor
NF-κB).
• studies
-- Albert et al, N Engl J 2011: A study (Albert et al, N
Engl J 2011) on 1142 COPD patients (with an incre-
ased risk of exacerbation) showed that the prophyl-
actic intake of azithromycin 250mg once a day signi-
ficantly reduced the number of exacerbations.
-- Uzun et al, Lancet Resp Med 2014: In 92 COPD pa-
tients with ≥ 3 exacerbations in the last year, it was
shown that the prophylactic intake of azithromycin
500mg 3 times a week could significantly reduce the
number of exacerbations
-- BACE study (Vermeersch et al, Am J Respir Crit
Care Med 2019): In the case of an acute exacerbati-
on of COPD (AECOPD) there were clear advantages
if azithromycin (500 mg daily for 3 days, then 500 mg
3 times/week for 90 days) was started immediately
in addition to (systemic) steroids and antibiotics.
• disadvantages:
-- increased hearing loss
-- (questionable) increased rate of cardiac arrhythmias
(especially due to prolongation of the QT interval;
Trifiro et al, CMAJ 2017: no increased rate of cardiac
arrhythmias due to azithromycin)
-- In a British study (Brill et al, Thorax 2015) long-term
antibiotic therapy (azithromycin, moxifloxacin or
doxycycline) did not lower the sputum germ count,
but increased antibiotic resistance.
• no general recommendation (good option especially
with bronchiectasis; possibly in recurrent exacerba-
tions by pseudomonas)
Pulmonology 711
• GOLD guidlines 2017: evidence B (1 x 250mg daily or
3 x 500mg weekly for 1 year for group D with frequent
exacerbations despite inhaled corticosteroid in previ-
ous smokers)
• no benefit in exacerbated bronchial asthma (AZALEA
study [Johnston et al, JAMA Int Med 2016])
INTERSTITIAL LUNG
DISEASES (ILD)
tors [e.g. ipilimumab, nivolumab])
▪▪ herbicides (e.g. paraquat)
▪▪ radiation (radiation pneumonitis
-- circulatory (chronic congestive lung)
-- neoplastic (e.g. lymphangiosis carcinomatosa, bron-
choalveolar carcinoma)
-- congenital (e.g. Hermansky-Pudlak syndrome: pul-
monary fibrosis, albinism, thrombocytopathy with
hemorrhagic diathesis and colitis [granulomatous];
especially in Puerto Rico)
• ILD without known cause (50%): idiopathic pulmonary
fibrosis (IPF), idiopathic interstitial pneumonia (IIP)

Definition
• disease of the lung interstitium
• pathogenesis:
-- activation of fibroblasts (most important)
-- activation of macrophages
-- aging pneumocytes type II
• Radiological (HR-CT [HR: high resolution]) and histolo-
gical (according to Liebow) there are different patterns.

Classification
• ILD with known causes (50%)
-- inflammatory
◦◦ infectious (e.g. viruses, pneumocystis jiroveci) Fig. 987  HR-CT in severe exogenous allergic alveolitis: You
◦◦ autoimmune ( most common cause): rheuma- can see honeycombs, bullae, traction bronchiectasis and a
toid arthritis, collagenosis (e.g. SLE, scleroder- ground glass opacities.
ma [systemic sclerosis], polymyositis, dermato-
myositis, Sjögren's syndrome), vasculitis (e.g.
Churg-Strauss syndrome [EPGA: eosinophilic
granulomatosis with polyangiitis]), sarcoidosis,
Bechterew´s disease, IBD (inflammatory bowel di-
sease), PBC (primary biliary cirrhosis), LAM (lym-
phangioleiomyomatosis), histiocytosis X (cause:
BRAF mutation; possibly therefore vemurafenib
as B-RAF inhibitor, which is approved for the the-
rapy of malignant melanoma)
-- toxic
◦◦ inhalative
▪▪ inorganic dusts: pneumoconiosis (silicosis, as-
bestosis, berylliosis)
▪▪ organic dusts: exogenous allergic alveolitis
(EAA; syn. hypersensitivity pneumonia; e.g.
farmer's lung, bird fancier's lung); like sarcoido-
sis a granulomatous disease; typically a mosaic
pattern in HR-CT, often also UIP pattern and
thus relatively similar to IPF; in the laboratory
detection of specific IgG antibodies against the
respective antigen (precipitins); in the BAL lym- Fig. 988  chest X-ray of a female patient with lymphangiolei-
phocytes > 40% (classic [as in sarcoidosis]) and omyomatosis (LAM; very rare disease, affects almost only
CD4/CD8 ratio < 1 (in contrast to sarcoidosis, women of childbearing age; pronounced cyst formation in
where the CD4/CD8 ratio is > 2) the lungs; caused by tuberin and hamartin mutations [pos-
sibly sirolimus as a possible therapy option])
◦◦ non-inhalative
▪▪ drugs (chemical pneumonitis; DILD [drug-
induced lung disease]; e.g. bleomycin [BIP:
bleomycin induced pneumonitis [see infobox]),
amiodarone, methotrexate, leflunomide, G-CSF,
nitrofurantoin, gold, immune checkpoint inhibi-

712 Pulmonology
Fig. 989  Bleomycin induced pneumonitis

Idiopathic pulmonary fibrosis (IPF)

Definition
• chronically progressive fibrotic interstitial pneumonia
of unknown cause (exclusion of known causes
• increase of connective tissue in the lung and finally
pulmonary fibrosis
• radiological (HR-CT) and histological pattern of UIP
(usual interstitial pneumonia)
• mean loss of FVC (forced vital capacity): 150-200ml
per year

Guidelines
• national (German): S2k guideline for diagnosis and
treatment of idiopathic pulmonary fibrosis 2013 of the
German Society for Pneumology and Respiratory Me-
dicine
• international: An official ATS/ERS/JRS/ALAT Clinical
Practice Guideline: Treatment of Idiopathic Pulmonary
Fibrosis - An Update of the 2011 Clinical Practice Gui-
deline; Am J Respir Crit Care Med 2015

Epidemiology
• incidence:
-- 8/100000
-- increasing
• m > w
• median age: 57 years (Below 50 years an IPF is very
unusual, here mostly a [possibly still subclinically pro-
nounced] collagenosis with UIP pattern is present.)

Pulmonology 713
• average survival time: 2-3 years, 5-year survival rate: • AIP (acute interstitial pneumonia; syn.: Hamann-Rich
only 25% (like a malignancy! note: However, the data syndrome; clinically and radiologically corresponding
originate before the introduction and approval of antifi- to ARDS; acute course with high mortality)
brotic therapy in 2015.) ) • COP (cryptogenic organizing pneumonia)
-- former name: BOOP (bronchiolitis obliterans organi-
Risk factors
zing pneumonia)
• smoking (main risk factor) -- picture like pneumonia (but without improvement
• environmental pollution despite multiple changes of antibiotics [but improve-
• viruses (i.a. EBV, CMV, HSV, hepatitis C) ment by steroids!]), procalcitonin, however, typically
• gastrointestinal reflux not increased
• genetic factors (i.a. mutation in MUC5B gene) -- etiology
◦◦ unknown (IPF)
Pattern ◦◦ known (especially pneumonia, aspiration, rheu-
• UIP (usual interstitial pneumonia) matological disease, drugs, e-cigarettes)
-- most common pattern -- HR-CT: spot-like alveolar consolidation, positive air
bronchogram, ground glass opacities, nodules
-- occurrence: classic in IPF (UIP pattern but also pos-
sible e.g. in rheumatoid arthritis, scleroderma [syste- -- BAL: lymphocytic alveolitis with a CD4/8 quotient < 1
mic sclerosis], vasculitis or EAA) -- very good response to steroids
-- worst prognosis (mean survival time: 2-3 years) ◦◦ both clinically and radiologically
-- HR-CT (HR: high resolution): ◦◦ prednisolone initially 1 mg / kg for 3 days, then
◦◦ localization: bilateral, basal (lower lung fields; not dose reduction (longer-term administration neces-
suitable: upper / middle field), peripheral, subpleu- sary)
ral
◦◦ findings: honeycombs ( the most important UIP Symptoms
criterion), reticulations, traction bronchiectases; • dyspnea (initially only during exercise, later also at
not suitable for UIP: ground glass opacity (pro- rest)
nounced; slight ground glass opacity possible), • dry chronic irritable cough
consolidations, nodules, cysts (without honey- • drumstick fingers, watch-crystal nails (syn.: hippocratic
comb pattern), mosaic pattern, air trapping, chan- nails [unguis hippocraticus])
ges of the pleura (calcifications, plaques, pleural • cyanosis
effusion), mediastinal lymph nodes > 1.5cm
• leg edema
◦◦ poor response to steroids (therefore also not re-
commended
-- biopsy: Histologically, the UIP pattern is characte- Leading symptom of idiopathic
rized by a heterogeneous appearance (alternating pulmonary fibrosis (IPF) : unclear
areas with strong and only weakly pronounced fib- exertional dyspnea!
rosis).
• LIP (lymphocytic interstitial pneumonia; syn.: GL-ILD
[granulocytic lymphocytic ILD]; frequently occurring in
CVID [common variable immunodeficiency]; similar to
sarcoidosis (in BAL lymphocytic alveolitis with increa-
sed CD4/CD8 ratio, in histology also granulomas)
• NSIP (non-specific interstitial pneumonia)
-- often in the context of rheumatological diseases
-- HR-CT: typically ground glass opacities (NSIP pat-
tern)
-- good response to steroids
• RB-ILD (respiratory bronchiolitis interstitial lung di-
sease)
-- almost exclusively in smokers (condensate / smoker
pneumopathy)
-- HR-CT: ground glass opacities, nodules, apical em-
physema
-- BAL: striking yellow-brownish color ("brown" BAL;
due to pigmented smokers' macrophages)
-- very good prognosis (if nicotine abuse is stopped)
• DIP (desquamative interstitial pneumonia): like RB-ILD
also almost exclusively in smokers, also ground glass
opacities

714 Pulmonology
 • lung biopsy with histology
-- transbronchial (mostly negative, therefore not re-
commended [obsolete today]; new: cryobiopsy)
-- thoracoscopic (VATS [video-assisted thoracoscopy])
◦◦ method of choice
◦◦ recommended sample size: walnut size
◦◦ mostly not necessary (only if HR-CT is not clear)
◦◦ cave: initiation of acute exacerbation (in 10%)
-- open (wedge resection)
Fig. 990  pronounced drumstick fingers and toes with hy-
pocratic nails (Pierre-Marie-Bamberger syndrome [hyper-
trophic pulmonary osteoarthropathy]: This is usually the
result of a non-small cell lung cancer [NSCLC; paraneo-
plastic], but can also be caused by an IPF as here.)

Diagnosis
• anamnesis (e.g. occupational anamnesis, environ-
mental pollution, hobbies, pets, drugs, concomitant
diseases [especially systemic diseases], family ana-
mnesis), physical examination (auscultation: crackling
sounds [sclerophonia; mostly basal on both sides, oc-
curs very early], door-stop phenomenon [sudden stop
of breathing with deep inspiration])
• lung function (spirometry; restriction: TLC ↓, VC ↓);
compliance ↓), diffusion capacity measurement (DL-
COSB ↓, DLCO/VA [Krough index; KCO] ↓ because of
pulmonary restriction)
• spiroergometry
• laboratory: i.a.
-- autoimmune serology
◦◦ rheumatoid arthritis: rheumatoid factor (note: wea-
kly positive rheumatoid factor also possible in
IPF), anti-CCP (CCP: cyclic citrullinated peptides)
◦◦ SLE (systemic lupus erythematosus): ANA (anti-
nuclear antibodies; note: weakly positive ANA titer
also possible in IPF), Anti-dsDNA (double-strand
antibody), Anti-Sm (Smith)
◦◦ scleroderma (systemic sclerosis): anti-centromer
antibody, scl-70 (anti-topoisomerase 1), PM1
◦◦ sarcoidosis: neopterin, ACE, sIL-2 receptor (solu-
ble interleukin)
◦◦ Sjögren syndrome: Anti-SS-A (Ro), Anti-SS-B (La)
◦◦ dermato- / polymyositis: anti-Jo-1 (Histidyl-tRNA
synthetase) HR-CT
◦◦ Sharp syndrome: anti-U1-RNP • findings:
◦◦ vasculitis: c-ANCA (Wegener´s disease [granulo- -- ground glass opacities (GGO)
matosis with polyangiitis]), p-ANCA ◦◦ increase in density (opacity; veil-like), in which the
-- allergological diagnostics (especially total IgE, spe- vessels inside are still recognizable
cific IgG antibodies [precipitins; in EAA]) ◦◦ always indicative for an inflammation
-- procalcitonin (classically not elevated) ◦◦ especially in EAA, NSIP, DIP, RB-ILD (not suitable
• BGA (especially pO2 ↓ [especially under exercise, e.g. for UIP)
in ergometry]) -- consolidations: increase in density (opacity) in which
• echocardiography (question: cor pulmonale / pulmona- the vessels inside are no longer recognizable
ry hypertension) -- honeycombs: grouped cystic formations (clusters)
• chest X-ray with thickened walls; absolutely typical for UIP
• HR-CT (HR: high-resolution; high significance today) -- traction bronchiectasis
• bronchoscopy with bronchoalveolar lavage (BAL [fin- -- reticulations (net-shaped drawing): especially for
dings: see infobox]; incl. microbiology [especially UIP, NSIP, EAA
pneumocystis jirovecii, herpes viruses, influenza, fun- -- noduli (e.g. EAA, sarcoidosis, silicosis)
gi]), if necessary with transbronchial biopsy (TBB) -- cysts (e.g. EAA)

Pulmonology 715
 -- mosaic pattern (especially EAA)
-- air trapping (e.g. EAA)
• localization (emphasis):
-- vertical plane
◦◦ basal: UIP (IPF), DIP, asbestosis
◦◦ apical: rheumatoid arthritis, collagenoses, sarcoi-
dosis, silicosis, histiocytosis X
-- horizontal plane
◦◦ central: sarcoidosis, EAA
◦◦ central: sarcoidosis, EAA ◦ peripheral: UIP (IPF),
DIP, asbestosis, collagenosis, COP; subpleural
recess: EAA, collagenosis, NSIP
Fig. 992  HR-CT: pronounced honeycombs (typical UIP pat-
tern) in IPF
central role in the diagnosis of intersti-
tial lung diseases: HR-CT!

Lung biopsy (VATS) only necessary if

HR-CT is not clear!

Fig. 993  HR-CT: IPF

Fig. 994  HR-CT: IPF (You can also see a significantly enlar-
ged right ventricle in the sense of the cor pulmonale.)
Fig. 991  chest X-ray: IPF (different examples)

716 Pulmonology
Differential diagnoses vival benefit).
• pneumonia • pneumothorax
• tuberculosis • pulmonary embolism
• chronic pulmonary congestion (cardiac induced) • decomposed cor pulmonale (pulmonary hypertension
[11% of all patients with IPF])
• diffuse alveolar hemorrhage (e.g. Goodpasture syn-
drome, ANCA-associated vasculitis) • iatrogenic (after extensive BAL, after lung biopsy
[VATS])
• lymphangiosis carcinomatosa
• bronchioalveolar carcinoma
• alveolar proteinosis Acute respiratory insufficiency in
IPF: always exclude reversible
-- definition: accumulation of surfactant in the alveoli
(treatable) causes (e.g. chest CT,
(overloaded phagocytic capacity of the alveolar ma-
echocardiography, bronchial
crophages)
secretion / BAL on germs
-- types
◦◦ primary (congenital; genetic [especially mutation
in the gene for surfactant proteins or GM-CSF])
◦◦ secondary (e.g. autoimmune [most common; anti-
bodies against GM-CSF], inhalative [dusts], infec-
tious, neoplastic)
-- epidemiology
◦◦ mostly men
◦◦ mean age: 40 years
-- diagnosis: i.a.
◦◦ bronchoscopy: PAS-positive macrophages in BAL
◦◦ HR-CT: crazy-paving pattern (mosaic pavement /
tile-like network pattern [through thickened lobular
septa] with ground glas opacities [mostly subfield];
also typical for COVID pneumonia [SARS-CoV-20;
for CT pictures see page Seite 924])
-- therapy: therapeutic bronchoalveolar lavage (30-40
liters of NaCl 0.9% per side; under general anest-
hesia)

Respiratory decompensation

Epidemiology
• per year in 14% acute respiratory decompensation in
patients with IPF
• especially in winter and spring
• median survival after an acute exacerbation: 6 months

Causes
• infections (40%; most common reason)
• acute exacerbation (AE-IPF), i.e. progression of the
underlying disease (30%; i.a. Song et al, Eur Resp J
2011): Therefore one should consider early whether
to initiate or escalate immunosuppressive therapy
(especially steroids, possibly in combination with cyc-
lophosphamide). The S2k guideline recommends ste-
roid therapy for acute exacerbation. Acute exacerbati-
on is defined as clinical worsening with no indication
of infection, pulmonary embolism, pneumothorax or
heart failure. Therefore, a bronchoscopy with sampling
of bronchial secretion (if necessary BAL) for germs, a Fig. 995  Chest CT of a ventilated patient with acute exacer-
chest CT and an echocardiography should always be bation of the previously known IPF
performed. The prognosis for AE-IPF is very poor with
a hospital mortality rate of 57% and a 6-month morta-
lity rate of 70% (i.a. Collard et al, AJRCM 2007). Even
with AE-IPF an antifibrotic therapy should be initiated
early (i.a. Matsumoto et al, ERS 2017: significant sur-

Pulmonology 717
Therapy sibly even with acute right heart failure) is engraved
by the hypoxic pulmonary vasoconstriction (Euler-
• known cause: causal therapy
Liljestrand-reflex) in the context of an acute respira-
• unknown cause (IPF): symptomatic therapy tory insufficiency, so that a corresponding pressure
-- immunosuppression: (PAP) lowering therapy with PH specific drugs (e.g.
◦◦ steroids with ilomedine) may be considered. However, ac-
▪▪ dosage: prednisolone 0.5 mg/kg for 4 weeks, cording to the current ESC/ERS guidelines on pul-
then 0.25 mg/kg for 8 weeks, then 0.125 mg/kg monary hypertension, PH specific drugs to reduce
for 6 months pressure (PAP) is clearly not indicated for pulmonary
▪▪ good response to steroids especially with NSIP, hypertension due to lung disease (IIIC recommen-
RB-ILD, DIP and COP dation). They are also not approved for this purpose.
▪▪ for acute exacerbation of IPF recommended Vasodilatation occurs as a result of the mechanism
(e.g. prednisolone 250mg i.v. daily for 3 days of action of the PH specific drugs. The lung, howe-
ver, remains ill. This leads to an increased perfusi-
◦◦ cyclophosphamide (Endoxan): either i.v. (15 mg/
on of not or only insufficiently ventilated alveoli, so
kg every 2-3 weeks; lower cumulative total dose)
that a shunt develops and the oxygenation disorder
or p.o. (1,5-2 mg/kg)
continues to increase consecutively. Selective endo-
◦◦ azathioprine (3 x 50mg; previously determination
thelin receptor antagonists are contraindicated here
of TPMT level [TPMT: thiomethylpurine transfera-
because the ARTEMESIS-IPF study (Raghu et al,
se; to exclude a polymorphism with consecutively
Ann Int Med 2013) even showed an increased pro-
decreased degradation of azathioprine and thus
gress. Riociguat is also contraindicated here (due to
need for dose reduction; note: no longer absolu-
an excess mortality in the RISE-IIP study [Nathan et
tely necessary]
al, ERJ 2017]).
-- ACC (now obsolete; high dose: 3 x 600mg); studies:
-- possibly lung transplantation
◦◦ IFIGENIA study (Demedts et al, N Engl J 2005):
◦◦ types:
advantage for triple therapy of prednisolone, aza-
▪▪ 1/3: unilateral (SLTX)
thioprine and additionally ACC
▪▪ 2/3: bilateral (DLTX)
◦◦ PANTHER-IPF study (Martinez et al, N Engl J
2012): even excess mortality for triple therapy; ◦◦ IPF is the second most common cause (after
therefore no longer recommended today COPD) of lung transplantation.
-- antifibrotic therapy ◦◦ 5-year survival rate after lung transplantation: 55%
(only!)
◦◦ substances (see infobox):
◦◦ the only curative therapy (If there is no option for
▪▪ pirfenidone (Esbriet)
lung transplantation, it is a palliative situation!)
▪▪ nintedanib (Ofev)
◦◦ both recommended in the 2015 revised guideline
of ATS/ERS/JRS/ALAT
◦◦ officially approved since 2015
◦◦ paradigm shift in the therapy of IPF: Today, an an-
tifibrotic and no longer immunosuppressive thera-
py is performed!
◦◦ prolongation of survival time from 5 to 10 years
(European IPF-Registry 2018)
◦◦ no combination therapy of pirfenidone and ninte-
danib recommended
-- no recommendation: colchicine, ciclosporine, INFγ,
etanercept, ACC (no longer recommended)
-- antibiotic therapy in case of infection (e.g. therapy
of pneumocystis jirovecii; mostly probatory broad-
spectrum antibiosis [e.g. piperacillin + tazobactam];
infections are the most common cause for an acute
respiratory insufficiency in IPF!)
-- if necessary, initiation of long-term oxygen therapy
(LTOT)
-- if necessary, initiation of intermittent self ventilation
(indicated alerady from pCO2> 45 mmHg)
-- vaccinations (influenza, pneumococci)
-- acute respiratory insufficiency → ventilation
-- rehabilitation (great benefit)
-- possibly treatment of pulmonary hypertension (in
11% already present in pulmonary fibrosis): Fre-
quently a pre-existing pulmonary hypertension (pos-

718 Pulmonology

paradigm shift in long-term therapy of
IPF since 2015: no more immunosup-
pressive therapy, but antifibrotic
therapy!
acute exacerbation of an idiopa-
thic pulmonary fibrosis (AE-IPF):
steroids + broad spectrum
antibiotics
Ventilation
• Mechanically ventilated patients with idiopathic pulmo-
nary fibrosis (IPF) have (without transplantation) an
extremely poor prognosis (mortality 90%) and almost
all die within a few days after intubation. Therefore,
routine ventilation (including NIV) is generally discou-
raged in the official recommendations (i.a. NICE Clini-
cal Guideline 2013 Idiopathic pulmonary fibrosis; S3
guideline Non-invasive ventilation as therapy for acute
respiratory insufficiency). Nevertheless, one should be
careful in case of the diagnosis "pulmonary fibrosis"
with a general renunciation of intubation:
-- On the one hand (with assured IPF) reversible and
potentially well treatable causes for acute respirato-
ry insufficiency such as pneumothorax (→ thoracic
drainage), pulmonary embolism (→ anticoagulation,
if necessary lysis), infection (→ antibiosis) or decom-
pensated cor pulmonale (→ recompensation with
loop-diuretics, if necessary PH specific drugs such
as ilomedine) should be excluded.
-- On the other hand, if idiopathic pulmonary fibrosis
(IPF) is not yet assured, other interstitial lung disea-
ses (possibly also with UIP pattern) with a signifi-
cantly better prognosis may be present.
• Ventilation per se leads to a worsening of pulmo-
nary fibrosis (vicious circle): The positive pressure ap-
plied during ventilation leads to fibroblast proliferation
and thus to a further increase in fibrosis (acceleration;
i.a. Kolb et al, ATS 2013). If hypercapnia (increase in
pCO2) occurs during mechanical ventilation, the patient
is mostly lost: Then the fibrosis has reached an extent
where it comes to mechanical impairment of ventilation
(restrictive ventilation disturbance; "stiffening").
• HFNOT (high-flow nasal oxygen therapy) and non-
invasive ventilation (NIV) are also possible here and
should always be tried first.
• settings on the ventilator:
-- low PEEP; reasons:
◦◦ Due to the restriction in the context of fibrosis,
compliance is massively reduced. Therefore, a
higher pressure gradient Δp from inspiration pres-
sure (IPAP) and PEEP is required so that a signifi-
cant tidal volume can be generated for ventilation
at all. The higher the PEEP, the smaller the pres-
sure amplitude and thus the tidal volume.
◦◦ The higher the PEEP, the higher the fibroblast pro-
liferation and the higher the mortality (i.a. Fernan-
dez-Perez et al, Chest 2008).
◦◦ The patients often have pulmonary hypertension/
cor pulmonale, which would be aggravated by a
high PEEP.
Pulmonology 719
 -- Mostly only a small tidal volume of 200-300ml can
be generated (with pressure-controlled mechanical
ventilation) due to the massively reduced compli-
ance. In order to avoid dead space ventilation, it is
often a good idea to completely remove the elbow
connector of the ventilator.
-- high respiratory rate (20-30/min)
-- FiO2 preferably < 0.30 (The higher the FiO2, the
stronger the fibroblast proliferation.)
-- long pressure rise rate (flat ramp; 1-2s)
• if necessary ECMO:
-- for faster weaning from ventilation
-- possibly to avoid intubation with awake ECMO
-- only bridging until transplantation if already listed,
otherwise ECMO very reserved (no "bridging to
nowhere")
BRONCHIAL HEMORRHAGE
Definition
• bleeding in the bronchi
• origin:
-- bronchial arteries (90%; large circulation [from the
thoracic aorta], i.e. high pressure in the vessels)
-- pulmonary arteries (10%; small circulation, i.e. low
pressure in the vessels)
• complications:
-- The main problem of bronchial hemorrhage is not
the hemoglobin-relevant blood loss with hemorrha-
gic anemia and shock, but the obstruction of the air-
ways with consecutive asphyxia (the most frequent
cause of death in bronchial hemorrhage)!
-- Furthermore, the blood can cause surfactant inacti-
vation, resulting in ARDS. .
• grade of severity (quantity however often not easy to
assess):
-- mild bleeding: < 200 ml/day
-- severe bleeding: > 200 ml/day
Symptoms
• hemoptysis: little blood in the sputum (small amount
of blood)
• hemoptea: massive coughing up of blood )large
amount of blood)
• in ventilated patients bloody aspiration
Etiology
• neoplastic:
-- bronchial carcinoma (most frequent cause in smo-
kers > 40 years), pulmonary metastases (e.g. renal
cell carcinoma), sarcoma (e.g. Kaposi sarcoma in
HIV), carcinoid (frequently pronounced bleeding!)
-- i.a. tumor corrosion of a vessel with "final" hemor-
rhage
• inflammatory:
-- hemorrhagic bronchitis (most frequent cause of
bronchial hemorrhage in industrial countries), pneu-
720 Pulmonology
monia, lung abscess, leptospirosis
-- tuberculosis
◦◦ most frequent cause of bronchial hemorrhage
in developing countries
◦◦ remind it especially when there are infiltrates con-
solidations in the upper lobe!
-- fungi (e.g. aspergilloma)
• hematological: coagulopathy (e.g. anticoagulants, he-
mophilia)
• circulatory:
-- pulmonary embolism, pulmonary infarction
-- cardiac (e.g. decompensated left heart failure [espe-
cially mitral valve stenosis] with postcapillary pulmo-
nary hypertension)
-- fistula (arterio-bronchial, aorto-bronchial [e.g. as
complication of aortic dissection])
-- pulmonary artery aneurysm
•
-- AV malformation (e.g. in Osler's disease)
traumatic / iatrogenic:
-- bronchoscopy with lesion of the bronchial wall
-- transbronchial lung biopsy: This is contraindicated in
◦◦ pulmonary hypertension with a systolic PA pressu-
re > 60 mmHg
◦◦ ventilated patients
-- pleural puncture
-- tracheotomy (i.a. tracheo-arterial fistula: very rare,
but catastrophic; endotracheal mass hemorrhage;
still occurring up to 6 weeks after tracheotomy)
-- pulmonary artery catheter (iatrogenic pulmonary ar-
tery rupture [see page 208])
-- pulmonary vein stenosis (mainly as complication of
pulmonary vein isolation [atrial fibrillation ablation])
-- thoracic trauma
-- foreign body
• constitutional:
-- bronchiectasis
-- endometriosis (bronchial bleeding at the same time
as menstruation [catamenial hemoptysis])
• autoimmune:
-- pulmo-renal syndrome with diffuse alveolar hemor-
rhage (DAH), especially Wegener´s disease (new
term: granulomatosis with polyangiitis [GPA]), Good-
pasture syndrome, systemic lupus erythematosus
(SLE)
-- Behçet´s disease (e.g. orogenital ulcers)
• phamacological-toxic (e.g. thrombocyte aggregation
inhibitors, anticoagulants; bevacizumab, cocaine, rio-
ciguat)
• pseudo-hemoptysis: bleeding which does not originate
in the bronchi, with aspiration and consecutive expec-
toration
-- nasopharyngeal cavity (epistaxis)
-- esophagus / stomach (hematemesis); good DD by
means of pH:
◦◦ bleeding source gastrointestinal: pH acidic
◦◦ bleeding source bronchial: pH alkaline
• idiopathic (30%; cryptogenic)
 The most common causes of
pulmo-renal syndrome are
Goodpasture syndrome,
Wegener´s disease and SLE!

Fig. 996  chest CT: bronchiectases (arrows)

The most common causes of hemopty-

sis are bronchitis and bronchial
carcinoma!

The most common cause of hemopty-

sis in smokers > 40 years of age is
bronchial carcinoma!

Pulmo-renal syndrome
Definition Fig. 997  typical saddle nose (various examples) in
• autoimmune Wegener's disease (granulomatosis with polyangiitis)
• vasculitis of the small vessels (capillaries), especially
of the pulmonary (pulmonary capillaritis) and renal (es- most important DD for pulmo-
pecially glomerular [glomerulonephritis]) vessels renal syndrome: pneumonia with
• consequences: secondary bronchial hemorrhage
-- lung: diffuse alveolar hemorrhage (DAH; endobron- and secondary (septic) kidney
chial bleeding) failure!
-- kidney: rapid-progressive glomerulonephritis
(RPGN) with acute kidney failure (intrarenal)
Diagnostics
Etiology • kidney: see also diagnostics of acute kidney failure
• ANCA-associated vasculitis (page 798)
-- c-ANCA associated: Wegener´s disease (new term: -- ANCA
granulomatosis with polyangiitis [GPA]) ◦◦ c-ANCA → Wegener´s disease (granulomatosis
-- p-ANCA associated: panarteriitis nodosa (PAN; with polyangiitis [GPA])
Kussmaul-Maier´s disease), especially microscopic ◦◦ p-ANCA → panarteriitis nodosa (Kussmaul-
panarteriitis nodosa (mPAN Maier´s disease)
• immune complex glomerulonephritis (classic: systemic -- ds-DNA antibodies → systemic lupus erythematosus
lupus erythematosus [SLE]) (SLE; typical for a severe active SLE is the comple-
• anti-basement membrane glomerulonephritis (syn.: ment consumption, i.e. C4 ↓)
Goodpasture syndrome; incidence: 1:1 million; m:w = -- anti-basement membrane-antibodies → Goodpastu-
2:1) re syndrome
• lung: see diagnostics of bronchial hemorrhage (page
722; i.a. in bronchoscopy in the BAL progressive
bloody "recovery", mostly diffuse multisegmental he-
morrhage)

Pulmonology 721
Therapy metimes significantly obstruct the airway and is often
• lung: see therapy of bronchial hemorrhage (page difficult to remove in the bronchoscopy. Strong suction
723) and the use of forceps can be helpful. When pulling
out, you have to briefly disconnect the tube from the
• kidney: see therapy of acute kidney failure (page
ellbow connector in order to retrieve it. It is best to use
800); i.a.
a "thick" bronchoscope (e.g. Olympus 180): However,
-- Goodpasture syndrome: this only passes through tube of the size 8 and not a
◦◦ plasma exchange (means of first choice) tube of the size 7. With the "thick" bronchoscope, on
▪▪ always indicated with pulmonary involvement the one hand, suction can be performed much more
▪▪ against FFP (18-22 FFP per session; cave citra- strongly and, on the other hand, larger forceps (e.g.
te accumulation and metabolic alkalosis) alligator forceps) can be inserted. Through the nor-
▪▪ mostly 7 sessions in 14 days (in the first three mal bronchoscope (e.g. Olympus 160) only the bio-
days daily, then alternating) psy forceps, which is relatively small, can be inserted.
◦◦ immunosuppression: steroids (prednisolone 1 mg/ Alternatively, if you don't have a large bronchoscope,
kg for 6 months) + cyclophosphamide (Endoxan) you can use a children's gastroscope. This also goes
1,5-2 mg/kg p.o. for 3 months) through a tube of the size 8.
-- ANCA-associated vasculitis:
◦◦ immunosuppression ( means of first choice):
combination of Do not confuse an endobronchially
▪▪ steroids: cortisone pulse therapy for 3 days organized blood clot with a tumor!
(prednisolone 250mg i.v. daily) +
▪▪ cyclophosphamide (Endoxan):either i.v. (15
mg/kg every 2-3 weeks; lower cumulative total
dose) or p.o. (1.5-2 mg/kg)
◦◦ in case of therapy failure:
▪▪ rituximab (Mabthera; anti-CD20 antibody)
▪▪ plasma exchange: in contrast to Goodpasture's
syndrome no longer relevant here (PEXIVAS
study [Walsh et al, Arthritis Rheumatol 2018]: no
difference in mortality or rate of end-stage kid-
ney disease compared to placebo)

Diagnostics
• anamnesis: i.a. smokers (indication for bronchitis or
bronchial carcinoma), angina pectoris (indication for
myocardial infarction with left heart failure or pulmona-
ry embolism), arthralgias, drugs (e.g. anticoagulants),
pre-existing conditions (i.a. hemophilia, HIV, tuberculo-
sis, vasculitis, cystic fibrosis [indication for bronchiec-
tasis])
• physical examination: i.a. fever (indication for infec- Fig. 998  diffuse alveolar hemorrhage in ANCA-associated
tion), telangiectasia (indication for Osler's disease), vasculitis
diastolic murmur (indication for mitral valve stenosis),
palpable purpura (indication for vasculitis
• laboratory
An inconspicuous chest CT does
-- standard laboratory: i.a. hemoglobin, blood count, not rule out bronchial carcinoma!
creatinine, urea, CRP, coagulation (thrombocytes, Therefore always chest CT AND
Quick / INR, PTT) bronchoscopy!
-- BGA
-- possibly special laboratory (i.a. c-ANCA, p-ANCA,
dsDNA antibodies, anti-basement membrane anti-
bodies)
-- possibly urine status and urine sediment
• chest X-ray
• chest CT
• bronchoscopy; note: An organized endobronchial
blood clot often looks very similar to tumor tissue and
should not be confused with a tumor. After a broncho-
scopic biopsy of the supposed tumor, the blood clot
is not infrequently confirmed histologically. It can so-

722 Pulmonology
 ▪▪ Univent tube (tube with integrated bronchus blo-
cker)
• hemostasis:
-- bronchoscopical
◦◦ flexible bronchoscopy
◦◦ rigid bronchoscopy (mostly, however, only availa-
ble at centres)
-- interventional (embolization by angiography)
◦◦ bronchial artery embolization (BAE; high success
rate): bronchial artery occlusion with coils or poly-
vinyl alcohol particles (cave: paraplegia due to ac-
cidental embolization of a spinal artery in the case
of atypical ramification), possibly stent implantati-
on in aorto-bronchial fistula
◦◦ pulmonary artery embolization (PAE)
-- surgical (thoracic surgery; e.g. lobectomy)

The main therapeutic goal in

bronchial hemorrhage is to
protect against asphyxia!

Fig. 999  Bronchoscopy: The endobronchial bleeding is re-

cognizable.

Therapy
• general measures:
-- oxygen administration
-- positioning on the bleeding side (So the blood flows
less into the healthy side.)
-- generous antibiotic prophylaxis (e.g. amoxicillin /
clavulanic acid)
-- coagulation therapy (e.g. administration of FFP)
-- in case of pronounced bleeding, immediate intubati-
on (danger of asphyxia), use of a large-lumen tube
(e.g. size 8-9; thus better bronchoscopy possibility
afterwards), ventilation with high PEEP
-- if necessary one-sided intubation (ventilation of only
one of the two lungs):
◦◦ with a conventional tube (bronchoscopically
placed in the main bronchus of the healthy side);
note: If the tube is inserted into the right main
bronchus during a left-sided bleeding, the outgo-
ing upper lobe bronchus, which goes off relatively
far up on the right, is frequently obstructed by the
cuff, which can lead to atelectasis and further de-
terioration of the gas exchange. It is therefore bet-
ter to use a bronchial blocker in case of bleeding
from the left side.
◦◦ with a special tube:
Fig. 1000  Double lumen tube
▪▪ double-lumen tube (disadvantage: no more
bronchoscopy possible then)
▪▪ Bronchosafe tube (bronchoscopically placed;
tube in the healthy side)

Pulmonology 723
Bronchoscopic hemostasis
• local application of a mixture of cold sodium chloride
solution and adrenaline (50ml NaCl 0.9% from refri-
gerator + 2 vials of adrenaline [Suprarenin]; 10ml
each applied via the working channel); xylometazoline
(Otriven) as an alternative to adrenaline also possible;
note: In case of a very pronounced irrigation, an ARDS
can develop by washing out the surfactant. .
• local application of tranexamic acid (1 vial = 5ml =
500mg; 2 vials in a 20ml syringe, fill with air) via the
working channel
• wedging according to Zavala: The bronchoscope
exerts a continuous suction. This causes a collapse
of the respective segment or sub-segment bronchus,
which has a tamponade effect on the bleeding. You Fig. 1002  Bronchus blocker (Rüsch): It is selectively placed
should set a maximum suction at the wall connection, in the main bronchus of the bleeding side via the working
channel of the bronchoscope and then the balloon (arrow)
take the plug down at the suction button of the bron-
is inflated. This protects the patient from asphyxia.
choscope and suck only with your finger.
• tamponade (Friedel's tamponade):
-- procedure: go through the working channel of the
bronchoscope with the forceps so that the forceps
looks out again; then grasp the swab or the cut tam-
ponade with the forceps, then bronchoscopy via the
tube with the swab grasped with the forceps in front
and advance the swab to the desired location and
leave it there for some time (note: The swab itself
cannot be pushed through the working channel with Fig. 1003  Resorbable tamponades (hemostatics; in this ex-
the forceps, as it is much too big.) ample Tabotamp [also bactericidal]) are excellently suited
-- material: either completely normal swabs (ball to tampon bronchial bleeding. They are stored in every
swabs) or (if available) self-absorbable tamponades central operation room. The correct size is simply cut with
scissors. They resorb themselves after 5-7 days.
(so-called absorbable hemostatics [available in eve-
ry central operating room] such as Equitamp, Tabo-
tamp). The patient must be covered with antibiotics
(e.g. amoxicillin / clavulanic acid) for the time during
which the tamponades are lying due to the increased
risk of infection.
• selective bronchus occlusion by bronchoscopic place-
ment of a Fogarty catheter or bronchus blocker bal-
loon (according to Arndt or Rüsch): This is selectively
placed in the main bronchus of the bleeding side via
the working channel of the bronchoscope and then
inflated so that the bleeding side is disabled and the
healthy side is protected. The balloon is filled with air
or sodium chloride. Alternatively, it can also be blocked
with a contrast medium so that a topographical locali-
zation is possible in X-ray. Fig. 1004  Endobronchial argon plasma coagulation (APC;
• argon plasma coagulation (APC) the APC probe is visible in blue)
-- good option especially for tumor bleeding
-- settings: 10-25 Watt, mode Pulsed 2
-- FiO2 must be < 40% (otherwise danger of an en-
dobronchial fire!)

Fig. 1001  bronchoscope [27]

724 Pulmonology
Pulmonology 725
Endocrinology

ENDOCRINOLOGICAL
EMERGENCIES
Diabetic coma
Definition
• disturbance of consciousness due to hyperglycemic
metabolic derailment
• causes of disturbance of consciousness in diabetics:
-- hypoglycemia (note: Patients with hypoglycemia
often also have hypothermia. The severe sweating
and hypoglycemia-induced reduced heat produc-
tion lead to cooling. Therefore one should always
measure the temperature in case of hypoglycemia!)
-- hyperglycemia
• limit values ​​for the measuring devices used in the res-
cue service (emergency vehicle):
-- from blood sugar < 30 mg/dl: "low"
-- from blood sugar > 600 mg/dl: "high"
Causes
• most frequent cause: infections (50%; e.g. urinary
tract infection, pneumonia, flu)
• initial manifestation of diabetes mellitus (25%)
• steroids
• dietary errors
• incompliance (e.g. omission of insulin application in
drug addicts or alcohol addicts)
• acute pancreatitis
• inadequate insulin therapy (e.g. defective insulin
pump, technical errors in insulin application, insuffici-
ent dosage, lack of availability [e.g. refugees])
• sGLT2 inhibitors (sGLT: sodium glucose cotransporter
2)
-- oral antidiabetics approved since 2012
728 Endocrinology
-- Glucose is completely reabsorbed in the proximal tu-
bule of the kidneys via the sodium-glucose cotrans-
porter 2. If the transporter is now inhibited, glucose
is lost via the kidneys and is excreted.
-- examples: canagliflozin (Invokana), dapagliflozin
(Forxiga), empagliflozin (Jardiance)
-- note: sGLT2 inhibitors have meanwhile become the
standard therapy for systolic heart failure (HFREF
[heart failure with reduced ejection fraction]), regard-
less of whether diabetes mellitus is present or not. In
the DAPA-HF study (McMurray et al, N Engl J 2019),
dapagliflozin showed a significant reduction in the
primary combined endpoint of death or hospitalizati-
on due to heart failure.
-- increased risk of diabetic ketoacidosis (DKA; life-
threatening side effect)
-- blood sugar often only slightly or not at all increased
(caution delayed diagnosis!)
-- risk factors: use in diabetes mellitus type I (not ap-
proved for this), alcohol, hypovolemia, diuretics, re-
duced carbohydrate intake, stressful situations (e.g.
surgery)
• surgery, accident
• myocardial infarction
• pulmonary embolism
• critical ischemia in PAD
• total parenteral nutrition (TPN) → risk of hyperglyce-
mia, possibly hyperosmolar coma
• hyperthyroidism
Complications
• massive exsiccosis with hypovolemic shock
• coma (i.a. aspiration)
• acute kidney failure
• thromboemboli, infarcts
• hypophosphatemia (possibly thereby rhabdomyolysis
as a result [CK ↑])
• acidosis
-- metabolic acidosis
-- respiratory acidosis (then mechanical ventilation ne-
cessary) by
◦◦ cerebral edema (consequence: bradypnea, i.e.
no more tachypnoea then as with Kussmaul brea-
thing!)
◦◦ hypophosphatemia (therapy: phosphate substitu-
tion)
Cerebral (brain) edema
• most feared complication in ketoacidotic coma
• mostly younger patients within the first 12h
• mortality: 22%
• occurrence: 0.5-1% in ketoacidotic coma
• osmotic disequilibration syndrome:
-- Along with urea, glucose is the substance with the
strongest osmotic effect, i.e. it binds water very
strongly. If glucose is removed (lowered) too quickly
from the blood vessels, the water is no longer retai-
ned intravascularly and passes into the tissue (espe-
cially brain tissue), causing cerebral edema.
 -- Decisive for the genesis is the osmotic gradient
between the intra- and extracellular space and the
blood brain barrier. Under hyperosmolar conditions,
brain cells protect themselves from swelling by pro-
ducing intracellular osmotically active molecules
(so-called idiogenic osmolecules). These molecules
dissolve only slowly. If the serum osmolarity is re-
duced too quickly (e.g. by the administration of free
water), a gradient is formed which draws water into
the brain cells.
• risk factors:
-- too rapid reduction of blood glucose (> 50 mg/dl per
hour [SI unit > 2.8 mmol/l])
-- therapy with sodium bicarbonate
-- pCO2 ↓ on admission (hyperventilation as a sign of
increased intracranial pressure)
-- urea ­↑
• signs:
-- headaches
-- blood pressure ↑­, heart rate ↓ (Cushing reflex)
-- disturbed pupil response
Types
• ketoacidotic coma (DKA: diabetic ketoacidosis; 75%)
• hyperosmolar coma (HHS: hyperglycemic hyperosmo-
lar syndrome; 25%)
• lower lethality (2-5%)
• note: Ketoacidosis can occur not only in diabetics (di-
abetic ketoacidosis), but also in alcoholics (alcoholic
ketoacidosis). This occurs primarily after excessive
alcohol intake and prolonged periods of sobriety (e.g.
malnutrition, prolonged sleep) or vomiting (e.g. alco-
hol-induced gastritis or pancreatitis).
Symptoms
• polyuria, polydipsia, exsiccosis
• weight loss, performance dip
• coma
• hypotension, tachycardia
• Kussmaul breathing (see page 777)
• acetone odor (nail polish remover, rotten apples)
• visual disturbance (due to loss of fluid with consecu-
tively reduced turgor of the lens)
• nausea, vomiting (note: Due to vomiting, the patient
himself often reduces the insulin dose for fear of hy-
poglycemia, which of course intensifies the hypergly-
cemia.)
• abdominal pain (diabetic pseudoperitonitis [very fre-
quent!])
• possibly cerebral edema (most feared complication)
Diagnostics

ketoacidotic hyperosmolar Laboratory

coma coma • glucose­ ↑ (p.d. blood sugar > 250 mg/dl); note: Even
frequency 75% 25% with a blood sugar < 250 mg/dl, a ketoacidotic coma
can still be present (euglycemic ketoacidosis ["sour but
type of diabetes type 1 diabetes type 2 diabetes
not sweet"]), especially in:
age younger older
-- pregnant women
insulin defici- absolute relative -- patients who consume only few carbohydrates
ency
-- sGLT2 inhibitors
blood sugar mostly < 800 mg/dl mostly > 800mg/dl • metabolic acidosis (pH ↓, bicarbonate ↓) with increa-
osmolarity normal increased sed anion gap (only with ketoacidotic, not with hyper-
onset rapid slow osmolar coma); degrees of severity of DKA:
lethality 2-5% 20-25%
-- mild:
◦◦ pH 7.3-7.2
◦◦ bicarbonate 15-18 mmol/l
Ketoacidotic coma -- moderate:
◦◦ pH 7.2-7.1
Definition ◦◦ bicarbonate 10-15 mmol/l
• diabetic ketoacidosis (DKA) -- severe:
• more frequent (75%) ◦◦ pH < 7.1
• mostly younger patients with diabetes mellitus type ◦◦ bicarbonate < 10 mmol/l
1 (especially children < 5 years), but also possible in • note: In hyperglycemia (ketoacidotic or hyperosmolar
type 2 coma), pseudohyponatremia is often found as a re-
• absolute insulin deficiency sult of a measurement error, i.e. hyponatremia with no
• no inhibition of lipolysis (Insulin is the strongest anti- reduced serum osmolarity (> 275 mosm/l). The true
lipolytic!) → fatty acids ↑ , formation of ketone bodies sodium value is obtained with the correction formula:
→ acidosis sodiumcorrected (mmol/l) = sodiummeasured (mmol/l) + 0.16
• hyperglycemia and exsiccosis (osmotic diuresis: From x (glucose [mg/dl] - 100). The sodium value from the
a serum concentration of 180 mg/dl the sugar can no BGA is not subject to this measurement error.
longer be reabsorbed via the kidneys and is lost via the
urine. It draws plenty of water with it.)
• in 25% initial manifestation of diabetes mellitus
• most feared complication: cerebral edema

Endocrinology 729
Urine • e.g. 4 liters in the first 6 hours
• glucosuria • rule of thumbs: 10% of body weight in 12h
• ketone bodies • balance target on the first day: + 4000 to +6000ml!
-- There are a total of three ketone bodies: acetoaceta- • control according to CVP (at best optional; target: 10-
te, acetone and β-hydroxybutyrate. In the urine test 12 cmH2O; CVC rarely required)
only acetoacetate is measured, in the blood test also • best Ringer solution (incl. potassium; best Ringer
β-hydroxybutyrate is measured.. acetate [Ionosteril]; no NaCl 0.9%, as it causes hyper-
-- rapid test: test strips (stix) for ketone bodies in urine chloremic acidosis!)
or blood (Patients should actually be equipped with • no hypotonic solutions such as glucose 5% (not even
these themselves!) in hypernatremia), only isotonic solutions because of
-- DD positive ketones: the risk of cerebral edema!
◦◦ fasting • blood sugar < 250 mg/dl: additionally glucose 10%
◦◦ alcoholism
◦◦ sGLT2 inhibitors (e.g. canagliflozin, dapagliflozin, Acidosis correction
empagliflozin) • Nabic 8.4%
• only from pH < 7.1 (risk of cerebral edema and se-
Hyperosmolar coma vere hypokalemia)
• dosage
Definition -- Nabic dose in mval = negative base excess x kgBW
• syn.: hyperglycemic hyperosmolar syndrome (HHS) x 0.3 (of which only give 1/4 within 2h)
• less frequent (25%) -- simpler rule: body weight = dose (e.g. 80 kg → 80
• mostly older patients with diabetes mellitus type 2 (Hy- mval Nabic in 2h)
perosmolar coma is not present in type 1.) • BGA every 4h (venous BGA sufficient [venous pH is
• relative insulin deficiency (still sufficient to inhibit lipoly- only 0.03 lower than arterial pH])
sis): therefore no ketone body formation, no (primary)
acidosis (therefore usually also no Kussmaul breathing
and no acetone odor)
• blood glucose derailment and exsiccosis (dehydration)
more pronounced than in ketoacidotic coma
• often insidious onset
• higher lethality (20-25%)

Diagnostics
• laboratory: Fig. 1005  Nabic 8.4% [8]
-- glucose ↑­­↑ (p.d. blood sugar > 600 mg/dl; signifi-
cantly higher than in diabetic ketoacidosis)
-- osmolarity­ ↑ (> 320 mosm/l; hence the name "hyper-
osmolar") ) Cave Nabic 8.4%
-- hence name "hyperosmolar") - primarily no acidosis
(no increased anion gap either), but this can occur
secondarily due to:
◦◦ tissue hypoxia
◦◦ lactic acidosis in metformin therapy and renal in-
sufficiency (mortality: 50%)
• urine: no ketone bodies

Therapy
• fluid administration
• acidosis correction
• insulin therapy
• potassium substitution
• other therapy
Buffering only from pH < 7.1 (risk of
Fluid administration cerebral edema and severe hypoka-
• fluid administration initially more important than in- lemia!)
sulin therapy (thereby alone blood sugar reduction by
approx. 50 mg/dl per hour)

730 Endocrinology
 -- potassium < 4.0 mmol/l: KCl 20-30 mval/h
uncritical administration of Nabic: -- potassium 4.0-5.5 mmol/l: KCl 10-20 mval/h
(almost) the only possibility that a -- potassium > 5.5 mmol/l: control
patient will die of diabetic ketoacido-
sis Other therapy
• antibiotics (50% of the causes are infections!)
• thrombosis prophylaxis (low-dose heparin [LMWH])
Insulin therapy • phosphate substitution: no longer generally recom-
• solely by rehydration decrease blood sugar by approx. mended (only in hypophosphatemia)
50 mg/dl/h (SI unit: 2.8 mmol/l) • in ARDS / pulmonary edema: negative balance
• fluid therapy before insulin therapy
• only with normal insulin (Actrapid)
• continuously via perfusor most important: fluid administrati-
• dosage: on (plus balance of 4-6 litres on
the first day); insulin administrati-
-- S3 guideline DDG (German Diabetes Society) 2011:
on is less important
initial bolus of 0.1 IU/kg, then 0.1 IU/kg/h (if no de-
crease > 10% from the initial value: increase to 0.15-
0.20 IU/kg/h)
-- alternative: no bolus, start with perfusor with initially
2-6 IU/h, increase to max. 8-10 IU/h
Lactic acidosis
• low-dose insulin therapy
• blood sugar decrease max. 50-100 mg/dl per hour (in
SI units: 2.8-5.5 mmol/l; risk of cerebral edema)
• initial hourly blood sugar measurement
• initially (i.e. in the first 48h) blood sugar reduction only
up to 250 mg/dl (if blood sugar < 250 mg/dl → additio-
nal glucose 10% [infusion rate 50-100 ml/h], but conti-
nue the insulin perfusor [do not pause] in low doses in
order to break the ketoacidosis!)
• insulin administration as long as ketones are positive
in urine (in diabetic ketoacidosis)
• In a patient with an insulin pump it is quite possible to
first increase the basal rate by 25-50% and only then,
if this is not sufficient, to switch off the pump and start
with an insulin perfusor. However, if you have little ex-
perience with insulin pumps and you are not sure whe- Definition
ther they actually work correctly (including cable and
• pH < 7.36 + lactate > 5 mmol/l (hyperlactatemia; note:
correctly seated needle), then you should start working
conversion lactate in mmol/l x 9 = lactate in mg/dl)
with an insulin perfusor.
• most frequent metabolic acidosis in hospitalized pati-
ents
Diabetic ketoacidosis: if blood sugar • most frequent metabolic acidosis with an increased
< 250 mg/dl: do not pause the insulin anion gap (see page 781)
perfusor, but keep it running and add • mostly hyperkalemia and hyperphosphatemia
glucose! • Note: The correct expression is "lactic acidosis" and
not "lactate acidosis" as commonly used. Acidosis is
caused by lactic acid (Latin: acidum lacticum) and not
Potassium substitution by lactate: Lactate is only the salt of lactic acid and
binds H+ ions as anion
• already with normal potassium levels (reason: The
• In the case of metabolic acidosis (p.d. pH < 7.36 +
administration of insulin via the H+/K+ exchanger [Ham-
standard bicarbonate < 22 mmol/l or BE [base excess]
burger shift] leads to potassium uptake into the cell
< -2 mmol/l) with increased lactate, it should always be
and thus to hypokalemia in the serum. Furthermore,
checked whether the reduction in bicarbonate is suffici-
the decrease in acidosis also leads to hypokalemia via
ently caused by increasing of lactate or whether there
the H+/K+ exchanger.)
is an additionall disorder. The rule here is that for every
-- p.o. mmol/l lactate, the bicarbonate drops by 1 mmol/l.
-- infusion (max. 40 mval KCl in a free-running infusi-
on)
-- perfusor (CVC necessary)
• dosage

Endocrinology 731

Lactate: always pay attention to the
specified units (big difference!): 1
mmol/l = 9 mg/dl!
Pathophysiology
• lactate: anion of lactic acid
• Pyruvate is degraded to lactate by the enzyme lactate
dehydrogenase (LDH).
• An increased lactate is always a sign of a decreased
oxygen supply for the cell (e.g. as a result of a de-
creased cardiac output [shock parameter], hemoglobin
or SaO2): Under hypoxia, pyruvate can no longer be
introduced via pyruvate dehydrogenase into the citra-
te cycle (syn.: citric acid cycle, Cori cycle) and is thus
consecutively degraded via lactate dehydrogenase
(LDH) to lactate.
• elimination of lactate by
-- kidney (30%)
-- liver (70%)
◦◦ end-oxidation in citrate cycle
◦◦ recycling (gluconeogenesis)
• increased production of lactate (e.g. hypoxia → anae-
robic glycolysis ↑)
• reduced clearance
-- renal insufficiency
-- hepatic insufficiency (gluconeogenesis ↓)
-- deficiency of thiamine (= vitamin B1: important co-
enzyme of pyruvate dehydrogenase: pyruvate →
acetyl-CoA → citric acid cycle ↓)
lactate glucose
lactate dehydrogenase
pyruvate
pyruvate dehydrogenase
(coenzyme: thiamine)
acetyl-CoA
citrate
cylce
Fig. 1006  Pyruvate can no longer be introduced into the
citrate cycle (= citric acid cycle = tricarboxylic acid cycle =
Cori cycle) under oxygen deficiency and is therefore degra-
ded to lactate via lactate dehydrogenase (LDH). It is simi-
lar to thiamine deficiency (e.g. in alcoholics): If glucose is
being administered, pyruvate cannot be introduced into the
citrate cycle because thiamine is an essential coenzyme of
pyruvate dehydrogenase. Consecutively it is degraded to
lactate and lactic acidosis develops.
732 Endocrinology
Etiology
• shock (any genesis)
• tissue hypoxia (any genesis)
• status post resuscitation
• congestive heart failure
• severe anemia
• sepsis
• liver insufficiency (e.g. acute liver failure, liver cirrhosis
[here often increased lactate values])
• renal insufficiency, uremia
• renal insufficiency, uremia - mesenteric infarction (is a
rare and not the most common cause!):
-- here the highest lactate values
-- Here typically the D-lactate is increased. With all
other causes the L-lactate is usually increased.
However, this differentiation is usually not offered in
most laboratories.
-- Like a reflex in an elevated lactate initially absurd-
ly almost always is thought of mesenteric ischemia.
However, this is only a very rare cause of lactic aci-
dosis. In the case of lactic acidosis, pseudoperitonitis
often also causes abdominal pain, so that unfortuna-
tely in clinical everyday life completely unnecessary
CT abdominal examinations with CT angiographies
are carried out far too often. If the lactate is already
elevated in mesenteric ischemia, it is usually alrea-
dy too late anyway: The intestine is usually already
necrotic, so that the abdomen is often only opened
briefly and then closed again immediately and the
patient dies (in statu moriendi). The only thing you
don't have to think about when you have an incre-
ased lactate, because it is already too late, is the
mesenteric ischemia (exaggerated)!
• malignancies (lactate-producing; e.g. lymphomas, leu-
kemias, lung tumors
• pheochromocytoma
• thiamine deficiency (e.g. alcoholics, beriberi, renal re-
placement therapy [loss of water-soluble vitamins!],
polyuria [e.g. diabetes mellitus], high-dose, long-term
diuretic therapy)
• hypomagnesemia (functional thiamine deficiency):
Magnesium is an important cofactor for pyruvate dehy-
drogenase (e.g. thiamine [= vitamin B1] as an impor-
tant coenzyme): It introduces pyruvate into the citric
cycle. In hypomagnesemia this enzyme does not func-
tion properly, so that pyruvate is degraded to lactate
and lactic acidosis can develop.
• diabetic coma (e.g. ketoacidotic coma)
• acute pancreatitis (often increased lactate)
• hyperventilation (almost always increased lactate)
• seizures
• intoxications
-- ethanol, methanol, ethylene glycol
-- salicylates
-- fire gases (mainly hydrogen cyanide, but also car-
bon monoxide)
-- paracetamol (lactate as a prognostic parameter)
-- arsenic (Arsenic inhibits i.a. the pyruvate dehydro-
genase.)
• drugs (e.g. INH, nitroprusside sodium, terbutaline, HIV
drugs [NRTI], β2-mimetics); important especially:
-- metformin → metformin-associated lactic acidosis
(MALA):
◦◦ high lethality (50%)
◦◦ especially in renal insufficiency (metformin there-
fore contraindicated from creatinine > 1.4 mg/dl)
◦◦ if necessary determination of the metformin level
for diagnostic confirmation (norm: 1-2 μg/ml
◦◦ Hemodialysis is the first choice in the case of an
overdose (intoxication) of metformin. Metformin is
very well dialysable.
◦◦ discontinue 24-48h before administration of con-
trast agent (note: According to current recom-
mendations, metformin no longer needs to be dis-
continued in normal renal function [GFR > 60 ml/
min; Goergen et al, Radiology 2010].)
◦◦ In principle, metformin should always be discon-
tinued in critically ill patients (intensive care unit)!
-- propofol (propofol infusion syndrome [see page
166])
• parenteral nutrition with sorbitol / fructose
• refeeding syndrome
• malignant hyperthermia (classic anesthetic incident)
• MELAS (mitochondrial encephalopathy, lactat acidosis
and stroke like episodes)
The most common cause of lactic
acidosis in intensive care is shock (and
not mesenteric ischemia!).
study
Severe hyperlactatemia, lactate clearance and mortality in
unselected critically ill patients
Haas et al, ICM 2016
• retrospective observational study
• 14,040 intensive care patients
• severe lactic acidosis (p.d. lactate > 10 mmol/l):
-- in 9.8%
-- mortality: 78%
• causes: mainly
-- sepsis (34%)
-- cardiogenic shock (19%)
-- cardiopulmonary resuscitation (14%)
-- mesenteric infarction ( only in 4%; here the
highest lactate values [17-18 mmol/l])
Classification (according to Cohen &
Woods)
• lactic acidosis type A: with systemic hypoxia (frequent)
• lactic acidosis type B: without systemic hypoxia (rare)
-- B1: diseases (e.g. liver failure, diabetes mellitus,
malignancies, sepsis, pheochromocytoma)
-- B2: drugs (e.g. metformin), toxins
-- B3: congenital metabolic defects (very rare; espe-
cially glucose-6-phosphate dehydrogenase defici-
ency, fructose-1,6-diphosphatase deficiency [here-
ditary fructose intolerance], pyruvate carboxylase
deficiency, MELAS)
Symptoms
• nausea, vomiting
• abdominal pain ("acute abdomen"; pseudoperitonitis)
• Kussmaul breathing (attempt of respiratory compensa-
tion)
• disturbance of consciousness, somnolence, coma
• circulatory insufficiency (cardiac decompensation [The
endogenous catecholamines are no longer sufficient in
acidosis.])
Therapy
• circulatory therapy
-- fluid administration
-- if necessary catecholamines
• possibly buffering with sodium bicarbonate (Nabic;
syn.: sodium hydrogen carbonate [NaHCO3]) 8.4%
-- perfusor (CVC)
◦◦ dosage: Nabic 8.4% in ml = BE x kgBW x 0.3; give
only half of it at first, then BGA control
◦◦ not undisputed (i.a. Cooper et al, Ann Intern Med
1990 and Mathieu et al, Crit Care Med: no positive
effects)
-- principle: Compensate chronic acidoses slowly, acu-
te acidoses quickly!
• lactic acidosis of still unclear etiology → immediate
probational administration of thiamine (vitamin B1) 300
mg i.v.; especially in chronic alcohol abuse)
• hemodialysis
-- Lactate is a small molecule and thus well removable
by hemodialysis
-- means of choice for therapy refractory lactic aci-
dosis (especially for type B)
-- especially for lactic acidosis due to metformin and
anuria!
• therapy of hyperkalemia (see page 765)
• Bohr effect: The affinity of oxygen for hemoglobin de-
creases with increasing pCO2 and decreasing pH, i.e.
the release of oxygen into the tissue increases. There-
fore, a metabolic acidosis occurring during resuscitati-
on or shock should only be buffered from a pH value of
< 7.15, since a moderate acidosis leads to an impro-
ved oxygen release to the tissue due to the Bohr effect.
no buffering of hypoperfusion-related
lactic acidosis with pH > 7.15
Endocrinology 733
Thyrotoxic crisis ▪▪ primarily thyrostatic (sufficient in 50%) for 12-18
months
▪▪ only in case of relapse: definitive therapy (ra-
dioiodine therapy or surgery [subtotal thyroid
resection])
-- rarely combination of Graves disease and thyroid
autonomy (Marine-Lenhart syndrome)
• usually triggered by the administration of large amounts
of iodine (e.g. contrast agents)
• no correlation between the severity of the thyrotoxic
crisis and the level of thyroid hormone concentration
(more a clinical and less a laboratory diagnosis!))
• w>m
• mortality: 30%

Definition
• severe life-threatening hyperthyroidism
• 1% of all patients with hyperthyroidism
• most common underlying diseases of the thyroid gland
with hyperthyroidism:
-- thyroid autonomy :
◦◦ most common cause of hyperthyroidism
◦◦ above all elderly patients
Fig. 1007  Young patient with Graves disease: One reco-
◦◦ slow ("creeping") onset of hyperthyroidism
gnizes a pronounced goiter and the exophthalamus. Ext-
◦◦ cause: iodine deficiency rathyroid involvement such as endocrine orbitopathy only
◦◦ struma nodosa occurs in Graves disease and not in other thyroid diseases
◦◦ types: unifocal, multifocal, disseminated (such as thyroid autonomy).
◦◦ diagnosis: especially scintigraphy (technetium)
◦◦ therapy: thyreostatics only until euthyroidism is
achieved, then domain of radioiodine therapy (nu-
clear medicine)
-- Graves disease (M. Basedow [named after the Ger-
man physician Carl Adolph von Basedow, 1799-
1854])
◦◦ immunogenic hyperthyroidism (autoimmune thy-
roiditis): stimulating TSH receptor antibodies
(TRAB)
◦◦ A thyrotoxic crisis occurs more often here than
with thyroid autonomy.
◦◦ above all younger patients
◦◦ rapid ("sudden") onset of hyperthyroidism
◦◦ struma diffusa
◦◦ w:m = 5:1
Fig. 1008  large visible goiter (grade II)
◦◦ in 60% endocrine orbitopathy
◦◦ Merseburg triad: goiter, exophthalamus, tachycar-
dia
◦◦ diagnosis:
▪▪ laboratory: TRAB (TSH receptor antibodies; in
95% positive), anti-TPO (thyroid peroxidase; in
70% positive)
▪▪ sonography: enlarged thyroid gland, hypo-
echoic, hypervascularization ("vascular inferno")
▪▪ scintigraphy (technetium): not necessary for
Graves disease
◦◦ therapy:

734 Endocrinology

Fig. 1009  sonography of the thyroid gland in Graves di-
sease: It is enlarged (goiter [p.d. > 18ml in women and >
25ml in men], here diffuse goiter, i.e. without knots), hypo-
echoic (i.e. it has the same echogenicity as the neighboring
neck muscles) and the pathognomonic hypervascularizati-
on can be seen in color duplex and in power mode ("vas-
cular inferno").
Trigger
• iodine-containing contrast agent (e.g. contrast CT,
coronary angiography)
• iodine-containing drugs, e.g..
-- amiodarone (note: Amiodarone often leads to a drop
in TSH and an increase in fT4 [possibly also an in-
crease in fT3], which is completely normal. It is only
necessary to discontinue amiodarone and also to
administer a thyreostatic if TSH < 0.01 U/l + fT3 ↑
and clinical symptoms of hyperthyroidism are pre-
sent. In amiodarone-induced hypothyroidism, amio-
darone does not have to be discontinued at all, only
hormone replacement [e.g. L-thyroxine 50μg] should
be performed.)
-- indocyanine green
-- external products
-- excessive intake of thyroid hormone tablets
◦◦ e.g. in the context of paranoid schizophrenia, e.g.
for weight reduction
◦◦ Most of them are T4 preparations, so that corres-
pondingly increased fT4 values can​​ also be mea-
sured in the laboratory.
◦◦ The administration of thyreostatic drugs, which
only inhibit the synthesis and secretion of new thy-
roid hormones and have no influence on externally
supplied thyroid hormones, is pointless.
• discontinuation of thyrostatic drugs
• definitive therapy, although there is still hyperthyroi-
dism and not yet euthyroidism:
-- radioiodine therapy for hyperthyroidism
-- surgery
Fig. 1010  pronounced goiter extending to the retroster-
nally with mediastinal widening (see arrow), which was
manifestly hyperthyroid in the laboratory (The patient was
admitted with a STEMI. Therefore, without waiting for any
laboratory tests, cardiac catheter examination with PCI
and stent implantation was carried out immediately. In the
further course the patient showed symptoms of an unclear
"sepsis". Ultimately it was a thyrotoxic crisis triggered by
the applied contrast medium.)
Symptoms
• sinus tachycardia (often > 140/min), tachyarrhythmia
absoluta
• fever; warm, wet skin ("sepsis")
• massive sweating
• vomiting, diarrhea ("gastroenteritis")
• dehydration, exsiccosis
• possibly thromboembolism (including increased risk of
sinus vein thrombosis)
• tremor (pronounced!)
• restlessness, anxiety
• muscular weakness (pronounced!), adynamia
• blood pressure
-- initial hypertensive (high BP amplitude [DD aortic
valve insufficiency])
Endocrinology 735
 -- later hypotensive (thyrotoxic cardiomyopathy)
• cardiomyopathy → acute heart failure
• pseudobulbar paralysis (clumsy language, swallowing
disorder → danger of aspiration!); note bulbar paraly-
sis: paralysis (tongue, palate) due to lesion of cranial
nerve nuclei in the medulla oblongata; pseudobulbar
paralysis: same symptoms, but without anatomical
correlate
• disturbance of consciousness, somnolence, psychotic
states

Scores
• Burch-Wartofsky score (according to Burch et al, En-
docrinol Metab Clin North Am 1993; see infobox)
• Akamizu criteria (according to Akamizu et al, Thyreoid
2012; see infobox)

736 Endocrinology

Therapy
• fluid administration (4000-6000 ml/day)
• electrolyte balance
• oxygen administration
• sufficient caloric nutrition (2500-3000 kcal/day)
• thyrostatics (inhibition of the synthesis [inhibition of
thyroid peroxidase] of new thyroid hormones and their
secretion; side effects: especially agranulocytosis [on
average only after 70 days], toxic hepatitis):
-- thiamazole (syn.: methimazole; Favistan)
◦◦ means of choice
◦◦ dosage:
▪▪ 1 amp. = 1ml = 40mg
▪▪ 80mg i.v., then 6 x 40mg / day or 240mg/day as
continuous infusion
-- propylthiouracil (Propycil):
◦◦ means of choice in pregnancy
◦◦ dosage: starting dose 500-1000mg, then mainte-
nance dose 300-600mg p.o. in 4-6 single doses
• perchlorate (Irenat) 3 x 20gtt daily
-- inhibition of iodide uptake
-- disadvantage: Thyroid scintigraphy and radioiodine
therapy is then no longer possible for several weeks.
• β-blocker:
-- cautious with sinus tachycardia (as on-demand ta-
chycardia)
-- best (e.g. in tachyarrhythmia absoluta) non-se-
lective β-blockers (as extracardiac metabolic effects
are desired); non-selective β-blockers also inhi-
bit the conversion of T4 [storage form] to T3 [acti-
ve hormone]), e.g. propranolol (4 x 20-80mg/day
p.o./nasogastric tube or 1-5mg i.v.) or carvedilol
• potassium iodide solution (5%; syn.: Lugol´s solution
[named after the French physician Jean Guillaume Au-
guste Lugol, 1786–1851]; "plummering")
-- 3 x 10gtt daily
-- only if iodine-induced crisis has been excluded
-- only 2h after thiamazole administration
-- This is mainly carried out in the Anglo-American lan-
guage area. In iodine deficient areas such as Ger-
many, use should be cautious, as this can even exa-
cerbate hyperthyroidism!
• lithium
-- thyrostatic effect by blocking the release of prefor-
med thyroid hormones from the thyroid gland
-- in iodine-induced crisis
-- infusion of lithium chloride solution 0.63% or 1.5g
p.o.
-- off-lable-use (not approved for this)
-- therapeutic lithium level (only very narrow!): 0.6-0.8
mval/l (cave: Symptoms of lithium intoxication are
very similar to those of thyrotoxic crisis [especially
tremor]!)
• steroids
-- reasons:
◦◦ inhibition of conversion T4 → T3 (T3 is the active
thyroid hormone, T4 only the storage form.)
◦◦ severe hyperthyroidism → adrenocortical insuf-
ficiency (Thyroid hormones lead to an increased
glucocorticoid clearance via the kidney.)
-- hydrocortisone 200mg/24h or prednisolone 50mg
i.v. 1-1-1
• bile acid binders (anion exchange resins)
-- to interrupt the enterohepatic cycle of thyroid hormo-
nes (Thyroid hormones have a long half-life: T3 24h,
T4 even 1 week!)
-- representatives:
◦◦ colestyramine (Quantalan): 3 x 1 sachet (1 sachet:
4g)
◦◦ colestipole (Cholestabyl): 3 x 1 sachet (1 sachet:
5g)
• temperature reduction
-- physically
Endocrinology 737
 -- pharmacologically
• low-dose heparin (LMWH) for the thrombosis prophy-
laxis
• if necessary sedatives
• if necessary plasmapheresis / hemofiltration (possibly
to reduce the circulating hormone quantity preopera-
tively or if surgery is not possible)
• if necessary emergency thyroidectomy (if conservative
therapy is ineffective; the most effective measure)

means of choice for TAA in hyperthy-

roidism: propranolol Fig. 1011  myxedematous swelling of the face

Myxedema coma

Definition
• syn.: hypothyroid coma
• severe hypothyroidism with coma
• first case described: 1879 in London, St. Thomas Hos- Fig. 1012  Myxedema on the lower leg: pasty swelling as
well as scaly and dry skin
pital
• mostly unknown (e.g. previous Hashimoto thyroiditis) /
inadequately treated hypothyroidism Diagnostics
• occurring more frequently in winter • laboratory
• occurring more frequently older women • ECG (i.a. low voltage, bradycardia, AV block)
• trigger for decompensation • echocardiography (ejection fraction ↓, pericardial effu-
-- trauma sion)
-- infections • chest X-ray (cardiomegaly)
-- anesthesia, sedatives
• very rare Laboratory
• high mortality (50%) • TSH ↑↑ (exception: secondary hypothyroidism [e.g. in
anterior pituitary lobe insufficiency])
• fT3 / fT4 ↓↓ (usually not measurable)
Symptoms
• hyponatremia (in 50%; ADH ↑, „water intoxication“)
• myxedematous swelling of the skin (doughy swelling
• CK ↑ (increased membrane permeability; seizures)
of the subcutis
• LDH ­↑
-- upper eyelids, back of the hand / foot
• hypoglycemia
-- not impressionable
• BGA: pCO2↑­, pH ↓
• scaly, dry, cold skin
• hypothermia
• hypoventilation → hypercapnia, respiratory acido-
Therapy
sis, possibly hypercapnic coma • ventilation (mostly necessary; non-invasive or inva-
• bradycardia sive ventilation)
• arterial hypotension • fluid administration (e.g. Ringer)
• myxedema heart • L-thyroxine:
-- heart failure (thyroid hormones ↓ → β-receptors ↓) -- d1 500μg i.v. (as short infusion with NaCl 0.9% over
30-60min)
-- pericardial effusion (low voltage in ECG)
-- from d2 100μg i.v./day
-- AV-block III
-- after 1 week change to p.o.
• hypo- / areflexia
• hypoglycemia → glucose infusion
• seizures (caused by hypercapnia)
• AV block III → temporary pacemaker
• constipation (up to ileus)
• hydrocortisone
• hypoglycemia
-- dosage: 100mg as bolus, then 100mg over 24h
-- reason: The administration of thyroid hormones
increases the glucocorticoid requirement (glucocor-
ticoid clearance ↑) and can thereby trigger an adre-
nocortical insufficiency up to Addison crisis!

738 Endocrinology
• hypothermia → warming up; cave at body temperature Addison crisis
< 30ºC no active-external (e.g. electric blankets, warm
air blower [Bair Hugger]), but only active-internal (e.g.
CoolGard) warming up (reason: danger of peripheral
vasodilation with consecutive circulatory insufficiency)

high dosage of thyroid hormones

(e.g. L-thyroxine 500μg i.v.):
always combine with hydrocorti-
sone 100mg i.v. (otherwise risk of
Addison crisis!)

Definition
• acute primary adrenocortical insufficiency
• adrenocortical insufficiency:
-- 80% primary (defect of both adrenal cortex; syn.: Ad-
dison disease)
-- 20% secondary (defect of the pituitary gland with
consecutively reduced ACTH release)
• named after the English physician Thomas Addison
(1793-1860), who first described it in 1855 ("bronze
disease")
• mostly pre-existing adrenocortical insufficiency (mostly
autoimmune) and insufficient or missing dose adjust-
ment in stress situations etiology
• with known Addison disease in 40% Addison crisis

Fig. 1013  adrenal gland: structure and function

Endocrinology 739
 phospholipid syndrome)
• bilateral adrenalectomy (e.g. in renal cell carcinoma
[RCC] with metastasis in the contralateral adrenal
gland; for the scheme of hormone substitution after
bilateral adrenalectomy see infobox; always issue an
emergency card)
• high-dose administration of thyroid hormones (e.g.
L-thyroxine 500μg as part of therapy of myxedema
coma): The administration of thyroid hormones increa-
ses the glucocorticoid clearance and can thus trigger
adrenocortical insufficiency up to Addison crisis!
• drugs: i.a.
-- etomidate (inhibition of the 11β-Hydroxylase →
steroid synthesis in adrenal cortex ↓ [adrenostatic
effect]; excessively increased mortality with conti-
nuous etomidate infusion → therefore only used as
short anesthetic; in patients with sepsis, even the
single dose as part of induction of anesthesia leads
to an increased rate of adrenocortical insufficiency
and increased mortality [for studies see boxes])
-- ketoconazole
• adreno-genital syndrome (AGS)
-- with or without salt losing syndrome
-- note: If children with a known AGS are acutely se-
riously ill or suffer a serious traffic accident, they
should immediately (preferably already preclinically)
receive hydrocortisone (alternatively prednisolone)!

Etiology
• decompensation (by certain triggers) of a pre-existing
chronic adrenocortical insufficiency; causes for chronic
adrenocortical insufficiency:
-- inflammatory (adrenalitis)
◦◦ autoimmune (most frequent cause [80%]); in 40%
isolated, in 60% associated with other autoim-
mune diseases in the context of polyglandular
autoimmune syndrome (PAS) II (syn. Schmidt-
Carpenter syndrome): diabetes mellitus type I,
autoimmune thyropathy (Hashimoto thyroiditis,
Graves disease); i.a. also possible with immune
checkpoint inhibitors (e.g. ipilimumab, nivolumab)
◦◦ infectious (tuberculosis, AIDS, CMV, mycoses)
-- neoplastic (metastases in the adrenal gland, e.g.
small cell lung cancer)
• adrenocortical atrophy under prolonged steroid thera-
py (cause of a secondary adrenocortical insufficiency)
-- too rapid weaning
-- missing increase in stress situations: Long-term ste-
roid therapy (e.g. polymyalgia rheumatica, Crohn's
disease) leads to adrenocortical atrophy. If these pa-
tients, who have been on steroid therapy for a long
time, suddenly experience an acute stress situation
(e.g. surgery for perforated appendicitis with septic
shock, traffic accident with polytrauma), 100 mg hy-
drocortisone must always be administered!
• Waterhouse-Friderichsen syndrome
• bleeding
-- meningococcal sepsis
-- oral anticoagulants (warfarin, NOAC)
• bilateral adrenal vein thrombosis (e.g. in HIT II, anti-

740 Endocrinology
Fig. 1014  left sided lung cancer with right sided adrenal
metastasis

study

Etomidate versus Ketamine for rapid sequence intubation

in acutely ill patients
Fig. 1015  sonography: right sided adrenal metastasis
Jabre et al, Lancet 2009

• multicenter randomized controlled study

• 655 intubated patients (emergency); induction of anes-
thesia:
-- etomidate 0.3 mg/kg
-- ketamine 2 mg/kg
• results: etomidate
-- no difference in mortality
-- significantly more frequent adrenocortical insufficien-
cy
-- subgroup sepsis: tendentially increased mortality (not
significant)

Fig. 1016  CT abdomen: left sided adrenal metastasis (ar-

rows)

Endocrinology 741
 by the detection of meningococcus in blood cultures.)
• lethality: 90%
• therapy: i.a.
study -- fluid administration (crystalloid; 20ml/kg as bolus
[that is a lot of volume!])
-- hydrocortisone 50 mg/m2/d
-- antibiotics (e.g. cefotaxime, ceftriaxone):
The effects of etomidate on adrenal responsiveness and
mortality in patients with septic shock ◦◦ Meningococci are very sensitive and actually easi-
Cuthbertson et al, Journal of Intensive Care Medicine 2009 ly treatable germs.
◦◦ possibly even preclinical administration (the only
• a priori planned analysis of the CORTICUS study (499 indication for the preclinical administration of anti-
patients with septic shock biotics as an emergency physician; then less likely
• subgroup: etomidate for induction of anesthesia (96 pa- positive blood cultures, but the children survive;
tients) but usually not available)
-- increased adrenocortical insufficiency (non-res- ◦◦ intramuscular administration also possible (if no
ponder in ACTH test)
intravenous or intraosseous access can be esta-
-- significantly increased mortality (28 days) blished quickly)
-- Casuistics showed positive effects for a short-term
lysis (urokinase 200000 IU as bolus, followed by
50000 IU/h; no general recommendation).
no induction of anesthesia
with etomidate in patients with
(suspected) sepsis (every 3rd
intensive care patient!):
increased rate of adrenocorti-
cal insufficiency!

study

Single-Dose Etomidate is not associated with increased

mortality in ICU patients with sepsis: Analysis of a large
electronic ICU database
McPhee et al, Crit Care Med 2013

• retrospective analysis (American database)

• induction of anesthesia in 1102 intensive care patients
with sepsis
-- etomidate
-- other hypnotics
• result: no increased mortality

Fig. 1017  meningococcal sepsis: distinct skin hemorrha-

ges and necrosis
Waterhouse-Friderichsen syndrome
• named after the English physician Rupert Waterhouse
(1873-1958) and the Danish pediatrician Carl Fride-
Trigger
richsen (1886-1979) • stress
• acute adrenal gland failure due to bacterial infections • surgery
(meningococcal sepsis [15%; usually no meningism], • accidents, trauma
OPSI [overwhelming post-splenectomy infection]) • severe infections (most common trigger at all: gastro-
• „adrenal apoplex" intestinal infections), sepsis
• pathophysiology: sepsis → DIC (mostly stage III) →
bleeding into adrenal glands
• mostly children most common cause of Addison
crisis: pre-existing adrenocortical
• petechial bleeding into the skin ("intravital cadaveric
insufficiency + insufficient / missing
spots"; inspection of the entire integument!)
dose adjustment in stress situations!
• cerebrospinal fluid puncture contraindicated here due
to the risk of bleeding (The diagnosis is confirmed here

742 Endocrinology
Symptoms
• vomiting, diarrhea ("gastroenteritis" [cave: also the
most common trigger!)
• exsiccosis
• arterial hypotension, hypovolemic shock
• oliguria
• fever ("sepsis")
• pseudoperitonitis ("acute abdomen")
• pigmentation of the skin (The negative feedback leads
to an increased production of CRH [corticotropin-re-
leasing hormone] in the hypothalamus: CRH not only
leads to an increased formation and release of ACTH,
but also of POMC [proopiomelanocortin] in the pituitary
gland. This in turn causes an increased melanin syn-
thesis in the melanocytes ["bronze disease"] via the
melanocyte-stimulating hormone (MSH; syn. Melano-
tropine.)
• in history
-- loss of weight (up to cachexia [not infrequently hos-
pital admission for tumor search])
-- loss of performance
• disturbance of consciousness, somnolence, coma
most common manifestation of an
Addison crisis: unclear shock!
therefore with unclear shock:
hydrocortisone 100mg i.v.
Diagnostics (Addison disease)
• hyponatremia, hyperkalemia
• cortisol (= hydrocortisone) ↓ (draw in the morning at 8
o'clock)
-- < 5 μg/dl: suspicious (typically in Addison disease <
2 μg/dl) → ACTH test
-- 5-20 μg/dl: grey area
-- > 20 μg/dl: exclusion
• ACTH test (Synacthen test)
-- cortisol determination basal and 60min after admi-
nistration of 250μg ACTH i.v. (cortikotropin, Synac-
then; 1 amp. = 250μg)
-- possible at any time of the day
-- Addison disease: no increase in cortisol > 9 μg/dl;
increase > 18 μg/dl → exclusion
• eosinophilia (differential blood count)
• possible etiological clarification:
-- adrenocortical autoantibodies (antibody against
the 21-hydroxylase; usually no therapeutic conse-
quence and therefore not absolutely necessary)
-- imaging of adrenal glands (sonography, CT)
Fig. 1018  Synacthen (ACTH; 1 amp. = 1ml = 250µg)
Laboratory
• electrolyte disorders
-- hyponatremia
-- hyperkalemia (with diarrhea often normal potassi-
um)
-- hypercalcemia
• hypoglycemia
• eosinohilia (differential blood count)
• metabolic acidosis
• hormones:
-- cortisol ↓
◦◦ syn.: hydrocortisons
◦◦ normal values ​​(circadian rhythm):
▪▪ 6-10 o'clock: 50-195 ng/ml
▪▪ 16-20 o'clock: 23-119 ng/ml
◦◦ A serum cortisol > 25 μg/dl [= 250 ng/ml] or
700 nmol/l in an intensive care patient excludes
adrenocortical insufficiency!
-- aldosterone ↓
-- ACTH ↑
suspected Addison crisis:
immediate determination of
cortisol, aldosterone and ACTH
and initiation of therapy!
first take the blood sample (serum; to
confirm the diagnosis), only then
hydrocortisone i.v. (is often forgotten!)
Therapy
• do not wait for laboratory chemical results of hormone
assay (but reserve serum sample for diagnosis)
• NaCl 0.9% + glucose 5% in a ratio of 1:1 (alternatively:
balanced solution), at the beginning 3000 ml/6h
• metabolic acidosis → possibly buffering with Nabic
8.4% (especially from pH < 7.10)
• hydrocortisone (syn.: cortisol)
-- 100mg i.v., then 100mg over 24h in glucose 5% (Al-
ternatively, if hydrocortisone is not available [e.g.
preclinical], prednisolone 25mg i.v. can also be gi-
ven. The conversion of hydrocortisone to predniso-
lone takes place in the ratio 1:4. Dexamethasone
[Fortecortin] or methylprednisolone [Urbason], on
the other hand, are not an option, since they no mi-
neralocorticoid effect at all.)
-- from day 3 reduction (daily halving of dose)
-- from 50mg additionally the mineralocorticoid fludro-
cortisone p.o. (Astonin H, Florinef; note: Hydrocorti-
sone has a sufficient mineralocorticoid effect from a
dose of 50mg and above.)
◦◦ 0.1-0.2 mg/d p.o. (target: renin in the upper normal
range [0.1-0.2 mg/dl]; note: not available i.v.)
◦◦ only necessary for primary, not secondary adre-
nocortical insufficiency (In contrast to the gluco-
Endocrinology 743
 corticoids, the synthesis of mineralocorticoids in Hypopituitarism
the adrenal cortex is not ACTH-dependent and
therefore not reduced in secondary adrenocorti-
cal insufficiency, in which the pituitary gland is di-
seased and not the adrenal glands.)
◦◦ note: The company Merck Serono ceased distri-
bution at the beginning of 2015, so that Astonin
H was no longer available for a certain time. As
a substitute there was fludrocortisone under the
trade name Florinef (company E.R. Squibb &
Sons Limited), which was however not approved
in Germany. Since February 2016, the Astonin H
has been delivered by Merck again.
-- An infection, which is a frequent cause of an Addison
crisis, is not a contraindication for the administration
of hydrocortisone.
-- finally, issue of an emergency patient ID card and of
an emergency set (1 amp. hydrocortisone for self-
application i.m. in the thigh with a 2ml disposable
syringe and two needles [yellow cannula for pulling
up, gray cannula for injection]; including training)

Definition
• overwiew: pituary insufficiency
-- anterior pituitary insufficiency: loss of anterior pitui-
tary gland function (anterior lobe; syn.: hypopituita-
rism)
-- posterior pituitary insufficiency loss of posterior pi-
tuitary gland function (posterior lobe; syn.: diabetes
insipidus [centralis])
• failure of the functions of the anterior pituitary lobe
• sequence of failure: GH (growth hormon [somatropin])
→ LH (luteinizing hormone [lutropin]) / FSH (follicle-
stimulating hormone [follitropin]) → TSH (thyroid sti-
mulating hormone [thyreotropin]) → ACTH (adrenocor-
ticotropic hormone [cortikotropin])

Types
• according to extent:
-- partial hypopituitarism ((most common form)
-- total hypopituitarism (syn.: panhypopituitarism, Sim-
monds' disease [named after the German patholo-
gist Morris Simmonds, 1855-1925])
• according to time:
-- acute hypopituitarism (= pituitary coma [see info-
box])
-- chronic hypopituitarism
• according to genesis:
-- primary hypopituitarism (defect of the pituitary gland;
most commen)
-- secondary hypopituitarism (defect of the hypothala-
mus; very rare)

Causes
• tumors:
-- macroadenomas
◦◦ most common cause (70%)

744 Endocrinology
 ◦◦ i.e. size > 1cm -- bradycardia
◦◦ by displacement of the pituitary gland • secondary hypogonadism
◦◦ examples: hormone-inactive adenoma, cranio- -- infertility
pharyngeoma, dermoid cyst, teratoma -- loss of libido
-- metastases -- loss of axillary and pubic hair
-- granulomas (e.g. sarcoidosis, tuberculosis, eosino- -- fine facial skin folds
philic granuloma) -- osteoporosis
• traumatic brain injury (TBI) -- women: estrogen deficiency
• intracranial bleeding (e.g. SAH) ◦◦ hot flushes
• surgery (cranial) ◦◦ vaginal atrophy, dyspareunia
• irradiation (cranial) ◦◦ amenorrhea
• hemochromatosis (iron deposits also in the pituitary -- men: testosterone deficiency
gland) ◦◦ abdominal alopecia
• Sheehan syndrome: ◦◦ decrease in muscle strength
-- named after the British pathologist Harold Leeming ◦◦ depression, lethargy
Sheehan (1900-1988)
• hyposomatotropism (growth hormone deficiency)
-- postpartum necrosis of the anterior pituitary lobe of
-- reduced growth / dwarfism in childhood
the mother after birth
-- increase in cardiovascular risk profile
• hypophysitis
◦◦ increase in abdominal obesity
-- autoimmune (i.a. immune checkpoint inhibitors [e.g.
ipilimumab, nivolumab; see also excursus page ◦◦ LDL increase, HDL decrease
745]) -- loss of performance
-- infectious (e.g. hantavirus infection) -- osteoporosis

Pathophysiology
• deficiency of ACTH → secondary adrenocortical insuf-
ficiency ( The secondary adrenocortical insufficien-
cy is more frequent than the primary adrenocortical
insufficiency!)
• deficiency of TSH → secondary hypothyroidism
• deficiency of gonatotropins → secondary hypogona-
dism
• Ausfall von STH → hyposomatotropism (lack of growth
hormone)

Symptoms
Diagnostics
• secondary adrenocortical insufficiency
• general (screening)
-- adynamia, weakness
• special
-- fatigue, apathy
-- loss of performance
General diagnostics (screening)
-- arterial hypotension
• corticotropic axis:
-- weight loss
-- cortisol (basal; in the morning) ↓
-- nausea, vomiting
-- ACTH ↓
-- pale skin coloration (alabaster pallor; no hyperpig-
mentation in contrast to primary adrenocortical insuf- • thyrotropic axis: fT4 ↓
ficiency ["white" Addison]: Due to the reduced ACTH • gonadotropic axis :
production, POMC is also reduced.) -- testosterone ↓
-- hypoglycemia -- LH, FSH ↓
-- hyponatremia • lactotropic axis: Prolaktin ↓
• secondary hypothyroidism • somatotropic axis: IGF-1 ↓
-- fatigue, lethargy
-- retardation Special diagnostics
-- dry skin • corticotropic axis (detection of secondary adrenocorti-
-- cold intolerance cal insufficiency):
-- brittle nails -- ACTH ↓
-- weight gain -- cortisol (basal; in the morning): normal value: 6-25
-- myxedema μg/dl

Endocrinology 745
 ◦◦ < 3.6 μg/dl: adrenocortical insufficiency proven
◦◦ > 18 μg/dl: adrenocortical insufficiency excluded
◦◦ 3.6 - 18 μg/dl: If the morning basal cortisol is in this
grey area, a stimulation test (one of the 3) must be
performed:
▪▪ insulin hypoglycemia test: 0.1 IU/kg insulin s.c.
(for a sufficient stimulus blood sugar level should
be < 40 mg/dl), then measurement of cortisol
(should increase to > 18 μg/dl, then secondary
adrenocortical insufficiency is excluded); gold
standard (cheapest)
▪▪ ACTH test: administration of 250 μg ACTH (cor-
ticotropin, synacthen) i.v., measurement of corti-
sol after 60 min; cortisol < 9 μg/dl → adrenocor-
tical insufficiency
▪▪ CRH test
• thyrotropic axis (detection of secondary hypothyroi-
dism)
-- TSH value is usually not decreased (usually nor-
mal)!
-- mostly fT3 and fT4 ↓
-- most important parameter: fT4 ↓
-- no stimulation test necessary (such as TRH test)
• gonadotropic axis (detection of secondary hypogona-
dism)
-- testosterone ↓
-- LH, FSH ↓
• somatotropic axis (detection of hyposomatotropism)
-- IGF-1 (often false normal)
-- stimulation tests:
◦◦ insulin hypoglycemia test
▪▪ 0.1 IU/kg insulin s.c., then measurement of
growth hormone (GH; should increase)
▪▪ GH < 3 μg/l: hyposomatotropism confirmed
◦◦ arginine test
▪▪ Arginine would stimulate the secretion of soma-
totropin (by suppression of somatostatin).
▪▪ GH < 9 μg/l: hyposomatotropism confirmed
◦◦ GHRH test
▪▪ Growth hormone releasing hormone would sti-
mulate secretion of somatotropin.
▪▪ GH < 9 μg/l: hyposomatotropism confirmed

Therapy
• corticotropic axis: hydrocortisone
• thyrotropic axis: L-thyroxine
combination of symptoms of
-- only after hydrocortisone (The administration of
Addison crisis + myxedema
thyroid hormones increases the need for glucocor-
coma: think of pituitary coma!
ticoids, increases renal clearance and can thereby
even worsen adrenocortical insufficiency! Too much
of thyroid hormones can trigger an Addison crisis!)
-- dose: 125-150 μg/d
• gonadotropic axis: sexual hormones
-- men: testosterone
-- women: estrogen
• somatotropic axis: growth hormone (only indicated in
children)

746 Endocrinology
Acute intermittent porphyria (AIP) glycin + succinyl-CoA
δ-ALA synthase Doss porphyria
δ-ALA
δ-ALA dehydratase AIP
porphobilinogen
PBG deaminase Guenther´s disease
uroporphobilinogen
uro-decarboxylase porphyria cutanea tarda
coproporphobilinogen
hereditäre heriditary
copro-oxidase
coproporphyria
protoporphobilinogen
proto-oxidase porphyria variegata

Definition
• syn.: Swedish porphyria, pyrroloporphyria
• most frequent acute porphyria (porphyria: congenital
disorder of heme synthesis [8 steps in total; initial sub-
stance: glycine + succinyl-CoA])
• a hepatic porphyria
• autosomal dominant (gene on chromosome 11; pene-
trance: 20%)
• typically symptoms occurring in crisis (hence the name
"acute intermittent")
• reduced activity (to 50%) of porphobilinogen deamina-
se (PBGD): This enzyme degrades porphobilinogen
(PBG) to uroporphyrinogen. Normally this residual ac-
tivity of 50% is still sufficient, so that the patients are
usually asymptomatic (compensated stage). If, howe-
ver, heme synthesis is stimulated by certain triggers,
this is no longer sufficient and porphyrin precursors
accumulate in the entire organism (decompensated
stage).
• Certain triggers (e.g. stress, infections, drugs) incre-
ase the activity of δ-ALA (ALA: aminolevulinic acid)
dehydratase in the liver. This enzyme stimulates the
conversion of delta-aminolevulinic acid (δ-ALA) into
porphobilinogen. However, since the activity of por-
phobilinogen deaminase (PBGD) is reduced, the cor-
responding precursors, i.e. porphobilinogen (PBG)
and delta-aminolevulinic acid (δ-ALA), accumulate.
• The accumulated porphyrin precursors are extremely
neurotoxic and cause massive nerve damage to the
PNS (motor and sensory polyneuropathy), CNS (ence-
phalopathy) and the autonomic nervous system (espe-
cially autonomic visceral neuropathy).
• average time to diagnosis: 6 years ("chameleon"; or-
phan disease)
• famous persons of contemporary history who also suf-
fered from an AIP: King George III, Vincent van Gogh
protoporphyrin
ferro-chelatase erythropoietic
protoporphyria
heme
Fig. 1019  Overview of the porphyria (δ-ALA: delta-aminole-
vulinic acid; PBG: porphobilinogen): The heme biosynthe-
sis is shown. In acute intermittent porphyria (AIP) there is
a reduced activity of porphobilinogen deaminase (PBGD),
so that precursors can accumulate, i.e. porphobilinogen
(PBG) and deltaaminolevulinic acid (δ-ALA), which can be
detected in urine because they are water-soluble.
Epidemiology
• prevalence: 1:10000 (among psychiatric patients:
1:500)
• w:m = 3:1
• typical age of onset: 20-40 years
• clinical manifestation mostly only after puberty
Trigger
• stress (e.g. surgery, accidents)
• infections, sepsis
• fasting, sobriety (e.g. preoperative)
• exsiccosis
• hypoglycemia
• alcohol (especially absinth)
• nicotine
• pregnancy, menstruation, oral contraceptives
• drugs (pharmacological [medication], toxica)
-- typically crises after drug intake
-- most common misdiagnosis: allergic drug reac-
tion (In contrast to allergy, however, the symptoms
of the AIP crisis do not develop immediately, but only
with a certain latency period of up to days.)
-- representatives (porphyrinogenic drugs): barbitura-
tes, benzodiazepines, etomidate, ketamine, inhalati-
on anesthetics (isoflurane, desflurane, sevoflurane),
clonidine, theophylline, NSAID (ibuprofen, diclofe-
nac), MCP, sulfonamides, anticonvulsants (phenyto-
in, valproic acid, carbamazepine), spironolactone,
sulfonylurea

Symptoms
• gastrointestinal:
-- nausea, vomiting
-- colicky abdominal pain (acute abdomen; "typical ap-
pendectomy scar")
◦◦ the leading symptom of AIP!

Endocrinology 747
 ◦◦ present in 90%
◦◦ caused by an autonomous visceral neuropathy
-- constipation, possibly ileus (caused by a paralysis;
a paralytic ileus)
• neurological:
-- pareses (acute paralyses!)
◦◦ involvement:
▪▪ on the arms especially distal (extensor muscles;
double-sided carpoptosis)
▪▪ on the legs especially proximal ("waddling gait")
◦◦ ascending paralyses up to tetraparesis (impor-
tant DD: Guillain-Barré syndrome [typically cyto-
albuminological dissociation in CSF in GBS, but
normal CSF findings in AIP])
◦◦ i.a. involvement of the respiratory muscles → res-
piratory paralysis / respiratory insufficiency
◦◦ cerebral nerve paresis (i.a. facial nerve palsy, ocu-
lomotor paresis [diplopia])
-- paresthesia (especially sock- and glove-like; in the
trunk area like a "bathing suit")
-- muscle pain (especially back and thigh)
-- seizures
-- PRES (posterior reversible encephalopathy syndro-
me; see page 540)
• psychical: adynamia, psychosis, hallucinations, para-
noia, delirium
• cardiovascular: tachycardia, hypertensive crisis (due
to angiospasms)
Triad: abdominal pain (leading
symptom acute abdomen!), psychosis,
tachycardia → AIP
Diagnosis
• laboratory: i.a.
-- mostly hyponatremia (caused by AIP-induced SI-
ADH)
-- transaminases ↑
• urine: reddish (in 50%; in crisis almost always), dar-
kening when standing (simple test!), dark spots in the
underpants
• detection of increased porphobilinogen (PBG) in
the urine (20ml spontaneous urine are completely
sufficient, no 24h urine collection necessary; shipping
protected from light; important: Take it during the crisis,
since after the crisis the concentration of porphobilino-
gen can no longer be increased!)
-- quantitative: increased concentration of porphobili-
nogen in urine
-- qualitative (today mostly abandoned)
◦◦ Schwartz-Watson-Test (Ehrlic reagent + chloro-
form)
◦◦ Hoesch test (dimethylbenzaldehyde)
• special diagnostics (especially indicated to clarify por-
phyria outside a crisis and for the clarification which
form of porphyria exactly is present)
-- urine (24h collecting urine; without additive; mainly
748 Endocrinology
indicated for porphyria clarification outside a crisis):
◦◦ coproporphyrin III (norm < 75 µg/d)
◦◦ delta-aminolevulinic acid (norm < 5 mg/d)
-- determination of porphobilinogen deaminase activity
in erythrocytes (confirms diagnosis of an AIP; also
suitable for gene carrier detection)
-- blood: detection of EPP (erythrocytic protoporphyrin;
norm < 50 µg/dl)
• The lead level in blood (toxicological laboratory; norm:
< 100 μg/l) should be determined to exclude lead into-
xication (important differential diagnosis to AIP!). Lead
also inhibits delta-aminolevulinic acid dehydratase,
which can cause secondary porphyria.
Therapy
• identification and discontinuation of potentially trigge-
ring substances
• glucose
-- inhibition of δ-ALA synthase ("glucose effect"; via
peroxisome proliferator-μ-coactivator-1a)
-- dosage: 1000ml G40% per day
• heme arginate (Normosang):
-- Heme as end product of biosynthesis inhibits its own
synthesis via negative feedback: Heme inhibits the
δ-ALA synthase. This is the rationale for why heme
(as preparation heme arginate) is administered as a
drug in AIP.
-- 1 amp. = 10ml = 250mg (For therapy over 4 days
you usually need 4 ampoules. One pack contains
exactly 4 ampoules.)
-- dosage: 3 mg/kg as a short infusion in 250ml NaCl
0.9% over 20 minutes 1 x daily over 4 days (up to
max. 7 days)
-- strongly irritating to veins, therefore preferably via
a CVC (necessary for the administration of G40%
anyway)
-- As this is a blood product, a batch book must be
kept.
-- relatively expensive (1 amp.: approx. 3000 €; usually
4 ampoules necessary)
-- not absolutely necessary for mild symptoms (Here
mostly glucose alone is sufficient.)
-- if necessary also permanent interval therapy (infusi-
on once per month) with persistently high excretion
of coproporphyrin III and delta-aminolevulinic acid in
the urine ((Then ferritin controls should be carried
out regularly, since iron is also supplied with heme.)
• forced diuresis
• if necessary intubation and ventilation (in case of res-
piratory failure)
• symptomatic therapy; permitted drugs:
-- hypertensive crisis, tachycardia → β-blockers (e.g.
metoprolol, propranolol)
-- abdominal colic → butylscopolamine, paracetamol,
opioids (e.g. pethidine)
-- nausea, vomiting → ondansetron, domperidone
(MCP is not allowed!)
-- sedation → benzodiazepines, promethazine, chlor-
promazine
 -- psychosis → haloperidol
-- infections → cephalosporins, penicillin (e.g. amoxi-
cillin / clavulanic acid, e.g. piperacillin / tazobactam),
meropenem, vancomycin, fluoroquinolones (e.g.
ciprofloxacin, levofloxacin), azithromycin, tetracycli-
nes
-- ileus → neostigmine
-- seizure → clonazepam, levetiracetam, gabapentin
-- pain → ASA, paracetamol, opiates (e.g. pethidine,
morphin fentanyl); NSAD mot allowes
-- analgosedation (e.g. in mechanically ventilated pati-
ents): propofol + sufentanil
• further permitted drugs (see especially Red list; also
www.porphyria-europe.org): opiates / opioids (e.g. fen-
tanyl), succinylcholine, steroids, ASA, PPI, ACE inhi-
bitors, ARBs, digoxin, nitrates, catecholamines, local
anesthetics (e.g. bupivacaine), lithium, insulin, metfor-
min, heparin (UFH / LMWH), warfarin
• if necessary liver transplantation (in case of very fre-
quent and strongly impairing attacks as ultima ratio;
by the liver transplantation the patients are cured, be-
cause AIP is a hepatic porphyria)
• issue of a porphyria emergency ID card
• genetic analysis, family examination
Fig. 1020  Heme arginate (Normosang): 1 amp. = 10ml =
250mg
Therapy of choice for AIP:
combination of glucose + heme!
Excursus: Immune checkpoint inhibi-
tors
Definition
• new and very effective chemotherapeutic agents (im-
mune oncology)
• Nobel Prize 2018 for the American immunologist La-
mes Allison and the Japanese immunologist Tasuku
Honjo
• initially introduced and approved for the treatment of
metastatic malignant melanoma (still the main indica-
tion)
-- 2011: ipilimumab
-- 2015: nivolumab, pembrolizumab
• indications (metastatic stage): malignant melanoma,
squamous cell carcinoma (skin; head and neck area),
bronchial carcinoma (especially NSCLC [non small cell
lung carcinoma]), renal cell carcinoma, urothelial carci-
noma, Hodgkin's lymphoma
• mechanism of action:
-- substances that block immune checkpoints with an
inhibitory effect, so that the immunological defense
(intended primarily against tumor tissue [but unfor-
tunately also against the body's own tissue]) is in-
creased
-- All immune checkpoint inhibitors are monoclonal an-
tibodies. That is why they all have the suffix "-mab"
(monoclonal antibody) in their names.
-- points of attack:
◦◦ CTLA-4 (cytotoxic T-lymphocyte-associated prote-
in 4; CD 152): a surface protein on T cells
◦◦ PD-1 receptor (programmed cell death protein 1;
CD 279): a receptor on T cells
◦◦ PD-L1: a ligand that binds to the PD-1 receptor
on T cells
• significantly lower effectiveness after previous anti-
biotic therapy (Pinato et al, JAMA Oncol 2019)
Classification
• CTLA-4 inhibitors
-- ipilimumab (Yervoy)
-- tremelimumab
• PD-1 inhibitors (inhibition of the PD-1 receptor)
-- nivolumab (Opdivo)
-- pembrolizumab (Keytruda)
-- cemiplimab (Libtayo)
-- spartalizumab
• PD-L1 inhibitors (inhibition of the ligand that binds to
the PD-1 receptor)
-- atezolizumab (Tecentriq)
-- avelumab (Bavencio)
-- durvalumab (Infimzi)
Side effects
• very frequent (in 90%) clinically relevant autoimmune-
related side effects that can affect all organs
• occurrence up to six months after the end of therapy
still possible
• The stronger the side effects, the stronger the main
effect against the tumor.
• degrees of severity (CTCAE [Common Terminology
Endocrinology 749
 Criteria for Adverse Events]):
-- grade I: no or only mild symptoms
-- grade II: moderate symptoms
-- grade III: severe symptoms (hospitalization neces-
sary; but not yet life-threatening); from here usually
therapy necessary
-- grade IV: life threatening
-- grade V: death (mainly due to colitis with perforation)
• therapy (necessary from grade III):
-- discontinuation of the immune checkpoint inhibitor
(mostly not necessary for grade I-II)
-- immunosuppression:
◦◦ steroids (methylprednisolone [Urbason] 1 mg/kg
p.o. daily; tapering over 28 Tage)
◦◦ if steroid refractory:
▪▪ TNFα blocker (e.g. infliximab 5mg i.v.)
▪▪ possibly mycophenolate mofetil, cyclophospha-
mide, tacrolimus, methotrexate (MTX)
Types
• cutaneous (most common; in 55%): pruritus, rash
(mostly maculopapular; therapy: topical steroids), xe-
• cardiac (in 5%):
rosis, vitiligo, possibly TEN (toxic epidermal necroly-
sis), SJS (Steven-Johnson syndrome)
• endocrinological (in 25%; here mostly hormone substi-
tution necessary [mostly lifelong]):
-- hypophysitis
◦◦ the most common endocrinological side effect
◦◦ especially with ipilimumab
◦◦ especially in men > 68 years
◦◦ generous MRI sella (enlarged pituitary gland)
◦◦ In the case of an anterior pituitary insufficiency
(hypopituitarism), appropriate hormone substituti-
on (hydrocortisone, L-thyroxine) takes place. The
immune checkpoint inhibitor can be continued.
The thyrotropic axis usually recovers, the cortico-
tropic axis usually no longer.
-- thyroiditis
◦◦ mostly temporary hyperthyroidism, then hypothy-
roidism
◦◦ therapy:
▪▪ discontinuation of the immune checkpoint inhi-
bitor
▪▪ hormone substitution with L-thyroxine (in case
of hypothyroidism)
-- adrenalitis (in case of adrenocortical insufficiency:
hormone substitution with hydrocortisone)
-- diabetes mellitus (therapy such as type 1 diabetes,
i.e. hormone substitution with insulin)
-- diabetes insipidus
• gastroenterological:
-- colitis (in 30%)
◦◦ especially with ipilimumab
◦◦ diarrhea, possibly perforation
◦◦ possibly CMV reactivation
◦◦ therapy:
▪▪ discontinuation of the immune checkpoint inhi-
bitor
750 Endocrinology
▪▪ grade I-II: loperamide; from grade III methyl-
prednisolone; if refractory to therapy: infliximab
(very good option here!)
-- hepatitis (in 20%), possibly acute liver failure
◦◦ especially with PD-1 inhibitors
◦◦ typically no detection of liver-specific antibodies
(ANA, SMA, LKM1, SLA) despite autoimmune he-
patitis; if further unclear: also determine hepatitis
E and perform a liver puncture if necessary
◦◦ Before starting immune checkpoint inhibitor thera-
py, hepatitis serology (HBV, HCV) is mandatory.
◦◦ therapy:
▪▪ if transaminases increased > 3 times the norm
or bilirubin > 1.5 times the norm: discontinuation
of the immune checkpoint inhibitor and methyl-
prednisolone 1 mg/kg daily (if transaminases in-
creased > 5 times the norm or bilirubin > 3 times
the norm, then even with 2 mg/kg daily)
▪▪ if refractory to therapy: mycophenolate mofetil
(good option [also used with severe autoimmu-
ne hepatitis]), tacrolimus (last choice)
-- pancreatitis (in 10%)
-- myocarditis (in 1%)
◦◦ almost always in the first 4 weeks after the start
of therapy
◦◦ mostly giant cell myocarditis (syn .: Fiedler myo-
carditis)
◦◦ diagnostics:
▪▪ ECG (abnormal in 89%): frequent cardiac ar-
rhythmias (especially atrial fibrillation, AV block,
VT)
▪▪ laboratory: troponin ↑ (in 94%; from > 1.5 ng/
ml 4 times increased MACE risk [MACE: major
adverse cardiac event]), pro-BNP ↑ (in 66%)
▪▪ echocardiography: mostly localized (similar to
cardiac sarcoidosis), in 50% reduced ejection
fraction
▪▪ cardiac catheter examination to exclude CHD
(We do it generously, provided it is not a very
young patient; especially with increased tropo-
nin and limited ejection fraction)
▪▪ cardiac MRI (LEG [late gadolinium enhance-
ment]; generous!)
▪▪ endomyocardial biopsy (not absolutely neces-
sary [only rarely performed]): lymphocytic infil-
tration, giant cells
◦◦ often fulminant course with high mortality(17%);
i.a. Mahmood et al, JACC 2018: in 46% a MACE
(major adverse cardiac event): AV block III (in 9%),
cardiogenic shock (in 9%), cardiovascular arrest
(in 11%), death (in 17%); also acute left heart failu-
re (in 42%) and atrial arrhythmias (in 26%)
◦◦ therapy:
▪▪ discontinuation of the immune checkpoint inhi-
bitor
▪▪ methylprednisolone (first choice; preferably in a
high dose, i.e. 2 mg/kg), possibly immunoglobu-
lins (0.4 g/kg body weight daily for 5 days), my-
cophenolate mofetil, ATG (anti-thymocyte glo-
 bulin), infliximab ( ave: deterioration possible)
-- pericarditis (therapy: methylprednisolone)
• pulmonary (in 5%):
-- pneumonitis (hypersensitivity pneumonia; therapy:
methylprednisolone [after excluding an infectious
cause], if refractory to therapy: infliximab, mycophe-
nolate mofetil, cyclophosphamide)
-- pleuritis
• renal (in 3%; possibly acute kidney failure):
-- interstitial nephritis
-- glomerulonephritis
• neurological (in 2%):
-- tremor
-- ataxia
-- seizures
-- PNP (peripheral polyneuropathy)
-- Guillain-Barré syndrome (GBS)
-- myasthenia gravis
-- meningitis, encephalitis
-- myelitis
• musculoskeletal:
-- myositis (possibly rhabdomyolsis)
-- fasciitis
-- arthritis (therapy: possibly MTX, TNFα blockers)
• ophthalmological: especially uveitis (most common),
conjunctivitis, episcleritis, keratitis, retinitis (up to blind-
ness), optic neuritis, inflammation of the orbit, endocri-
ne orbitopathy
• hematological:
-- hemolysis
-- anemia, leukopenia, thrombopenia (pancytopenia)
-- thrombotic microangiopathy (TMA)
-- hemophilia
-- arteritis
• psychical: fatigue (very often [in 25%]!)

Endocrinology 751
 the kidneys.
ELECTROLYTE • isovolemia: Volume is regulated by the sodium balance
(volume regulation). It stands above all in the service
DISORDERS of circulatory regulation. A sufficient effective blood vo-
lume is crucial for organ perfusion.If the effective blood
volume changes, the following changes occur:
-- Baroreceptors in the juxtaglomerular apparatus of
the kidney lead to an increased release of renin and
thus to activation of the RAAS (renin-angiotensin-
aldosterone system), when the effective blood volu-
me is reduced: Renin stimulates the conversion of
angiotensinogen to angiotensin I, which is converted
to angiotensin II by the ACE (angiotensin converting
enzyme). Angiotensin II leads to an increased re-
lease on the one hand of aldosterone in the adrenal
cortex (zona fasciculata) and on the other hand of
ADH in the hypothalamus. It also causes an incre-
ased renal vasoconstriction. Aldosterone causes an
increased sodium reabsorption and an increased po-
tassium excretion via mineralocorticoid receptors in
the distal tubules and collecting ducts of the kidneys.
the most important ions: The concentration of sodium in the urine decreases
- extracellular: sodium and the effective blood volume increases again. With
- intracellular: potassium an increased effective blood volume, less renin is re-
leased. There is a reduced reabsorption of sodium
in the kidneys and thus an increased natriuresis and
consecutive diuresis. Sodium binds a lot of water
Disorders of sodium and carries it away. "Salt water" is excreted.
-- Via volume receptors in the heart (atria [released by
atrial dilation]) and in large vessels (e.g. internal ca-
rotid artery [carotid sinus]) there is an increased re-
lease of natriuretic peptides (especially ANP, BNP),
when the effective blood volume is increased, so that
renal sodium and water retention decreases and na-
triuresis and consecutive diuresis increases.

water balance ("fresh water"

balance; goal: isotonicity): osmore-
gulation (measurement: serum
osmolarity, regulation: urine
osmolarity)
sodium balance ("salt water"
• hypernatremia (sodium > 150 mmol/l) balance; goal: isovolemia): volume
• hyponatremia (sodium < 135 mmol/l) regulation (measurement: effective
blood volume; regulation: urine sodi-
The aim of regulation is isotonicity and isovolemia in the um
intravascular space.
• isotonicity: The serum osmolarity is kept constant
(280-290 mosmol/l) by osmoregulation. It is monitored Disorders of the sodium balance are
by osmoreceptors in the hypothalamus. If there is an almost exclusively caused by
increase in serum osmolarity, more ADH (antidiuretic disorders of the water (and not of the
hormone; syn.: vasopressin) is released in the hypo- electrolyte) balance!
thalamus. ADH causes an increased incorporation of
aquaporins into the membrane of the tubular epithe-
lial cells of the kidneys via V2 receptors and thus an
antidiuresis (water retention; reduced renal excretion
of osmotically free water ["fresh water"]) and via an in-
creased feeling of thirst an increased water intake. It
is drunk more (namely fresh water and not salt water).
The urine molarity increases. When the serum osmo-
larity falls, the ADH secretion is reduced, so that more
osmotically free water ("fresh water") is excreted via

752 Endocrinology
 disorder finding therapy died.)
-- drinking of salt water (e.g. in the context of emergen-
too much restriction of drinking quantity,
water hyponatremia possibly tolvaptan cies at sea)
-- hypercortisolism (e.g. Cushing's disease, hydrocorti-
ad water (H2O; "fresh water")
(let drink or via gastric tube)
sone therapy in septic shock [hydrocortisone contra-
too little or G5% i.v., possibly desmo- indicated in sodium > 150 mmol/l!])
water hypernatremia pressin -- hyperaldosteronism (Conn's disease)
-- refeeding syndrome (sodium retention)
too much hyperhydrati- increase sodium excretion -- essential central hypernatremia (target value adjust-
sodium on (edema) (loop diuretics) ment due to a hypothalamic lesion)

too little dehydration full electrolyte solution ("salt

sodium (exsiccosis) water") Hypernatremia almost always means
lack of free water!

Hypernatremia

Epidemiology Hypernatremia does not mean that

• especially elderly (geriatric) patients (decreased thirst,
decreased fluid intake)
• frequency in intensive care units: 9% (IAH [intensive
care-unit associated hypernatremia]; mostly acquired
in the intensive care unit [80%], only rarely [20%] al-
ready on admission)
• independent risk factor (poor prognosis [5-fold in-
creased mortality])
Ätiology
• water deficiency (lack of water; too little water: al-
most ever!)
-- extrarenal loss of water
◦◦ exsiccosis, volume deficiency (e.g. vomiting, di-
arrhea, short bowel syndrome, entero-colic fistu-
la, excessive diuretic therapy, profuse sweating,
burns)
◦◦ disturbed thirst sensation (especially elderly pati-
ents) and thus reduced fluid intake
◦◦ perspiratio
-- renal loss of water
◦◦ osmotic diuresis (e.g. glucosuria-induced in the
context of derailed diabetes mellitus)
◦◦ diabetes insipidus
• sodium surplus (excess; too much sodium: almost
never!)
-- infusion of hypertonic (but also isotonic ["physiolo-
gical"]) saline solution, Nabic (contains highly con-
centrated sodium!), Citrate anticoagulation (citrate is
infused as sodium citrate)
-- sodium containing antibiotics (e.g. penicillin G,
piperacillin / tazobactam [mostly only slight hyper-
natremia], fosfomycin)
-- total parenteral nutrition (TPN)
-- intoxication (poisoning)
◦◦ suicidal (e.g. excessive ingestion of spice sauces
[e.g. "Maggi"])
◦◦ accidental (example: A three-year-old child was
forced against its will by his mother to eat the
pudding whole. However, the mother mistook the
sugar bowl for the salt bowl. The child ultimately
there is too much salt in the blood,
but too little water!
Diabetes insipidus
• definition:
-- decreased ability of the kidneys to concentrate urine
(asthenuria) due to a lack of ADH (central form) or
a decreased response of the kidneys to ADH (peri-
pheral form)
-- ADH: antidiuretic hormone (syn.: vasopressin)
• leading symptoms:
-- polyuria (p.d. > 5l/24h)
-- polydipsy
• laboratory :
-- serum: osmolarity ↑, sodium ↑
-- urine: osmolarity ↓, sodium ↓ (asthenuria: lack of ca-
pability of concentration of the kidneys)
-- thirst test:
◦◦ interpretation: In healthy people, osmoregulation
leads to a release of ADH, so that the urine mola-
rity increases (> 750 mosmol/kg) and the diuresis
decreases (< 30 ml/h). In diabetes insipidus, the
urinary osmolarity does not increase (remains <
300 mosm/l) and the serum osmolarity increases
(> 295 mosm/l). The urine osmolarity is smaller
than the serum osmolarity. The polyuria persists
and the diuresis does not decrease.
◦◦ implementation (e.g. on IMC): The patient is not al-
lowed to drink anything for 12 hours. At the begin-
ning and at the end of the test, the blood is drawn
and sodium, serum osmolarity and ADH are ema-
sured. The patient should urinate every two hours.
The amount of urine is measured and the patient
is weighed. Urine molarity is determined every
two hours. If the urine molarity increases > 750
mosmol/kg, the test can be finished (maximum
duration: 12 hours). A modified test, in which 3%
NaCl is given and copeptin (precursor of ADH) is
measured, is even more accurate in the diagnostic
(A Copeptin-Based Approach in the Diagnosis of
Diabetes Insipidus; Fenske et al, N Engl J 2018).
• types (differentiation possible by a test administration

Endocrinology 753
 desmopressin [10µg intranasal or 4µg i.v./s.c.] or ADH:
In central diabetes insipidus the urine osmolarity incre-
ases, in peripheral diabetes insipidus not.):
-- diabetes insipidus centralis (syn.: diabetes insipidus
neurohumoralis)
◦◦ reduced production of ADH in the hypothalamus or
impaired storage or secretion in the posterior lobe
of the pituitary gland
◦◦ cause:
▪▪ neoplastic (e.g. pituitary tumor [especially ranio-
pharyngioma], brain metastases); possibly also
anterior pituitary insufficiency (hypopituitarism)
here
▪▪ traumatic (TBI, after neurosurgical surgery)
▪▪ inflammatory (meningitis, encephalitis)
▪▪ metabolic (especially acute fatty liver of preg-
nancy [AFLP])
◦◦ therapie: desmopressin (Minirin)
-- diabetes insipidus renalis (peripheral; nephrogenic)
◦◦ definition: end organ resistance of the collecting
ducts to ADH (defective aquaporins)
◦◦ cause:
▪▪ congenital (very rare)
▪▪ acquired (by tubular damage): electrolyte dis-
order (hypokalemia, hypercalcemia), kidney di-
seases (i.a. interstitial nephritis, pyelonephritis,
polyuric phase of acute renal failure), drugs (e.g.
lithium, gentamicin, colchicin, amphotericin B,
cisplatin, rifampicin, tolvaptan)
◦◦ therapy: thiazide
Diabetes insipidus: generous cerebral
sectional imaging (CCT, MRI) on the
question of a brain tumor!
Symptoms
• thirst (leading symptom; however, often absent in
elderly patients)
• disturbance of consciousness
-- qualitative (confusion, disorientation)
-- quantitative (somnolence, coma)
• dizziness
• weakness, lethargy
• heart failure (due to decreased myocardial contracti-
lity)
• seizures
• hyperthermia (Hypernatremia leads to an increase in
body temperature ["salt fever"].)
• rhabdomyolysis
• hyperglycemia (hypernatremia leads to insulin resis-
tance.)
754 Endocrinology
Therapy
• p.o. / gastric tube: application of water (H2O, i.e. tap
water ["fresh water"]; note: If you are thirsty, you do not
drink sea water [salt water], which would even be dan-
gerous due to the high salt content [table salt content
3.5%, i.e. 100ml sea water contains 3.5g NaCl], but
osmotically free water [fresh water]!)
• i.v. glucose 5% (best with NaCl 0.9% in the ratio 1:1)
• cave: Do not correct too quickly (< 0.5 mmol/l per hour
or <1 0 mmol/l per day) in chronic hypernatremia: Here
the brain cells have already adapted to the hypernatre-
mia, i.e. they are no longer shrunk, but have returned
to their normal filling volume due to the infiltration of
osmolytes. If the sodium is now lowered too quickly,
more water flows into the brain cells and brain ede-
ma occurs. Here the compensation should take place
slowly (over 48-72h). In acute hypernatremia, howe-
ver, the brain cells are shrunk, so that the correction
must be made quickly.
• if necessary hemodialysis (in therapy refractory cases)
Hyponatremia
Definition
• most frequent electrolyte disorder (20% of all inpa-
tients and 30% of all intensive care patients)
• prevalence: 1-2% of the general population (17% at
age > 80y years)
• w>m
• mostly multifactorial
• Hyponatremia is a prognostic factor in several under-
lying diseases (e.g. heart failure, liver cirrhosis) and is
associated with increased mortality.
• Hyponatremia does not mean sodium deficiency,
but excess of water (through increased intake or redu-
ced excretion)!
• Although hyponatremia is the most frequent electrolyte
disorder, many physicians have no idea at all about
management and make management completely
wrong. As a rule, the patient is only "salted" (by ad-
ministering sodium chloride tablets [salt tablets; "Swe-
dish tablets"] or NaCl 20% in the infusion), it is usually
not enough for more. An observational study (Hoorn et
al, QJM 2005) showed that 90% of physicians treated
hyponatremia incorrectly. The genesis of hyponatre-
mia in the majority is not clarified at all and more than
one third of all patients do not receive any therapy at
all (Tzoulis et al, Postgrad Med J 2014).
Hyponatremia: ignorance and
mismanagement unfortunately typical
in clinical everyday life!
Hyponatremia only occurs when the
water intake is greater than the water
excretion!

Fig. 1021  Hyponatremia: In most cases the patient is
senselessly salted only!
Etiology
• sodium loss via the gastrointestinal tract (vomiting,
diarrhea, gastroenteritis), skin (heavy sweating), third
space (ascites, pleural effusion, ileus); blood loss
• adrenocortical insufficiency
-- hyocortisolism
-- hypoaldosteronism (aldosterone deficiency [e.g. due
to spironolactone; also here, as with hyocortisolism,
hyponatremia, hyperkalaemia and metabolic acido-
sis]; see infobox)
• renal insufficiency (loss of sodium; "salt loss kidney")
• SIADH (see page 761)
• non-osmotic stimulation of ADH secretion in intrava-
scular volume deficiency via baroreceptors (although
edema, but the effective blood volume is reduced! [hy-
povolemia!]):
-- decompensated heart failure (in 27% hyponatremia)
-- decompensated liver cirrhosis (in 50% hyponatre-
mia)
-- nephrotic syndrome
• drugs (pharmacological):
-- diuretics [most frequent cause: thiazides [hydro-
chlorothiazide, xipamide, indapamide, chlortalido-
ne]! note: Loop-diuretics such as furosemide do not
cause hyponatremia and therefore do not have to
be discontinued compulsorily. They are more likely
to lead to hypernatremia through increased water
diuresis! Loop diuretics mainly cause hypokalemia.)
-- neuroleptics (e.g. haloperidol), tricyclic antidepres-
sants, SSRI (e.g. citalopram [frequent!])
-- anti-epileptic drugs (especially carbamazepine [clas-
sical], lamotrigine)
-- cyclophosphamide, vincristine
-- tranexamic acid
-- terlipressin
-- colonoscopy preparation solutions (cave not rarely
severe hyponatremia!)
-- morphine, NSAID
-- infusions with G5%,
• drugs (toxical): especially amphetamines, ecstasy
• hypothyroidism - pregnancy
• ventilation: venous return flow to the right heart ↓ →
left atrial filling ↓ → ADH release (diuresis ↓, water and
sodium retention [hyponatremia], edema)
• strong beer drinkers ("beer potomania"; potomania:
"drinking madness" [Latin "potus": drinking); like SI-
ADH euvolemic hyponatremia, but urinosmolarity <
100 mosm/l; therapy: fluid restriction),
• water intoxication (mostly in psychosis, but also as
part of an extreme diet; e.g. excessive consumption
of green tea)
• psychogenic polydipsia
• malnutrition
• exercise associated hyponatremia (EAH)
-- due to endurance sports (e.g. after marathon run-
ning)
-- mostly due to wrong (too much!) drinking (too much
supply of free water ["overdrinking"])
-- EAH is the most frequent non-cardiac cause of death
in endurance sports!
• TUR syndrome: hypotonic hyperhydration by infusing
salt-free rinsing solution in the course of a TUR of the
prostate (transurethral resection; frequency: 2%) via
injured veins in the surgical area
• renal tubular acidosis type I (see infobox page <?>)
• cerebral salt losing syndrome (CSW: cerebral-salt-
wasting)
-- occurring after damage to the CNS (e.g. subarach-
noid hemorrhage)
-- hyponatremia with increased sodium excretion via
the urine (urine sodium > 40 mmol/l, urine osmolarity
> 100 mosmol/l)
-- reduced intravascular volume
◦◦ In contrast to SIADH an exsiccosis is present, the-
rapy therefore consists of fluid administration (iso-
tonic NaCl 0.9%).
◦◦ The diagnosis may be made only with clear signs
of volume deficiency (e.g. skin folds, increased ha-
ematocrit)!
Endocrinology 755

frequent causes of hyponatremia:
diuretics (thiazides), reduced blood
volume (vomiting, diarrhea, bleeding),
SIADH
most frequent cause ever of hyponat-
remia: hydrochlorothiazide (HCT)!
The diuretics that cause the most
severe hyponatremia are the
thiazides (and not the loop
diuretics)!
Electrolyte disorders due to
diuretics:
- thiazides → hyponatremia
- loop diuretics → hypokalemia
756 Endocrinology
Symptoms
• calf cramps
• hypotension
• weakness
• rhabdomyolysis
• cerebral edema (brain emema; hyponatremic ence-
phalopathy):
-- nausea, vomiting (may be cause or consequence of
hyponatremia
-- increased irritability
-- headache
-- confusion
-- tiredness, apathy
-- ataxia, recurrent falls
-- adynamia
-- disturbance of consciousness, somnolence, coma,
possibly respiratory arrest
-- hyperreflexia
-- seizures (especially grand mal seizures)
-- possibly neurogenic pulmonary edema (hyponatre-
mia induced)
Hyponatremia: Especially the
cerebral symptoms are in the
foreground (hyponatremic
encephalopathy)!
Classification
according to volume status
• hypovolemic (diarrhea, vomiting, bleeding, diuretics)
• euvolemic ( most frequent form; most frequent
cause of euvolemic hyponatremia: SIADH)
• hypervolemic
-- decompensated heart failure
-- decompensated liver cirrhosis
-- nephrotic syndrome
Hyponatremia: always assess volume
status first: eu-, hypo- or hypervolemic!
according to severity
• mild: sodium 125-135 mmol/l
• moderate: sodium 115-125 mmol/l
• severe: sodium < 115 mmol/l
according to time
• acute hyponatremia (< 48h; symptoms more pro-
nounced; correction should be made quickly; typical
examples: marathon run, party with drug consumption
[especially ecstasy], colonoscopy preparation solution,
TUR syndrome)
• chronic hyponatremia (> 48h; symptoms less pro-
nounced; correction should be made slowly)
according to serum osmolarity
• hypoosmolar (< 275 mosm/l; syn.: hypotonic hyponat-
remia): True hyponatremia is always associated with
reduced serum osmolarity. The osmolarity is mainly
determined by sodium, so that a drop in sodium must
always be accompanied by a drop in osmolarity.
• isoosmolar (275-295 mosm/l): pseudohyponatremia
• hyperosmolar (> 295 mosm/l; syn.: hypertonic hypo-
natremia): hypertonic solutions (glucose, mannitol),
hyperglycemia, intoxication with methanol or ethylene
glycol
Terms:
• osmolarity: concentration of osmotically active partic-
les relative to the volume of a solution (unit: osmol/l)
• osmolality: concentration of osmotically active partic-
les relative to the weight of a solution (unit: osmol/kg)
The serum osmolarity is predominantly determined by
sodium and is calculated from the following formula:
osmolarity = 2 x sodium + urea + glucose
(all in mmol/l)
Diagnostics
• sodium < 135 mmol/l
• determination of volume status (clinical, sonographic,
radiological)
• serum osmolarity:
-- always reduced in hyponatremia
-- if not reduced, i.e. > 275 mosml/l: only pseudohyp-
onatremia
◦◦ occurrence:
▪▪ hyperglycemia (e.g. in ketoacidotic or hypergly-
cemic coma); correction formula: sodiumcorrected
(mmol/l) = sodiummeasured (mmol/l) + 0,.16 x (glu-
cose [mg/dl] / 100)
▪▪ hyperlipidemia
▪▪ hyperproteinemia (e.g. plasmocytoma,
Waldenstrom's disease),
▪▪ hypothyroidism
▪▪ mannitol infusions
▪▪ hyperosmolar contrast agent
◦◦ a metrological incorrect determination: In case of
an increase in fats, proteins or sugar, an incorrect-
ly low sodium concentration is measured (artifact).
With a special measurement (ion-selective), which
is not standard, normal sodium values would be
measured.
◦◦ The sodium value from the BGA is not subject
to this artefact!
• urine sodium (spot urine sufficient, no collecting urine
necessary; prerequisite for assessment: no diuretics):
-- > 20 mmol/l: renal loss
◦◦ SIADH (mostly > 40 mmol/l)
◦◦ renal insufficiency
-- < 20 mmol/l: extrarenal loss
• urine osmolarity (Norm: 400-1400 mosm/l): Because
functioning kidneys concentrate the urine, the urine
osmolarity is higher (2-3 times) than the serum osmo-
larity. The determination of the urine molarity is helpful
especially for the questions:
-- DD loss
◦◦ urine osmolarity > serum osmolarity → extrarenal
loss (e.g. SIADH)
◦◦ urine osmolarity < serum osmolarity → renal loss
(dysfunctional kidneys)
-- DD euvolemic hyponatremia
◦◦ urine osmolarity > 100 mosm/l: SIADH
◦◦ urine osmolarity < 100 mosm/l: water intoxication,
exercise associated hyponatremia, potomania,
psychogenic polydipsia
• urine / plasma ratio (UPR; syn.: free water clearance)
-- UPR = (sodiumurine + potassiumurine) / sodiumserum
-- spot urine sufficient
-- interpretation:
◦◦ < 1: The patient retains free water. In the case of
euvolemic hyponatremia (SIADH), fluid restriction
would make sense here.
◦◦ > 1: The patient excretes free water. In the case of
euvolemic hyponatremia (SIADH), fluid restriction
would not. make sense here.
in hyponatremia always determine in
the laboratory: serum osmolarity, urine
sodium, urine osmolarity
the 4 key questions in hyponatremia:
volume status, serum osmolarity,
urine sodium and urine osmolarity!
Endocrinology 757
 -- raising of sodium (e.g. 1-2 vials of NaCl 20% in
500ml NaCl 0.9%)
-- possibly hypertonic NaCl (3%)
◦◦ preparation:
▪▪ 1000 ml NaCl 0.9% + 7 amp. NaCl 20% a 20ml
(9g [1000ml NaCl 0.9%] + 7 x 4g [7 x NaCl 20%
a 20ml] = 37g to 1140ml → 3g to 100ml [3%]) or
▪▪ 500 ml NaCl 0.9% + 3 ½ amp. NaCl 20% a 20ml
◦◦ infusion rate: 0.5 ml/kg/h
◦◦ electrolyte controls every 6h are obligatory
◦◦ 1-2 ml/kg/h according to sodium deficit
◦◦ 1ml of NaCl 3% = 0,5 mmol sodium; 513 mmol/l
sodium
◦◦ 1 liter NaCl 3% → sodium increase by 10 mmol/l
• eu-/ hypervolemic:
-- water restriction (sufficient in asymptomatic patients
-- no additional supply of sodium (This even aggra-
vated hypervolemia!)
-- if necessary with hypervolemia additional loop diu-
retics (e.g. 80mg furosemide/day, e.g. add 2 x 40mg
to the hypertonic NaCl infusion), thiazides should be
discontinued!
-- possibly with edemas: hypertonic NaCl 3% + furo-
semide 40mg
-- hyponatremia with heart failure → ACE inhibitor
-- hyponatremia with liver cirrhosis → aldosterone ant-
agonists (e.g. spironolactone)
-- In severe cases of overhydration combined with re-
duced diuresis renal replacement therapy can be
used.

Therapy
• hypovolemic
-- volume administration only (NaCl 0.9%; 1000ml
NaCl 0.9% contain 9g NaCl and 154 mmol sodium
[1ml NaCl 0.9% corresponding to 0.154 mmol sodi-
um])
Fig. 1022  NaCl 20% ampoules: 1 amp. = 10ml = 2g sodium
-- possibly discontinuation of diuretics
chloride; 1ml contains 3.4 mmol sodium [8]
-- possibly food rich in sodium chloride (bouillon, NaCl
wafers; not a general recommendation)
-- tablets / pills containing sodium chloride (salt tablets,
"Swedish tablets"; not a general recommendation); Do not salt hypervolemic patients
p.o. substitution only up to 130 mmol/l; if sodium < (very frequent error)! This aggrevates
130 mmol/l: i.v.; note: Salt tablets should be used the hypervolemia!
very cautiously. They increase the patient's thirst so
that they drink more, which further aggravates hyp-
onatremia!

758 Endocrinology
 Correction rate
• acute hyponatremia: water can cross the blood-brain
barrier, sodium cannot. In hyponatremia, the sodium
content in the blood is reduced, but normal in the brain
cells. Therefore, water flows from the blood across the
blood-brain barrier into the brain cells with consecutive
swelling of the brain cells (especially the connective
tissue cells [astrocytes]) and cerebral edema. In acute
hyponatremia, the brain has not yet had enough time
to get used to the hyponatremia. There is a risk of se-
vere complications from the cerebral edema, so that a
rapid increase in sodium (4-6 mmol/l per hour) up to a
normal sodium level is necessary.
• chronic hyponatremia: Here the brain cell had enough
time to adapt to the changed situation. Through a se-
ries of intracellular processes (i.a. intracellular release
and then discharge of osmolytes), the brain cell has
managed to stop it swelling. The patient is adapted to
the hyponatremia (osmotic equilibrium). If the sodium
increases too quickly here, water will leak out of the
brain cell and thus the brain cell will shrink: Central
pontine myelinolysis develops. Therefore the sodium
may only be increased slowly here, i.e. < 10 mmol/l
in 24h and < 18 mmol/l in 48h. In case of an excessi-
ve correction, G5% (2 liters in 12h) or minirin (desmo-
pressin; 2-4μg) should be administered. As a rule of
thumb: 1 ml/kg NaCl 3% increases the sodium level
by 1 mmol/l.

Emergency therapy
In the case of hyponatremia with acute danger (e.g. vo-
miting [signs of increased intracranial pressure], somno-
lence, coma, respiratory insufficiency, seizures) there is
no time to wait for the results of laboratory diagnostics
(especially serum osmolarity, urine sodium). The emer-
gency therapy here consists in the administration of 150-
200ml (2ml/kg bw) 3% saline solution over 10 minutes.
Fig. 1023  For illustration, a comparison with plums, which
These can be easily prepared by yourself: 1000ml NaCl are supposed to represent the brain cells, should be made.
0.9% + 7 amp. NaCl 20% a 20ml. In case of a volume On the left, the situation in acute hyponatremia: The leaking
overload (hypervolemia) loop diuretics are additionally of water causes the brain cells to swell. These had here
administered (e.g. furosemide 40mg i.v. [note: Loop di- at all no time to adapt accordingly. Therefore, the sodium
uretics do not lead to hyponatremia!]). In case of acute in the blood should be increased quickly again so that the
hyponatremia the sodium must be increased immediately water can escape from the swollen brain cells and the brain
and rapidly (regardless of acentral pontine myelinolysis)! swelling decreases. The situation is different with chronic
hyponatremia: Through various mechanisms, the brain cell
The therapy is less oriented to the laboratory grade of the
has now managed to remove the water again and is adap-
hyponatremia, but rather to the severity of the symptoms! ted to the hyponatremia. The brain cells are no longer swol-
len. If the sodium in the blood is raised too quickly here,
severe acute hyponatremia: water escapes and the brain cells shrink (right).
immediately 2 ml/kg NaCl 3% i.v.

sodium increase (correction rate):

- acute hyponatremia: rapid
- chronic hyponatremia: slow

Endocrinology 759
Fluid management
• hypervolemic (edema [e.g. decompensated heart fai-
lure]) → fluid removal (no additional supply of sodium);
Loop diuretics instead of thiazide (e.g. HCT)
• euvolemic (SIADH) → fluid restriction
• hypovolemic → fluid administration

Central pontine myelinolysis

Definition
• syn.: osmotic demyelinization syndrome (ODS)
• demyelinating in the area of ​​the pons of the brain stem
• histology: symmetrical isolated myelin loss without in-
flammation with intact axons
• cause: too rapid an increase in sodium in chronic hyp-
onatremia ( not possibly in the correction of acute
hyponatremia)
• time: only occurring with a delay, not immediately (usu-
ally 4-8 days after the correction, which then often no-
body reminds anymore)

Risk factors
• alcoholics
• malnurtition
• acute hypernatremia (e.g. as part of a refeeding syn-
drome)
• hypokalemia
• elderly women
• liver failure, liver transplant
• burn victims

Symptoms
• dysphagia
• dysarthria
• diplopia
• nystagmus
• coma
• tetraparesis, bulbar paralysis (paralysis of the cra-
nial nerve nuclei in the medulla oblongata), possibly
locked-in-syndrome
• delirium
• respiratory depression

Diagnosis
• anamnesis, clinical (especially neurological) examina-
tion
• cerebral imaging:
-- CCT (cranial)
-- MRI (method of choice) Fig. 1024  MRI: pronounced myelinolysis of almost the en-
◦◦ Myelinolysis in the area of the
​​ pons can best be tire pons (hence also called pontine myelinolysis); here hy-
perdense in the T2 weighting
visualized here.
◦◦ representation: Therapy
▪▪ in the T1 weighting: hypointense • especially supportive
▪▪ in the T2 weighting: hyperintense • There are case reports on the administration of TRH
(TSH-releasing hormone), methylprednisolone, im-
munoglobulins and plasmapheresis. However, these
measures have not been proven in randomized stu-
dies and therefore cannot be generally recommended.

760 Endocrinology
Prognosis
• potentially reversible
• 25% rule:
-- 25% die (mortality: 25%).
-- 25% remain severely disabled.
-- 25% remain slightly disabled.
-- 25% recover without any neurological deficit.
• The prognosis is mostly seen as too poor! Suppor-
tive and rehabilitative measures are definitely worth it!
Prophylaxis
• slow raising of sodium in chronic hyponatremia, i.e. <
10 mmol/l in 24h and < 18 mmol/l in 48h
• Almost everyone knows that sodium should not be
raised too quickly due to the risk of central pontine
myelinolysis. However, this only applies to chronic
hyponatremia and not to acute hyponatremia. Expe-
rience has shown that sodium is usually raised far too
slowly: Leaving a patient with severe hyponatremia for
a longer period of time is also unhealthy for the brain
(cerebral edema)!
SIADH
Definition
• syndrome of inadequate ADH secretion
• syn.: Schwartz-Bartter syndrome
• increased ADH secretion from the posterior pituitary
gland or tumor tissue (paraneoplastic) associated with
increased thirst
• ADH secretion is inadequate because it is ou of os-
motic control.
• result: water retention and dilution hyponatremia
• SIADH is the most common cause of euvolemic hyp-
onatremia!
Etiology
• paraneoplastic (No.1 [80%]):
-- carcinomas (especially small cell lung cancer, tu-
mors from the gastrointestinal tract; cerebral meta-
stases)
-- sarcomas
-- lymphomas
• pulmonary:
-- pneumona ( i.a. in legionellosis in 50%!)
-- tuberculosis
-- sarcoidosis
-- acute respiratory insufficiency
-- mechanical ventilation with high PEEP
• postoperative: especially after neurosurgical opera-
tions (especially transsphenoidal surgery of the pitui-
tary gland)
• pharmacological: especially psychotropic drugs (espe-
cially SSRI such as citalopram [often!], tricyclic anti-
depressants [rarely], haloperidol), anti-epileptics (car-
bamazepine, valproic acid), chemotherapeutic agents
(cisplatin, vincristine, cyclophosphamide), drugs (e.g.
ecstasy)
• neurological:
-- CNS: trauma, meningitis, subarachnoid hemorrhage
(in 25%), stroke (in 25%), alcohol withdrawal
-- PNS (e.g Guillain-Barré syndrome)
• endocrinological:
-- hypothyroidism
-- adrenocortical insufficiency (here additionally hyper-
kalemia)
◦◦ hyocortisolism
◦◦ hypoaldosteronism (aldosterone deficiency)
-- acute intermittent porphyria (AIP)
Symptoms
• loss of appetite
• nausea, vomiting
• headache
• muscle cramps
• irritability, personality changes
• calf cramps
• seizures (water intoxication)
• no edema with SIADH (because the amount of
water retention is 2-3 liters only; memo: For the
development of edema at least 5 liters of water are
necessary!)
Diagnostics
• serum:
-- decreased sodium ( often < 110 mmol/l !)
-- decreased osmolarity (< 275 mosm/l)
• urine (spot urine sufficient, no 24h collecting urine ne-
cessary):
-- increased sodium (> 30 mmol/l)
-- normal (concentrated) urine (urine osmolarity > 100
mosm/l
• - remarkably low values for urea (typical!), creatinine,
uric acid
• After administration of NaCl 0.9%, there is typically no
increase or even further decrease in serum sodium.
• fractional excretion of urea (FEUrea):
-- FEUrea = (urinary urea / serum urea) / (urinary crea-
tinine / serum creatinine)
-- In contrast to all other causes of hyponatremia,
fractional excretion of urea in SIADH is increased (>
35%).
• water stress test (rarely necessary)
• ADH ↑ ( (ADH determination is not necessary!)
Endocrinology 761

suspected SIADH → urine: sodium,
osmolarity, creatinine, urea
Types
• type A (30%): uncontrolled ADH secretion (mainly ec-
topic ADH production, e.g. in small cell lung cancer)
• type B (30%): incomplete suppression of ADH secre-
tion in serum osmolarity < 280 mosmol/l in damaged
neurohypophysis (e.g. TBI, SAH)
• type C (30%): changed threshold value of osmoregu-
lation
• type D (10%): strong water reabsorption in the distal
tubules with a serum osmolarity of < 280 mosmol/l wit-
hout an increased ADH concentration
Therapy
• causal (always check whether a causal therapy is pos-
sible), e.g.
-- adrenocortical insufficiency
◦◦ hypocortisolism → hydrocortisone
◦◦ hypoaldosteronism → fludrocortisone
-- hypothyroidism → L-thyroxin
-- drugs (especially antidepressants): discontinue or
change (significantly less SIADH with tricyclic anti-
depressants, for example, than with SSRIs)
-- therapy of legionella pneumonia
• fluid restriction (restriction of the trinking quantity; "let
thirst!):
-- means of choice!
-- 1 liter/day or 500 ml/day under the total urine excre-
tion over 24h (balance!)
-- Fluid restriction, however, is pointless if the urine /
plasma ratio UPR = (sodiumurine + potassiumurine) /
sodiumserum (spot urine sufficient). Then the electroly-
te-free water clearance is negative. Fluid restriction
only makes sense with a urine / plasma ratio < 1.
• diet rich in sodium chloride
• possibly hypertonic NaCl
-- NaCl 3%, 500ml NaCl 0.9% + 1-2 amp. NaCl 20%
-- but with SIADH always only in combination with furo-
semide (e.g. 1 x 40mg)
-- severe forms: Especially in acute hyponatremia with
acute danger (e.g. vomiting [signs of increased ce-
762 Endocrinology
rebral pressure], somnolence, coma, respiratory in-
sufficiency, seizures) the i.v. administration of 2ml/kg
NaCl 3% should always be given independently of
the presence of SIADH!
• possibly lithium 900-1200 mg/day
• if necessary vasopressin antagonists (vaptans, aqua-
retics
-- tolvaptan (Samsca)
-- moxavaptan
-- lixivaptan
-- conivaptan
SIADH: always determination of
TSH, cortisol and aldosterone to
exclude hypothyroidism and
adrenocortical insufficiency, as
causal therapy is possible here!
SIADH → fluid restriction
CSW → fluid administration (NaCl
0.9%)
Tolvaptan (Samsca)
• approvals:
-- SIADH (approved since 2009; apporval study: SALT
[Schrier et al, N Engl J 2006])
-- also approved in the USA for the treatment of hypo-
natremia in heart failure and liver cirrhosis
-- since 2015 also approved in Europe for polycystic
kidney disease (reduces the progression of cyst
formation [TEMPO study 2012]; drug name here:
Jinarc; here significantly higher dosage: 1st month
60mg daily [45mg-15mg], 2nd month 90mg daily
[60mg-30mg], then maintenance dose with 120mg
daily [90mg-30mg])
• a V2 receptor antagonist (prevents the incorporation
of the water transport protein aquaporin-2 into the cell
membrane in the kidneys)
• dosage: 15mg/day p.o. (1 tablet = 15mg; increase eve-
ry 24h by 15mg to max. 60mg possible; dose should
be increased if sodium increase < 5 mmol/l per day; in
most cases 15mg once daily over 2-3 days is sufficient,
long-term therapy is only very rarely necessary [e.g. in
small cell lung cancer])
• It is also possible to administer it grinded up via a gas-
tric tube (e.g. in intensive care patients).
• For pharmaceutical (galenic) reasons, the tablet can-
not be divided into two pieces, so half a starting dose
(7.5 mg) is not possible.
• maximum effect after 2-4h (first sodium control after
6h necessary)
• no restriction of drinking quantity during the therapy
(Patients should drink when they are thirsty!)
• increase of sodium by approx. 8-9 mmol/l per day
• side effect: especially
-- excessive increase of sodium with the risk of central
pontine myelinolysis
 -- hepatotoxicity (Red-Hand-Letter 2013)
• daily therapy costs: 88€
• guidelines (recommendations):
-- European guideline (Clinical Practice Guidelines
2014 [Spasovski et al, Eur J Endocrinology]):
not recommended (in the case of severe hyponatre-
mia even clearly rejected) as, on the one hand, the
studies did not show any mortality advantage and,
on the other hand, the risk of an excessive increase
of sodium and thus central pontine myelinolysis is
too high; note: It is noteworthy that in this guideline
the administration of urea is recommended as the
second choice for SIADH after fluid restriction. Urea
causes increased water excretion via osmotic diu-
resis. A dose of 30-120g per day is recommended.
On the one hand, this therapy principle is almost not
validated, and on the other hand, due to the extre-
mely bitter taste of urea (like urine; even if dissolved
in orange juice), it is often impossible to implement.
-- American guideline (Verbalis et al, Am J Med 2013;
Expertenkonsensus): recommended (second
choice at SIADH after the fluid restriction)
Disorders of potassium
• hyperkalemia (potassium > 5.5 mmol/l)
• hypokalemia (potassium < 3.5 mmol/l)
98% of potassium is intracellular and only 2% extracellu-
lar. The intracellular potassium concentration (Ki) is 120-
140 mmol/l, the extracellular potassium concentration
(Ke) only 3.5-5.5 mmol/l. The measured concentration in
the serum can therefore only be used with restrictions.
ECG is therefore very valuable diagnostically, especially
in the case of acute changes in potassium! Potassium
is the most important intracellular ion. The ratio of int-
ra- and extracellular potassium (Ki/Ke) determines the
membrane potential and thus the neuromuscular excita-
bility of the cell. The sodium-potassium-ATP-ase (syn .:
sodium-potassium pump) maintains this ratio by actively
transporting potassium into the cell and sodium out of
the cell. The enzyme is magnesium dependent. Insulin
and a stimulation of β-receptors stimulate the sodium-
potassium-ATP-ase and thus lead to a decrease in the
extracellular potassium in the serum via an increased
potassium uptake in the cells. Hyperkalemia lowers the
membrane potential and increases excitability, hypokala-
emia increases the membrane potential and reduces ex-
citability.The daily potassium intake with food is approx.
50-150 mmol/l. 90% of the potassium is excreted renally
and 10% enterally. In case of renal insufficiency, enteral
excretion is increased as compensation (up to 25%), but
the mechanism is limited. Potassium is filtered glomeru-
larly in the kidney and almost completely reabsorbed in
the proximal tubule. A small part is secreted in the distal
tubule and collecting tube. The excretion of potassium
is stimulated by mineralocorticoids (especially aldoste-
rone) via mineralocorticoid receptors in the distal tubule
and collecting tube. The higher the distal urine flow rate
(diuresis; e.g. polyuria in derailed diabetes mellitus), the
more potassium is excreted in the urine.
Via the H+/K+ exchanger (Hamburger Shift), potassium
also has an influence on the acid-base balance: Hyper-
kalaemia leads to acidosis and hypokalaemia to alkalo-
sis. Similarly, acidosis leads to hyperkalaemia and alka-
losis to hypokalaemia.
Hyperkalemia
Etiology
• acute kidney failure, renal insufficiency ( most fre-
quent cause)
• drugs
-- potassium-sparing diuretics (mineral corticoid recep-
tor antagonist [MRA], syn .: aldosterone antagonists:
spironolactone, eplerenone)
-- RAAS inhibitors (ACE inhibitors, ATII antago-
nists, ARNI [angiotensin receptor neprilysin inhibi-
tor]): from potassium > 5.0 mmol/l dose reduction by
50%, from potassium > 5.5 mmol/l contraindicated!
-- NSAID
-- digitalis (inhibition of the sodium-potassium-ATP-
ase)
-- β-blockers (inhibition of the sodium-potassium-ATP-
ase)
-- heparin (inhibition of aldosterone synthesis →
hypoaldosteronism; usually only in case of long-term
therapy)
-- cotrimoxazole (inhibition of potassium secretion in
the distal tubule and collecting tube)
-- succhinylcholine
-- ciclosporin
• Addison disease
• acidosis (H+/K+ exchanger [Hamburger shift]):
-- A decrease of the pH value by 0.1 leads on average
to increase of potassium of 0.6 mmol/l.
-- not the case with lactic acidosis and ketoacidosis
• cytolysis with consecutive release of potassium:
-- myolysis (e.g. rhabdomyolysis)
-- hemolysis
-- tumorlysis
• transfusion of erythrocyte concentrates (especially ol-
der preparations, massive transfusion)
• pronounced constipation
• crush syndrome
• diabetes mellitus (hyporeninemic hypoaldosteronism =
Endocrinology 763
 Schambelan´s syndrome [i.a. bicarbonate loss via the
kidney with consecutive metabolic acidosis]); therefo-
re, the potassium is often chronically elevated in long-
term diabetics])
• pseudohyperkalemia: release of potassium from blood
cells
-- iatrogenic (too long venous stasis during blood coll-
ection, too long standing of the sample)
-- pronounced leukocytosis/thrombocytosis
Fig. 1025  ECG in hyperkalemia: classically high T wave
Symptoms
• neuromuscular:
-- muscle paralysis (leading symptom of hyperkale-
mia: generalized muscle paralysis, possibly also of
the respiratory muscles!)
-- paresthesia (e.g. tingling tongue)
• cardiac: cardiac arrhythmia (especially bradycardia
[AV-Block]; note: Just think of the cardioplegic solution
[Bretschneider solution], which contains a lot of potas-
sium and paralyzes the heart besides the cold.)

hyperkalemia → bradycardic
arrhythmias
hypokalemia → tachycardic
Fig. 1026  ECG in hyperkalemia: high T wave, wide QRS
arrhythmias
complexes, short QT interval and the no longer recogniz-
able P wave.

ECG
• elevated, tent-shaped T waves (high T wave)
• PQ interval ↑­, possibly AV-Block II/III
• QT interval ↓ (early sogn!)
• QRS widening (often extreme; ultra-wide [> 180ms;
always sign of severe hyperkalaemia, i.e. potassium
usually > 8 mmol/l])
• sinus wave-like QRS complexes (always sign of
very severe hyperkalaemia [potassium usually > 9
mmol/l])
• flattening or loss of the P wave (often no longer visible
→ misdiagnosis: escape rhythm)
• possibly ventricular fibrillation
• note: Since potassium occurs predominantly intra-
cellularly and less extracellularly (i.e. in the blood), the
potassium concentration (intracellular; Ki) can often
even be estimated better with the ECG than with the
laboratory!
Fig. 1027  ECG in hyperkalemia: Typical features are the
wide QRS complexes, the short QT interval and the (almost)
undetectable P wave.

764 Endocrinology

Fig. 1028  ECG in severe hyperkalaemia: The QRS comple-
xes are, on the one hand, ultra-wide (only available here)
and, on the other hand, like a sine wave. It is a broad QRS
tachycardia, but not a ventricular tachycardia.
DD high T wave
• vagotonia (e.g. young athletes)
• acute myocardial infarction stage I (initial stage [hyper-
acute T wave])
• De Winter´s sign (sign of proximal RIVA occlusion,
considered STEMI equivalent; see page 348)
• hyperkalemia
• hypermagnesemia
• Short-QT syndrome
• complete left bundle branch block
Therapy
• sodium bicarbonate (Nabic) 8,4%
-- independent of pH-value (actually only effective if
metabolic acidosis is present at the same time)
-- 50mval (50ml) in 5min, repetition after 15min or Na-
bic perfusor (40mval/40ml pure) with 10ml/h
-- onset of action only after 30-60min
• calcium
-- fastest effect in hyperkalemia
-- It does not lower the potassium level, but acts as a
direct antagonist especially on the myocardium by
stabilizing the membrane potential and thus largely
neutralizes the toxic effect of potassium on the myo-
cardium.
-- dosage (administration over 10min):
◦◦ 10ml of calcium chloride 10% (rule of 10 or
◦◦ 30ml of calcium chloride 10%
-- not with patients taking digitalis!
• glucose-insulin infusion
-- e.g. 500ml G40% + 16 IU insulin over 1h
-- best separate administration (insulin perfusor)
-- rule of 20: 200ml Glucose 20% with 20IU of insulin
over 20min
• loop diuretics (to increase renal potassium elimination
e.g. furosemide 40-80mg i.v.) either alone (if hypervo-
lemic) or in combination with fluid (if eu- or even hypo-
volemic) as a forced diuresis: NaCl 0.9% (2000-3000
ml) + furosemide 40mg i.v. every 4 hours
• β2-mimetics (stimulation of sodium-potassium-ATP-
ase; cave: triggering of cardiac arrhythmias)
-- inhaled (e.g. Berotec-Spray)
-- s.c. (terbutaline [Bricanyl])
• potassium binder (anion exchange resins; to increase
enteral potassium elimination):
-- polystyrene sulfonate (PSS): p.o. / rectal (enema)
1-3x daily (daily dose 15-60g; side effect: i.a. intesti-
nal necrosis [especially with enema])
◦◦ sodium salt (Na-PSS): Resonium
◦◦ calcium salt (Ca-PSS): CPS powder
-- new: p.o.
◦◦ sodium zirconium cyclosilicate (ZS-9; (not yet ap-
proved): 1x daily, daily dose 5-15g, rapid onset of
action (1h)
◦◦ patiromer (RLY5016; Veltassa; already approved
in the EU):
▪▪ 1 sachet = 8.4g
▪▪ daily dose 8.4-16.8g (one sachet of 8.5g usually
sufficient)
▪▪ slow onset of action
▪▪ at least 3 hours away from taking other drugs
▪▪ sodium free
• therapy refractory hyperkalemia → insertion of a
Shaldon catheter and emergency hemodialysis (not
CVVH: Small molecules such as potassium are only
removed by hemodialysis and not by hemofiltration!
Following this [especially with only short "potassium
dialyses"] a post-dialytic rebound phenomenon with
potassium increase may occur.)
No calcium administration in
patients who take digitalis!
Hypokalemia
Ätiologie
• drugs
-- diuretics (most frequent cause; especially loop
diuretics)
-- insulin
-- steroids (e.g. prednisolone, hydrocortisone)
-- antiinfectives
◦◦ antibiotics (e.g. penicillin, aminoglycosides)
◦◦ antifungals (especially amphotericin B)
-- catecholamines
Endocrinology 765
 -- β2-mimetics
-- theophylline
-- acetazolamide
• intestinal losses:
study
-- gastroenteritis
-- laxatives
• alkalosis (H+/K+ exchanger [Hamburger shift]) Hypokalemia in acute medical patients: risk factors and
• hypercortisolism prognosis
• hyperaldosteronism Jensen et al, American Journal of Medicine 2014
-- primary (Conn's disease)
• prospective cohort study
-- secondary
• 11,988 inpatients (i.e. admitted to hospital)
◦◦ heart failure, liver cirrhosis, nephrotic syndrome • incidence of hypokalemia (potassium < 3.4 mmol/l):
◦◦ renal artery stenosis 16.8% (in 3.3% < 2.9 mmol/l)
◦◦ malignant nephrosclerosis (malignant hypertensi- • Every 6th hospitalized patient has hypokalemia!
on) • risk factors (for hypokalemia):
◦◦ renal tumor (paraneoplastic renin production) -- age
◦◦ licorice (The containing glycyrrhizic acid [a natural -- female sex
ingredient in licorice root] causes in large quanti- -- diuretics
ties. hyperaldosteronism.) -- alcohol abuse
• hypomagnesemia (Hypokalemia is often a result of -- liver disease
magnesium deficiency, because the sodium-potassi- -- malignancies
um-ATP-ase is magnesium dependent!) • increase in mortality:
-- potassium 2.9-3.3 mmol/l: by 48%
• hypothermia (e.g. after resuscitation)
-- potassium < 2.9 mmol/l: by 90% (doubling mortality
• Bartter syndrome, Gitelman syndrome (see infobox compared to normokalemic patients!)
page 774)
• Pseudo-Bartter syndrome
-- symptoms similar to Bartter syndrome (see infobox Symptoms
page 774) • paresis (ascending, possibly also of the respiratory
-- abuse of laxatives or diuretics (possibly detection in muscles), paresthesia
the urine) • constipation, paralytic ileus, possibly acute intestinal
-- frequent younger women (especially anorexia ner- pseudo-obstruction (Ogilvie syndrome)
vosa) • urinary retention
• anorexia nervosa • hypo- / areflexia
• refeeding syndrome • cardiac arrhythmia (especially tachycardia)
• renal-tubular acidosis (RTA) • possibly polyuria, polydipsia (hypokalemic renal diabe-
• familial hypokalemic paralysis (autosomal dominant) tes insipidus)
• rhabdomyolysis (Severe hypokalemia can trigger
rhabdomyolysis by disturbing the membrane potential.
This in turn can lead to hyperkalemia.)

ECG
• ST-depressions, T-negativations
• QT inteval ↑­, U wave, possibly TU-fusion wave
• PQ inteval ↓

Therapy
• causal
• symptomatic (potassium substitution)
Fig. 1029  Sonography of the abdomen: kidney tumor (renal -- oral; preparations (examples):
cell carcinoma; often paraneoplastic renin production with ◦◦ Kalinor retard (potassium chloride): 8 mM
hyperaldosteronism and consecutive hypokalemia) ◦◦ Kalinor verla (potassium citrate): 20 mM
◦◦ Kalinor fizzy powder (potassium hydrogen carbo-
nate): 40 mM (contains most potassium!)
-- parenteral
◦◦ maximum 0.2 mmol/kg/h or 2-3 mval/kg/d
◦◦ potassium deficit:
▪▪ A decrease of 1 mmol/l means a deficit of 200

766 Endocrinology
 mval (200 mval necessary to increase potassi-
um by 1.0 mmol/l).
▪▪ potassium deficit in mval = (4.5 mval - serum-
potassium) x 0.4 x kgBW
◦◦ up to 40 mval KCl possible in a free-running infu-
sion as peripheral administration, otherwise CVC
placement necessary
◦◦ The sodium-potassium-ATP-ase (Na+/ K+ pump)
is magnesium dependent: Magnesium is a cofac-
tor of the sodium-potassium-ATP-ase. Therefore,
in addition to potassium, you should also give a
generous amount of magnesium. Our potassium
perfusor is drawn up with magnesium as standard
(KCl 40ml + MgVerla 10% 10ml). Alternatively, in
therapy refractory cases Inzolen vials can also be
given (peripheral venous application also possib-
le): In addition to potassium, magnesium aspar-
tate is also contained here, which activates the
sodium-potassium-ATP-ase and thus leads to a
further increase in potassium.
The most common cause of refractory
hypokalaemia is hypomagnesaemia
(→ administration of magnesium)!
Always fill potassium perfusor
together with magnesium! The
sodium-potassium-ATP-ase (Na+/
K+ pump) is magnesium depen-
dent!
Disorders of calcium
• hypercalcemia (total calcium > 2.6 mmol/l or ionized
calcium > 1.3 mmol/l)
• hypocalcemia (total calcium < 2.2 mmol/l or ionized
calcium < 1.1 mmol/l)
The calcium level in the serum is extremely constant
(biological constant; homeostasis). Four organs are in-
volved in calcium metabolism:
• parathyroid glands: for calcium regulation; via parathy-
roid hormone (PTH):
-- protein from 84 amino acids with a very short half-life
(only 3 minutes)
-- norm value: 15-65 pg/ml (1.5-6.5 pmol/l)
-- The lower the calcium concentration at the calcium-
sensing receptors of the epithelial cells, the more
PTH is released from the epithelial cells (opposing
behavior of calcium and parathyroid hormone).
-- effects:
◦◦ release of calcium from the bone (main effect)
◦◦ decreased excretion (tubular reabsorption) of cal-
cium and increased excretion of phosphate from
the urine
◦◦ stimulation of 1α-hydroxylase in the kidneys →
1-25-OH-vitamin D (calcitriol) ↑ → calcium absorp-
tion from the intestine ↑
-- note: Calcitonin from the C cells of the thyroid gland
has only a subordinate role for regulation as an an­
tagonist to the parathyroid hormone.
• bones: for calcium storage (99% of the total calcium
is stored in the bone [in the form of hydroxyl phospha-
tide]. Only 1% is found intravascularly in the serum.)
• intestine: for calcium absorption (Calcium is absorbed
through the intestine. Under normal conditions, only
about 20% is absorbed, 80% of the calcium is excre-
ted with the stool. The absorption from the intestine is
increased by the active form of vitamin D [1-25-OH-
vitamin D; calcitriol].)
• kidney: for calcium excretion (calcium can only be ex-
creted via the kidneys. This is used, for example, in
forced diuresis to treat hypercalcemia.)
Calcium is only to 50% available as free calcium (ionized
calcium). Only the free (ionized) calcium is biologically
active. 45% of calcium is bound to proteins (especially
to albumin [90%]), and 5% is bound to complexes (lac-
tate, bicarbonate, phosphate). High or low albumin con-
centrations can therefore simulate high or low total cal-
cium concentrations (so-called pseudohypercalcemia or
pseudohypocalcemia). Therefore, an albumin correction
(Payne's formula) is necessary:
Cacorrected = Cameasured - 0.025 x albumin (g/l) + 1
Rule of thumb: A decrease of albumin by 1 g/dl causes
a decrease of total calcium by 1 mg/dl or 0.25 mmol/l.
Furthermore, the ionized calcium can also be determined
using a BGA. The ionized calcium (degree of protein bin-
ding) is pH dependent:
• In alkalosis, the protein binding is higher, so that the
ionized calcium decreases (increase of pH by 0.1 →
decrease of ionized calcium by 0.05 mmol/l). This is by
the way the reason for the tetany as a result of hyper-
ventilation: Here a respiratory alkalosis develops.
• In acidosis, the protein binding is lower, so that the
ionized calcium increases (decrease of pH by 0.1 →
increase of ionized calcium by 0.05 mmol/l).
Endocrinology 767
Hypercalcemia

Etiology
• malignancies (No.1; tumor hypercalcaemia 25% of all
cancer patients; parathyroid hormone [PTH] ↓): i.a
-- bone metastases (e.g. prostate cancer, lung cancer,
breast cancer)
-- plasmocytoma (multiple myeloma)
-- paraneoplastic (PTH-related peptide; especially
squamous cell carcinoma such as esophageal or
cervical cancer)
• primary hyperparathyroidism (pHPT; No.2; see excu-
rus; parathyroid hormone [PTH] ↑, furhtermore phos-
phate ↓ and alkaline phosphatase [AP] ↑)
• immobilization
• granulomatous diseases (especially sarcoidosis, tu-
berculosis)
• vitamin D intoxication (p.d. 25-OH-vitamin D in the se-
Fig. 1030  Hypercalcemia in multiple bone metastases (The
rum > 150 μg/l or > 375 nmol/l), vitamin A intoxication
extremely bright bones are conspicuous [a classic finding
• drugs: i.a. thiazides, lithium, theophylline, antiestro- in metastatic prostate cancer]!)
gens, omeprazole, hepatitis B vaccination
• endocrinological:
-- adrenocortical insufficiency (Addison disease)
-- hyperthyroidism
-- pheochromocytoma
• milk-alkali syndrome
-- syn.: Burnett syndrome
-- result of an excessively excessive simultaneous
supply of calcium (milk, cheese, vitamin D) and alka-
line substances (e.g. bicarbonates, antacids)
-- known from the beginning of the last century, when
patients with gastric ulcers were treated with a com-
bination of milk and alkali powder
-- today e.g. result of ingestion of betel nut with oyster
shell powder or buffered aspirin tablets
• benign familial hypocalcemia (FHH)
-- Here there is an inactivating mutation of the calcium-
sensing receptor of the parathyroid glands, so that
the treshold is adjusted with an increased parathyro-
Fig. 1031  The extremely bright bones are pathognomonic
id hormone level.
for an osseous metastatic prostate carcinoma! Here the pa-
-- important differential diagnosis to primary hyperpa- tient is also cardially decompensated.
rathyroidism (since no surgery [and no other thera-
py] is necessary here)
-- absolutely asymptomatic and benign!
• malignant hyperthermia (anesthetic incident)

Fig. 1032  plasmacytoma (multiple myeloma) with multiple

osteolyses in the skull bone ("shotgun skull"); Chemothe-
rapy standard today for plasmacytoma: VCD scheme (Vel-
cade [bortezomib; a proteasome inhibitor] + cyclophospha-
mide + dexamethasone)

768 Endocrinology
Fig. 1033  CT: multiple metastases are visible in the spinal Fig. 1035  CT: multiple bone metastases in the femur and
column. acetabulum

Symptoms
• neurological:
-- confusion, psychosis
-- somnolence, coma
• musculoskeletal:
-- muscle weakness
-- hyporeflexia
-- fatigue
• gastrointestinal:
-- nausea, vomiting, exsiccosis
-- constipation, subileus (up to ileus)
-- pancreatitis
-- gastrointestinal ulcer
• renal:
-- polyuria, polydipsia (hypercalcemic renal diabetes
insipidus), exsiccosis
-- hypercalciuria, nephrocalcinosis, kidney stones
(urolithiasis)
Fig. 1034  X-ray: multiple osteoblastic bone metastases in a -- renal insufficiency
patient with metastatic prostate cancer • cardiovascular:
-- arterial hypertension
-- QT interval shortening
-- arrhythmias (especially bradycardias
-- Osborn wave (syn.: J wave [see page 349]; camel
hump-like elevated ST segment; no indication of a
STEMI and therefore no reason for a cardiac cathe-
ter examination)
-- hypersensitivity to digitalis

hypercalcemic crisis: lack of

volume, hyperpyrexia, psychosis,
coma

Endocrinology 769
Therapy
• causal (e.g. treatment of malignancy, surgery for pri-
mary hyperparathyroidism)
• symptomatic
-- forced diuresis to increase renal calcium elimination:
NaCl 0.9% (2000-3000 ml) + loop diuretics (e.g. fu-
rosemide 40mg i.v. every 4h)
-- calcitonin (Karil)
◦◦ very effective and rapid onset of action (how-
ever only effective in acute situations, not in long-
term therapy)
◦◦ 1 amp. = 1ml = 100IU
◦◦ dosage: 2 IU/kg 1-0-1 s.c.; in case of vital threat: 1
IU/kg i.v. in 50ml NaCl 0.9%
-- bisphosphonates ( means of choice for tumor
hypercalcaemia; maximum effect only after 2 days;
contraindicated in renal insufficiency with a GFR <
35 ml/min); they are strong acids that are given as
salt:
◦◦ pamidronate (pamidronic acid; Aredia) in 500ml
NaCl 0.9% over 2h i.v.
▪▪ calcium 2.6-3.0 mmol/l: 15mg
▪▪ calcium 3.0-3.5 mmol/l: 30mg
▪▪ calcium 3.5-4.0 mmol/l: 60mg
▪▪ calcium > 4 mmol/l: 90mg
◦◦ ibandronate (ibandronic; acid Bondronat) 2-6mg in
500ml NaCl 0.9% over 4h i.v.
◦◦ clodronate (clodronic acid Ostac, Bonefos)
1500mg in 500ml NaCl 0.9% over 4h i.v.
◦◦ zoledronate (zoledronic acid; Zometa) 4mg in
50ml NaCl 0.9% over 15min
-- steroids (onset of action only after 2 days; over 4d;
mainly effective in plasmocytoma)
◦◦ dexamethasone 40mg daily
◦◦ prednisolone 1-2 mg/kg daily
-- cinacalcet (Mimpara)
◦◦ a calcimimetic (inhibition of secretion of parathy-
roid hormone; a parathyroid hormone antagonist)
◦◦ only in case of inoperable hyperparathyroidism
(e.g. parathyroid cancer)
◦◦ dosage:
▪▪ primary hyperparathyroidism (including parathy-
roid carcinoma): initially 2 x 30mg, then increase
every 2-4 weeks according to calcium level by
30mg (maximum 4 x 90 mg daily)
▪▪ secondary hyperparathyroidism (in terminal
kidney failure requiring dialysis): initially 1 x 30
mg, then increase every 2-4 weeks according to
PTH level (target value: 150-300 pg/ml) by 30
mg (maximum 2 x 90 mg daily)
-- if necessary hemodialysis
◦◦ especially with severe hypercalcaemia (calcium >
3.5 mmol/l) and renal insufficiency (Otherwise cal-
cium excretion is no longer possible here!)
◦◦ using a calcium-free dialysate
770 Endocrinology
Excursus: Primary hyperparathyroidism
(pHPT)
Definition
• primary disease of the parathyroid gland with increa-
sed production of parathyroid hormone (PTH)
• 3rd most common endocrinological disease
• An important (harmless) differential diagnosis to pHPT
that does not require any therapy at all is familial hypo-
calzuric hypercalcemia (FHH; see page 765).
Epidemiology
• prevalence: 0.1% (frequent!)
• w:m = 3:1
• age peak: 60-75 years (In younger patients, especially
think of a MEN syndrome [multiple endocrine neopla-
sias]!)
Causes
• solitary adenoma of the parathyroid gland (80%; "one-
gland disease")
• parathyroid hyperplasia (19%; "multi-gland disease")
• parathyroid carcinoma (1%)
Genesis
• sporadically (mostly)
• familial (rare): in the context of a MEN syndrome (then
hyperplasia!)
-- MEN I (Wermer syndrome): pHPT, pituitary adeno-
ma, islet cell neoplasia
-- MEN IIa (Sipple syndrome): pHPT, medullary thyroid
carcinoma, pheochromocytoma
Symptoms
• in 50% asymptomatic (discovered by chance during a
hypercalcemia investigation)
• stones: especially
-- kidney stones (urolithiasis; often [in 50%], possibly
nephrocalcinosis)
-- gall stones (cholelithiasis)
• bones
-- "brown tumors" (Osteodystrophia cystica genera-
lisata von Recklinghausen; the demineralization of
the bones leads to small fractures with hemorrhage;
today only very rarely)
-- subperiosteal resoption zones
-- acroosteolysis
-- osteopenia (diffuse) due to demineralization, possib-
ly pathological fractures
• gastroduodenal ulcers (hypercalcemia → gastrin ↑)
• arterial hypertension
• symptoms of hypercalcaemia
primary hyperparathyroidism: "stones,
bones, abdominal groans, thrones and
psychiatric overtones"
Diagnosis
• laboratory:
-- calcium ↑, phosphat ↓ (only in 50%)
-- PTH ↑
-- AP (alkaline phosphatase) ↑
-- calcium in the 24h urine collection ↑ (also phosphat
↑)
-- possibly lipase ↑ (in case of pancreatitis)
• imaging:
-- sonography (neck); Pitfall: If you examinate thyroid
gland with suspected primary hyperparathyroidism
you shouldn't rejoice too soon, when you detect a
lesion: It could also be a normal thyroid node that
every fourth adult has! Therefore one should always
do a scintigraphy with this question of whether the
lesion is also accumulates the marker.
-- cross-sectional imaging (CT, MRI): rarely indicated
(mostly not necessary)
-- parathyroid scintigraphy (sestamibi scan)
• osteodensometry (important for the therapy decision):
determination of the T-score
localization diagnosis in pHPT:
sonography + parathyroid scintigraphy
Fig. 1036  small adenoma of the parathyroid gland in prima-
ry hyperparathyroidism (various examples)
Fig. 1037  large adenoma of the parathyroid gland in prima-
ry hyperparathyroidism (The parathyroid tissue is slightly
hypoechoic than the thyroid tissue.)
Fig. 1038  parathyroid scintigraphy (technetium-99m-sesta-
mibi scan) in primary hyperparathyroidism: One recogni-
zes the pathological accumulation.
Therapy
• surgical (by an experienced surgeon; intraoperative
parathyroid hormone measurements)
-- surgery - types:
◦◦ adenoma → exstirpation
◦◦ hyperplasia → total parathyroidectomy with simul-
taneous autologous transplantation of remains of
epithelial cells in the forearm (brachioradialis mu-
scle) or sternocleidomastodieus muscle (cryopre-
servation of removed epithelial cells)
-- surgery - indications:
◦◦ symptomatc pHPT
◦◦ asymptomatic pHPT
▪▪ calcium in the serum > 3 mmol/l
▪▪ calcium in the 24h urine collection > 400 mg/d
ore > 10 mmol/d (no longer listed as an indica-
tion in the current guidelines)
▪▪ creatinine Clearance < 60 ml/min
▪▪ osteodensometry T-score < -2.5 (i.e. osteoporo-
sis)
▪▪ age < 50 years (The younger the patient, the
higher the cumulative lifetime risk of fractures,
which may immobilize the patient and even
make them wheelchair-bound!)
• conservative: i.a.
-- sufficient hydration
Endocrinology 771
 -- avoidance of certain drugs (thiazides, digitalis, lithi-
um)
-- osteoporosis prophylaxis (with vitamin D [increases
slightly the calcium level, but is essential!])
-- if necessary cinacalcet (Mimpara): drug of choice if
inoperable or surgery is refused
Hypocalcemia
Etiology
• hypoproteinemia (especially hypalbuminemia;
pseudohypocalcemia; No.1)
• vitamin D deficiency
• hypoparathyroidism
-- postoperative (after strumectomy or neck-dissection
[so-called parathyroprival hypoparathyroidism; the
most frequent cause after pseudohypocalcemia!)
-- congenital (aplasia)
-- autoimmune
-- metabolic (hemochromatosis, Wilson's disease)
• pseudo-hypoparathyroidism (end organ resistance to
parathyroid hormone)
• medullary thyroid cancer (overproduction of calcitonin)
• acute pancreatitis (caused by saponification; important
prognostic parameter!)
• hyperphosphatemia
• refeeding syndrome
• renal-tubular acidosis type I
• blood transfusions (binding of calcium by citrate)
• drugs: especially
-- loop diuretics
-- calcimimetics
-- bisphosphonates
-- Ringer lactate (e.g. Sterofundin; by binding ionized
calcium)
-- laxatives for colonoscopy (containing phosphate
[e.g. Fleet])
-- sodium bicarbonate (Nabic 8,4%)
• citrate anticoagulation in renal replacement therapy
(CVVH)
• intoxication with hydrofluoric acid (often severe hypo-
calcemia!)
• hypothermia (e.g. after resuscitation)
Excursus: Vitamin D deficiency
• definition: vitamin D (exactly: 25-OH-Vitamin D) in se-
rum < 20 μg/l (severe deficiency: < 12 μg/l)
• epidemiology: very frequent (40% of all Europeans
are vitamin D deficient [Cashman et al, Am J Clin Nutr
2016]!)
• syn.:
-- children: rickets (rachitis; very rarely today)
-- adults: osteomalacia
• physiology:
-- Vitamin D3 (cholecalciferol; calciol; i.a. used for the
therapy of osteoporosis) is either formed in the skin
by UV radiation (sunlight [therefore vitamin D defi-
ciency more frequent in winter]) or is absorbed with
772 Endocrinology
food. In the liver the hydroxylation to 25-OH-vitamin
D (calcidiol [storage form]) takes place, in the kid-
neys the hydroxylation to 1-25-OH-vitamin D (calci­
triol [active form; from now on p.d. a hormone]; i.a.
used for the therapy of hypoparathyroidism). Calci-
triol acts via vitamin D receptors (VDR), which are
present on almost all cells in the body.
• effects:
-- osseous: calcium
​​ metabolism (calcium ↑)
◦◦ intestine (gut; main effect): increase of the intesti-
nal calcium and phosphate absorption
◦◦ bones: inhibition of osteolysis (i.a. via suppression
of parathyroid hormone in the parathyroid gland)
◦◦ kidney: decrease of calcium excretion (increase of
tubular reabsorption)
-- extraosseous (pleiotropic): especially
◦◦ immunological: lack of vitamin D → increased rate
of infections (especially nosocomial) and sepsis
◦◦ muscular: lack of vitamin D → myopathy (including
difficult weaning, heart failure)
• occurrence: often in intensive care units (60% of
all seriously ill patients [i.a. Lee et al, N Engl J 2009])
• causes:
-- dermatological: insufficient UV radiation
-- gastrointestinal: malabsorption (i.a. sprue, Whipple´s
disease, Crohn´s disease, after bowel resection,
exocrine pancreatic insufficiency), malnutrition
-- hepatic (liver insufficiency [also often caused by drug
interactions, e.g. steroids, anticonvulsants]; distur-
bance of the hepatic hydroxylation, i.e. the formation
of 25-OH-vitamin D [calcidiol])
-- renal (renal insufficiency [also disturbed in sepsis!];
disturbance of renal hydroxylation, i.e. the formation
of 1-25-OH-vitamin D [calcitriol])
• laboratory:
-- hypocalcemia
-- hypophosphatemia
◦◦ In the case of therapy-refractory hypophosphate-
mia, one should always think of a vitamin D defi-
ciency!
◦◦ in renal failure, however, hyperphosphataemia
-- alkaline phosphatase (AP) ↑
• diagnosis:
-- 25-OH-vitamin D in the serum < 20 μg/l or < 50 nmol/l
-- We routinely determine 25-OH-vitamin D in seriously
ill patients who are in the intensive care unit longer
than 3 days.
• therapy:
-- substitution with Decristol oil 20000E (Vitamin D3,
cholecalciferol) p.o. or via gastric tube once a week
-- Vitamin D is not (yet) available as an i.v. formulation
(alternatively i.m. administration possible).
-- in case of renal insufficiency: calcitriol (Rocaltrol)
0.5-3 μg/d p.o. (also i.v. administration possible)
-- tight control of calcium and phosphate
• evaluation: Whether the substitution actually is useful
remains controversial: Intervention studies came to dif-
ferent results. In the study by Bjelakovic et al (Cochra-
ne Database Syst Rev 2011) a mortality advantage
 could be shown in intensive care patients with proven
vitamin D deficiency through substitution, whereas this
was not the case both in the VITdAL-ICU and in the
VIOLET study (see box). It is possible that a vitamin
D deficiency is only a sign (surrogate parameter) of
a correspondingly severe underlying disease. In the
case of severe vitamin D deficiency (<12 μg/l) in cri-
tically ill patients, substitution is recommended (S2k
guideline of the DGEM [German Society for Nutritional
Medicine] "Clinical Nutrition in Intensive Care Medici-
ne" 2018.
Fig. 1039  Vitamin D metabolism
VITdAL-ICU study
Effect of high-dose vitamin D3 on hospital length of stay in
critically ill patients with vitamin D deficiency
Amrein et al, JAMA 2014
• VITdAL: Vitamin D Deficiency in Critically Ill
• first large vitamin D intervention study in intensive care
patients
• monocentric (Graz University Hospital; Austria) prospec-
tive randomized study
• 492 intensive care patients with proven vitamin D defici-
ency (25-OH vitamin D < 20 μg/l)
-- with substitution of vitamin D (loading dose of 540000
IU, then monthly maintenance dose of 90000 IU)
-- without substitution of vitamin D
• results: substitution of vitamin D
-- duration of hospital stay (primary endpoint): no reduc-
tion
-- mortality: no reduction (In the subgroup with severe
vitamin D deficiency [p.d. < 12 μg/l] however, a signifi-
cant reduction of mortality was observed!)
VIOLET study
Early High-Dose Vitamin D3 for Critically Ill, Vitamin D–De-
ficient Patients
PETAL-Network, N Engl J 2019
• VIOLET: Vitamin D to Improve Outcomes by Leveraging
Early Treatment
• multicenter (USA) prospective randomized controlled
study
• 1078 critically ill patients (intensive care unit) with pro-
ven vitamin D deficiency (25-OH vitamin D < 20 μg/l)
-- with substitution of vitamin D (540000 IU p.o. / gastric
tube)
-- without substitution of vitamin D
• results: substitution of vitamin D → no difference
(premature termination of the study)
-- primary endpoint (mortality after 90 days)
-- secondary endpoints (i.a. length of hospital stay, ven-
tilation-free days, ARDS, acute kidney failure, quality
of life after 90 days)
Symptoms
• neuromuscular (hypocalcemic tetany):
-- paresthesia (tingling; mostly perioral)
-- carpopedal spasms, spasm of the muscles of the
hand and forearm (paw position), carp mouth
-- possibly laryngospasm (especially in children [dan-
gerous!])
-- Chvostek's sign: twitching of the corners of the
mouth when tapping the facial nerve
-- Trousseau´s sign: spasm of the muscles of the hand
and forearm (paw position) when measuring blood
pressure
-- seizures with preserved consciousness
-- rhabdomyolysis
• cardiovascular:
-- QT interval prolongation
-- heart failure
-- arterial hypotension
• gastrointestinal: diarrhea
• hemostasiologic: increased risk of bleeding
-- Hypocalcaemia as a co-factor for bleeding!
-- Calcium is an essential part of the coagulation cas-
cade and is even referred to as factor IV (free cal-
cium ions). The activation of numerous coagulation
factors is calcium-dependent: factor I (fibrin), factor II
(thrombin), factor X (Stuart-Prower factor) and factor
VIII (fibrin-stabilizing factor). Furthermore, calcium
as a cation (positively charged) mediates the bond
("bridging function") between the negatively char-
ged coagulation factors and the negatively charged
phospholipids of the platelet membrane. Last but not
least, calcium is a component of the two most impor-
tant membrane-bound enzyme complexes in coagu-
lation: prothrombin kinase and tenase (intrinsic and
Endocrinology 773
 extrinsic.)
• other (especially in chronic hypocalcemia [In spite of
hypocalcemia, calcification occurs here: The reason is
an increased calcium phosphate product.]):
-- hair and nail growth disorders, poor tooth status
-- eye: cataract ["tetanic cataract"])
-- calcification of the basal ganglia (Fahr's disease) →
Parkinson's syndrome, chorea
-- osteosclerosis
-- headache (due to vascular spasm)
-- psychological alterations (irritability, depressive
mood, anxiety)
Fig. 1040  native CCT: Fahr's disease (pronounced calcifi-
cation of the basal ganglia [not to be confused with intrace-
rebral hemorrhage!])
Therapy
• calcium administration (goal: calcium levels in the lo-
wer normal range [2,0-2,2 mmol/l], calcium phosphate
product < 4,4 mmol2/l2; not in patients on digitalis)
774 Endocrinology
-- p.o. (500-1500 mg/d)
-- i.v.: calcium gluconate 10% 10-40ml over 10min (hy-
pocalcemic crisis → 2 ampoules of calcium 10% i.v.)
• hypoparathyroidism (Note: the only disease in endocri-
nology that is not treated [yet] with the hormone that is
actually missing [parathyroid hormone]) → additionally
vitamin D preparation (possibly also in the future re-
combinant parathyroid hormone [Natpara; expensive,
already approved in the USA, not yet in Europe] s.c.):
-- cholecalciferol (Vitamin D3): Dekristol oil, Vigantol oil
20000-100000 IU per week p.o. / gastric tube
-- 1α-hydroxy-cholecalciferol (1α-Hydroxy-Vitamin D3)
◦◦ 1000 times the potency of cholecalciferol
◦◦ trade names: EinsAlpha, Bondiol, Doss
◦◦ doasage: 0.5-3 μg/d
-- 1,25-dihydroxy-cholecalciferol (1,1α-Dihydroxy-
citamin D3)
◦◦ 1000-1500 times the potency of cholecalciferol
◦◦ trade names: Calcitriol, Rocaltrol
◦◦ dosage: 0.25-1.5 μg/d
◦◦ means of choice (best cinetic)
-- dihydrotachysterol
◦◦ 2,5 times the potency of cholecalciferol
◦◦ trade names: AT10 Perlen, Tachystin
◦◦ dosage: 0.5-1.5 mg/d
Disorders of magnesium
• hypomagnesemia (magnesium < 0,70 mmol/l)
• hypermagnesemia (magnesium > 1,60 mmol/l)
Hypomagnesemia
Definition
• magnesium < 0.70 mmol/l
• 65% of all intensive care patients (Tong et al, J In-
tensiv Care Med 2005)
• consequences:
-- hypokalaemia (The sodium-potassium-ATP-ase is
magnesium dependent!)
-- hypocalcemia
• Magnesium is cofactor of about 300 enzymes in
the body, i.a.:
-- pyruvate dehydrogenase (i.a. thiamine [= vitamin
 B1] as an important coenzyme): This introduces
pyruvate into the citric acid cycle (citrate cycle). In
hypomagnesemia this enzyme does not function
properly, so that pyruvate is degraded to lactate and
lactic acidosis can develop (functional thiamine de-
ficiency).
-- sodium-potassium-ATP-ase (Na+/K+ pump): If hypo-
magnesemia is present at the same time as hypoka-
lemia, potassium does not increase by the administ-
ration of potassium alone. Magnesium must also be
administered.
Etiology
• loss
-- gastrointestinal (e.g. frequent nasogastric suctions,
malabsorption syndrome, diarrhoea, fistulas)
-- renal
• parenteral nutrition
• acute pancreatitis
• alcoholics
• liver cirrhosis
• malnutrition
• laxative abuse
• refeeding syndrome
• drugs (i.a. diuretics, digitalis, catecholamines, proton
pump inhibitors, aminoglycosides, ciclosporin, cispla-
tin)
• renal tubular acidosis (RTA)
Therapy
• causal (therapy of the underlying disease)
• symptomatic: substitution (2g of magnesium i.v. [2
amp. of magnesium sulfate 10% in 50ml NaCl 0.9%
over 3h])
Hypermagnesemia
Definition
• magnesium > 1,60 mmol/l
• mostly occurring together with hyperkalemia
• mostly iatrogenic
Etiology
• renal insufficiency (most common cause)
• excessive intake: e.g.
-- too high parenteral dose /e.g. in the context of
eclampsia prophylaxis)
-- magnesium-containing laxatives or antacids (e.g.
magnesium-containing laxatives for colonoscopy:
Magnesium-containing laxatives [e.g. Citrafleet] are
therefore contraindicated from a GFR < 30 ml/min
and should be replaced by magnesium-free laxati-
ves [e.g. Moviprep].)
• Addison's disease, Cushing's disease
• hypoaldosteronism
• hypothyroidism

Symptoms Symptoms
• neuromuscular • neuromuscular
-- tetany, carpopedal spasms -- muscular weakness
-- tremor -- respiratory paralysis
-- muscle weakness -- paresthesia
-- paresthesia • cerebral
• cerebral -- hypo- to areflexia (Therefore the patellar reflex is
-- depression also recommended as a monitoring parameter in
eclampsia prophylaxis with magnesium!)
-- psychosis
-- disturbance of consciousness ("magnesium anest-
-- possibly stroke
hesia")
• cardiovascular
• gastrointestinal
-- QT interval ↑, possibly torsade de pointes
-- nausea, vomiting
-- QRS widening
-- constipation, possibly ileus
-- PQ interval ↑
• cardiovascular
-- tachycardia (especially tachyarrhythmia absoluta)
-- hypotension
-- angina pectoris (coronary spasms [Prinzmetal angi-
-- high T wave
na]), possibly myocardial infarction
-- QRS widening
• gastrointestinal
-- bradycardia, AV blocks, possibly asystole
-- abdominal pain (intestinal spasms)
-- diarrhea
Therapy
• causal (therapy of the underlying disease)
Hypomagnesemia: frequent • symptomatic: therapy like hyperkalemia (preferably
tachyarrhythmias! calcium gluconate)

Endocrinology 775
Disorders of phosphate Symptoms
• hypophosphataemia (phosphate < 1.0 mmol/l) • neurological:
• hyperphosphataemia (phosphate > 1.5 mmol/l) -- muscle weakness, i.a. respiratory muscles (CIP,
CIM) → respiratory insufficiency, weaning problems
-- paresthesia
-- confusion, delirium, coma
-- seizures
• cardiac: myocardial weakness → heart failure
• hemolysis (Due to the lack of ATP, the erythrocytes are
destroyed.)
• rhabdomyolysis (Due to the lack of ATP, the muscle
cells are destroyed.)

Hypophosphatemia: frequently
occuring in intensive care units →
determine phosphate regularly (e.g.
twice a week)! Think of hypophospha-
Fig. 1041  Phosphate (PO4) is the salt of phosphonic acid temia especially in case of unclear
and consists of 1 atom of phosphorus (central) and 4 atoms
circulatory insufficiency / weaning
of oxygen (peripheral).
problems!

Hypophosphatämie
Therapy
Definition • p.o.: 3 x 20 mval / day (1-3g)
• phosphat < 1,0 mmol/l • i.v.: sodium phosphate 0.02 mmol/kg/h (in hypernat-
remia alternatively potassium phosphate); perfusor: 2
• Phosphate is essential for the formation of ATP (ade-
amp. sodium phosphate a 20ml = 40mval (pure) → 1
nosine triphosphate; "energy currency") and thus an
mval/ml
important energy supplier
-- for the substitution of 40mval (mostly sufficient): infu-
• phosphate 99% intracellular
sion rate 10 ml/h for 4h
• 30% of all ICU patients (in sepsis even in 80% [due
-- for the substitution of 80mval (necessary in case of
to increased consumption]!)
severe hypophosphatemia, i.e. phosphate < 0.50
• shift of the oxygen binding curve of hemoglobin to the mmol/l): infusion rate 20 ml/h for 4h
left → reduced release of oxygen
• with proven vitamin D deficiency (< 20 μg/l) substituti-
on with Dekristol oil 20000 IU p.o. or via gastric tube
Etiology once a week
• sepsis (most frequent cause)
• renal replacement therapy (relatively frequent [in
50%!]; the substitution solutions are phosphate-free)
• long-term parenteral nutrition
• malnutrition
• refeeding syndrome (Here the hypophosphataemia
is the most important marker!)
• chronic alcohol abuse
• acute liver failure
• diabetic ketoacidosis
• COPD
• drugs:
-- antacids (containing aluminum; e.g. sucralfate)
-- diuretics
-- insulin
• vitamin D deficiency (reduced absorption; therefore in
Fig. 1042  sodium phosphats: 1 amp. = 20ml = 20 mval
case of unclear hypophosphatemia determination of phosphate
25-OH vitamin D and in case of proven vitamin D defi-
ciency [< 20 μg/l] substitution with Dekristol oil 20000
IU p.o. or via gastric tube once a week)
• hyperparathyroidism
• hypothermia (e.g. after resuscitation)

776 Endocrinology
 therapy refractory hypophospha-
temia: always exclude vitamin D
deficiency!

Hyperphosphatemia

Definition
• phosphate > 1,5 mmol/l
• most frequent in dialysis patients (most frequent cause:
chronic kidney disease!)

Etiology
• reduced excretion: acute kidney failure, chronic kidney
disease
• endocrinological:
-- hypoparathyroidism
-- hyperthyroidism
-- acromegaly
-- lactic acidosis
• increased accumulation:
-- cytolysis:
◦◦ hemolysis
◦◦ rhabdomyolysis
◦◦ tumorlysis
-- laxative for colonoscopy (containing phosphate [e.g.
Fleet])
-- acute mesenteric ischemia (hyperphosphatemia in
80%!)
• bisphosphonates
• vitamin D intoxication

Symptoms
• acute hyperphosphatemia: leading are the symptoms
of hypocalcemia (see there [page 773])
• chronic hyperphosphatemia: exceeding of the calcium-
phosphate product → vascular calcification (e.g. myo-
cardial infarction, stroke)

Therapy
• phosphate binder
-- aluminum-containing (algedrate [Antiphosphat, Alu-
drox])
-- calcium-containing (calcium carbonate [CalciGry,
CC-Nefro, Dreisacarb])
• NaCl 0.9%
• hemodialysis

Endocrinology 777
 -- pCO2: normally approximately equal (in the venous
DISORDERS OF THE ACID- BGA only 3-4mmHg higher than in the arterial BGA;
so called veno-arterial pCO2 difference [dCO2], usu-
BASE BALANCE ally the central veno-arterial pCO2 difference is used,
i.e. BGA from CVC and BGA from artery; a dCO2 >
8mmHg is typical for shock [cardiac output ↓, anae-
robic metabolism ↑])
-- pH: normally approximately equyl (in venous BGA
only 0.02 higher than in arterial BGA; a veno-arterial
pH difference > 0.1 is typical for shock)
-- blood sugar (glucose): in the venous BGA about 10
mg/dl (0.6 mmol/l) lower than in the arterial BGA
• hemodynamics:
-- acidosis → vasodilatation (tip: just think of the COPD
patients who almost always have quite good and
thick veins.), hypotension (on the one hand due to
vasodilatation, on the other hand due to the fact that
in acidosis the endogenous catecholamines no lon-
ger act sufficiently [weakening of the effect of the ca-
techolamines in an acid environment]), reduction of
contractility
Basics -- alkalosis → vasoconstriction (i.a. cerebral [seizures,
neurological deficits], coronary [coronary spasm,
• pH-value:
cardiac arrhythmia])
-- pH: "potentia hydrogenii"
• hemostaseology: The lower the pH, the higher the
-- negative decadic logarithm of H+ ion-concentration:
risk of bleeding. The activity of the coagulation factors
pH = - log [H+]
decreases with decreasing pH. At a pH of 7.15, only
• acids: 50% of the activity of the coagulation factors is pre-
-- volatile (especially carbonic acid): are eliminated sent. Therefore, acidosis (in addition to hypothermia
pulmonary and anemia) is part of the "lethal triad" in polytrauma.
-- fixed: are eliminated renally • oxygen binding curve (hemoglobin):
• buffer systems: -- alkalosis → left shift → deterioration of oxygen deli-
-- open buffer system: bicarbonate system (most im- very to tissue
portant; largest capacity): The pH-value (H+ ions; -- acidosis → right shift → improvement of oxygen de-
protons) depends on the bicarbonate (HCO3-) and livery to tissue (Bohr effect)
pCO2. This relationship is described by the Hender-
son-Hasselbalch equation (syn.: buffer equation):
pH ~ log (HCO3- / pCO2)
-- closed buffer systems (low capacity only):
◦◦ phosphate
◦◦ proteins (i.a. albumin, hemoglobin)
◦◦ ammonia
• disorders:
-- acidoses (pH < 7.36)
-- alkaloses (pH > 7.44)
• changes:
-- respiratory disorders: primary change of pCO2 (lung)
◦◦ respiratory acidosis: pCO2 ↑
◦◦ respiratory alkalosis: pCO2 ↓
Fig. 1043  BGA meter (blood gas analysis; syn.: Astrup [na-
-- metabolic disorders: primary change of HCO3- (kid-
med after the Danish physiologist Poul Bjørndahl Astrup,
ney) 1915-2000])
◦◦ metabolic acidosis: HCO3- ↓
◦◦ metabolic alkalosis: HCO3- ↑
• most important diagnostic: blood gas analysis (the
most frequent laboratory examination in the intensive
care unit!)
• differences between arterial and venous BGA:
-- pO2: in the arterial BGA higher than in the venous
BGA

778 Endocrinology

Fig. 1044  different BGA syringes
Basic rules
• Disorders of the acid-base balance are always accom-
panied by disorders of the electrolytes
• First and foremost the clinic (symptoms) should be tre-
ated and not values.
• The decisive factor is the dynamic: While fast chan-
ges are dangerous, slow changes are usually rather
harmless.
• Often several disorders of the acid-base balance are
present at the same time, which unfortunately are of-
ten overlooked.
• A normal pH does not rule out a disorder of the acid-
base balance at all. According to the Henderson-Has-
selbalch equation, the pH is always only determined by
the ratio between HCO3- and pCO2. Both an HCO3- of
24 mmol/l and a pCO2 of 40mmHg as well as an HCO3-
of 12 mmol/l and a pCO2 of 20mmHg have a normal
pH, since the ratio HCO3- / pCO2 is the same in both
cases; example:
-- pH = log (HCO3- 24 mmol/l / pCO2 40mmHg) = 7.4
(This is a normal finding.)
-- pH = log (HCO3- 12 mmol/l / pCO2 20mmHg) = 7.4
(This is not a normal finding. There are even two
disorders: a metabolic acidosis and a respiratory al-
kalosis!)
A normal pH value does not exclude
a disturbance of the acid-base
balance at all!
Compensation
• Definition: There is often a respiratory compensation of
a metabolic disorder and vice versa a metabolic com-
pensation of a respiratory disorder.
• types:
-- pH not yet normal: partial compensation
-- pH normal again: complete compensation
• mechanisms (secondary changes):
-- metabolic: pCO2 (Lunge; lung; reacts quickly; limited
capacity)
◦◦ acidosis: pCO2 ↓ (hyperventilation)
◦◦ alkalosis: pCO2 ↑ (hypoventilation)
-- respiratory: HCO3- (kidney; reacts slowly; [nearly]
unlimited capacity [Arthur Clifton Guyton (American
physiologist, 1919-2003): "The buffer capacity of the
kidneys is inexhaustible!"])
◦◦ acidosis: HCO3- ↑
◦◦ alkalosis: HCO3- ↓
• limitations:
-- In patients with lung diseases (e.g. COPD) the respi-
ratory compensation mechanisms are considerably
reduced, so that metabolic disorders have a consi-
derably stronger effect here than in patients without
lung diseases.
-- In patients with kidney diseases (e.g. hemodialysis
patients) the metabolic compensation mechanisms
are considerably reduced, so that respiratory disor-
ders have a considerably stronger effect here than in
patients without kideny diseases.
• extent: It is always important to check whether the BGA
findings can be explained by the compensation alone
or whether there is an additional disorder of the acid-
base balance, which is often the case! The following
compensations are normal (normal value for pCO2
40mmHg, for HCO3- 24mmol/l) and can be expected:
-- metabolic
◦◦ metabolic acidosis: decrease of pCO2 ΔpCO2 = 1.2
x ΔHCO3-
◦◦ metabolic alkalosis: increase of pCO2 ΔpCO2 = 0.7
x ΔHCO3-
-- respiratory
◦◦ respiratory acidosis:
▪▪ acute (pH not yet balanced): increase of bicar-
bonate ΔHCO3- = 0.1 x ΔpCO2
▪▪ chronic (pH already balanced): increase of bi-
carbonate ΔHCO3- = 0.35 x ΔpCO2
◦◦ respiratory alkalosis:
▪▪ acute (pH not yet balanced): decrease of bicar-
bonate ΔHCO3- = 0.2 x ΔpCO2
▪▪ chronic (pH already balanced): decrease of bi-
carbonate ΔHCO3- = 0.4 x ΔpCO2
Example 1:
• pH 7.31, pCO2 20mmHg, HCO3- 12 mmol/l
• There is a metabolic acidosis with partial respiratory
compensation
• extent of respiratory compensation (expected): ΔpCO2
= 1.2 x ΔHCO3- = 1.2 x (24-12) = 1.2 x 12 = 14, i.e. only
a decrease of pCO2 to 40-14 = 26mmHg would be ex-
Endocrinology 779
 pected, but the pCO2 measured in the BGA is 20mmHg
and is thus significantly lower than the expected pCO2
value, i.e. there is also a respiratory alkalosis!

Example 2:
• pH 7.10, pCO2 40mmHg, HCO3- 12 mmol/l
• There is a metabolic acidosis with partial respiratory
compensation.
• extent of respiratory compensation (expected): ΔpCO2
= 1.2 x ΔHCO3- = 1.2 x (24-10) = 14, i.e. a decrease of
pCO2 to 40-14 = 26mmHg would be expected, but the
pCO2 measured in the BGA is 40mmHg and is thus
significantly higher than the expected pCO2 value, i.e.
there is also respiratory acidosis (usually caused by
exhaustion, so that there is even already an indication
for mechanical ventilation)!

Example 3:
• pH 7.40, pCO2 73mmHg, HCO3- 42 mmol/l Acidoses
• There is a respiratory acidosis with complete metabo- • metabolic acidosis
lic compensation. The already balanced pH and the • respiratory acidosis
clearly increased bicarbonate speak against an acute
event and rather for a chronic process (The compen-
sation via the kidney takes longer!).
Metabolic acidosis
• extent of respiratory compensation (chronic; expec-
ted): ΔHCO3- = 0.35 x ΔpCO2 = 0.35 x (73-40) = 0.35 x Definition
33 = 11.5, i.e. only an increase of HCO3- to (24+11.5) • pH < 7.36
= 35.5mmol/l would be expected, but the HCO3- mea- • standard bicarbonate (HCO3-) < 22 mmol/l or base ex-
sured in the BGA is 42mmol/l and is thus significantly cess (BE) < -2 mmol/l
higher than the expected HCO3-, i.e. there is also a me- • possibly respiratory compensation by Kussmaul
tabolic alkalosis! breathing (named after the German physician Adolf
Kussmaul [1822-1902]): hyperventilation (pCO2 < 36
For compensations, always check mmHg) with high respiratory frequency (tachypnoea)
whether the expected value and large amplitude
corresponds to the measured • causes:
value in order not to overlook an -- excess of H+ ions (mostly)
additional disorder! -- deficiency of bicarbonate (rare; e.g. loss of bicarbo-
nate in diarrhea)
• In case of an unclear metabolic acidosis one should
pH pCO2 HCO3- always determine the so-called gaps:
metabolic ↓ (compensa- -- anion gap (see infobox)
acidosis ↓ tory) ↓ (causal) ◦◦ metabolic acidosis with increased anion gap: DD
respiratory ↑ (compensa- mnemonics "KUSMALE", "KARMEL", "MUDPI-
acidosis ↓ ↑ (causal) tory) LERS" (see infobox)
metabolic ↑ (compensa- ◦◦ metabolic acidosis without increased anion gap:
alkalosis ↑ tory) ↑ (causal) DD mnemonics "HARD UP", "USED CARPS" (see
respiratory ↓ (compensa- infobox), furthermore ionic balance in urine: (Na+
alkalosis ↑ ↓ (causal) tory) + K+) - Cl-
▪▪ negative (< 0): gastrointestinal bicarbonate loss
rule of thumb: In metabolic disorders all three parame- (e.g. diarrhea)
ters (pH, pCO2 und HCO3-) always change in the same ▪▪ positive (> 0): renal tubular acidosis (RTA)
direction: either all three increase or decrease! -- delta gap (ratio between anion gap and bicarbonate;
syn.: Δgap; see infobox)
-- osmotic gap (see infobox)
• In case of an unclear metabolic acidosis in the intensi-
ve care unit one should think about it:
-- thiamine deficiency (especially alcoholics, malnutris-
hed patients)
-- intoxications (poisoning)
-- propofol infusion syndrome

780 Endocrinology
 -- hyperchloremic acidosis due to too much NaCl 0.9%
(with a chloride content of 154 mM completely un-
physiological, so that hyperchloremic acidosis can
occur)

Fig. 1045  Above normal breathing, below Kußmaul brea-

thing (high breathing frequency and large amplitude): By
the hyperventilation an attempt is made to compensate for
the metabolic acidosis through increased exhalation of
CO2.

unclear metabolic acidosis → determi-

The hyperventilation in the context of nation of the anion gap
Kussmaul breathing in metabolic
acidosis is physiological (attempt of
respiratory compensation) and not to
be seen as a sign of exhaustion of
the respiratory pump! No premature
cations 140
intubation!
sodium

AG

DD unclear metabolic acido- anions 103 25 12

sis in ICU chloride bicarbonate

Fig. 1046  normal anion gap (AG)

cations 140
sodium

AG

anions 103 12 25
chloride bicarbonate

Fig. 1047  increased anion gap (causes: mnemonics KUS-

MALE, KARMEL, MUDLIPERS)

Endocrinology 781
 KUSMALE HARD UP
causes of metabolic acidosis with causes of metabolic acidosis
increased anion gap without increased anion gap

KARMEL USED CARPS

causes of metabolic acidosis with causes of metabolic acidosis
increased anion gap without increased anion gap

MUDPILERS
causes of metabolic acidosis with
increased anion gap

In metabolic acidoses with an

increased anion gap (increased
accumulation of acids [exogenous /
endogenous]) sodium bicarbonate
does not help at all (only the consci-
ence)! only reasonable option: renal
replacement therapy (RRT)!

782 Endocrinology

Types
• addition acidosis (accumulation of too many acids):
i.a. lactic acidosis, ketoacidosis, intoxications; see esp.
KUSMALE; here administration of sodium bicarbo-
nate pointless; classification:
-- endogenous
◦◦ ketoacidosis
▪▪ diabetic
▪▪ alcoholic
▪▪ starving
◦◦ lactic acidosis (see chapter endocrinological
emergencies [page 727])
-- exogenous
◦◦ intoxications (poisoning)
◦◦ hyperchloremic acidosis (most frequent cause in
intensive care units: NaCl 0.9%)
• retention acidosis (reduced renal excretion of acids)
-- acute kidney failure, renal insufficiency
-- renal tubular acidosis (RTA) type I (disturbance of
H+ excretion)
• subtraction acidosis (loss of bicarbonate)
-- enteral loss of bicarbonate (e.g. gastroenteritis)
-- renal loss of bicarbonate; e.g.
◦◦ ureterosigmoidostomy (implantation of both ure-
ters into the sigmoid after bladder removal [cy-
stectomy] in bladder cancer, bladder replacement
(ileum neobladder
◦◦ renal tubular acidosis (RTA) type II (loss of bicar-
bonate)
◦◦ hyporeninemic hypoaldosteronism (Schambelan
syndrome): typical in diabetic patients (renal loss
of bicarbonate with consecutive metabolic acido-
sis and hyperkalemia)
Therapy
• causal (i.a. therapy of the underlying disease, optimi-
zation of hemodynamics)
• buffering
-- Principle: Chronic acidosis should be compensa-
ted slowly, acute acidosis should be compensated
quickly.
-- agents (buffer):
◦◦ sodium bicarbonate (Nabic) 8.4% (first choice)
◦◦ TRIS buffer (second choice)
• lactic acidosis of still unclear etiology → immediate
probational administration of thiamine (vitamin B1; e.g.
300 mg i.v.; especially in chronic alcohol abuse)
• therapy of hyperkalemia (frequently in acidosis due to
the H+/K+ exchanger [Hamburger shift]: A decrease of
the pH value by 0.1 leads on average to an increase of
potassium by 0.6 mmol/l! see page 765)
Sodium bicarbonate (Nabic) 8,4%
• NaHCO3 (sodium hydrogen carbonate)
• Single administration via a peripheral venous access
possible, with longer-term administration (via perfu-
sor), however, central venous access is necessary
(CVC).
• dosage: Nabic 8.4% in ml = BE x kgBW x 0.3; first give
only half of this, then BGA control
• not undisputed; pointless especially in metabolic aci-
dosis with an increased anion gap, i.e. increased accu-
mulation of acids (exogenous / endogenous)
• Only a warning can be given against too uncritical buf-
fering with sodium bicarbonate: On the one hand, the
affinity of oxygen to hemoglobin decreases with incre-
asing pCO2 and decreasing pH, i.e. the release of oxy-
gen into the tissue increases (Bohr effect). Therefore,
a metabolic acidosis should only be buffered from a
pH value < 7.15, since a moderate acidosis leads to
an improved oxygen release to the tissue due to the
Bohr effect. Buffering leads to a left shift in the oxygen-
hemoglobin binding curve. If it is buffered too early, the
tissue hypoxia increases (i.a. recognizable by an incre-
ased lactate). Buffering to ensure that the catecholami-
nes work better should also be omitted as long as the
pH is > 7.15. On the other hand, sodium bicarbonate
has considerable side effects: The buffering reaction
produces pCO2, which increases intracranial pressu-
re (ICP). In addition, Nabic leads to hypokalemia (via
H+/K+ exchanger [Hamburger shift]) and hypernat-
remia (Nabic contains a lot of sodium.). In metabolic
acidosis with hypernatremia, TRIS buffer, which does
not contain sodium, is a good alternative. Furthermo-
re, glycolysis is stimulated (cave hyperglycemia) and
the stimulation of 6-phosphofructokinase with conse-
cutive release of organic acids can even lead to an
increase in metabolic acidosis! In addition, excessive
Endocrinology 783
 alkalization may occur, resulting in cerebral (seizures,
neurological deficits) and coronary (coronary spasms,
arrhythmias) vasoconstriction and central respiratory
depression (cave in spontaneously breathing patients)
due to inhibition of the respiratory drive. Sodium bicar-
bonate can also cause hypocalcaemia.
BICAR-ICU study
Sodium bicarbonate therapy for patients with severe meta-
bolic acidaemia in the intensive care unit
Jaber et al, Lancet 2018
• multicenter prospective randomized controlled study
• 389 critically ill patients with severe metabolic acidosis
(pH < 7.20, bicarbonate < 20 mmol/l); within 48 hours of
admission to the intensive care unit:
-- sodium bicarbonate (target-pH > 7.30)
-- placebo
• results: sodium bicarbonate
-- primary endpoint (combined from death by day 28
and at least one organ failure by day 7): no difference
(significant reduction only in the subgroup of patients
with pre-existing renal failure stage AKIN 2 or 3)
-- secondary endpoints: i.a. significant reduction in the
need for renal replacement therapy (RRT)
TRIS buffer
• active ingredient: tromethamine (THAM [trishydroxy-
methylaminomethane])
• strongly alkaline (pH = 10), cave tissue necrosis in ext-
ravasation (therefore best via CVC), dilution with G5%
(1:10; only if applied peripherally; if applied via CVC,
the perfusor is filled with pure TRIS)
• indications:
-- metabolic acidosis and hypernatremia: TRIS buf-
fer is a good option for buffering with simultaneous
hypernatremia because it does not contain sodium
in contrast to sodium bicarbonate.
-- increased intracranial pressure (ICP; TRIS buffer
crosses the blood-brain barrier much better than
sodium bicarbonat and lowers ICP by lowering the
intracerebral acidosis; target-pH 7.50-7.55, only as
ultima ratio)
• side effects:
-- TRIS buffer leads (especially if administered too
quickly) via a decrease in pCO2 to a reduction in re-
spiratory drive or even to respiratory depression and
must therefore not be used in cases of respiratory
insufficiency without mechanical ventilation.
-- Hyperkaliämie
-- hyperkalemia
-- hypoglycemia (due to increased insulin release
• contraindications:
-- renal insufficiency with anuria (risk of accumulation;
excretion of H+-THAM via the kidneys)
-- Hyperkaliämie
784 Endocrinology
-- respiratory insufficiency without mechanical ventila-
tion
• dosage:
-- TRIS 36.34%: 1 amp. = 20ml = 60mmol (1ml = 3
mmol [3-molar solution; note: available as 0.3-molar
solution])
-- TRIS 36.34% in ml = BE x kgBW x 0.1
-- maximum dose: 1.7ml/kg, maximum infusion rate:
0.3 ml/kg/h
no buffering of hypoperfusion-indu-
ced metabolic acidosis at pH > 7.15
oxygen saturation SO2
pH ↑ pH ↓
left shift right shift
oxygen partial pressure pO2
Fig. 1048  Bohr effect (named after the Danish physiolo-
gist Christian Bohr [1855-1911]: Shown here is the oxygen
binding curve of the hemoglobin, which shows the relati-
onship between oxygen partial pressure (pO2) and oxygen
saturation (SO2). In acidosis (regardless of whether it is re-
spiratory or metabolic) the oxygen binding curve is shifted
to the right (Bohr effect) due to the decrease of the pH: This
effect is beneficial because it increases the oxygen release
to the tissue. If you buffer here uncritically (e.g. with sodi-
um bicarbonate), the increase of pH leads to a left shift in
the oxygen binding curve, with the result that oxygen can
only less be released to the tissue and thus tissue hypo-
xia occurs. Therefore, buffering should only pe performded
from a pH below 7.15.
metabolic acidosis + hypernatremia:
TRIS buffer (instead of sodium
bicarbonate)!
Respiratory acidosis
• hypercapnic respiratory failure (see especially also
page 93)
• failure of the respiratory pump
• disorder of the ventilation
• key parameter: pCO2­ ↑
• most frequent cause: exacerbated COPD
• therapy: mehanical ventilation (non-invasive, invasive
• An increased base excess (BE) or an increased bi-
carbonate (HCO3-) at normal pCO2 and pH (at normal
 renal function) indicates chronic insufficiency of the
respiratory pump (compensatory renal counter regu-
lation). The following bicarbonate values can be used
to draw conclusions about the corresponding chronic
CO2 level in a simplified manner:
-- bicarbonate 30 mmol/l → chronic CO2 level 55mmHg
-- bicarbonate 35 mmol/l → chronic CO2 level 70mmHg
No buffering of respiratory acidosis! A
respiratory acidosis must be ventila-
ted!
Alkaloses
• metabolic alkalosis
• respiratory alkalosis
Metabolic alkalosis
Definition
• most frequent disorder of the acid-base balance
(general)
• pH > 7.44
• standard bicarbonate (HCO3-) > 26 mmol/l ore base
excess (BE) > +2 mmol/l
• possible respiratory compensation (hypoventilation!)
• Metabolic alkalosis reduces the respiratory drive,
which can lead to problems especially in weaning.
Etiology
• loss of gastric acid (gastric juice: pH = 1)
-- vomiting ( most frequent cause; hypochloremic
alkalosis)
-- too much discharge via the gastric tube
• diuretics (second most frequent cause; loss of protons
and chloride via the kidneys), steroids
• hypochloremia (chloride deficiency)
• hypokalemia (etiology see there [page 762])
• hypalbuminemia (protein deficiency; Albumin is a
weak acid!)
• increased intake of bicarbonate
• citrate
-- citrate anticoagulation (conversion of citrate to bicar-
bonate in the liver)
-- citrate accumulation (e.g. in the context of citrate
anticoagulation in CVVH, e.g. after administration of
large amounts of FFP [especially in plasmaphere-
sis!])
• Ringer solutions with metabolizable anions (especially
Ringer lactate: Lactate can bind H+ ions as salt of lactic
acid and thus cause metabolic alkalosis.)
• mineralocorticoid excess (Conn´s syndrome, Cushing's
disease)
• renal artery stenosis
• chronic liver diseases
• Bartter-, Gitelman syndrome
Types
• chloride-sensitive form
-- after administration of 1000ml NaCl 0.9% excretion
of chloride in 24h collection urine < 10 mmol/l
-- causes: mainly loss of acid gastric, diuretics
-- Alkalosis can be corrected by infusions with NaCl
0.9%.
• chloride-resistant form
-- after administration of 1000ml NaCl 0.9% excretion
of chloride in 24h collection urine > 10 mmol/l
-- cause: mineralocorticoid excess
-- Alkalosis cannot be corrected by infusions with NaCl
0.9% (means of choice here: aldosterone antagonist
[e.g. spironolactone]).
Therapy
• causal: therapy of the underlying disease
• symptomatic
-- proton pump inhibitor (drug of choice, especially in
case of loss of gastric acid)
-- NaCl 0.9% in chloride-sensitive form
-- spironolactone in chloride-resistant form
-- acetazolamide (Diamox): a carboanhydrase inhibitor
(means of choice actually for acute glaucoma attack;
dosage: 1 amp. = 500mg as short infusion)
-- acids:
◦◦ amino acid preparations (e.g. arginine hydrochlo-
ride 20%: 1 amp. = 20ml = 20 mmol H+; dosage:
BE x 0.3 x kgBW; dilution necessary [e.g. 40ml in
500ml NaCl 0.9%], only via CVC)
◦◦ hydrochloric acid i.v. (as ultima ratio; hydrochloric
acid 7.25%: 1 amp. = 10ml = 20 mmol H+; dosage:
BE x 0,3 x kgBW; dilution necessary [e.g. 20ml in
500ml NaCl 0.9%], only via CVC)
Respiratory alkalosis
Definition
• most frequent disorder of the acid-base balance espe-
cially in intensive care
• pH > 7.44
• pCO2 < 36 mmHg
• Almost always the lactate is also increased here.
• cause: hyperventilation
Etiology (hyperventilation)
• psychogenic (mostly)
• physogenic
-- pain
-- fever
-- increased intracranial pressure (e.g. stroke [e.g. ma-
lignant media infarction], intracerebral hemorrhage,
hepatic encephalopathy, encephalitis)
-- hypoxemia (compensatory hyperventilation [on-
demand hyperventilation e.g. pulmonary embolism,
pulmonary edema, pneumonia])
-- intoxication (e.g. salicylates [stimulation of the respi-
ratory centre])
Endocrinology 785
 -- mechanical ventilation with a too high respiratory mi-
nute volume

Symptoms sodium
• hyperventilation cations
• tetany (pH value ↑ → free calcium ↓; normocalcemic
tetany)
-- paresthesia albu-
min, bicar-
-- carpopedal spasms
chloride lactate UMA bonate
-- Chvostek´s sign, Trousseau´s sign anions
• paleness Fig. 1049  Simplified Stewart approach (ionogram: Due to
• sweating the principle of electroneutrality, the sum of the anions is
• tachycardia equal to the sum of the cations.)
• dyspnea
• angina pectoris
• cave reduced cerebral perfusion caused by alkalo- Stewart approach: a good option for
sis induced vasoconstriction (especially from pCO2 < differentiated assessment of metabo-
25mmHg): Pronounced hypocapnia can even lead to lic acidosis
cerebral ischemia via cerebral vasoconstriction!
Electrolyte effect
respiratory alkalosis: cave • The relevant ions (strong ions) that affect the acid-ba-
cerebral hypoxia! se balance are sodium (cation) and chloride (anion).
All other ions (potassium, calcium, magnesium, phos-
phate) can be neglected. The difference between sodi-
Therapy um and chloride is usually 38 mmol/l.
• calculation: sodium - chloride - 38
• calming ("verbal anesthesia")
• assessment:
• CO2 rebreathing via plastic bag
-- < - 2 mmol: hyperchloremic acidosis
• if necessary benzodiazepines (e.g. midazolam)
◦◦ supply of too much chloride (infusion NaCl 0.9%)
• if necessary optimization of mechanical ventilation
◦◦ diarrhea
◦◦ renal tubular acidosis (RTA)
Excursus: Stewart approach (acid-ba-
◦◦ renal failure with tubular damage
se analysis according to Stewart) ◦◦ compensation (counter-regulation) of a respiratory
• an alternative (or additional) acid-base analysis to the alkalosis (hypocapnia)
classic acid-base analysis according to Henderson- ◦◦ supply of free water
Hasselbach (equivalent [Kimura et al, SAGE Open
-- > 2 mmol: hypochloremic alkalosis
Med 2018])
◦◦ recurrent vomiting with loss of gastric acid
• named after the Canadian physiologist Peter Arthur
Robert Stewart (1921-1993) ◦◦ diuretics
• for assessing metabolic (not respiratory) disorders ◦◦ dehydration
• differentiated assessment and quantification of the in- ◦◦ compensation (counter-regulation) of a respiratory
dividual components of the metabolic part of the acid- acidosis (hypercapnia)
base balance ◦◦ Compensation (counter-regulation) of ketoacido-
• aslo assessment of several simultaneous metabolic sis
disorders possible • A deviation of 1 mmol/l explains a deviation in the BE
• in its original form too complex for everyday clinical of 1 mmol/l.
practice, therefore mostly used in a simplified form Albumin effect
(simplified Stewart approach [according to Story et al,
Br J Anaesth 2004]) • calculation: (42 - albumin [g/l]) / 4
• standard base excess (SBE) • assessment: > 2 mmol/l → hypoalbuminemic alka-
losis (Albumin is a weak acid!)
-- norm: -2 to +2 mmol/l
-- liver synthesis disorder (e.g. liver cirrhosis)
◦◦ < -2 mmol/l: net metabolic acidosis
-- malnutrition
◦◦ > 2 mmol/l: net metabolic alkalosis
-- catabolism
-- SBE: sum of 4 effects
-- loss of albumin
◦◦ capillary leak (typical in sepsis)
SBE = electrolyte effect + albumin effect +
lactate effect + UMA effect ◦◦ abdominal surgery, larger wounds, burns
◦◦ nephrotic syndrome

786 Endocrinology
 ◦◦ protein losing enteropathy (PLE; Gordon syndro-
me)
• A decrease of albumin by 10 g/l increases the BE by
2.5 mmol/l.

Lactate effect
• calculation: 1 - lactate [mmol/l]
• assessment: < 2 mmol/l → lactic acidosis (see page
727)
• The lactate value in mmol/l explains the decrease of
BE in mmol/l, i.e. a lactate of 10 mmol/l explains a BE
of -10 mmol/l.

UMA effect
• UMA: unmessured anions
• "KUSME": ketoacidosis, uremia, salicylates, methanol,
ethylene glycol
• calculation: SBE - electrolyte effect - albumin effect -
lactate effect
• assessment < 2 mmol/l → metabolic acidosis due to
UMA
-- uremia
-- ketoacidosis
-- intoxications (including salicylates, methanol, ethy-
lene glycol)

Endocrinology 787
Nephrology
 Epidemiology
ACUTE KIDNEY FAILURE • 4.3% of all patients in intensive care unit
• the most frequent organ failure in intensive care
unit
• most common cause in the intensive care unit: sepsis
42% of all patients with severe sepsis / septic shock
• 5% of all intensive care patients require renal replace-
ment therapy (RRT).
• significant increase in the incidence of acute kidney
failure requiring dialysis in the last 10 years ("AKI epi-
demic"; by 10% per year [Hsu et al, Am Soc Nephrol
2013])
• mortality: 23% (Susantitaphong et al, Clin J Am Soc
Nephrol 2013; septic-related acute kidney failure with
the need for renal replacement therapy: even 70%!)
• costs (Germany): approx. 1.5 billion € annually (Kerr et
al, Nephrol Dial Transplant 2014)
• FINNAKI study (Nisula et al, Intensive Care Med 2013):
-- 39.3% of all intensive care patients have acute kid-
ney failure.
-- 10% of them require a renal replacement therapy.
• AKI-EPI study (Hoste et al, Intensive Care Med 2015):
-- 57% of all intensive care patients have acute kidney
Definition failure.
• syn.: acute kidney injury (AKI; according to the KDIGO
-- 25% of them require a renal replacement therapy.
guidelines only this term should be used today)
• a syndrome (not a disease) of various causes (ana-
logous to acute lung failure) Classifications
• approx. 30 different definitions
• RIFLE (according to Bellomo et al, Crit Care 2004; de-
• criteria (official according to AKIN [Acute Kidney Inju-
veloped by ADQI [Acute Dialysis Quality Initiative])
ry]):
• AKI(N) (Acute Kidney Injury; according to Mebta et al,
-- increase of creatinine by
Crit Care 2007)
◦◦ 0.3 mg/dl (only!) or
• KDIGO (Kidney Disease Improving Global Outcome;
◦◦ > 50% of the baseline (initial value) according to Levey et al, Kidney Int 2011; proposed
-- oliguria (urine excretion < 0.5 ml/kg/h for > 6h) merging of RIFLE and AKIN)
• 15% of acute kidney failure is not oliguric, but normal
or polyuric. RIFLE classification
• 30% remain chronic kidney insufficient after acute kid-
GFR urine output
ney failure, 5% require dialysis permanently.
• Structural kidney damage occurs, leading to acute tu- Risk creatinine­x 1.5 < 0.5 ml/kg/h for
(≈ AKIN stage 1) GFR ↓ > 25% 6h
bule necrosis (ATN).
Injury creatinine­x 2 < 0.5 ml/kg/h for
(≈ AKIN stage 2) GFR ↓ > 50% 12h
creatinine (mg/dl)

creatinine­x 3 or
> 4 mg/dl with an
acute increase ≥ < 0.3 ml/kg/h for
Failure 0,5 mg/dl 24h or anuria for
(≈ AKIN stage 3) GFR ↓ > 50% 12h
persistent renal
Loss failure > 4 weeks
creatinine ESKD (end stage persistent renal
4 blind kidney disease) failure > 3 months
range
2

20 40 60 80 100 GFR (ml/min)

Fig. 1050  Exponential relationship between creatinine and
GFR: Already with an increase of creatinine > 0.3 mg/dl an
acute kidney failure is present (also in the near-normal ran-
ge)!

790 Nephrology
AKI(N) classification Rhabdomyolysis
stage increase in creatinine urine eoutput
Definition
by > 0.3 mg/dl or > 50% of the < 0,5 ml/kg/h
• disintegration of the striated muscles (skeletal musc-
1 baseline (initial value) for 6h
les)
< 0,5 ml/kg/h
• pathophysiology: obstruction of the renal tubules by
2 200-300% of the baseline for 12h
pigment cylinders (a pigment nephropathy; due to the
< 0,3 ml/kg/h released myoglobin)
creatinine > 4 mg/dl or > for 24h or anu-
3 300% of the baseline ria for 12h
• diagnostics:
-- laboratory: i.a. creatine kinase CK > 10000 U/l, myo-
mnemonic: creatinine increase > 2-fold → stage 2, crea- globin ↑, myoglobinuria (dark brown urine), hyperka-
tinine increase > 3-fold → stage 3 lemia, hyperphosphatemia
Renal replacement therapy is usually required from sta- -- urine sediment: myoglobin cylinders
ge 3.

Etiology
• prerenal (70%)
• intrarenal (25%)
• postrenal (5%)

Fig. 1051  The urine in rhabdomyolysis is typically dark

brown ("Coca-Cola" urine) due to myoglobinuria. This
should not be confused with blood in the urine in the sense
of macrohematuria!

Prerenal acute kidney failure
• hypovolemia (including diarrhea, vomiting, burns,
high-output ileostoma); note: Hypervolaemia (overhy-
dration) can also cause acute renales failure. It leads
to a reduced venous outflow, to an increased inter-
stitial pressure and thus to a decrease in the GFR.
Renal perfusion depends on the difference between
MAP and CVP (renal perfusion pressure RPP = MAP -
CVP). The CVP, which actually still has a certain value
here, should not be higher than 13 mmHg, otherwise
venous congestion will occur.
• shock
• ventilation high PEEP
• hemolysis (tubular obstruction by free hemoglobin)
• rhabdomyolysis ("crush-syndrome")
• tumor lysis
• vascular:
-- renal artery embolism
-- renal vein thrombosis
• hepatorenal syndrome
• intraabdominal compartment syndrome
Etiology
• traumatic (most common): trauma, surgery, defibrilla-
tion / cardioversion, bruises, compartment syndrome,
tourniquet syndrome, lying trauma, electrical acci-
dents, third-degree burns
• thermal: heat stroke, malignant hyperthermia, neuro-
leptic malignant syndrome
• medicinal-toxic: medication (i.a. statins, propofol [pro-
pofol infusion syndrome], fluoroquinolones, dapto-
mycin, neuroleptics, ciclosporin, L-Dopa), drugs (i.a.
cocaine, ecstasy, heroin), mushroom poisoning (e.g.
tricholoma equestre)
• ischemic (e.g. arterial vascular occlusion, shock, re-
suscitation)
• metabolic
-- hypokalaemia (Severe hypokalaemia can trigger
rhabdomyolysis by disrupting the membrane poten-
tial. Rhabdomyolysis itself then leads to hyperkale-
mia.)
-- hypophosphataemia (The lack of ATP leads to the
destruction of the muscle cells. Rhabdomyolysis its-
elf then leads to hyperphosphataemia.)
-- hypocalcemia
-- hyponatremia
• neurological: alcohol withdrawal delirium, seizures, te-
tany, excessive physical strain
• infectious
-- viruses (especially influenza, Coxsackie, EBV, CMV,
HSV, HIV)
-- bacteria (especially legionella, klebsiella, salmonel-
la, streptococcus, leptospira)

Nephrology 791
 -- protozoa (e.g. plasmodium falciparum [tropical ma-
laria])
-- fungi
• autoimmune (polymyositis, dermatomyositis)
• genetic (enzyme defects such as myophosphorylase
deficiency [McArdle disease], phosphofructokinase
deficiency [Tarui disease], carnitine palmityl transfera-
se deficiency)
Therapy
• volume administration and alkalization of urine (tar-
get urine pH > 6.0; e.g. 1000ml NaCl 0.9% + 1000ml
glucose 5% + 100 mmol bicarbonate; alternatively po-
tassium-sodium-hydrogen citrate [Uralyt; 1 measuring
spoon = 2.5g; dosage: 5g 2 x daily p.o. / gastric tube])
• no diuretics
• renal replacement therapy:
-- on therapy: clearly indicated (if acute kidney failure
requiring dialysis has occurred
-- on prophylaxis: It has long been discussed whether
renal replacement therapy should be used in severe
rhabdomyolysis to prevent renal failure. Myoglobin
has a relatively low sieving coefficient, so that myo-
globin cannot be removed with conventional filters.
This is only possible with special filters (so-called
high-cut-off filters). However, since there is no proof
(Heyne et al, Nephron Clin Pract 2012), that this can
actually reduce the rate of kidney failure (which re-
quires hemodialysis), no renal replacement therapy
is currently recommended for the removal of myo-
globin.
Intrarenal acute kidney failure
• rapid-progressive glomerulonephritis (RPGN)
• thrombotic microangiopathies (TMA):
-- ANCA-associated vasculitis (70%)
◦◦ c-ANCA: Wegener´s disease (new term: granulo-
matosis with polyangiitis [GPA])
◦◦ p-ANCA: panarteriitis nodosa (Kussmaul-Maier´s
disease)
-- immunocomplex glomerulonephritis (20%; e.g. sys-
temic lupus erythematosus [SLE])
-- anti-basal membrane glomerulonephritis (syn.:
Goodpasture syndrome; 10%)
• acute interstitial nephritis
-- mostly allergic reaction to drugs, especially:
◦◦ proton pump inhibitors (most common cause)
◦◦ antibiotics (especially penicillin)
• acute tubule necrosis (ATN
◦◦ allopurinol
◦◦ 5-ASA (mesalazine)
-- symptoms:
• tubular obstruction
◦◦ exanthema (misdiagnosis: allergic reaction to the
drug), fever, arthralgia
◦◦ haematuria, proteinuria
-- laboratory: eosinophilia
-- therapy: prednisolone 1 mg/kg (Steroids are the re-
medies of choice!)
• hanta virus infection
• toxic, i.a.:
-- contrast agent → contrast-induced nephropathy
792 Nephrology
(CIN)
-- NSAIDs (should therefore generally be avoided in
intensive care units!)
-- antinfectives: mainly aminoglycosides, cephalospo-
rins, colistin, vancomycin (induction of a cast neph-
ropathy [Luque et al, J Am Soc Nephrol 2017], lower
nephrotoxicity with continuous than with bolus ad-
ministration [Cataldo et al, J Antimicrob Chemother
2012]), amphotericin B ("conventional nephrecto-
my")
-- ACE-Hemmer, ARB
-- cytostatic agents (cisplatin, MTX
-- gold
-- calcineurin inhibitors
-- paracetamol (especially in case of overdose: The
metabolite N-acetyl-midochinone is not only hepa-
totoxic but also nephrotoxic. Therefore, paracetamol
intoxication usually leads not only to liver failure, but
also to kidney failure.)
-- immune checkpoint inhibitors (e.g. ipilimumab, nivo-
lumab) → autoimmune interstitial nephritis or glome-
rulonephritis
-- volume replacement therapy:
◦◦ NaCl 0.9%: In large quantities, "physiological" sa-
line solution can trigger acute kidney injury as the
containing chloride is a strong renal vasoconstric-
tor that leads to reduced renal blood flow. NaCl
0.9% is nephrotoxic!
◦◦ colloids (hydroxyethylic starch, gelatine, dextrane)
-- mushrooms
◦◦ phalloides syndrome (poisoning with amanita
phalloides)
◦◦ oranellus syndrome (latency period 1-2 weeks
-- HUS (see especially chapter haematology )
◦◦ haemolytic uremic syndrome (Gasser syndrome)
[named after the Swiss pediatrician and hematolo-
gist Conrad Gasser, 1912-1982])
◦◦ most frequent cause of acute kidney failure in
children
◦◦ types
▪▪ enteropathic HUS: EHEC, VTEC
▪▪ non-enteropathic HUS: neuraminidase-produ-
cing pneumococci
-- TTP (thrombotic thrombocytopenic purpura, M.
Moshkowitz: in 50% acute kidney injury)
-- ischaemic (i.a. sepsis [frequent!)
-- nephrotoxic
-- plasmocytoma
◦◦ diagnostic of choice: protein electrophoresis + im-
munofixation
◦◦ kidney biopsy is obligatory
◦◦ hemodialysis with special HCO membrane (HCO:
high cutoff)
-- hyperuricemia
-- oxalates (precipitation of oxalate crystals in case of
glycol intoxication)
• renal crisis (scleroderma [systemic sclerosis]) Infection
• cholesterol embolism (atheroembolism) • cleaning of rooms where mice live (mainly stables, bar-
-- arterial vascular occlusion by cholesterol crystals ns, sheds, attics, summer houses) without wearing a
-- most frequently occurring after cardiac catheteriza- mask and gloves
tion • work in forestry
-- renal failure usually only later (after 2-4 weeks; re- • gardening, composting, woodworking
member this!) • camping
-- skin changes: livores, "blue toe" • improper disposal of dead mice or cleaning of mouse
-- laboratory: eosinophilia traps

"allergic" reaction to drugs with
increased creatinine and eosino-
philia in differential blood count:
acute interstitial nephritis!
Hantavirus infection
Symptoms
• such as influenza (suddenly high fever, aching limbs,
myalgia, headaches
• back and abdominal pain
• bleeding (often massive; typical; especially skin
[petechiae], also conjunctiva
• visual disturbances (frequent!)
• oliguria

acute kidney failure with high

fever, skin bleeding and thrombo-
penia: think of hantavirus infec-
tion!

Definition
• zoonosis (transmission as aerosol mainly by faeces,
urine and saliva of mice
• ethymology: river "Hantaan" in Korea (In the Korean
War 1950-1953 about 3000 soldiers died of a severe
haemorrhagic fever.)
• syn.:
-- haemorrhagic fever with renal syndrome (HFRS)
-- nephropathia epidemica
• mortality: 10%
• in Germany obligation to report by name (§6 and §7
Infection Protection Act; already on suspicion)
• Hanta viruses: in Germany mainly .
-- Puumala virus (most common; mainly in the south
and west of Germany; vector: bank vole)
-- Dobrava Belgrade virus (especially in northern and
eastern Germany; vector: striped field mouse)
-- tulavirus (very rare; vector: field mouse)
Epidemiology
• incidence
-- 0.8/100000
-- increasing (2012 Robert-Koch institute: 2824 repor-
ted cases [record number!] in Germany)
• incubation period: 2-3 weeks
• accumulation mainly in spring and summer
• m:w = 2:1
• age: 30-50 years
Complications
• acute kidney failure (classic; often falsely attributed to
the NSAIDs previously used to lower fever)
• acute lung failure (ARDS)
• shock:
-- haemorrhagic (due to bleeding)
-- septic
-- cardiogenic (e.g. cardiac involvement in the sense
of myocarditis)
• hepatitis, myocarditis, cholecystitis, thyroiditis, hypo-
physitis (possibly panhypopituitarism), encephalitis
Laboratory
• thrombocytopenia (typical), leukocytosis
• creatinine ↑, urea ↑
• urine: proteinuria (pronounced), microhaematuria
Diagnosos
• serology blood (detection of IgM and possibly IgG
by ELISA)
• Subtyping of Hantaviruses is theoretically possible (by
means of focus reduction neutralization test), but very
time-consuming (only in special laboratories with safe-
ty level 3) and clinically not relevant.
Therapy
• symptomatic
• no specific antiviral therapy generally recommended
(possibly ribavirin)
• no vaccination available
• no isolation necessary (As it is a zoonosis there is no
human-to-human transmission.)

Nephrology 793
Contrast-induced nephropathy (CIN)
Definition
• increase of serum creatinine by > 0.5 mg/dl or by more
than 25% from baseline
• occurring within the first 3 days after contrast agent
application
• exclusion of other causes
Causes
• mainly iodine-containing contrast agent
-- e.g. CT, coronary angiography
-- higher risk with arterial than venous administration
• non-iodine-containing contrast agent (e.g. gadolinium
in MRI → nephrogenic systemic fibrosis [NSF; mainly
occurring in patients with impaired renal function])
Risk factors
• renal insufficiency (creatinine > 1.5 mg/dl; most im-
portant risk factor! creatinine > 1.8 mg/dl → in 37%
contrast-induced nephropathy)
• heart failure
• diabetes mellitus
• diuretic therapy
• age
• nephrotoxic drugs
• plasmacytoma: The administration of contrast medium
is only contraindicated in light chain plasmacytomas
(20% all plasmacytomas; syn .: Bence Jones plasma-
cytoma). This is because the light chains precipitate
in the presence of a contrast agent, so that they fall
out and clog the renal tubules. This also applies when
kidney function is normal.
• exsiccosis (hypovolemia)
• arterial hypotension
• anemia (increases renal ischemia)
• type and amount of contrast agent

Mechanisms
• direct: tubulotoxic
• indirect: renal vasoconstriction with consecutive renal
ischemia (especially in the region of the external me-
dulla)

Epidemiology
• occurring in 2-3% after contrast agent administration
• The risk of developing renal failure after administration
of contrast medium is, however, rather low and is usu-
ally overestimated.
• maximum of creatinine levels on day 4-5 after contrast
agent administration
• in 11% cause of acute kidney failure occurring in hos-
pital
• In a retrospective cohort study (Hoste et al, Intensive
Care Med 2010) it could be shown that contrast agent
nephropathy was surprisingly frequent with 16% in in-
tensive care patients who received contrast agent. In
11% even renal replacement therapy was necessary.
• In 21%, after contrast medium-induced acute kidney
failure, terminal renal insufficiency requiring dialysis
remains permanently.

Every 5th patient with a contrast

induced AKI remains permanently Prophylaxis
on dialysis! • Hydrierung (Wässerung):
-- hydration: 1 ml/kg/h at least 6h before and 6h after
administration of contrast agent
-- cave: overhydration (especially with heart failure)
-- overall only useful in patients with hypovolaemia
-- no advantage of hydration with NaCl 0.9% (AMA-
CING study [Nijssen et al, Lancet 2017])
• discontinuation of potentially nephrotoxic drugs (at

794 Nephrology
 GFR < 60 ml/min): especially contradicting results overall: Three studies in patients
-- diuretics (Discontinuation of the diuretics is often undergoing cardiothoracic surgery, in whom acute kid-
forgotten!) ney failure frequently occurs postoperatively, overall
-- NSAIDs showed contradictory results: While the RenalRIPC
study (Zarbock et al, JAMA 2015) reduced the rate of
-- ACE inhibitors, ARB
postoperative renal failure by preoperative ischemic
• use of as little contrast agent as possible ( rule of preconditioning, the RIPHeart study (Meybohm et al,
thumb: maximum amount of contrast agent in ml = 3 x N Engl J 2015) and the ERICCA study (Hausenloy et
GFR in ml/min; e.g.. GFR 30 ml/min → A maximum of al, N Engl J 2015) did not. A meta-analysis (Menting
180 ml of contrast agent should be given.) et al, Cochrane Database Syst Rev 2017) showed no
• ACC (acetylcysteine) overall advantages. Ischemic preconditioning cannot
-- dosage: 600mg i.v. / p.o. twice daily on the day befo- be generally recommended yet, but it is very simple
re and after the examination and virtually free of side effects, so that it can be per-
-- studies: formed prophylactically in patients with an increased
◦◦ The earlier studies (i.a. Tepel et al, N Engl J 2000 risk of contrast-induced nephropathy.
[omly 84 patient]; Marenzi et al, N Engl J 2006) • note: In vital indications (e.g. coronary angiography in
showed altogether contradictory data. acute myocardial infarction, e.g. focus search in unc-
◦◦ ACT studie (see box): verly large study on this lear sepsis with septic shock) the risk of contrast-indu-
subject wihich clearly showed that ACC brings ced nephropathy is absolutely secondary! The motto
nothing at all! "Life before kidney!" also applies here.
◦◦ PRESERVE study 2017 (see box): largest study
on this topic, which also clearly showed that ACC
(like Nabic) brings nothing at all!
ACT study
• theophylline (e.g. 200mg i.v.)
-- Huber et al, Radiology 2006: can be considered if
hydration is not sufficiently possible (e.g. in heart
failure)
Acetylcysteine for prevention of renal outcomes in patients
-- not (generally) recommended undergoing coronary and peripheral vascular angiography:
• sodium bicarbonate i.v. (urine alkalization) main results from the randomized Acetylcysteine for Con-
-- dosage: 150ml Nabic 8.4% + 850ml G5%, of which trast-induced nephropathy Trial
3 ml/kg 1h before and 1 ml/kg over 6h after exami- ACT-Investigators, Circulation 2011
nation
• multicenter randomized controlled study
-- studies: • 2308 patients with at least one risk factor for contrast
◦◦ REMEDIAL study 2007: nephroprotective effect agent nephropathy (age > 70 years, kidney failure, dia-
◦◦ However, in recent multicenter studies (McGui- betes mellitus, heart failure or hypotension)
ness et al, Crit Care Med 2013; Haase et al, Plos -- ACC 1200mg (2 x p.o. before and after contrast agent
Med 2013; PRESERVE study 2017 [see box]) the administration)
administration of sodium bicarbonate showed no -- placebo
nephroprotective effect. • results: ACC
-- not recommended -- primary endpoint (occurrence of contrast-induced
nephropathy): no reduction
• prophylactic hemodialysis ("contrast agent" dialysis;
e.g. immediately after coronary angiography) → no -- secondary endpoint (combined endpoint of morta-
benefit lity and need for dialysis): no reduction
• possibly forced diuresis (MYTHOS study [see box])
• possibly statins (i.a. PRATO-ACS study [Leoncini et
al, J Am Coll 2014], Han et al, J Am Coll 2014: sig-
nificant reduction of contrast-induced nephropathy by
prophylactic administration of statins; [still] no general
recommendation)
• ischemic preconditioning: It has long been known that
ischemia of one organ protects against ischemia of the
other organ (RIP: remote ischemic preconditioning).
The frequency of contrast-induced nephropathy could
be reduced by generating ischemia, for example on
the upper arm (blood pressure cuff inflated for 5 min
at suprasystolic blood pressure value and then de-
flated, after 5 min again; a total of 4 cycles) shortly
before the administration of contrast agent (RenPro
study, Ann Emerg Med 2011). Three studies in car-
diac thoracic surgery patients, in whom acute kidney
failure frequently occurs postoperatively, showed

Nephrology 795

PRESERVE study
Outcome after Angiography with Bicabonate and Acetyl-
cysteine
Weisbord et al, N Engl J 2017
• multicenter randomized controlled study
• 5177 patients with a GFR 15-30 ml/min or GFR 30-60
ml/min + diabetes mellitus and contrast agent administ-
ration as part of an angiography (in 90% coronary angio-
graphy); double arm study:
-- Nabic / NaCl 0.9% as a periprocedural infusion so-
lution
-- ACC (1200mg 2 x p.o. for 5 days) / placebo
• results: applied to both Nabic and ACC
-- primary endpoint (combined endpoint of death,
need for dialysis or creatinine increase > 50% after 90
days): no reduction
-- secondary endpoint (rate of contrast-induced ne-
phropathy [creatinine increase by 25% after 5 days]):
no reduction
no more ACC for the prophylaxis of a
contrast-induced nephropathy!
absolutely pointless!
MYTHOS study
Prevention of Contrast Nephropathy by Furosemide With
Matched Hydration: The MYTHOS (Induced Diuresis With
Matched Hydration Compared to Standard Hydration for
Contrast-Induced Nephropathy Prevention) Trial
Marenzi et al, JACC 2012
• randomized controlled study
• 170 patients with known chronic renal insufficiency befo-
re cardiac catheterization
-- 83 patients: NaCl 0.9%
-- 87 patients: forced diuresis + NaCl 0.9% (250ml NaCl
0.9% over 30min, then bolus furosemide 0.5 mg/kg
i.v.; cardiac catheterization was performded if diuresis
> 300 ml/h)
• results:
-- significantly less contrast-induced nephropathy
-- significantly less frequent hemodialysis
The only rational and effective measu-
re for the prophylaxis of contrastindu-
ced nephropathy is volume administra-
tion in hypovolemic patients!
796 Nephrology
Critical note
Whether there is actually a contrast agent-induced kid-
ney failure or whether it is just a myth (phantom) is dis-
cussed more and more. Possibly it is more of a contrast
agent-associated kidney failure. Especially ritically ill
patients have per se already a basic risk of developing
an acute kidney failure. The most common organ failure
in critically ill patients in the intensive care unit is kid-
ney failure. And whether this is actually caused by the
contrast agent or not the blue color of the intensive care
shirt of the nurse is an open question. In more recent
studies (i.a. Mc Donald et al, Radiology 2014; Wilhelm-
Leen et al, Clin J Am Soc Nephrol 2017; Hinson et al,
Ann Emerg Med 2017) there was at least no connection
between the administration of contrast medium and an
increased risk for kidney failure, even if kidney function
was previously impaired (i.a. Kumar et al, Clin J Am Soc
Nephrol 2009 [mean creatinine level here: 3,5 mg/dl]). In
everyday clinical practice, it is therefore unfortunately not
uncommon that due to excessive fear on the one hand
urgently indicated diagnostics (e.g. CT) or therapy (e.g.
cardiac catheterization with PCI) are omitted and, on the
other hand, the patients are unnecessarily watered and
often drifted in the hypervolemia with deleterious con-
sequences (including acute kidney failure as a result of
overhydration). Overhydration only causes dilution and
thus a decrease in the creatinine concentration without
improving the kidney function itself.
Septic kidney failure
• Sepsis is the most common cause of acute kidney
failure in intensive care.
• 42% of all patients with severe sepsis or septic shock
develop acute kidney failure.
• pathophysiology:
-- prerenal (septic shock)
-- renal (tubular ischemia [lipopolysaccharides → di-
rect tubule damage] → tubule necrosis)
• pre-existing renal dysfunction in 30%
• mortality of septic renal failure requiring RRT: 70%
study
Acute kidney failure in Critically Ill Patients
A Multinational, Multicenter Study
Uchino et al, JAMA 2005
• prospective observational study
• 29269 patients on intensive care units → in 5.7% acute
kidney failure
-- pre-existing renal dysfunction in 30%
-- most frequent cause: septic shock (47.5%)
-- RRT (renal replacement therapy) in 83%
-- mortality: 60%
 septic renal failure + need for
renal replacement therapy →
excessively increased mortality!

independent risk factor ("One does not

die with, but by AKI!")

Postrenale acute kidney failure (obst-

ructive uropathy)
• benign prostatic hyperplasia (BPH), prostate carcino-
ma
• urethral stenosis
• tumor
• retroperitoneal fibrosis (Ormond's disease) Fig. 1053  Urinary obstruction of the right kidney (postrenal
• pinched or blocked urinary catheter (Especially the acute kidney failure); note: Even a one-sided urinary obst-
pinched urinary catheter as the cause of kidney failu- ruction can trigger an acute kidney failure (not necessarily
re should not be overlooked! Otherwise it is relatively on both sides).
embarrassing!)

with every acute kidney failure

always perform sonography of the
kidneys to exclude urinary obstruc-
tion (do not forget)!

Fig. 1054  A stone (see arrow) in the ureter was shown to be

the cause of urinary obstruction on the right side.

Fractional excretion
If it is unclear whether pre-, intra- or postrenal acute kid-
ney failure is present, the fractional excretion of sodium
or urea should be determined. The following speaks for a
prerenal acute kidney failure:
• fractional excretion of sodium (FE-Na) < 1%
-- FE-Na = (sodium in urine / sodium in serum) / (crea-
tinine in urine / creatinine in serum)
-- Here the kidney tries to save water by increasing the
sodium reabsorption.
-- not applicable under diuretics
• fractional excretion of urea (FE-UN) < 35%; FE-UN =
(urea in urine / urea in serum) / (creatinine in urine /
creatinine in serum)
-- very suitable for differential diagnosis pre- / intra­
Fig. 1052  sonography: urinary obstruction renal
-- FE-UN:
◦◦ < 35% → prerenal
◦◦ > 35% → intrarenal

Nephrology 797
 -- independent of pre-treatment with diuretics (in cont-
rast to fractional sodium excretion)
-- For the determination a spot urine is sufficient, a 24h
urine collection is not necessary
unclear whether acute renale failue is
prerenal or intrarenal → determination
of fractional urea excretion!
Stages
• stage I: damage
• stage II: oliguria, anuria
• stage III: polyuria
-- p.d. > 2000 ml/d
-- The tubule function recovers later than the glomeru-
lar function!
-- The urine is not yet sufficiently concentrated be-
cause the kidneys are not yet fully functional. The
urine omolarity is accordingly reduced.
-- risk of hypovolemia (exsiccosis), loss of sodium and
potassium
• stage IV: restitutio with normuria
Complications
• cardiovascular:
-- hypertensive crisis (due to overhydration)
-- heart failure
-- pericarditis
-- arrhythmia (mainly due to hyperkalemia)
• pulmonary: pulmonary edema ("fluid lung"), ARDS
("shock lung"), pulmonary hemorrhage
• gastrointestinal:
-- stress-ulcer, possibly ulcer bleeding
-- uremic gastroenteritis
-- uremic peritonitis (pseudoperitonitis)
-- increased bacterial translocation
• neuromuscular: uremic encephalopathy (brain ede-
ma), neuropathy, myopathy
• haematological: anaemia, thrombocytopenia, throm-
bocytopathy (thrombocyte dysfunction caused by ure-
mia), possibly bleeding
• metabolic: acidosis (possibly Kussmaul breathing),
protein catabolism, insulin resistance
• endocrinological: hyperkalemia, hypocalcaemia
• immunological: immune deficiency due to uremia →
infections, sepsis
AKI: The kidney is here not only a
"victim", but also a "perpetrator" (can
itself be a trigger for further organ
failure)! AKI is a systemic disease!
798 Nephrology
Diagnostics
• anamnesis (e.g. initial creatinine level; excretion), clini-
cal examination (e.g. volume status)
• laboratory: i.a.
-- azotaemia (increase of urinary substances):
◦◦ creatinine (metabolic product of creatine, which is
predominantly found in the skeletal muscles; cave
in CIP / CIM with consecutive muscular atrophy or
in patients with liver cirrhosis therefore often false
low values! Likewise, the creatinine can be diluted
after administration of a lot of volume and therefo-
re incorrectly low.)
◦◦ urea (note: An increased urea in normal creatinine
is either a sign of malnutrition [caused by catabo-
lism; mostly] or a sign of an upper gastrointestinal
bleeding and not of renal failure!)
-- creatinine clearance (glomerular filtration rate [GFR])
◦◦ formulas for estimating GFR (eGFR [e: estima-
ted]):
▪▪ MDRD formula (modification of diet in renal di-
seases; better correlation with the GFR than
Cockcroft-Gault formula): creatinine clearance =
1.86 x creatinine (mg/dl) - 1.154 x age - 0.243
(with women: x 0.742)
▪▪ Cockcroft-Gault formula: creatinine clearance =
[(140-age) x kg wb / 72 x creatinine (mg/dl)] x F
(F women: 0.85, F men: 1)
◦◦ assessment:
▪▪ applies only in steady-state (state in which
creatinine production corresponds to creatinine
excretion), i.e. at constant creatinine, i.e. not in
acute kidney failure
▪▪ The formulas do not apply to acute kidney fai-
lure! For example, a patient may still have an
estimated GFR of 40-60 ml/min on the first day
after bilateral nephrectomy (e.g. in renal cell
carcinoma) because the creatinine in the serum
has only increased to 1.4 mg/dl. De facto howe-
ver it has a GFR of 0 ml/min!
-- electrolytes (mostly hyperkalemia)
-- possibly autoimmune serology, i.a.:
◦◦ ANCA
▪▪ c-ANCA → Wegener´s disease (granulomatosis
with polyangiitis [GPA])
▪▪ p-ANCA → panarteriitis nodosa (Kussmaul-
Maier´s disease)
◦◦ ds-DNA antibodies → systemic lupus erythemato-
sus (SLE; typical for a severe active SLE is the
complement consumption, i.e. C4 ↓)
◦◦ anti-basement membrane-antibodies → Good-
pasture syndrome
-- possibly hantavirus-serology
-- new biomarkers (see infobox)
-- BGA (Venous BGA is sufficient.)
◦◦ with hypervolemia: metabolic acidosis
◦◦ with hypovolemia: metabolic alkalosis
• urine
-- appearance:
◦◦ bright:
 ▪▪ mostly cell-poor without cylinders If the kidneys are no longer functioning, reabsorption
▪▪ acute tubulus necrosis: improbable in the proximal tubules is disturbed, so that sodium is
▪▪ low risk for the necessity of a renal replacement lost in the urine (urine sodium> 20 mmol/l).
therapy -- specific weight
◦◦ dark: -- creatinine, urea
▪▪ mostly cell-rich with cylinders • sonography of the kidneys
▪▪ acute tubulus necrosis: probable -- mainly to exclude postrenal acute kidney failure (uri-
▪▪ high risk for the necessity of a renal replacement nary obstruction)
therapy -- findings in intrarenal acute kidney failure:
-- status ◦◦ enlarged kidneys
-- sediment ◦◦ parenchyma: broad and hypoechoic
◦◦ fresh urine necessary ◦◦ prominent hypoechoic renal papillae
◦◦ microscopic investigation ("liquid biopsy") -- assessment of perfusion
◦◦ frequently very helpful (unfortunately often for- • chest X-ray (congestion, pleural effusion, pulmonary
gotten) edema)
◦◦ With increasing severity of the kidney damage the • if necessary kidney biopsy
quantitative portion of cellular components in the -- gold standard in suspected rapid-progressive glo-
urine increases. merulonephritis (RPGN)
◦◦ findings: -- also possible in mechanically ventilated patients
▪▪ acanthocytes ("mickey mouse ears"), dysmor-
phic erythrocytes, erythrocyte cylinders → acute
GFR not usable in acute kidney
glomerulonephritis (indicate a glomerular cause)
failure! no urine → GFR = 0 ml/min!
▪▪ myoglobin cylinder → rhabdomyolysis
▪▪ granulated cylinders, tubule cells → septic renal
failure
▪▪ leukocyturia (sterile) → acute interstitial neph-
ritis
-- protein (A high quantitative protein content in normal
dipstick is strongly suspicious of a light chain plas-
mocytoma!)
-- albumin / creatinine quotient:
◦◦ to quantify proteinuria
◦◦ In the past, only albumin was determined in the
24-hour urine collection as standard for quantify-
ing proteinuria. The measurement is relatively
error-prone and complex and also depends on the
dilution of the urine. Much better and more practi-
cable in everyday clinical practice is the determi-
nation of the albumin / creatinine quotient in the
urine: You only need a spontaneous urine (no 24h
collection necessary). Furthermore, the measure-
ment is independent of dilution effects.
◦◦ assessment:
▪▪ normal value: < 100 mg/g creatinine (i.e. normal
kidney function)
▪▪ 100-300 mg/g creatinine: microalbuminuria
▪▪ 300-3000 mg/g creatinine: macroalbuminuria
▪▪ > 3000 mg/g creatinine: "large" proteinuria (ne-
phrotic syndrome!)
-- osmolarity: The urine omolarity provides good
information about the functionality of the kidneys.
Functioning kidneys can concentrate the urine so
that the urine osmolarity is 2-3 times higher than the
serum osmolarity. Functionless kidneys, on the other
hand, can no longer do this and there is a decrease
in urine molarity up to an adjustment to serum osmo-
larity (isosthenuria).
-- sodium: The sodium level in the urine (spot urine suf-
ficient) is also a good parameter for kidney function.

Nephrology 799

DD functional oliguria
functional
oliguria AKI (intrarenal)
specific weight > 1020 g/l < 1020 g/l
osmolality (urine;
mosm/kg) > 800 < 800
urea (mg/dl) > 1000 < 1000
sodium (mmol/l) < 30 > 30
note: useless after administration of diuretics
Therapy
• conservative therapy
• renal replacement therapy (necessary in 5% in acute
kidney failure)
Conservative therapy
• optimization of haemodynamics (target MAP > 65
mmHg; most important!)
-- volume administration:
◦◦ type: Despite the increased potassium in the
context of AKI, paradoxically not NaCl 0.9%, but
Ringer should be given: NaCl 0.9% is completely
unphysiological (e.g. severe hyperchloremic aci-
dosis. Due to hyperchloremic acidosis, NaCl 0.9%
can even increase hyperkalemia via the H+/K+ ex-
changer (Hamburger shift)! The amount of potas-
sium in the Ringer solution is completely negligib-
le: The organism contains 6500 mval potassium, 1
liter of Ringer solution contains just 5 mval potas-
sium, so this does not matter at all. In the context
of a kidney transplant it could be shown that the
potassium values were significantly higher under
NaCl 0.9% than under Ringer lactate (Khjavi et al,
Ren Fail 2008). NaCl 0.9% can even aggravate
acute kidney failure because the containing chlo-
ride is a strong renal vasoconstrictor leading to re-
duced renal blood flow! NaCl 0.9% is nephrotoxic!
◦◦ amount: For a long time it was wrongly belie-
ved that a generous administration of volume
("flushing" / "purging" the kidneys) could improve
kidney function. Hypervolaemia should be avoi-
ded. It leads (in the context of a polycompartment
syndrome) to a reduced venous outflow, to an in-
creased interstitial pressure and thus to a decrea-
se in the GFR, so that kidney failure can even be
triggered or further aggravated by hypervolemia!
-- catecholamines
◦◦ noradrenalin, dobutamine
◦◦ dopamine in "renal dose": no benefit in acute kid-
ney failure, not nephroprotective (i.a. Bellomo et
al, Lancet 2000); completely obsolete (no use at
all!)
• avoidance of hyperglycemia (target blood glucose le-
vel < 180 mg/dl)
• discontinuation of triggering / aggravating drugs (espe-
cially NSAIDs, ACE inhibitors / ARBs)
• possibly diuretics (for volume management)
• Early nephrological consultation in the intensive care
unit improves the outcome of the patient with acute
kidney failure (EARLI study). In addition, further neph-
rological care is also useful afterwards. If acute kidney
failure is overcome, this leads to an increased risk of
(i.a. Coca et al, Kidney Int 2012; Sawhney et al, BMJ
2015):
-- chronic renal insufficiency (9-fold increased)
-- need for dialysis (3-fold increased)
-- death (mortality 2-fold increased)
• If the patient is completely anuric, the indwelling urina-
ry catheter should be removed as it is only an unneces-
sary source of infection. The restart of urine production
can also be determined with a single catheterization or
ultrasound of the urinary bladder.
• possibly recombinant alkaline phosphatase (reCAP;
nephroprotective effect, anti-inflammatory effect
through dephosphorylation of pro-inflammatory medi-
ators) in septic kidney failure:
-- STOP-AKI study (Pickkers et al, JAMA 2018; phase
II study): The administration of recombinant alkaline
phosphatase at a dose of 1.6 mg/kg i.v. over 3 days
did not improve renal function after one week, but
after one month. Furthermore, the mortality was re-
duced, although the mortality was not a predefined
endpoint of the study.
-- no general recommendation (yet)
Crystalloid of choice in acute kidney
failure despite hyperkalemia: Ringer
acetate (not NaCl 0.9%!)
Diuretics
• types (loop diuretics)
-- torasemide perfusor (Torem, Unat) 10 mg/ml → ma-
ximum infusion rate: 1 ml/h
-- furosemide perfusor (Lasix) 10 mg/ml → maximum
infusion rate: 2 ml/h
• The use of loop diuretics in acute renale failure is
based on the hypothesis that they inhibit tubular sodi-

800 Nephrology
 um absorption and thereby reduce oxygen consumpti-
on in the renal tubules.
• In case of acute kidney failure, higher doses of loop
diuretics are generally required. SPARK study
• Loop diuretics can only convert an oliguric into a non-
oliguric renal failure, but the renal failure still persists!
• no influence on mortality, recovery of renal function
or frequency of dialysis The effect of low-dose furosemide in critically ill patients
with early acute kidney injury: A pilot randomized blinded
• Mehta et al, JAMA 2002: Loop diuretics even increase controlled trial
mortality in ICU patients! Bagshaw et al, J Crit Care 2017
• Diuretics are not a therapy for acute kidney failure!
• if necessary to avoid hypervolemia (only if diuresis has • multicenter randomized pilot study
been maintained; for volume management) • 73 critically ill patients with acute kidney failure
• Diuretics only make sense if excretion is still present -- furosemide (0.4 mg/kg as bolus i.v., then 0.05 mg/kg/h
via perfusor)
(oliguria), no longer in anuria!
-- placebo
• max. 24h trial
• result: furosemide
• Diuretics should be discontinued as soon as a renal
-- no advantage in terms of further deterioration in kid-
replacement therapy has been initiated. ney function (RIFLE criteria)
• furosemide stress test (FST): -- no difference in the need for RRT
-- administration of furosemide 1 mg/kg (usually 80mg; -- significantly more frequent electrolyte disorders
1.5 mg/kg for previous therapy with a loop diuretic)
as bolus i.v.
-- interpretation:
◦◦ urine excretion after 2h > 200ml or quotient diure-
RENAL REPLACEMENT
sis quantity (in ml/h) / furosemide quantity (in mg) THERAPY (RRT)
> 1 → positive → continue diuretics
◦◦ urine excretion after 2h < 200ml or quotient diu-
resis quantity (in ml/h) / furosemide quantity (in
mg) < 1 → negative → discontinue diuretics (no
benefit!)
-- not applicable in case of pre-existing renal dysfunc-
tion (GFR < 30 ml/min)
-- contraindicated in hypovolemic patients (note: In
order to avoid hypovolemia, the excreted volume
should always be replaced on principle.)

meta-analysis

Meta-analysis of furosemide to prevent or treat acute kid-

ney failure
Ho et al, BMJ 2006
• meta-analysis (Cochrane analysis; 849 patients): furo-
semide
-- 3 studies: for prevention of acute kidney failure
-- 6 studies: for therapy of acute kidney failure
• results:
-- no influence on hospital mortality
-- no influence on the necessity of a renal replacement
therapy
-- increased rate of deafness and tinnitus
Definition
• syn.: "artificial kidney"
• extracorporeal procedures to replace the excretory
function of the kidney
• The term "renal replacement therapy" is misleading: It
can definitely not replace the kidney, only the excreto-
ry function of the kidney, but not the endocrinological,
metabolic or immunological function.
• necessary in 5% of all intensive care patients
• necessary in 5% of all patients wirth acute kidney fai-
lure
• first successful dialysis in 1945 by the Dutch nephro-
logist Willem Kolff (1911-2009) using a drum kidney
(wooden drum with cellophane tube) in one patient
(Sephra Schaffstadt) with septic renal failure due to
cholecystitis

Nephrology 801
 Vascular access
• Shaldon catheter (2-lumen [double lumen catheter];
named after the Scottish nephrologist Stanley Shaldon
[1931-2013])
• a central venous catheter: The tip of the catheter lies in
the superior (mostly) or in the inferior vena cava
• diameter: 11-12 French
• flow rate: 300-400 ml/min (per lumen)
• sites:
-- 1st choice: internal jugular vein (standard; right
length 15cm, left length 20cm); note: best from the
right side due to the straight course (left often techni-
cal problems due to the oblique confluence of the left
brachiocephalic vein into the superior vena cava and
thus also an increased risk of wall perforation, more
frequent wall contact on the left and thus thrombosis)
-- 2nd choice: femoral vein (length 20cm)
-- In principle, no Shaldon catheter should be in-
serted into the subclavian vein, as thrombosis and
stenosis often occur here after a short time. The sub-
clavian vein is certainly the last choice. If a Shaldon
catheter is actually placed in the subclavian vein, it
should always be placed on the dominant side of
the patient (i.e. in right-handed patients on the right
side). If the catheter is placed on the non-dominant
side and stenosis or thrombosis of the vein occurs,
Fig. 1055  renal replacement system (here Prismaflex, Baxter in case of permanent hemodialysis dependence the
[formerly Gambro]) [18] shunt must be placed on the dominant side so that
the patient cannot move his dominant side during
the hemodialysis sessions.
• length in cm: formulas (note: In our clinic only Shaldon
catheters with a length of 15cm or 20cm are availab-
le.):
-- internal jugular vein
◦◦ right: (height / 10) - 1
◦◦ left: (height / 10) + 3
-- subclavian vein
◦◦ right: (height / 10) - 2
◦◦ left: (height / 10) + 2
• placement like conventional CVC via Seldinger tech-
nique, best sonographically controlled (then always
position control by X-ray)
• marking of the two lumina:
-- red: leading away from the patient ("arterial")
-- blue: leading to the patient ("venous")
• blocking: heparin sodium 5000 IU (heparin ampoule
5ml = 25000 IU → 1ml; cave for HIT II)
• Shaldon catheters should only be used for renal repla-
cement therapy and not for infusions / nutrition (other-
wise significantly increased infection rate!).
• CVVH is not possible via a lying atrial catheter (syn.:
Demers catheter; usually single-lumen; e.g. patient
with known chronic renal insufficiency requiring dialy-
sis, who is now haemodynamically unstable, so that
no haemodialysis but only CVVH is possible), since
Fig. 1056  renal replacement system (here PrisMax [succes- an atrial catheter usually has only one lumen. In this
sor system to Prismaflex; Baxter]) case an additional Shaldon catheter has to be placed.
In these patients, however, it should not be placed in
the subclavian vein if possible, since thrombosis or
stenosis of the subclavian vein can occur frequently

802 Nephrology
 in this case, with the result that the venous pressure correct connection of the lumina
in the shunt arm increases and complications can oc-
cur frequently in the Cimino shunt (e.g. formation of
aneurysms, bleeding). However, if the atrial catheter
has two lumina, the CVVH can also be performed over
it and and no additional Shaldon catheter has to be
installed.
unpurified blood
purified blood
Fig. 1060  Shaldon catheter: connection of the lumina [17]

Types
• according to the principle of substance separation
-- hemodialysis (HD)
-- hemodialysis (HD)
-- hemodiafiltration (HDF; mixture of both methods;
Fig. 1057  Shaldon catheter [18]
most frequently in intensive care)
• according to duration of use
-- kontinuierliche procedures
Place of first choice for the shaldon
catheter: right internal jugular vein! ◦◦ CAVH (continuous aterio-venous hemofiltration;
driving force: blood pressure; abandoned today)
◦◦ CVVH (continuous veno-venous-hemofiltration;
driving force: pressure generated by a pump)
-- intermittent procedures (e.g. intermittent hemodialy-
sis [IHD])

heparin substitute

"arterial" "venous"

ultrafiltrate (UF)

Fig. 1058  Shaldon catheter set: catheter, Seldinger needle

and Seldinger wire, dilator
heparin

"arterial" "venous"

heparin substitute

"arterial" "venous"

dialysate + UF dialysis solution

"out" "in"

Fig. 1061  Overview of the various renal replacement me-

Fig. 1059  Shaldon catheter in the internal jugular vein [17]
thods [17]
Hemodialysis
Definition
• principle: diffusion (diffusive method)
• The driving force for substance transfer is the diffe-
rence in concentration between two liquids separated
by a semi-permeable membrane. The basis for diffu-

Nephrology 803
 sion is the Brownian molecular motion (named after filter
the Scottish botanist Robert Brown [1773-1858]), i.e.
the random thermal movement of molecules in a liquid,
blood
which results in the independent mixing of the different
substances. The process is comparable to a tea bag,
the contents of which are dissolved and distributed in
hot water.
• In the filter, the blood and the dialysis solution always
run in opposite directions (counter current principle). dialysis
If blood and dialysis solution were to flow in the same solution
direction (equal current principle), the difference in
concentration would decrease in the course of the fil-
ter and dialysis would become increasingly ineffective.
With the counter current principle, on the other hand,
the difference in concentration is maintained over the
entire length of the filter, so that the effectiveness of
Fig. 1062  principle of diffusion [17]
dialysis remains undiminished.
• separation limit: molecular weight 15-20 kD
-- lower than with hemofiltration, i.e. smaller molecules Emergency therapy for hyperkale-
are removed than with hemofiltration mia: hemodialysis and not
-- Dialysis is suitable for the removal of smaller mole- hemofiltration (no CVVH)!
cules (e.g. potassium, protons [in metabolic acido-
sis], lactate, ammonia). Therefore, hemodialysis
and not hemofiltration should also be performed in air detector
the case of life-threatening hyperkalemia! backflow pressure
+ air separator
+ hose detector
+ blood detector
• standard at ICU in the USA
backflow clamp
• responsibility: staff of the dialysis department syringe pump + hose separator

• dialysis membrane: synthetic (made of polysulfone; hemofilter

filter blood inlet
biocompatible) outlet pressure pump pressure
pressure
• HIV and hepatitis serology must always be drawn prior BLD (blood leck
to the start of hemodialysis in order to prevent trans- detector)

mission to patients who are subsequently treated with

PBP infusion
the same dialysis machine. In the event that a patient dialysate
outflow (pre blood pump)
with HIV or hepatitis has actually been dialyzed, the
dialysis machine must then be completely disinfected
and some parts completely replaced. In some facilities,
machines for infectious dialysis are available. Fig. 1063  CVVHD [18]
• In intensive care patients, CVVH is usually the first
RRT to be performed in clinical routine, as those pa- Dose
tients are usually hemodynamically unstable. Hemodi- • frequency:
alysis only takes place when the renal failure has still -- 3-4 x / week (standard) or daily (Schiffl et al, N Engl
not improved after stabilization of the circulation. J 2002 [see box]; has not become established in
• In hemodialysis, unlike hemofiltration, water is remo- practice)
ved within just a few hours, which can lead to hemo- -- KDIGO recommendation: 3 x / week for 5h each
dynamic instability. For this reason, haemofiltration is
• The dose in dialysis is described by the clearance of
usually the only option for a patient requiring catecho-
a dissolved substance (especially urea): Kt/V (K: urea
lamines and haemodialysis is not possible. There are,
clearance; t: duration of treatment; V: distribution volu-
however, some options to improve hemodialysis in the
me of urea).
case of hemodynamic instability:
• The effectiveness of hemodialysis depends on:
-- often moderate BP drop shortly after connection →
short-circuiting of the system (simultaneous connec- -- blood flow
tion of the venous and arterial system with recircula- -- dialysate flow
tion of the saline solution used to rinse the system) -- pore size
-- prolonged hemodialysis (e.g. 6h instead of 3h) -- surface of the dialyzer
-- reduction of blood flow (e.g. to 150 ml/min) • Relatively high flow rates are used in hemodialysis:
-- reduction of dialysate temperature to < 37°C -- blood flow: 200-300 ml/min
-- dialysate flow: 500-800 ml/min

804 Nephrology
 study

Daily Hemodialysis and the Outcome of Acute kidney fail-

ure
Schiffl et al, N Engl 2002

• single-center (Munich [Germany]) prospective rando-

mized controlled study
• 160 patients with acute renale failure
-- daily dialysis
-- intermittent dialysis
• result: daily hemodialysis → significantly lower mortality
(28% versus 46%)

Peritoneal dialysis
• principle: osmosis (displacement of water across a se-
mipermeable membrane to equalize the concentration
of substances that cannot pass through the membra-
ne)
• means of choice for acute kidney failure in child-
ren (especially small children [e.g. in hemolytic uremic
syndrome])
• (almost) no significance in adult intensive care medi-
cine

Hemofiltration
Definition
• principle: convection (convective method: Substances
dissolved in water are simply transported with the wa-
ter ["entrainment with the current"].)
• The driving force for substance transfer is the pressure
difference between blood and filtrate.
• The pressed liquid, which also contains the substan-
ces to be removed, is called filtrate (also called ult-
rafiltrate). In the intensive care unit, a patient deve-
lops approx. 12-18 litres of ultrafiltrate per day during
haemofiltration. This loss of water must then of course
be replaced for the patient. The replacement solution
is called substitute. The fluid balance can be controlled
by changing the quantity of the replacement solution
supplied. In cases of acute kidney failure, sepsis or
metabolic acidosis, bicarbonate and non-lactate-buf-
fered solutions should be used. Standard buffer
today is bicarbonate (not lactate). Previously acetate
and lactate were used as buffers, both are now obso-
lete as buffers.
• separation limit: molecular weight 20-40 kD (higher
than in haemodialysis; i.e. larger molecules are remo-
ved than in haemodialysis)

Nephrology 805
• standard at ICU in Europe
• responsibility: staff of the intensive care unit
• maximum pump flow (CVVH): 500 ml/min
• advantage especially in
-- haemodynamic instability
-- cerebral edema (lower sodium shifts; lower risk of
dysequilibrium syndrome in continuous procedures)
-- acute liver failure (also mainly due to cerebral edema
hydrostatic pressure
Types
• CAVH(F): continuous arterio-venous hemofiltration
(blood pressure generates pressure gradient; aban-
doned today)
• CVVH(F): continuous veno-venous hemofiltration
(pump generates pressure gradient; standard today

heparin

filter

filtrate

Fig. 1064  Hemofiltration is illustrated by a simple example

from everyday life, the coffee filter. The driving force here
is the hydrostatic pressure difference between the top and Fig. 1066  scheme CAVH: The pressure gradient is generated
bottom of the coffee machine caused by gravity. The coffee by the blood pressure (arterio-venous pressure difference;
powder ("grounds"; analogous to blood: blood cells, larger heart as pump). Arterial cannulation is necessary here. This
proteins) is retained by the filter, which is only permeab- procedure is abandoned today.
le for smaller particles. The liquid that now arrives in the
coffee pot, i.e. the coffee, corresponds in analogy to the
ultrafiltrate.

dialysis: diffusion ("tea bag")

filtration: convection ("coffee filter")

pressure gradient heparin

filter
filter
blood pump

filtrate

Fig. 1067  scheme CVVH: The pressure gradient is generated

by a pump. Arterial cannulation is not necessary. This pro-
cedure is standard today.
filtrate

Fig. 1065  principle of convection [17]

806 Nephrology
 Dose
air detector
backflow pressure + hose detector • recommendation (KDIGO): 20-25 ml/kg/h (with fre-
+ air separator + blood detector
quent discrepancies between the prescribed and the
syringe pump backflow clamp actually achieved outflow dose [e.g. intensive care
+ hose separator
transport, catheter exchange] 30 ml/kg/h)
hemofilter
outlet
filter blood
pump
inlet • filtration fraction (FF):
pressure pressure
pressure
-- proportion of ultrafiltration rate in blood flow
upper swit- BLD (blood lower swit-
ching valve leck detector) ching valve -- FF = ultrafiltration rate / blood flow x 100
-- should be max. 20% (The filtration flow should be
PBP infusion
substitute outflow substitute (pre blood pump) max. 20% of the blood flow, otherwise the haemo-
concentration will be too high!)
-- The blood flow should therefore be at least 5 times
ultrafiltrate
as high as the ultrafiltration rate.
Fig. 1068  CVVH [18] Procedures (dilution methods)
Filter (hemofilter) • predilution
-- addition of the substituate solution before the filter
• material: polysulfone
-- consequence: hemodilution
• The filter is a foreign body with a tendency to thrombo-
sis. Anticoagulation is therefore necessary. -- Clotting of the filter occurs less frequently (The blood
is already diluted.).
• A filter lasts on average three days (filter running time),
then it must be changed. Protein deposits reduce the -- Clearance is worse (20-30% loss of effectiveness in
permeability of the membrane. The filters are officially comparison to the postdilution).
only approved for the use for a maximum of three days. -- i.a. used in the context of citrate anticoagulation
• sieving coefficient (SC): • postdilution
-- measure of the permeability of a substance through -- addition of the substituate solution after the filter
the membrane -- consequence: haemoconcentration (The filtration
-- SC = concentration of a substance in the filtrate / flow must not exceed 20% of the blood flow.)
concentration of a substance in the blood -- Clotting of the filter occurs more frequently
-- If the sieving coefficient is 1, the membrane is com- -- Clearance is better (The postdilution is much more
pletely permeable to the substance effective!).

substitute
heparin

filter
„arterial“ „venous“
Fig. 1069  different haemofilters [18]

blood flow
filtrate

filter fibers dialysate

flow

Fig. 1071  Predilution: The substitute solution is already ad-

ded previous to the filter (in the "arterial" branch). This has
the advantage that the blood in the filter is already diluted
(haemodilution) and thus the filter thromboses less fre-
dialysate quently (less clotting). However, this has the disadvantage
flow that the detoxification function (clearance) is worse.
blood flow inside the
filter fibers
dialysate flow outside the blood flow
filter fibers

Fig. 1070  structure of a hemofilter [17]

Nephrology 807
 the creatine formed in the liver takes place in the mu-
scles.) can be produced, which can simulate a normal
kidney function. Evaluation of the kidney function with
cystatin C would make make sense here.
• If the renal function does not recover (this is rarely the
case), but the patient is now circulatory stable, it can
be switched to intermittent hemodialysis.

substitute Special form: SCUF (slow continuous ultrafilt-

ration)
heparin
• only ultrafiltration (= filtration of water due to a diffe-
filter rence in pressure) of plasma water (only drainage), no
„arterial“ „venous“ detoxification
• only indicated in individual cases (e.g. in cardiac de-
compensation and simultaneous anuria [cardiorenal
filtrate syndrome in the context of a cardiogenic shock]: Here,
only the water should be removed.)

air detector
Fig. 1072  Postdilution: The substitute solution is only added backflow pressure
+ air separator
+ hose detector
+ blood detector
past the filter (in the "venous" branch). This has the advan-
tage that the clearance function is better. However, this has backflow clamp
the disadvantage that a haemoconcentration occurs in the syringe pump
+ hose separator
filter due to the pressing of the filtrate, so that filter throm- hemofilter
boses more frequently (more clotting). filter blood inlet
outlet pressure pump pressure
pressure
Pressure measurements (monitoring) in the BLD (blood
leck detector)
system
• arterial pressure: PBP infusion
-- before the filter (pre-filter) outflow (pre blood pump)

-- target: -50 to -100mmHg (Suction is generated by

the pump.)
-- Most frequent cause for arterial pressure < - Fig. 1073  SCUF: slow continuous ultrafiltration [18]
100mmHg is a contact of the catheter with the vessel
wall, which can usually be corrected manually.
The combination of hemodialysis and
• venous pressure:
hemofiltration (CVVHDF) is most
-- after the filter (post-filter) frequently used in the intensive care
-- target: +50 to +150mmHg unit!
• transmembrane pressure (TMP):
-- pressure gradient in the filter at the membrane, i.e.
between the blood and fluid compartment backflow pressure
air detector
+ hose detector
-- TMP = (filter pressure + inlet pressure) / 2 - outlet + air separator
+ blood detector
pressure
-- An increase in TMP (> 200mmHg) is the typical sign syringe pump
backflow clamp
+ hose separator
of clotting (decrease in membrane permeability due
hemofilter
to clotting) of the filter. With a TMP > 300mmHg the filter blood inlet
outlet pressure pump pressure
filter must be changed. pressure

upper swit- BLD (blood lower swit-

Termination ching valve leck detector) ching valve

• If the renal function recovers (usually the case), hemo-

filtration can be stopped. In the case of a spontaneous dialysate outflow
PBP infusion
(pre blood pump)
substitute
(i.e. without diuretics) diuresis > 500 ml/d, an omissi-
on attempt is justified (i.a. Uchino et al, Crit Care Med
2009). Be careful not to stop the hemofiltration too ear-
ly. The elimination function (drainage [tubule function])
of the kidney recovers earlier than the detoxification
Fig. 1074  CVVHDF (hemodiafiltration) [18]
function (glomerulum function])! Hemofiltration can
only be stopped when this function has also recovered.
It is not uncommon for the patient to experience musc-
le atrophy during a prolonged intensive care stay with
the result that only little creatinine (Phosphorylation of

808 Nephrology
 -- control according to ACT (activated clotting time):
12 target 150-200s
-- Since 2011 we have introduced citrate anticoagula-
tion in our clinic.
• mode: CVVHDF
10 • pump settings:
-- pre-blood pump: 200 ml/h
-- substitute pump: 800 ml/h
-- dialysate pump: 1000 ml/

11 SLED
13 • slow extended dialysis (sustainded low-efficiency dia-
14 lysis)
• syn.:
-- PIRRT (prolonged intermittent renal replacement
therapy)
-- Kolff dialysis (according to the Dutch internist Willem
Johan Kolff [1911-2009]))
15 9
8 -- tank dialysis
• hybrid procedure of CVVH and IHD (intermittent he-
6 modialysis)
7 • extended (8-12h) daily dialysis
• single-pass batch GENIUS system ("tank kidney"; Fre-
16 senius Medical Care)
• 90 litre tank for the dialysis fluid
• without industrially produced substitute solution (less
5 expensive)
• low flow rates:
-- blood flow: 100-200 ml/min
-- dialysate flow: 100-200 ml/min
• evaluation (i.a. Kielstein et al, Am J Kidney Dis 2004)
SLED versus CVVH:
-- equally effective (with regard to urea reduction)
1 2 4 -- equal hemodynamic stability
3 -- lower consumption of anticoagulants
Fig. 1075  Construction: 1: drain bag, 2: citrate bag, 3 and 4:
substitute bag, 5: pressure sensor, 6: pump for the blood, -- In contrast to the CVVH, which runs 24 hours a day,
7: pumps for the substitute and citrate, 8: hemofilter, 9: air here the patients are "free" for a few hours a day, so
bubble detector ("air trap"), 10: heating, 11: equipotenti- that for example CT transport trips or interventions
al bonding, 12: operating window (touchscreen), display can be carried out.
(prescription, anticoagulation, pressures), 13: blood leak • citrate anticoagulation also possible here
detector (BLD; indicates leakage of erythrocytes; can be
• SLED is not a therapy mode which can be easily set on
caused by a filter rupture [e.g. due to too high TMP]), 14:
connection for MARS system (as additional module in acu- the device. If one decides in a hospital to accomplish
te liver failure), 15: syringe with calcium, 16: connection for a SLED, first the appropriate infrastructure, which is
heparin (if anticoagulation is performed with it [in our clinic relatively complex (among other things storage of the
it is performed with citrate]) tanks), must be created.

Settings
(example for Prismaflex Gambro Hospal)
• substitute: Kalilactasol (electrolyte solution with lactate
and potassium
• filter: Prismaflex M 100 (Pre)
• dilution method: predilution
• blood flow rate: start with 80ml/h and increase to at
least 150 ml/h
• anticoagulation:
-- unfractionated heparin
-- 10000 IU of heparin-Na in 20ml NaCl 0.9% syringe
→ 500 E/ml

Nephrology 809
Fig. 1076  SLED: Genius system [17]

study

Sustained low efficiency dialysis using a singlepass

batch system in acute kidney injury - a randomized inter-
ventional trial: the REnal Replacement Therapy Study in
Intensive Care Unit PatiEnts
Schwenger et al, Crit Care 2012

• prospective randomized study

• 232 intensive care patients with acute kidney failure and
RRT
-- CVVH
-- SLED
• results: SLED
-- primary endpoint: mortality → no difference
-- secondary endpoints
◦◦ hemodynamic stability: no difference
◦◦ significantly more ventilator-free days
◦◦ significantly less RCC transfusions
◦◦ significantly less effort for the ICU staff and lower
costs

Anticoagulation renal replacement

therapy:
Anticoagulation - continuous: RCA (regional
To avoid clotting of the filter, which is a foreign body, an- citrat anticoagulation)
ticoagulation is necessary. The systemic administration - intermittent: heparin (UFH)
of unfractionated heparin was therefore standard for a
long time. However, this has some disadvantages: The
main problem is the increased risk of bleeding. . The-
re are numerous alternatives to unfractionated heparin
Citrat anticoagulation
(so-called alternative anticoagulants). If necessary, the Principle
renal replacement therapy can also be performed even
without any anticoagulation if there is a high risk of blee- • Calcium: important co-factor for blood coagulation
ding (e.g. thrombocytopenia < 80000/μl, severe plasma- (Only the ionized calcium is biologically active.)
tic coagulopathy). An overview of the various options for • Citrate (the salt of citric acid) binds divalent cations
anticoagulation in a renal replacement therapy is given (calcium, magnesium).
in the infobox.

810 Nephrology
• Citrate blocks coagulation by inactivating calcium calcium chlorid substitute
(chelation). Coagulation is inhibited from an ionized solution
calcium < 0.4 mmol/ . Hypocalcaemia inhibits the co-
agulation factors.
• pre-filter supply of citrate (predilution) → regional an-
ticoagulation (RCA: regional citrate anticoagulation):
The administration of citrate makes the blood in the
filter uncoagulable. 0.2-0.4 mmol of citrate is required
per 100 ml of blood.
• decomposition of the chelate complex (consisting of
citrate and calcium) and therefore regeneration of the
calcium in the liver (prerequisite: normal liver function patient hemofilter
→ no systemic anticoagulation (especially advantage-
ous in patients at risk of bleeding citrate

• liver insufficiency: In liver cirrhosis the half-life of citra-

te is doubled (70min instead of 35min [Kramer et al, fltrate
(ultrafiltrate)
Crit Care Med 2003]), so that citrate accumulation can
occur. Severe hepatic insufficiency was therefore long
regarded as a contraindication for citrate anticoagulati- Fig. 1077  Citrate anticoagulation: scheme [17]
on. Citrate anticoagulation is also possible in liver failu-
intrinsic pathway extrinsic pathway
re under close calcium control (i.a. daily determination
of the Ca2+ ratio [quotient of total calcium and ionized
calcium]) and corresponding citrate adjustment (dose
reduction). Citrate anticoagulation can also be safely
applied in advanced liver diseases (i.a. Faybik et al,
Crit Care Med 2011; Schultheiß et al, Crit Care 2012;
L-CAT study [Slowinski et al, Crit Care 2015; Klingele
et al, Crit Care 2017]).
• Past the filter, calcium chloride is infused to avoid hy-
pocalcemia.
• Regional citrate anticoagulation is the only method that
does not cause anticoagulation-related bleeding.
• use of a calcium-free substitute
• Citrate also acts as a buffer substance: It is converted citrate
into bicarbonate in the liver (1 molecule of citrate → 3
molecules of bicarbonate). Therefore, metabolic alka-
losis can develop. prothrombin thrombin
• Citrate is administered as a sodium citrate solution (tri-
sodium citrate 4% [Na3Citrate 4%]), so that hypernat-
remia can occur. fibrinogen fibrin
• Only regional anticoagulation takes place and not sys-
temic anticoagulation. Therefore one should not forget Fig. 1078  Citrate anticoagulation: effect of citrate [17]
the thrombosis prophylaxis (e.g. LMWH s.c.)!
• Citrate anticoagulation is not only possible with CVVH,
but also with dialysis (e.g. in patients with HIT II) or
SLED. However, it is not yet established in intermittent
procedures (dialysis) and represents an off-label use
in Germany. Heparin (UFH) is still the standard here.
• Citrate is officially not a drug (medicine), but a medical
product.

Advantages
• Citrate anticoagulation only occurs regionally in the fil-
ter and not systemically, so that the risk of bleeding is
not increased.
• longer filter lifespan
• possibly even mortality advantage (Dudemans-van
Straaten et al, Crit Care Med 2009 [see box], but could
not be confirmed in the study by Hetzel et al, Nephrol
Dial Transpl 2011 [see box])
Fig. 1079  Citrate anticoagulation: flow circulation [17]

Nephrology 811
 study meta-analysis

Citrate anticoagulation for continuous venovenous hemo- Regional citrate versus heparin anticoagulation for conti-
filtration nuous renal replacement therapy in critically ill patients: a
Dudemans-van Straaten et al, Crit Care Med 2009 meta-analysis with trial sequential analysis of randomized
controlled trials
• single center prospective randomized controlled study Lui et al, Crit Care 2016
• 215 patients with acute kidney failure and CVVH; anti-
coagulation: • meta-analysis (14 randomized controlled trials)
-- LMWH (Nadroparin) • 1134 critically ill patients with RRT; anticoagulation:
-- citrate -- heparin (UFH systemic / regional)
• results: citrate -- citrate
-- no longer filter lifespans • results: citrate
-- no reduction of bleeding events -- significantly longer filter lifespans
-- significant reduction of mortality (3 months) -- significantly less bleeding
• note: -- significantly less HIT
-- The data are only from a posthoc analysis and are -- mortality: no difference
therefore statistically only hypothesising.
-- The study did not have sufficient power to demonstra- Complications
te reduced mortality.
• hypocalcemia → therefore calcium infusion (subs-
titution) obligatory (immediately before the blood is
returned to the patient); possibly iatrogenic hyperpa-
rathyroidism (stimulation of PTH release caused by hy-
study pocalcemia; secondary hyperparathyroidism) with in-
adequate calcium substitution; ; in case of longer-term
(> 14 days) citrate anticoagulation the bone parame-
ters (AP [alkaline phosphatase] and PTH [parathyroid
Regional citrate versus systemic heparin for anticoagula- hormone]) should also be determined
tion in critically ill patients on continuous venovenous hae- • hypomagnesemia (Citrate can bind not only calcium
mofiltration: a prospective randomized multicentre trial but also magnesium.)
Hetzel et al, Nephrol Dial Transpl 2011
• hypernatremia (Citrate is infused as sodium citrate so-
• multicenter prospective randomized controlled study
lution.)
• 174 patients with acute kidney failure and CVVH; anti- • metabolic alkalosis
coagulation: -- Citrate also acts as a buffer substance as it is broken
-- unfractionated heparin (UFH) down into bicarbonate in the liver.
-- citrate -- especially occurring when too much citrate is admi-
• results: citrate nistered
-- primary endpoint (efficacy of therapy [acid-base ba- -- the most frequent complication (mostly, however,
lance]): no difference only slightly pronounced and mostly not clinically
-- secondary endpoints relevant)
◦◦ lower bleeding risk • citrate accumulation
◦◦ longer filter lifespans
-- frequency: 5%
◦◦ no difference in mortality
-- risk factors:
◦◦ impaired liver function (most important)
◦◦ circulatory shock
◦◦ lactic acidosis
-- signs:
◦◦ progressive hypocalcaemia (increased substituti-
on rate)
◦◦ increased total calcium with normal-value io-
nized calcium (increased quotient total calcium /
ionized calcium [Ca2+ ratio] > 2.5)
◦◦ metabolic acidosis with increased anion gap (> 16
mmol/l; citrate is not measured)
◦◦ Meanwhile there is already a commercial assay

812 Nephrology
 for measuring the citrate concentration. The mea-
sured citrate level correlates very well with the
quotient of total calcium and ionized calcium (Het-
zel et al, Nephrol Dial Transplant 2001).
-- therapy:
◦◦ increase in citrate elimination (via the filter)
◦◦ reduction in citrate intake (possibly complete stop)
◦◦ increase in the dialysate flow
◦◦ reduction in the blood flow
◦◦ administration of calcium

Monitoring
• BGA
-- BGA extracorporeal (post filter)
◦◦ measurement of ionized calcium
◦◦ 10min after start of therapy or change in citrate
dose, then control every 4-6h
◦◦ taregt: 0.25-0.40 mmol/l
-- BGA intracorporeal (systemic)
◦◦ 60min after start of therapy or change in citrate
dose
◦◦ values: sodium, potassium, calcium (ionized; tar-
get: 1.1-1.3 mmol/l [Systemically, the ionized cal-
cium should be in the normal range!]), acid-base
balance
• laboratory
-- once daily
-- total calcium, magnesium (target: 0.7-1.6 mmol/l;
possibly substitution), phosphate
Control
• extracorporeal calcium (post filter; target: ionized calci-
um 0.25-0.40 mmol/l): via citrate intake
-- < 0.25 mmol/l: Too much citrate was infused. The
citrate intake must be reduced.
-- > 0.40 mmol/l: Too little citrate was infused. The cit-
rate intake must be increased.
• intracorporeal calcium (systemic;target: ionized cal-
cium 1.1-1.3 mmol/l [i.e. normal range]): via calcium
intake
-- < 1.1 mmol/l: Too little calcium was infused (substitu-
ted). The calcium intake (substitution) must be incre-
ased (note.: If persistent, then one should also think
about a citrate accumulation and determine the quo-
tient total calcium / ionized calcium [Ca2+ ratio > 2.5).
-- > 1.3 mmol/l: Too muchcalcium was infused (sub-
stituted). The calcium intake (substitution) must be
decreased.
Systems (examples)
• CiCa (Fresenius)
• Regiocit (Baxter)
Fig. 1080  Citrate anticoagulation
Indications
• patients at risk of bleeding
• HIT II
• Citrate anticoagulation should be standard in all pati-
ents with CVVH today! This makes it possible for an-
ticoagulation to be present only regionally (i.e. in the
filter) and not systemically throughout the entire body
(increased risk of bleeding!). Also the current guideli-
nes of KDIGO (Kidney Disease Improving Global Out-
comes) explicitly recommend citrate anticoagulation
as the first choice! About one third of all intensive care
units in Germany already use citrate anticoagulation
(Schmitz et al, Med Klin Intensivmed Notfmed 2015).
Citrate anticoagulation should be
standard in all intensive care
units today!
Selection of the procedure
• haemodynamically unstable (or stable + increased int-
racranial pressure) → continuous (usual; CVVH, CVV-
HDF)
• haemodynamically stable → intermittent (haemodialy-
sis)
In several prospective randomized studies (Vinonneau et
al, Lancet 2006 [see box], OMAKI-Studie [Wald et al, Crit
Care 2012], CONVINT study [see box]) the comparison
of CVVH and hemodialysis showed no advantages for
one or the other type of renal replacement therapy.

Nephrology 813
 study
Continuous venovenous haemodiafiltration versus inter-
mittent haemodialysis for acute kidney failure in patients
with multiple-organ dysfunction syndrome: a multicentre
randomised trial
Vinsonneau et al, Lancet 2006
• multicenter prospective randomized study
• 360 intensive care patients with acute kidney failure and
need for a renal replacement therapy
-- CVVH
-- intermittent hemodialysis (daily)
• results:
-- no difference in mortality
-- no difference in hemodynamic stability
CONVINT study
The effect of continuous versus intermittend renal replace-
ment therapy on the outcome of critically ill patients with
acute renale failure
Schefold et al, Crit Care 2014
• single center prospective randomized study
• 252 intensive care patients with acute kidney failure and
need for a renal replacement therapy
-- CVVH
-- intermittent hemodialysis (daily)
• results:
-- no difference in mortality
-- no difference in hemodynamic stability
-- no difference in renal function recovery
-- no difference in ventilation duration
There is no survival benefit of any
particular renal replacement procedu-
re!
In two retrospective cohort studies (Wald et al, Crit Care
Med 2013 [RENAL-RECOVER study; see box]; Sun et
al, Crit Care 2014), the use of CVVH compared to he-
modialysis in acute kidney failure in critically ill patients
showed a faster recovery of renal function and less fre-
quently a permanent renal failure requiring hemodialysis.
814 Nephrology
RENAL-RECOVER study
The association between renal replacement therapy mo-
dality and long-term outcomes among critically ill adults
with acute kidney injury
Wald et al, Crit Care 2013
• retrospective cohort study
• 4630 intensive care patients with acute kidney failure
and need for a renal replacement therapy
-- CVVH
-- intermittent hemodialysis
• results: CVVH
-- siginificantly less frequent necessity of permanent he-
modialysis in the long-term course
-- no difference in mortality
Nevertheless, it is common practice and is clearly recom-
mended by KDIGO to carry out a continuous procedure
in hemodynamically unstable patients or in patients with
increased intracranial pressure.
hemodynamically unstable patients or
patients with increased intracranial
pressure → continuous procedure!
Indications
• renal
• extrarenal
Renal indications
• therapy refractory hypervolemia
• therapy refractory hyperkalemia (here hemodialysis,
not CVVH, because only hemodialysis removes small
molecules! Following this [especially with only short
"potassium dialyses"] a postdialytic rebound pheno-
menon with potassium increase may occur.)
• therapy refractory metabolic acidosis (especially in
metabolic acidosis with high anion gap: This is caused
by an increased attack of endo- or exogenous acids.
The administration of sodium bicarbonate does not
help here at all. The only reasonable option here is re-
nal replacement therapy!)
• uremic complications (e.g. pericarditis, encephalopa-
thy, neuropathy)
• creatinine > 10 mg/dl, urea > 200 mg/dl ("dialysis
threshold")
-- only relative (applies more to chronic kidney disease;
more important than the level of the retention para-
meters is the volume overload including the resulting
organ complications)
-- Basically, RRT occurs earlier in acute kidney failu-
re than in chronic kidney disease due to the lack of
 adaptation.
-- From AKI classification 3 (creatinine > 4 mg/dl or >
300% of the initial value; urine volume < 0.3 ml/kg/h
for at least 24 hours) renal replacement therapy is
usually required.
-- Its use can be considered in patients with refractory
septic shock who are already on CVVH
-- but possibly also adsorption of anti-infectives (König
et al, Int J Artif Organs 2019), so that concentration
of anti-infectives can be a reduced with a subse-
quent weakening of the effect
-- guidelines:
◦◦ international (SSC guidelines 2016): no recom-
mendation given (as insufficient data)
◦◦ national (Germany: S3 guideline sepsis 2018): not
recommended (This should be avoided outside of
clinical studies.)

Extrarenal indications
• intoxications (e.g. lithium, ASA, theophylline, alcohols,
methemoglobin formers; see chapter toxicology
• removal of proinflammatory cytokines (i.a. DAMP
[damage-associated molecular patterns such as heat
shock proteins] and PAMP [athogen-associated mole-
cular patterns such as endotoxins like lipopolysaccha-
rides]):
-- There are numerous special filters (i.a. CytoSorb,
oXiris, MATISSE, septeX, Toraymyxin [Polymyxin
B], CPFA [coupled plasma filtration with adsorption]),
which can be integrated into the circuit of an ongoing
renal replacement therapy (CVVH) in order to re-
move proinflammatory cytokines in sepsis ("sepsis"
filters).
-- These are relatively expensive (e.g. CytoSorb ap-
prox. 1000 € for 24 hours) and are definitely not ge-
nerally recommended. There are no special filters
for septic patients!
-- studies: There are mostly only small case studies on
this topic (i.a. Kogelmann et al, Crit Care 2017; Frie-
secke et al, J Artif Organs 2017). A multicenter ran-
domized study (EUPHRATES [Dellinger et al, JAMA
2018]) showed no mortality advantage in patients
with septic shock (by a toraymyxin hemoperfusion
[polymyxin B]). In a randomized controlled study
(Schädler et al, PLOS ONE 2017), the interleukin 6
level could not be reduced in invasively ventilated Fig. 1081  examples for "sepsis"filters (first oXiris [company
Baxter], then CytoSorb [company CytoSorbens])
patients with sepsis (by a CytoSorb hemoperfusion).
There was even an excess mortality that was only
no longer significant in the analysis adjusted to the
patient characteristics. In a pilot study (Hawchar et
al, J Crit Care 2019), CytoSorb hemoperfusion in
patients with septic shock was able to lower the no-
repinephrine concentration as well as the levels of
PCT and of the cytokine big endothelin-1. The multi-
center, randomized-controlled EXCHANGE study is
currently ongoing.

Nephrology 815

Side effects
Renal replacement procedures have numerous side
effects, so that one also speaks of "dialysate / filtration
trauma":
• circulatory:
-- hypotension (less pronounced with hemofiltration
than with hemodialysis)
-- hypothermia (therefore integrated heating systems,
which, however, are often insufficient, especially with
large exchange volumes)
• haemostasiological:
-- bleeding (due to anticoagulation [not with citrate an-
ticoagulation])
-- thrombocytopathy, thrombocytopenia (due to the
blood-membrane contact)
• infectiological: inflammation ↑ (i.a. bioincompatibility of
membranes [The contact of blood to foreign surfaces
leads not only to an activation of coagulation, but also
of inflammation. Therefore, the CRP is often in-
creased under renal replacement therapy without an
infection that requires treatment with antibiotics being
present!], loss of anti-inflammatory mediators), infec-
tions ↑
• mechanical: catheter problems (i.a. thromboses, endo-
carditis [especially tricuspid valve])
• metabolic: loss of
-- electrolytes (especially phosphate, magnesium)
-- vitamins (water-soluble: Under renal replacement
therapy an increased loss of water-soluble vitamins
occurs. Therefore, the dose of water-soluble vit-
amins must be doubled!) )
-- amino acids (Renal replacement therapy is catabo-
lic!)
◦◦ dialysis: 2 g/h (The body loses 2g amino acids per
hour of dialysis!)
◦◦ CVVH: : per litre filtrate x 0.2 g/kg amino acids
-- drugs (medications; especially antibiotics [cave un-
derdosage in sepsis!])
Principles
Timing
• early (probably)
• The optimal time for starting a renal replacement the-
rapy is still unclear.
816 Nephrology
• studies:
-- A small retrospective case series (Carl et al, Hemo-
dial Int 2010) showed a mortality benefit in septic
patients if renal replacement therapy was initiated
early (i.e. urea < 200 mg/dl) instead of late (i.e. urea
> 200 mg/dl). However, this could not be confirmed
prospectively.
-- A large meta-analysis (Bagshaw et al, J Crit Care
2009) showed a mortality advantage if renal repla-
cement therapy was initiated within two days of ad-
mission to intensive care.
-- Both in the STARRT-AKI study (Wald et al, Kidney
Int 2015) and in the AKIKI study (Gaudry et al, N
Engl J 2016), the early start of renal replacement
therapy showed no reduction in mortality.
-- In the ELIAN study (see box), which, however, was
only a single center study, the early start of renal re-
placement therapy showed a significant reduction in
mortality.
-- IDEAL-ICU (see box)
• A renal replacement therapy should be initiated in any
case before uremic complications occur.
• rule of thumb: urea > 200 mg/dl (only relative: More
important than the level of the retention parameters
is the volume overload including the resulting organ
complications [e.g. difficult ventilation situation due to
hypervolemia]).
ELAIN study
Intensity of Continuous Renal-Replacement Therapy in
Critically Ill Patients
Zarbock et al, JAMA 2016
• monocenter randomized study (Germany)
• 231 critically ill patients with acute kidney failure (i.a.
NGAL > 150 ng/ml); time of initiation of renal replace-
ment therapy (RRT):
-- early (already from KDIGO stage 2 [within 8h]: creati-
nine increase > 200%, urine < 0.5 ml/h/kg)
-- delayed (only from KDIGO stage 3 [within 12h]: creati-
nine increase > 300%, urine < 0.3 ml/h/kg
• results: early RRT
-- primary endpoint (90-day mortality): significant reduc-
tion (39% versus 54%)
-- secondary endpoints: i.a.
◦◦ significantly more frequent recovery of renal func-
tion after 90 days
◦◦ significantly earlier termination of RRT (9 versus 25
days)
◦◦ significantly shorter hospital stay
◦◦ no difference: dialysis dependence at 90 days, rate
of organ failure, length of intensive care stay
 IDEAL-ICU study
Timing of Renal-Replacement Therapy in Patients with
Acute Kidney Injury and Sepsis
Barbar et al, N Engl J 2018
• multicenter randomized study (France)
• IDEAL-ICU: Initiation of Dialysis EArly Versus deLayed
in Intensive Care Unit
• 488 patients with septic shock and severe acute kidney
failure (i.e. "failure"-stage according to RIFLE [for the
criteria see page 790]; no life-threatening complica-
tions yet); time of initiation of renal replacement therapy
(RRT):
-- early (within 12h)
-- delayed (only after 48h)
• Ergebnis: early RRT → no reduction in mortality (af-
ter 90 days; primary endpoint)
Dose
• hemodialysis: 3 x / week for 5h each
• hemofiltration: According to the study by Ronco (Lan-
cet 2000), in which a mortality advantage could be
demonstrated by very high ultrafiltration volumes (35-
45 ml/kg/h), the principle of high dosage filtration was
applied for a long time. This has now been invalidated
by subsequent studies ("dose studies": ATN, RENAL,
IVOIRE [see box]) and no longer applies today (obso-
lete). The currently recommended dosage for the ultra-
filtration volume is 20-25 ml/kg/h today.
ATN study
Intensity of Renal Support in Critically Ill Patients with
Acute Kidney Injury
The VA/NIH Acute Renal Failure Trial Network, N Engl J
2008
• multicenter prospective randomized controlled study
• 1124 patients with acute kidney failure
-- standard renal replacement therapy
◦◦ hemodialysis / SLED 3x/week or
◦◦ CVVH 20 ml/kg/h
-- intensified renal replacement therapy
◦◦ daily hemodialysis / SLED or
◦◦ CVVH 35 ml/kg/h
• results: intensified renal replacement therapy
-- no reduction in mortality
-- significantly more electrolyte disorders (hypokale-
mia, hypophosphatemia
RENAL study
Intensity of Continuous Renal-Replacement Therapy in
Critically Ill Patients
The RENAL Replacement Therapy Study Investigators, N
Engl J 2009
• multicenter prospective randomized controlled study
• 1508 critically ill patients (largest study on acute kidney
failure!) with CVVH in acute kidney injury
-- high-intensity group (filtration flow 40 ml/kg/h)
-- low-intensity group (filtration flow 25 ml/kg/h)
• results
-- primary endpoint (mortality): no difference
-- secondary endpoints (i.a. duration of ventilation,
ICU length of stay): no difference
IVOIRE study
High-volume versus standard-volume haemofiltration for
septic shock patients with acute kidney injury
Joannes-Boyau et al, Intensive Care Med 2013
• multicenter prospective randomized controlled study
• 140 patients with septic shock and acute kidney failure
with CVVH
-- high-intensity group (filtration flow 70 ml/kg/h)
-- low-intensity group (filtration flow 35 ml/kg/h)
• results: high-intensity group
-- primary endpoint (mortality after 28 days): no diffe-
rence
-- secondary endpoints (i.a. mortality after 90 days, du-
ration of ventilation, duration of renal replacement the-
rapy, length of ICU stay): no difference
-- significantly more electrolyte disorders (hypokalemia,
hypophosphatemia
recommended dose for CVVH: 20-25
ml/kg/h
Nephrology 817
Infectiology
 1955): discovery of penicllin (1928; coincidence: After
Sepsis returning from vacation, he discovered molds of the
genus Penicillium, which inhibited bacterial growth, on
an agar plate on which he grew bacteria. In 1945 he
received the Nobel Prize for the discovery.)
• Hugo Schottmüller (German physician and microbio-
logist, 1867-1936): “Sepsis is present if a focus has
developed from which pathogenic bacteria, constantly
or periodically, invade the blood stream in such a way
that this causes subjective and objective symptoms”
(1914).

Definitions

Sepsis is a syndrome of various

causes and not a disease!

History
• Hippokrates (Greek physician [the most famous doctor
of antiquity]; 460-370 BC)
-- illness that starts with fever after injury and often
leads to death
-- caused by putrefying matter
-- „sepsis“ (Greek): putrefaction
-- originator of miasmic therapy in which it is said that
diseases arise out from rank haze / smell („miasma“
Greek: rank haze)
• Avicenna (Persian physician, 980-1037 AC): „canon of
medicine“ (book)
• Joseph Lister (British physician; 1827-1912): founder
of asepsis (He used carbolic acid dressings as anti-
septic agent on infected wounds.)
• Ignaz Semmelweis (Hungarian physician; 1818-1875):
decrease in mortality of puerperal fever from 18% to
2.5% (NNT of only 7!) by using hand hygiene with the
aid of chlorine chalk solution (1847)
• Louis Pasteur (French chemist and biologist, 1822-
1895) discovered that microorganisms (bacteria) are
the cause of infectious diseases.
• Rudolf Virchov (German physician; 1821-1902) SIRS
-- Putrefying fluids penetrate the tissue and arouse 2 criteria have to be met:
new processes of development (1856). • temperature
-- just in seminal manner -- hyperthermia > 38°C (fever [Rectal temperature
• Robert Koch (German physician and microbiologist; should be measured. Tympanal temperature is rela-
1843-1910): tively unreliable!) or
-- originator of bacteriology -- hypothermia < 36°C
-- 1860: Robert Koch and Louis Pasteur discovered • tachycardia > 90/min
bacteria. • respiratory
• Emil von Behring (German microbiologist; 1854-1917) -- tachypnea >20 breaths per minute or
was the first to develop antiinfective sera (mostly anti-
-- hyperventilation: pCO2 < 35mmHg (spontaneous
serum against diphteria).
breathing)
• Sir Alexander Fleming (Scottish bacteriologist; 1881-

820 Infectiology
• leukocytes (white cell count)
-- > 12000 or < 4000/μl or
-- > 10% banded neutrophils (immature granulocytes)

SIRS criteria have a relatively high sensitivity (90%, i.e.

if negative sepsis is most probably excluded), but only a
low specifity (only 13%; every patient with flu would have
sepsis; "Everytime you have sex you have SIRS!").

Sepsis
= SIRS + infection (clinically or microbiologically proven)

Severe sepsis
signs of organ dysfunction (sepsis with organ related
complications):
• lung: arterial hypoxemia
-- room air: paO2 < 75 mmHg or
-- oxygen application: paO2/FiO2 < 250 mmHg (conver-
sion in spontaneous breathing: FiO2 = 0.21 + 0.03 x
liter O2 per minute)
• kidney: septic renal failure, renal dysfunction
-- oliguria: diuresis < 0.5 ml/kg/h (for at least 2 hours)
-- raise in creatinine > 2 times ULN
• heart: septic cardiomyopathy
-- decreased cardiac index or relatively inadequate in-
crease of cardiac index at a low systemic vascular
resistance (SVR; often not an established diagnose!)
-- possibly elevated troponin / pro-BNP­
• brain (septic encephalopathy): vigilance, agitation,
confusion (an early symptom!)
• liver: septic liver failure (bilirubin > 4 mg/dl)
• metabolic acidosis:
-- BE (base excess) < -5 mmol/l
-- lactate > 5 mmol/l or > 20 mg/dl (sign of tissue hy-
poxia)
• thrombopenia:
-- platelets < 100000/μl
-- decrease of platelets > 30% in 24h

Septic shock
= Sepsis +
• SBP < 90 mmHg, MAP < 65 mmHg or
• requiring catecholamines
• note: despite sufficient fluid administration!

Infectiology 821

new sepsis definition (Sepsis-3):
Especially the organ dysfunction
is in the foreground!
The disadvantage of the old definition with the SIRS cri-
teria was certainly the low specificity. The advantage,
however, was the high sensitivity, i.e. almost no patient
with sepsis has been overlooked ("early warning sys-
tem"). At most it only happened that one patient was ad-
mitted to the intensive care unit for one night for nothing.
The disadvantage of the new sepsis definition, however,
is that sepsis can only be recognized very late, i.e. only
when organ failure has occurred, i.e. when "the horse
has left the barn". The SIRS criteria are out as definition
criteria for sepsis, but they are certainly still important
criteria for an infection!
Epidemiology
• sepsis: main cause of death on intensive care units
• incidence sepsis:
-- 300/100000
-- increasing
• incidences (according to ICD-10-GM; Heublein et al,
Intensiv-News 4/13)
-- sepsis: 106/100000 (hospital mortality: 10.5%)
-- severe sepsis: 84/100000 (hospital mortality: 43%)
-- septic shock: 23/100000 (hospital mortality: 60.5%)
• severe sepsis / septic shock: 75,000 cases per year
in Germany
• approx. 70,000 deaths per year in Germany (third most
822 Infectiology
common cause in Germany; approx. 15,000 would be
avoidable)
• the 5th leading cause of death worldwide (in 40% child-
ren < 5 years.; w > m [Rudd et al, Lancet 2020])
• 30% of all intensive care patients (sepsis in every
3rd patient in intensive care units!)
• median age: 67 years
• acquisition:
-- in 50% community acquired
-- in 50% hospital acquired (nosocomial; mostly VAP)
• SIRS → in 6% septic shock
• 47 percent of the community never heard the term
„sepsis“ although incidence and mortality is comparab-
le to myocardial infarction (also 300/100000; Rubulotta
et al, Crit Care Med 2009).
• costs: 5.8 billion euros annually (Germany)
• sepsis resolution of the WHA (World Health Assembly;
the decision-making body of the WHO [World Health
Organization]) at 26/05/2017: classification of sepsis
as a health problem to combat with priority
Sepsis: main cause of death in
intensive care units!
Every 6-7 minutes a person dies of
sepsis (in Germany)!
Etiology
• pneumonia (most common cause at all of sepsis,
escpecially ventilator associated pneumonia [VAP])
• surgical infection (perioperative), intraabdominal fo-
cus; peritonitis (classification see infobox; most com-
mon germs: E. coli [No.1], Bacteroides fragilis [No.2],
anaerobic germs; mostly mixed infections; note: Pseu-
domonas does not play a pathogenic role in this case!)
• cholangitis, cholezystitis, Mirizzi syndrome (→ cholan-
giosepsis)
• pancreatitis
• meningitis, encephalitis
• urogenital (→ urosepsis)
• endocarditis
• catheter related blood stream infection (e.g. central-
venous catheters)
• ENT- and dental related infections (teeth, sinusitis,
ears); i.a. Ludwig angina (see infobox)
• gynecological (e.g. postpartal, after abortion)
• septic arthritis
• skin and soft tissue infections (SSTI; 3rd most common
cause! e.g. erysipelas, phlegmon, necrotizing fasciitis),
wound infections
• spondylodiscitis (see infobox)
• pleural empyema
• status post resuscitation → sepsis like syndrome
• shock
• polytrauma
• unclear in 20% (idiopathic; poor prognosis)
Fig. 1082  pneumonia: the most common cause of sepsis

Fig. 1083  CT abdomen: emphysematous cholecystitis (pro-

nounced air in the gallbladder wall)

Infectiology 823
 Fig. 1085  The most feared complication after polypectomy
(with the electric snare) is perforation. You can see the hole
in the wall of the colon. As a result, peritonitis developed.
Fig. 1084  ERCP in Mirizzi syndrome (various cases): named
after the Argetine physician Pablo Luis Mirizzi (1893-1964);
obstructive jaundice caused by compression (see arrow)
oft he common hepatic duct by a concrement in the cystic
duct (first picture) or in the gallbladder (mostly in the neck
[second picture]); therapy: first ERCP with stent implantati-
on in the common hepatic duct to ensure an outflow again,
then cholecystectomy (often non-laparoscopic but open
surgery)

824 Infectiology
 Predisposition
• immunosuppression
• Diabetes mellitus
• liver cirrhosis
• cancer
• collagenosis
• malnutrition (common; 30 percent of all in-patient ca-
ses)
• status post splenectomy
• high age
• male gender

Bacteria

• mostly gram-negative germs; gram-positive germs,

however, increasing (even leading in the SOAP study)
• germs:
-- No.1: S. aureus (most common pathogen of sepsis)
-- No.2: E. coli
• portals of entry:
-- No.1: pulmonary
-- No.2: abdominal
-- No.3: dematologic
-- No.4: urogenital

SOAP study

Fig. 1086  MRI of the spine: extensive destructing spondylo- Sepsis occurance in acutely ill patients
discitis of vertebral body 9/10 with distinct abscess (indica- Vincent et al, Crit Care Med 2006
tion for surgery)
• observational study
• 198 intensive care units in 24 European countries
Most common causes of sepsis: • 3147 patients in intensive care units treated > 24h
1. pulmonary • 37% of the patients suffered from sepsis.
2. abdominal • ICU mortality
3. dermatologic (SSTI) -- general: 19%
4. urogenital -- patients with sepsis: 27%

Infectiology 825
 Classification
• uncomplicated
study • complicated (if one of the criteria is met)
-- endocarditis, septic emboli
-- presence of non-removable foreign material / pros-
theses
Epidemiology of Sepsis in Germany - a national prospec- -- positive follow-up blood cultures
tive multicenter study -- persistent fever > 72h
Engel et al, J Int Care Med 2007
Therapy
• 454 intensive care units in Germany (hospitals with all
service levels) • duration: at least 2 weeks (complicated SAB: 4-6
• incidence: 76-100/100000 weeks [SSC 2016: 6 weeks])
• prevalence • antibiotics:
-- sepsis: 11-14% -- MSSA (note: In case of MSSA both substances are
-- severe sepsis, septic shock: 10-12% far more effective than vancomycin!)
• mortality: ◦◦ flucloxacillin (Staphylex; means of choice) 4 x
-- sepsis: 20% 2g (in endckarditis 6 x 2g) i.v. or
-- severe sepsis: 47% ◦◦ cefazolin (Gramaxin) 3 x 2g i.v. (slightly more fre-
-- septic shock: 62% quent recurrence as with flucloxacillin, worse CNS
• 40000-57000 deaths caused by septic diseases penetration than flucloxacillin; therefore only in un-
complicated SAB [not in complicated SAB])
-- MRSA:
Staphylococcus aureus bacteremia ◦◦ vancomycin (always loading dose with 30 mg/kg,
(SAB) then according to trough serum level; goal: 15-20
mg/dl [with continuous administration: 20-25 mg/
dl]) or
◦◦ daptomycin (not effective with pulmonary focus as
it is inactivated by surfactant)
◦◦ annotations:
▪▪ Linezolid is significantly less effective in MRSA
bacteremia! Linezolid is only bacteriostatic but
vancomycin and daptomycin are bactericidal!
▪▪ 5th generation cephalosporins (ceftobiprol [Zev-
tera], ceftarolin [Teflaro]) also effective against
MRSA, but not approved for MRSA bacteremia
• combination therapy with rifampicin (3 x 300mg i.v. /
p.o.; alternatively also with fosfomycin 3 x 5g i.v.)
-- indications (and only here: A general combination
with rifampicin at SAB has no advantages [ARREST
study Thwaites et al, Lancet 2018]):
◦◦ presence of non-removable foreign material /
Definition prostheses
• staphylococcus aureus: ◦◦ abscesses, deep-seated infections (especially os-
-- gram-positive heap cocci (eponymous golden yellow teomyelitis, spondylodiscitis)
colour of the colonies on the agar plate) ◦◦ endocarditis (but only recommended for MRSA
-- in 20% colonization of nasal vestibule and skin and not for MSSA)
-- second most common pathogen of bacteriemia -- best biofilm- penetrating antibiotic agent
(N0.1: E. coli) -- always observe the eating distance when administe-
-- property for biofilm formation on foreign surfaces ring p.o. (at least 30 minutes before or 120 minutes
• incidence: 25/100000 after eating), otherwise reduced bioavailability (Po-
• mortality: 35% lasa et al, J Clin Pharmacol 1983)
• note: If staphylococcus aureus is proven in the uri- -- hepatotoxic (if GOT > 100 U/l: contraindicated)
ne, it is mostly not a primary but a secondary urinary -- red urine (normal and harmless)
tract infection, i.d. staphylococcus aureus was filtered -- The combination of rifampicin with linezolid leads to
through the calyx system into the urine in presence of a weakening of effect of linezolid because its level
bacteremia. S. aureus is not a typical pathogen of uri- decreases.
nary tract infections. There is usually S. aureus bacte- • possibly oralization of antibiosis (currently ongoing
remia, which you should always search for thoroughly, study: SABATO; in presence of non-removable foreign
and thus urosepsis! material / prostheses combination with rifampicin)

826 Infectiology
 -- not suitable (since no sufficient oral bioavailability):
◦◦ flucloxacillin
◦◦ oral cephalosporins (exception: cefalexin [a 1st
generation cephalosporin; oral bioavailability: 90-
100%; 3 x 1g])
-- clindamycin (also effective for MRSA) 3 x 600mg
-- cotrimoxazol (trimethoprim / sulfamethoxazol; also
effective for MRSA) 3 x 960mg
-- doxycyclin 1 x 200mg
-- levofloxacin 2 x 500mg
-- linezolid 2 x 600mg (especially a very good option
for MRSA, but also effective for MSSA)
-- note: possibly dalbavancin (see page 1120; only sin-
gle dose i.v. necessary, then effect for 14 days; effec-
tive for both MSSA and MRSA; but not approved for
this [approved only for complicated skin soft tissue
infections and catheter-associated infections])
• focus search and control:
-- in 15% endocarditis → therefore always TEE (if
negative: repeat generously after one week; note:
From own experience, significantly less than 15%
have endocarditis, so that many TEE examinations
are carried out completely for nothing in everyday
clinical practice. Helpful for the decision which pati-
ent with S. aureus bacteremia actually needs a TEE
is the VIRSTA score [see infobox]: According to this,
you only have to carry out a TEE if the VIRSTA score
delivers at least 3 points.)
-- if necessary CT / MRT of the spine (spondylodis-
citis), if necessary FDG-PET/CT (especially for the
identification of deep foci)
-- abscess: incision, drainage Special types of sepsis
• subsequent blood cultures (49-96h after initiation of • meningococcal sepsis (Waterhouse-Friderichsen syn-
antimicrobial therapy) drome; see page 914)
• removal of foreign bodies (especially central venous • toxic shock syndrome (TSS)
catheters); if impossible (e.g. artificial heart valves), • overwhelming postsplenectomy infection syndrome
combination therapy with rifampicin (best biofilm pe- (OPSI)
netrating antibiotic agent); in S.aureus bacteraemia it • purpura fulminans
is also recommended to explant pacemakers / AICD • hemophagocytic syndrome (HPS)
including electrodes (even if there is no evidence of • Lemierre syndrome
vegetation on the electrode) [expert consensus Wilkoff
-- named after the French bacteriologist André Le-
et al, Heart Rhythm 2009 and Kusumoto et al, Heart
mierre (1875-1956)
Rhythm 2017: IB recommendation; so called Byrd cri-
-- septic emboli (especially septic pulmonary infarc-
teria]; note: This is not handled so strictly in our hospi-
tions [melting processes; similar to tricuspid valve
tal. We usually start a conservative therapy approach
endocarditis]) as a result of an infected thrombosis
with antibiotics. Only when this fails [e.g. repeated
of the internal jugular vein after angina tonsillaris
positive blood cultures], then the entire system is re-
(e.g. pharyngitis, ponsillitis; postangina sepsis)
moved.)
-- main germ: fusobacteria
• obligation to notify the authorities if MRSA-bactera-
emia is proven (just as if MRSA is being diagnosed in -- antibiosis: ceftriaxon + metronidazole i.v.
CSF [cerebrospinal fluid]) • Landouzy sepsis
-- named after the French neurologist Louis Theophile
Joseph Landouzy (1845-1917)
good oralization with MSSA: combina- -- sepsis by mycobacterium tuberculosis
tion levofloxacin + rifampicin
Toxic shock syndrome (TSS)
Definition
• multi-system-disease caused by toxins of grampositive
bacteria with fever, hypotension and skin rash as car-
dinal symptoms

Infectiology 827
• often multi-organ failure
• first described by Todd 1978 in children
Types
• menstrual TSS (80%; mostly girls and young women;
mortality: 8%)
• non-menstrual TSS (20%; mortality: 15%)
Symptoms
• high fever, shivering (abrupt onset)
• dermatologic: exanthem
-- diffuse erythematous (erythrodermia; just as in a
sunburn), often scarlatiniform
-- lesions mostly absent on the head
-- "allergy" sometimes an erroneous diagnosis
-- subsequent (mostly 1-2 weeks later during convale-
scence) plantar and palmar desquamation (SSSS:
staphylococcal scalded skin syndrome), hair and
nail loss 2-3 months later
• gastrointestinal: nausea, vomiting, diarrhea
• muscular: myalgia, extensive increase of CK
• circulatory: shock
• renal: acute kidney failure
• hepatic: acute liver failure
• cardiac: congestive heart failure
• pulmonary: ARDS
• hematologic: DIC
• ophthalmologic: conjunctivitis
• central nervous: headache, confusion
Fig. 1087  toxic shock syndrome: extensive whole-body
flush (“sunburn”) with skin desquamation
Pathophysiology
• bacterial exotoxins of grampositive bacteria (toxin-in-
duced disease)
• These exotoxins act as super-antigens: They bypass
conventional T-cell activation via the Vß-part of the T-
cell receptor (naturally over MHC) leading to a massive
T-cell activation (20% of the total T-cell pool) and ex-
tensive release of cytokines.
Etiology
• staphylococci (most common)
-- exotoxines:
◦◦ TSST1 (toxic shock syndrome toxin; most com-
mon; note: Only 1% of all S. aureus phyla are pro-
ducing that kind of toxin.)
◦◦ SEB (staphylococcal enterotoxin B)
-- from the vaginal area of (mostly younger) women
during menstruation (colonized in 20% with S. aure-
828 Infectiology
us; optimal milieu; mostly when using a highly absor-
bent tampon (“tampon illness”)
• group A streptococci (GAS; e.g. in wound infections,
necrotizing fasciitis, myositis)
Diagnosis
• anamnesis, clinical examination
• laboratory
• serology: antibodies against TSST1 and SEB
• microbiological diagnostic:
-- blood cultures for S. aureus: only in 5% positive
-- smear (e.g. vagina, wounds)
Therapy
• antibiosis
-- to reduce the amount of toxin-forming bacteria
-- Means of choice is clindamycin. Due to insecurity
of initial differentiation between staphylococci and
streptococci broad-spectrum antimicrobial therapy
(in analogy to skin and soft tissue infections) should
be performed: e.g. combination therapy with
◦◦ piperacillin 4g / tazobactam 1g 1-1-1 i.v. +
◦◦ clindamycin 900mg 1-1-1 i.v. +
◦◦ penicillin G 10 Mio 1-1-1-1-1-1 i.v.
• infectious source control
-- gynaecological (removal of foreign body, e.g. infec-
ted contraceptive coil)
-- surgical especially in case of necrotizing fasciitis
(debridement, amputation)
• possibly immunoglobulins
-- to neutralize exotoxins (superantigens)
-- Pentaglobin (i.v. IgG + IgM): infusion solution with
5g/100ml → dosage 5ml/kg (0.25g/kg) i.v. daily for
3 days
-- costs: approx. 1000€ daily
-- especially for cases where infectious source control
is not possible
-- exclusion of IgA deficiency prior to administration ne-
cessary (otherwise potential risk of allergic reaction)
-- study Darenberg et al, Clin Infect Dis 2003: tendenti-
ally lower risk of mortality
• no isolation necessary (not contagious)
Triad fever, shock, skin rash in
young women → think of TSS!
OPSI
• definition: overwhelming postsplenectomy infection
syndrome
• occurence:
-- after splenectomy (most common indication: trau-
matic splenic rupture [note: Nowadays treatment
of a splenic rupture takes place predominantly in a
conservative way.]; often occurring even after years)
-- approx. 8000 splenectomies annually in Germany,
approx. 82000 asplenic patients in Germany
• clinical course: mostly peracute (fulminant)
• clinic: leading severe DIC and gangrene
• mortality: 45%
• pathogens (especially encapsulated bacteria):
-- pneumococci (most common; 88%)
-- haemophilus influenzae type B (6%)
-- neisseria meningitides (3%)
• prophylaxis:
-- vaccination against pneumococci, haemophilus in-
fluenzae, meningococci and influenza (if possible 2
weeks prior to splenectomy, otherwise as soon as
possible after postoperative stabilization; booster
shot every 5 years [recommendation of the German
Vaccination Committee STIKO 2010])
-- emergency medical ID
Purpura fulminans
Definition
• haemorrhagic skin necrosis due to protein C deficiency
• Protein C has an anticoagulant effect. With a lack of
protein C a procoagulatory state is present followed
by DIC with microthrombi in all organs (visible on the
skin; therefore eponymous) and consecutive multi or-
gan failure.
• Protein-C-deficiency can be congenital (incidence
1:160000 births) but is mostly acquired (commonest in
the course of an infection due to increased consumpti-
on: SAPF [sepsis associated purpura fulminans]).
• European registry database: SAPFIRE
Epidemiology
• especially children and adolescents
• incidence 1:100000 ("orphan disease")
• mortality: 50%
Bacteria
• meningococci (meningococcal sepsis: Waterhouse-
Friderichsen syndrome)
• pneumococci
• haemophilus influenzae
• group B streptococci
• staphylococcus aureus
Symptoms
• skin: petechiae, livid discoloration (often map-like),
cyanosis (without dyspnea), gangrene, haemorrhages
• fever
Fig. 1088  pronounced gangrene
If purpura fulminans is suspec-
ted: determine protein C level!
Therapy
• supportive care (e.g. circulatory stabilization)
• antibiotics (e.g. ceftriaxone in meningococcal infection)
• anticoagulant therapy:
-- protein C
◦◦ recombinant protein C (Xigris; no longer produ-
ced, but still existing depots in Germany),
◦◦ human protein C (Ceprotin; 100 E/kg kg as a short
infusion; very good results [i.a. Knoebl et al, Disor-
ders of Coagulation 2013])
-- antithrombin (Kybernin)
• surgical: if necessary fasciotomy (often compartment
syndrome), amputation (unfortunately often inevitable)
Hemophagocytic syndrome (HS, HPS)
Definition
• syn.: hemophagocytic lymphohistiocytosis (HLH)
• a hyperinflammatory syndrome due to a massive over-
reaction of the immune system
• pathophysiology: decreased inhibition of natural killer
cells and T cell activation
Epidemiology
• mostly children
• incidence: 1:1 million
• mortality: 75%
Types
• primary (family HS [FHS]; less common; syn.:
Farquhar´s didease): 5 different FHS forms
-- FHS I: mutation unknown
-- FHS II: mutation in the PRF1 gen
-- FHS III: mutation in the UNC13D gen
-- FHS IV: mutation in the STX11 gen
-- FHS V: mutation in the STXBP2 gen
• secundary: aquired (more common)
-- infections
◦◦ viruses (esp. EBV, CMV, HIV, coronaviruses
[SARS-CoV-1 and 2])
◦◦ bacteria (esp. mykobacteria)
◦◦ parasites (esp. leishmania)
Infectiology 829
 ◦◦ fungi
-- malignancies (esp. lymphomas, leukaemias)
-- autoimmune diseases (esp. rheumatoid arthritis,
systemic lupus erythematosus, Still´s disease, Ka-
wasaki syndrome, dermatomyositis)
most common triggers for
hemophagocytic syndrome: EBV
and lymphoma!
Therapy
• immunosuppression
-- especially with steroids
-- mostly combination of high-dose steroids (dexame-
thasone), etoposide and ciclosporin; possibly ana-
kinra
-- possibly i.v. immunoglobulines
• in relapse: stem cell transplantation (allogeneic)

Pathophysiology
Symptoms
• Sepsis pathogens are no special high virulent germs:
• fever (mostly continua)
They are “usual” bacteria causing a “usual” infection.
• jaundice For some inexplicable reason a completely hyperergic
• ascites reaction (systemic inflammation) of the endogenous
• hepatosplenomegaly immune system occurs following the inundation of bac-
• lymphadenopathy teria / toxins (L.Thomas 1972: „It is our response that
• panzytopenia makes the disease“).
• often presentating as a fulminant sepsis • In the course of this hyperergic reaction of the endo-
genous immune system a massive cytokine release
Diagnosis takes place (cytokine release syndrome [CRS], (“cy-
• serum: tokine storm”, “mediator explosion”): TNFα, interleukin
-- hyperferritinemia (classically ferritin > 500 μg/l, if 1, 3 (i.a. Weber et al, Science 2015), 6, 8. INF-β, NO
> 10000 μg/l: [nearly] almost proven!) (nitric oxide; by up regulating of iNOS [onducible nitric
oxide synthase], NO is bacteriotoxic) with the following
-- hypertriglyceridemia
consequences:
-- hypofibrinogenemia (Ferritin may be false normal in
-- increased vasopermission (caused by damage of
sepsis, as it is an acute phase protein.)
the endothelial glycocalyx): increased vasoperme-
-- blood count: bi- / trinary cytopenia ability („capillary leak“, "vascular leakage") → volu-
-- soluble interleukin 2 receptor (sIL2-R; CD 25) ↑ (> me depletion (intravascular) and edema (Albumin
2400 U/ml) escapes through the leaky vessel wall. The oncotic
• bone marrow puncture (signs of hemophagocytosis) [syn. colloid-osmotic] ​​pressure decreases and ede-
ma develops. The edema extends the diffusion path
fulminant sepsis (unknown focus) for oxygen from the erythrocytes into the tissue or
with trinary cytopenia and ferritin into the cells, so that tissue hypoxia occurs.)
> 10000 μg/l → think of the HS! -- increased vasodilatation (vasoplegia; distributive
shock): decrease of systemic vascular resistance
(SVR < 600 dyn x s x cm-5) and consecutive under-
perfusion of organs
-- activation of coagulation (sepsis associated coagu-
lopathy)
◦◦ procoagulatory
◦◦ cytokine- and endotoxin-induced activation of PAF
(platelet-activation factor) and TF (tissue factor)
on monocytes and endothelial cells
◦◦ formation of microthrombi → dysfunction of micro-
circulation (visible in intravital microscopy), organ
failure
• activation of endogenous systems:
-- plasmatic
◦◦ complement (Activated complement factor C5
leads to an inhibition of cortisol [syn.: hydrocorti-
sone] synthesis in the adrenal cortex followed by
adrenocortical insufficiency.)
◦◦ coagulation
-- cellular (macrophages, endothelium, platelets)
• disorder of tissue oxygenation and oxygen extraction
• increased intestinal permeability with bacterial trans-
location (“bowel acts as motor of multi-organ failure”)
• dysfunction of hemostasis:

830 Infectiology
 -- plasmatic coagulation disorder
-- decrease in platelet count (thrombocytopenia as an
early sign of sepsis!)
-- DIC
• in the further clinical course CARS (compensatory an-
tiinflammatory response syndrome): caused by apop-
tosis of T helper cells (CD4, CD8) leading to increased
susceptibility to infection (especially for hospital acqui-
red pneumonia)
• in the end-stage: multi-organ failure (MOF)

the most important pathomecha-

nisms of sepsis: systemic
inflammation, sepsis-associated
coagulopathy, endothelial
dysfunction and disorder of
microcirculation!

Fig. 1089  The typical septic patient has oedematous swel-

ling (especially on the back of the hand and the lower legs).
Despite the oedema patients have a high fluid requirement!
A frequent mistake is to reduce fluid therapy or to achieve
negative fluid balance due to peripheral oedema. Those oe-
demata are common in septic patients and are caused by
capillary leak and not by volume overload!

Diagnostics
• focus search (identification; screening for infectious
foci)
• pathogen search
• sepsis markers
• hemodynamic monitoring
Hemodynamic phases of septic shock
• hyperdynamic phase Focus search
-- in the beginning • pulmonary:
-- CO ↑­ -- chest X-ray, chest CT
-- SVR ↓ -- tracheal / bronchial secretion
• hypodynamic phase • abdominal:
-- in the end -- sonography (e.g. acute cholecystitis, free intraabdo-
-- CO ↓ minal fluid, pendulum [non-propulsive] peristalsis as
-- SVR ↑ sonographic sign for bowel obstruction [note: Sono-
graphy is far more sensitive in terms of diagnosing
bowel obstruction than abdominal X-ray!], signs of
Symptoms appendicitis)
• depending on the cause of sepsis -- possibly abdomen CT
• Fever, shivering • urogenital:
• skin: -- urine status, urine alysis
-- warm, reddish -- sonography (especially to exclude urinary stasis)
-- warm sweat • cardiac (if endocarditis is suspected: TEE)
-- possibly mottling (disturbed vasomotion) • cerebral: possibly lumbar puncture
• dehydration • foreign bodies (e.g. central venous catheter):
• hypotension, tachycardia -- putrid secretion, reddened puncture site
• agitation, confusion, somnolence (septic encephalopa- -- in case of fever of unknown origin: central and peri-
thy) pheral blood cultures followed by catheter removal
as the circumstances require it; if necessary the
• symptoms of organ dysfunction
catheter tip has to be sent in to the institute for mi-

Infectiology 831
 crobiology; note: A routinely performed exchange of
intravenous catheter has no benefit!
• if necessary CT of sinuses, neck, thorax, abdomen
and pelvis

Fig. 1093  perforated gastric ulcer with massive free air and
consecutive peritonitis
Fig. 1090  right-sided lobar pneumonia
Pathogen search
• blood
-- cultural (blood cultures (still the absolute gold stan-
dard!)
-- molecular biological (multiplex PCR), e.g.
◦◦ Light Cycler SeptiFast PCR (Roche)
◦◦ SeptiTest CE IVD (Molzym)
◦◦ IRIDICA (Abbott Molecular; already off the market
again)
◦◦ Magicplex (Seegene)
◦◦ cobas-Liat (Roche)
◦◦ VYOO Sepsis-Test (SIRS-Lab)
◦◦ Prove-it Sepsis (Mobidiag)
• tracheal / bronchial secretion
• urine analysis

Fig. 1091  CT thorax: right-sided pneumonia with melting Blood culture

sign and pleural empyema
• essential (often forgotten or done wrong, respec-
tively)
• 2-3 pairs (aerobic, anaerobic) on different (!) sites (You
can only remove all pairs from one puncture site if the
venous conditions are very poor.)
• amount: 10ml per bottle (i.e. 20ml for one pair)
• peripheral (non-arterial, not from [except recently] in-
serted intravenous cannula or an indwelling CVC [ex-
ception: In the course of CVC insertion blood cultures
can be removed at any time under sterile conditions.])
• exposure time of antiseptic agent: 1 minute (not only
10 seconds! Wait at least as long as the disinfectant is
well dried), then do not re-palpate (if re-palpate, then
only with sterile gloves)
• effective even if fever is not present (i.a. Li et
al, J Clin Microbiol 1994, Baron et al, Clin Infect Dis
2013; bacteraemia is continuous! Sampling blood
cultures during fever spikes even diminishes the pro-
spect of success for positive blood cultures because
Fig. 1092  CT abdomen: gallbladder empyema

832 Infectiology
 fever spikes are mainly caused by mouldering bacteria Light Cycler SeptiFast (Roche)
which are already necrotic and therefore no longer gro- • verification of 25 pathogens (90% of all pathogens
wing on the agar plate!) of sepsis including candida and aspergillus) by using
• removal of the cap of the blood culture bottles, disin- multiplex PCR from the blood
fection of the rubber plug (has to be dry prior to inocu- • evaluation (applies generally to PCR measurements)
lation, otherwise the antiseptic agent finds its way into
-- advantages:
the blood culture bottle!)sStorage: at room tempera-
ture (neither in the refrigerator nor in the incubator!) ◦◦ result within 6 hours (blood cultures: 48-72 hours)
• only positive in 30% of sepsis (Bloos et al, Int Care ◦◦ detection of pathogens possible even during anti-
Med 2010: only in 16%; in Germany only in 9.6% biotic therapy
[Brunkhorst, Deut Ärzteverl 2011; disastrously low ra- ◦◦ in 53% positive (blood cultures only in 30%); i.a.
tes of bacteraemia in Germany due to common errors Bloss et al, Int Care Med 2010: positive results
in sampling blood culture!]; frequently diagnostically 2-2.5 times more often; sensitivity of 75% and
not helpful) specifity of 92% concerning bacteraemia and fun-
• sampling always prior to initiation of antibiotic therapy gaemia (Chang et al, Public Lib Sc 2013)
-- Otherwise, the probability of detection is reduced to -- disadvantages:
only 30-40%! ◦◦ costs: 200-400 €/PCR (blood cultures: 15-20 €)
-- If antibiotic therapy has already been started, the ◦◦ no antibiogram
sampling should be got immediately prior to the next ◦◦ Contaminations complicate an interpretation.
administration. • PCR can be done in addition to blood cultures (no sub-
• contamination with skin flora in 2-3%; typical germs: stitute) if the circumstances do require that.
-- propionibacteria, corynebacteria, bacillus spp.,
α-hemolytic (greening [viridans]) streptococci (note:
in chemotherapy-induced neutropenia [v.a. Cytara-
bine in AML] however mostly infection and not con-
tamination!)
-- coagulase-negative staphylococci (especially S. epi-
dermidis: contamination in 70%, but infection in 30%
[S. epidermidis is the commonest pathogen of cathe-
ter associated infections!])
◦◦ if only positive in one blood culture → contamina-
tion
◦◦ if positive in several blood cultures → infection
• Time to incubate (interval from drawing the blood to the
initiation of inoculation in the microbiological laborato-
ry) should not exceed 12 hours (Seifert, microbiologi-
cal- infectiological quality standards, Elsevier 2007).
• A positive blood culture is not required for the diagno-
sis of sepsis. This applies to both the old and the new
sepsis definition.

Samples from the respiratory tract

have to present in the microbiological
laboratory within 4 hours!
Fig. 1094  blood culture: there are only little examinations
where errors are that common!!

Infectiology 833
Problem: diagnosing sepsis
• In a survey (Poeze et al, Crit Care 2004), only 22%
of the intensive care physicians and only 5% of the
other physicians knew the correct sepsis definition.
The old sepsis definition (ACCP / SCCM criteria) was
still valid in this survey. With regard to the new definiti-
on of sepsis, it won't look much better either!
• 82% assume that a positive blood culture is a sine qua
non for the diagnose of sepsis.
• A very huge problem in sepsis is the diagnose itself. A
disease cannot be treated properly if one doesn’t make
a diagnose. In this context Roger C. Bone (1941-1997;
Crit Care Med 1997) said: "We should spend more
time to achieve an accurate diagnosis and less time
for searching for a magic bullet".
• To solve this problem sepsis markers have been iden-
tified to render assistance.
The gods placed diagnosis before
therapy!
Sepsis markers
• LBP
• Il-6
• procalcitonin (most common sepsis marker; standard)
• new sepsis markers (currently undergoing clinical tes-
ting, not yet clinical routine): :
-- suPAR (soluble urokinase-type plasminogen activa-
tor receptor)
-- sTREMI (soluble triggering receptor expressed on
myeloid cells-1)
-- MR-pro-ADM (midregional fragment of pro-adreno-
medullin)
-- Presepsin (sCD14-ST; PATHFAST device [Mitsubi-
shi Chemical])
LBP
• lipopolysaccharide (LPS; bacterial endotoxin) binding
protein
• elevation → bacterial infection (elevated only in bacte-
rial and not in other types of infection)
• norm: < 15 μg/ml
• no significance in the clinical routine
Interleukin-6
• main mediator of the acute phase
• earlier increase than CRP
• ein Frühmarker für Entzündung / Sepsis, ferner Prog-
nose-Parameter für Sepsis
• early marker for inflammation/sepsis, moreover a pro-
gnostic parameter for sepsis
• can also be obtained from local body fluids
• norm: < 150 pg/ml (> 1000 pg/ml: severe sepsis)
• relatively expensive, only low significance in the clini-
cal routine
834 Infectiology
Procalcitonin (PCT)
Definition
• precursor of the hormone calcitonin
• protein containing 116 amino acids
• production
-- usual: thyroid gland (C cells)
-- sepsis: extrathyroidal (i.a. monocytes, liver)
• synthesis
-- induction by
◦◦ bacterial endotoxins (LPS)
◦◦ cytokine: TNFα, Il-1β (main inductor)
-- inhibition e.g. by IFN-γ (viral infections) and by fungi
(especially Candida)
• kinetics
-- early (2 hours) increase (much earlier than CRP)
-- maximum after 8 hours
-- T½ 24h (CRP: 48h)
• increase in acute bacterial systemic infection, i.e. not
in
-- chronic infection
-- viral, allergic or autoimmune infection
-- localized infection
• concerning sepsis (Dusemund et al, Eur J Clin Micro-
biol Infect Dis 2013):
-- sensitivity: 77%
-- specifity: 78%
• for differential diagnosis infection (PCT increased) / in-
flammation (PCT not increased)
• 14% of alle German intensive care units are already
using PCT as a biomarker of sepsis (PREVALENCE-
study). Our own surveys during intensive-care courses
show that around 90% of intensive care units already
use PCT.
• costs for one PCT assay: 21-23 € (depending on the
laboratory)
Indications
• biomarker for the identification of acute systemic bac-
terial infections
• differential diagnosis between bacterial and abacterial
infection (e.g. exacerbated COPD, meningitis, acute
pancreatitis [According to the FACS study, an increa-
sed PCT is good for predicting severe course, but poor
for predicting infection of necrosis.])
• sepsis guidelines: recommendation as a parameter for
diagnose, course, prognosis (severity)
-- national
◦◦ S2k guideline 2010: grade C
◦◦ S3 guideline 2018: strong recommendation to
shorten the duration of antibiosis
-- international (SSC guideline 2016): weak recom-
mendation (suggestion)
• antibiotic therapy
-- indication (PCT not increased → no antibiosis)
-- assessment of success (with correct antibiosis, the
PCT should be halved daily
-- abbreviation by PCT control (guidance)
 -- note: PCT should less be used to initiate, but Interpretation
more to terminate antibiotic therapy! • norm: < 0.5 ng/ml
• 0.5-2.0 ng/ml: rrey area
Studies
• 2.0-10.0 ng/ml: sepsis
• Nobre et al, Am J Resp Crit Care 2008: reduction of
• > 10 ng/ml: severe sepsis/septic shock
duration of antibiotic therapy by 3.5 days and ICU stay
by 2 days Differential diagnosis of increased PCT
• PRORATA study (Bouadma et al, Lancet 2010): signi- • gungal infection (However, high PCT values are ​​ com-
ficant reduction of indication and duration of antibiotic pletely atypical for a fungal infection. Fungi inhibit PCT
therapy in critically ill patients without an increase in synthesis. PCT > 5.5 ng/ml almost securely excludes
rate of infection or mortality cadidaemia [Charles et al, Intensive Care Med 2006].
• Numerous meta-analyses (Tang et al, Infection 2009; Therefore, in the case of unclear sepsis with a very
Kapterides et al, Crit Care Med 2010; Wilke et al, Eur J high CRP on the one hand and only a low or no increa-
Med Res 2011 [PCT algorithm → see infobox]; Wacker sed PCT on the other hand, one should always think of
et al, Lancet Infect Dis 2013; Prkno et al, Crit Care a fungal infection in addition to an abscess)
2013) showed a significant reduction in the duration of • ARDS
the administration of antibiotic drugs without an incre-
• polytrauma
ase in mortality.
• post-surgery (e.g. visceral surgery, cardiothoracic sur-
• Also a retrospective cohort analysis (Balk et al, Chest
gery)
2016), the use of procalcitonin showed a reduction in
the length of ICU and hospital stay as well as of the • malaria
costs without increasing mortality. • burns
• In a large randomized Danish multicentre study (PASS • heat stroke (here often extremely high values!)
study: Jensen et al, Crit Care Med 2011; see infobox) • calcitonin-producing tumors (medullary thyroid cancer,
however the procalcitonin controlled antibiotic therapy carcinoid, small cell lung cancer
regimen showed one the one hand no advantage with • note: PCT is typically not elevated in sepsis due to
regard to mortality but on the other hand only disan- -- endocarditis
vantages. -- pseudomonas
• In a multicenter, prospective-randomized Dutch study
(de Jong et al, Lancet Infect Dis 2016), procalcitonin PCT > 0,5 ng/ml
controlled antibiotic therapy resulted in lower antibiotic + 2 SIRS criteria
consumption and even a significant reduction in mor-
tality.
start antibiosis
• SIS-PCT study (Bloos et al, JAMA Intern Med 2016; daily PCT
see page 859): no benefit

increase PCT from d2 to d3

PASS study
YES NO
inadequate antibiosis adequate antibiosis
change + daily PCT every 2d PCT

Procalcitonin-guided interventions against infections to in- PCT < 0,25 ng/ml:

terminate antibiosis
crease early appropriate antibiotics and improve survival in
the intensive care unit: A randomized trial Fig. 1095  PCT algorithm for the management of antibiotic
Jensen et al, Crit Care Med 2011 therapy (according to Wilke et al, Eur J Med Res 2011)

• PASS: The Procalcitonin and Survival Study

• 1200 critically ill patients (9 intensive care units in Den-
mark),
Therapy
• daily PCT assay
• results
-- no difference in mortality
-- increased duration of mechanical ventilation
-- increased length of ICU stay
-- deterioration of renal function
-- increased consumption of antibiotic drugs
-- increased costs

Infectiology 835
Guidelines
• international: Surviving Sepsis Campaign (SSC)
• national (Germany):
-- S2k guideline 2010 (1st revision; „Prevention, Dia-
gnosis, Therapy and Follow-Up Care of Sepsis") of
the German Sepsis Society (DSG) and the the Ger-
man Interdisciplinary Association of Intensive Care
and Emergency Medicine (DIVI)
-- S3 guideline 2018 (Sepsis - Prevention, Diagnosis,
Therapy and Follow-Up Care; as of 31/12/2018. but
only published on 18/02/2020) of the German Sepsis
Society (DSG)
SSC guidelines
• SSC guidelines 2002 (Dellinger et al, Intensive Care
Med 2004)
• SSC guidelines 2008 (Dellinger et al, Intensive Care
Med 2008; i.a. introduction of a new assessment sys-
tem: GRADE system: grades of recommendation, as-
sessment, development and evaluation [see infobox])
• SSC guidelines 2012 (Dellinger et al, Intensive Care
Med 2013)
• SSC guidelines 2016 (Rhodes et al, Intensive bzw. Crit
Care Med 2017; i.a. PICO as a new methodological
approach [P: Population, I: Intervention, C: Compera-
tor, O: Outcome])
-- level of recommendation:
◦◦ recommendation (strong)
◦◦ suggestion (weak)
◦◦ BPS (best practice statements; absolutely proven
and clear, but evidence grading is difficult and
therefore not done; a non-graduate strong recom-
mendation)
-- level of evidence:
◦◦ strong
◦◦ moderate
◦◦ weak
al fluid administration or initial lactate > 4mmol/l:
measurement of central venous pressure (CVP)
and central venous oxygen saturation (ScvO2)
◦◦ repeated measurement of lactate
In the meantime, only the 1-hour bundle is recommen-
ded after an update of Surviving Sepsis Campaign 2018:
• measurement of lactate (repeated measurement if in-
creased [> 2 mmol/l])
• drawing of blood cultures (before application of an an-
tibiotic)
• application of a broad spectrum antibiotic
• administration of crystalloids 30 ml/kg for hypotension
or lactate > 4 mmol/l (or > 36 mg/dl)
• vasopressor if hypotensive during or after fluid admi-
nistration with targeted MAP > 65mmHg (note: After
the 2018 update, a vasopressor [noradrenaline] should
be applied early!)
In New York, the sepsis bundles already have the cha-
racter of a law as "Rory's Regulations": Rory Staunton
was a 12-year-old boy who presented himself with a
fever in a New York emergency department in 2012 af-
ter an arm graze after an injury in basketball and was
discharged from the emergency department und sent
home again. The sepsis was overlooked and not recog-
nized. He died three days later (in an intensive care unit)
of septic shock.

Sepsis bundles
• In former SSC-guidelines there has been a differenti-
ation between resuscitation (< 6 hours) and manage-
ment bundle (6-24 hours). The latter have now been
abandoned.
• The resuscitation bundles then were split into:
-- 3-hour bundle (especially for the emergency depart-
ment): S2k guideline 2010
◦◦ measurement of lactate (repeated measurement if according to Oxford Centre for Evidence-based Medicine
increased [> 2 mmol/l]) • level of evidence (see infobox)
◦◦ drawing of blood cultures (before application of an • level of recommendation (see infobox)
antibiotic)
◦◦ application of a broad spectrum antibiotic
◦◦ administration of crystalloids 30 ml/kg for hypoten-
sion or lactate > 4 mmol/l (or > 36 mg/dl)
-- 6-hour bundle (especially for the intensive care unit):
◦◦ administration of vasopressors with a targeted
MAP of > 65mmHg if initial fluid administration was
not sufficient
◦◦ in case of persistent hypotension in spite of initi-

836 Infectiology
 Keystones (columns)

• causal (infectious source control, antibiotic therapy)

• supportiv (i.a. circulatory therapy, renal replacement
therapy, ventilation)
• adjunctive

Causal therapy
• infectious source control; within 6-12 hours; per hour
delay in finfectious source control, mortality increases
by 1% [MEDUSA study: Bloos et al, Intensiv Care Med
2017]!)
• antibiotic therapy (within 1 hour)

Since sepsis is a syndrome and not a

disease, the therapy of the underlying
disease is in the foreground!

Infectious source control

• incision or CT / sonography targeted drainage of ab-
scess or pleural empyema („Ubi est pus ibi evacua!“),
decortication if necessary (thoracoscopy, thoracotomy)
• lancing of wounds, debridement, necrosectomy, am-
putation, fasciotomy
• treatment of peritonitis (i.a. median laparotomy, intra-
S3 guideline 2018 abdominal lavage with up to 30 litres of warm infusion
according to Oxford Centre for Evidence-based Medicine solution; relaparotomy only on demand [no longer pro-
• levels of evidence grammed second-look relaparotomy]), anastomosis
-- high insufficiency, ileus
-- moderate • removal of infected implants (e.g. central venous ca-
-- low theters, vascular prosthesis, osteosynthetic material,
• levels of recommendation artificial replacement joints
-- strong (recommendation)
-- weak (suggestion)

Fig. 1096  peritonitis (perforating appendicitis; courtesy Dr.

Hanzlick, former senior physician of surgery, Caritas Hos-
pital St. Joseph Regensburg [Germany])

Infectiology 837
 Basics

Fig. 1097  abdominal X-ray: numerous air-fluid levels (small

bowel obstruction)

Fig. 1098  abdominal sonography: small bowel obstruction

(keyboard sign, free fluid)

Antibiotic therapy

838 Infectiology
concentration

Antibiotics
classes
MIC

time
concentration

MIC

time
Fig. 1099  The pharmacodynamics of time-dependent anti-
biotics are shown here. The time in which the concentra-
tion is above the MIC (minimum inhibitory concentration)
is decisive for their effectiveness. This time (shown in blue
in the graphic) is significantly shorter with only three bolus
doses (top) than with prolonged infusions (bottom) or con-
tinuous administration.

Infectiology 839
 Penicillins Cephalosporins
parenteral

Carbapenems
β-lactamase inhibitors

Fluorchinolones

840 Infectiology

Macrolides
Aminoglycosides
Principles
• early („hit early“; „golden hour“)
-- immediately after drawing of blood cultures!
-- ideally in the emergency department!
-- SSC guidelines: application of a broad spectrum an-
tibiotic within 1 hour
◦◦ 2012: in septic shock
◦◦ 2016: even in sepsis (and not just in septic shock
[due to the changed sepsis definition]); note: Here,
even if rapid i.v. access is not possible, i.m. admi-
nistration of the antibiotic is recommended, what is
possible e.g. with β-lactam antibiotics such as pi-
peracillin / tazobactam or meropenem or also with
3rd and 4th generation cephalosporins.)
• high dose („hit hard“; cave: frequent underdosing of
antibiotic drugs in renal insufficiency! In the first three
days full dosing should be given regardless of renal
function!)
• adequate: Initially inadequate antibiosis leads to
a doubling of mortality (in the case of septic shock, it
even increases fivefold [Kumar et al, Chest 2009])!
• broad (no place for “hobby microbilogists”!)
• reevaluation on day 3 (antibiogram, clinical improve-
ment) and de-escalation
• duration: 7 days (not longer!)
-- ProRespII study AJRCCM 2006: antibiotic therapy
for 13 days versus 6 days → no difference
-- CRP of 0 mg/dl is not the goal of the therapy!!
-- exceptions:
◦◦ infective endocarditis: 4-6 weeks
◦◦ pseudomonas aeruginosa (Chastre et al, JAMA
2003: increased relapse rate in the short-time the-
rapy cohort): 14 days
◦◦ S. aureus (both MSSA and MRSA): 14 days
◦◦ legionellosis: 14 days
◦◦ CDAD (clostridium difficile associated diarrhoea),
pseudomembranous colitis): 10 days
-- possibly procalcitonin control (i.a. SIS-PCT study
2016 [see page 859]: no advantage)
• β-lactam antibiotics (i.a. carbapenems) should al-
ways be administered as prolonged infusion (e.g. pi-
peracillin / tazobactam 4.5g 1-1-1 over 4 hours each,
e.g. meropenem 1g 1-1-1 over 4 hours each; also
possible regarding stability [note: imipenem, however,
only over 2 hours, since it quickly disintegrates]). The-
se antibiotics are the more effective the longer their
drug level is above their minimum inhibitory concen-
tration. However, this is an off-label- use (exception:
ampicillin, ceftazidime). In a non-selected patient co-
hort suffering from severe sepsis prolonged infusion
compared to bolus application was not able to reduce
mortality (BLING-II study [Dulhunty et al, Am J Resp
Crit Care Med 2015]). A Meta- analysis (Shiu et al,
Cochrane Database Sys Rev 2013) didn’t show a be-
nefit in terms of mortality and relapse either. In another
meta-analysis (Roberts et al, Am J Resp Crit Care Med
2016), however, a significantly lower hospital morta-
lity in patients with severe sepsis could be shown by
the prolonged administration of β-lactam antibiotics. In
the BLISS study (Abdul-Aziz et al, Intensive Care Med
2016), the continuous administration of β-lactam anti-
biotics in patients with severe sepsis showed a higher
clinical cure rate and more ventilation-free days with
no effect on mortality. A meta-analysis (Vardakas et
al, Lancet Infect Dis 2018) showed that patients with
sepsis had a mortality advantage from prolonged ad-
ministration Initially, however, a bolus should always
be administered in order to quickly achieve a therapeu-
tically effective level.
• Antibiotics are frequently underdosed in impaired renal
function due to false regard to the kidney: The fear is
that dialysis dependent kidney failure could be trigge-
red ("nephrex-forte" therapy). In internistic intensive
care patients with sepsis antibiotics are often the only
effective weapon: This has to stay sharp and must not
be blunted by underdosing in consideration of the kid-
ney. Underdosing is much more dangerous than over-
dosing!
• In 50% antibiotics are being underdosed in patients
with sepsis (Taccone et al, Crit Care 2010). In sepsis
the increased vasopermeability (capillary leakage)
leads to a distinct increase in the volume of distributi-
on. This can be aggravated by too aggressive volume
therapy (overwatering). The result is a suboptimal con-
centration of antibiotics. Furthermore, in the beginning
of sepsis renal clearance is often augmented due to
hyperdynamic circulation (augmented renal clearance;
renal hyperfiltration; especially in younger [< 50 years]
obese men).
Infectiology 841
 The first shot has to be a winner! A
miss is lethal!
MEDUSA study

common error concerning antibiotic

therapy in sepsis: Underdosing due
to false regard to the kidney ("life
before kidney!")! full-dose application
in the first three days (regardless of
the renal function)!
study
"Kumar" study
Duration of hypotension before initiation of effective anti-
microbial therapy is the critical determinant of survival in
human septic shock
Kumar et al, Crit Care Med 2006
Effect of a multifaceted educational intervention for anti-
infectious measures on sepsis mortality
Bloos et al, Intensive Care Med 2017
• prospective multicenter (43 centers in Germany) cluster
randomized study ("before and after"-intervention study)
• 4183 patients with severe sepsis or septic shock
-- with multimodal intervention (i.a. quality improvement
teams, training, audits, benchmarking of quality indi-
cators)
-- without multimodal intervention
• results: with multimodal intervention
-- significant reduction in mortality
-- per hour time delay
◦◦ to initiation of of antibiotic therapy: increase of mor-
tality by 2%
◦◦ to surgical infectious cource control: increase of
mortality by 1%

• retrospective cohort study

• 2731 patients with septic shock
• Each hour of delay in initiation of the antibiotic thera-
py is associated with an increased mortality of 7%!
Hourly fatal!
Antibiotic administration (whene-
ver possible) already in the
emergency department!
antibiotic therapy: Start broadly, but
then de-escalate after receiving the
microbiological results including
antibiogram!
no "never change a winning team" →
"change the doctor!"

generous de-escalation with clinical

improvement (is done far too rarely)!

study

Empiric antibiotic treatment reduces mortality in severe

sepsis and septic shock from the first hour: results from a
guideline-based performance improvement program
Ferrer et al, Crit Care Med 2014

• retrospective analysis (Surviving Sepsis Campaign Da-

tabase)
• 17990 patients with severe sepsis or septic shock
• results:
-- The longer the time delay to the first antibiotic admi-
nistration, the higher the mortality.
-- Each hour of delay in initiation of antibiotic therapy is
associated with an increase in mortality by 1-2% (not
as high as 7% like in the Kumar study).

842 Infectiology

Agents
• piperacillin (Pipril) 4g (not 2g!) + β-lactamase inhibitor
1-1-1
-- types:
◦◦ tazobactam 0.5g (piperacillin + tazobactam = Ta-
zobact; fixed combination)
◦◦ sulbactam (1g; Combactam; free combination):
cheaper, but less effective than the fixed combi-
nation (especially less effective against E. coli)
and more renal side effects (especially interstitial
nephritis; therefore not recommended in case of
renal insufficiency)
-- the most commonly used antibiotic in the treat-
ment of sepsis worldwide
-- dose reduction only from creatinine clearance < 20
ml/min (to 2 instead of 3 x daily; however, full dose in
the first 3 days regardless of renal function or renal
replacement therapy!); in case of renal replacement
therapy:
◦◦ piperacillin + tazobactam:
▪▪ HD: 4g/0.5g 1-0-1 (including a supplement dose
of 2g/0.25g after each dialysis)
▪▪ CVVH: normal dosage
◦◦ piperacillin + sulbactam:
▪▪ HD: 4g/0.5g 1-0-1 (including a supplement dose
of 2g/0.25g after each dialysis)
▪▪ CVVH: 4g/1g 1-0-1
-- dose increase from creatinine clearance > 130 ml/
min (augmented renal clearance; renal hyperfiltrati-
on): 4-5x daily
• cephalosporins
-- ceftazidime (Fortum; no therapeutic effect in gram-
positive spectrum [especially not against staphylo-
cocci and pneumococci], therefore never as a mono-
therapy; e.g. combination with a macrolid) 2g 1-1-1
-- cefepime (Maxipime) 2g 1-0-1 (cave severe neuro-
logical side effects [esp. encephalopathy] if GFR <
50 ml/min)
• carbapenems
◦◦ ertapenem (Invanz) 1g 0-1-0 (not effective against
pseudomonas!)
◦◦ meropenem (Meronem; no dose reduction in case
of renal insufficiency as well as renal replacement
therapy in the first 3 days), on day 1 even 3 x 2g
(regardless of renal function or renal replacement
therapy) , then day 2+3 3 x 1g
◦◦ Zienam (imipenem + cilastatin [Cilastin inhibits the
renal inactivation of imipenem; side effect: i.a. lo-
wering the seizure threshold]) 0.5g 1-1-1
◦◦ doripenem (Doribax) 0.5g 1-1-1-1 (approved since
2008; excellent efficacy against pseudomonas;
prolonged infusion; in the meantime withdrawn
from market)
Combination therapy
• no combination with aminoglycosides
-- no survival benefit
-- increased rate of renal failure
-- exception: sepsis due to endocarditis
• possibly combination therapy in the first three days
(especially with a complicated course, i.e. in septic
shock), e.g.
-- piperacillin / tazobactam + moxifloxacin
-- meropenem + moxifloxacin
-- SSC guidelines: New in the SSC guidelines 2016 is
the recommendation to always perform combination
therapy in septic shock (in the initial phase). In con-
trast, combination therapy in sepsis with an uncom-
plicated course (i.e. without septic shock) is explicitly
not recommended.
• Combination therapy in sepsis only makes sense in
the case of:
-- community-acquired pneumonia
-- endocarditis
-- CNS infections
-- pseudomonas
-- high risk for multi-resistant pathogens
-- toxic shock syndrom (TSS)
• Neutropenia: The S3 guideline Sepsis 2018 explicitly
does not recommend combination therapy for neutro-
penia and sepsis!
• studies:
-- Canadian Critical Care Trial Group (Heyland et al, N
Engl J 2006): No benefit for the combination therapy
Infectiology 843
 meropenem + ciprofloxacin in VAP (ventilator-asso-
ciated pneumonia)
-- meta-analysis Kumar et al, Crit Care Med 2010: si-
gnificant survival benefit for combination therapy in
patients with septic shock
-- CATSS study (a propensity-matched analysis; Ku-
mar et al, Cit Care Med 2010): significant survival
benefit for combination therapy in patients with sep-
tic shock
-- MAXSEP study (Brunkhorst et al, JAMA 2012 [see
box]): no benefit for the combination therapy mero-
penem + moxifloxacin in patients with severe sepsis
/ septic shock

MAXSEP study

Effect of Empirical Treatment With Moxifloxacin and Mero-

penem vs Meropenem on Sepsis-Related Organ Dysfunc-
tion in Patients With Severe Sepsis: A Randomized Con-
trolled Trial
Brunkhorst et al, JAMA 2012

• multicenter randomized study

• 44 German intensive care units
• 551 patients with severe sepsis / septic shock
-- 273 patients: meropenem
-- 278 patients: meropenem + moxifloxacin
• results:
-- primary endpoint: morbidity (SOFA- score) → no dif-
ference
-- secondary endpoints
◦◦ mortality (28 days, 90 days) → no difference
◦◦ length of ICU and hospital stay: no difference
◦◦ ventilator-free days: no difference
◦◦ vasopressor-free days: no difference

septic shock: always initial

combination therapy (SSC
guideline 2016)

844 Infectiology
 • volumen therapy
-- cristalloids
-- colloids
• catecholamine therapy
-- vasopressors (especially noradrenaline)
-- inotropics (especially dobutamine)
• if necessary extracorporeal circulatory support (va-
ECMO)

Target blood pressure

• SEPSISPAM study (Asfar et al, N Engl J 2014): Here,
with a target MAP of 80-85 mmHg (high MAP group)
compared to a target MAP of 65-70 mmHg (low MAP
group), there were no advantages in terms of mortality,
but more frequent atrial fibrillation. However, if there
was a pre-existing chronic arterial hypertension, kid-
ney replacement procedures had to be used less fre-
quently in the high MAP group. The ESC Tasc Force
(Cecconi et al, Intensive Care Med 2014) therefore
recommends a target MAP of 80-85 mmHg in septic
patients with pre-existing chronic arterial hypertension
(however only Level 2).
• OVATION study (Lamontagne et al, Intensive Care
Med 2016; Optimal Vasopressor Titration): There was
no advantage of the high-MAP group (target MAP 75-
80 mmHg) compared to the low-MAP group (target
MAP 60-65 mmHg). In patients > 75 years mortality
was even increased in the high MAP group!

Circulatory therapy target MAP (mean arterial pressu-

re): > 65 mmHg (SSC 2016)

Volume therapy
• initially mostly high fluid demand
-- in some circumstances 6-10 litres on the first 24
hours (aggressive fluid therapy!)
-- initial 1000ml of crystalloids within 30 minutes in the
emergency department flowed by 500ml every 30
minutes
-- SSC guidelines
◦◦ 2012: according to the dem 3-hour resuscitation
bundle of the SSC guideline 2012 30 ml/kg crystal-
loids in case of hypotension or lactate >4 mmol/l
◦◦ 2016: 30 ml/kg crystalloids within 3 hours

Infectiology 845
 -- frequent error: too little fluids (but too early and too three negative studies (30%) than in the Rivers study
high doses of catelochamines instead) (44%). "Early therapy” is still crucial! If the “goals” (e.g.
-- But excessive volume therapy (hypervolemia) can CVP) however are appropriate, remains to be seen. It
also have negative effects: e.g. pulmonary edema, is for example for sure not necessary to insert a CVC
hypertension, ileus, anastomotic leakage, bacteri- in the emergency room immediately in every patient
al translocation, wound healing disorders, edema) and to determine the central venous oxygen saturation
(i.a. Bagshaw et al, Crit Care Med 2008; Lee et al, J and the CVP. Orientation of hemodynamic therapy on
Intern Med 2014). This leads to damage of the en- the CVP anyway is more than controversial and is no
dothelial glycocalyx and to an increase in vasoper- longer recommended in the SSC guidelines 2016. It
meability (capillary leakage). A mean positive fluid is not uncommon that the physician primarily inserts
balance of 4-5 litres per day should not be exceeded the cables into the patient (central venous catheter and
(this cannot be generalised and has to be proved in- arterial line) as a skipping action because he doesn’t
dividually, e.g. high fluid requirement in patients with have any idea at all of what the patients problem is
peritonitis). actually. Installation of a central venous catheter is not
• In the initial phase (especially with septic shock) there a causal therapy and therefore does not save patient´s
is usually a high volume requirement. After stabilizati- life! Furthermore red cell concentrate are not manda-
on (mostly after 48 hours) however, the volume then tory to be generously given (in 64% in the EGDT arm
should only be applied restrictively to avoid hypervole- in the Rivers study!).
mia (i.a. advantages in the CLASSIC study [Hjortrup et
al, ICM 2016; i.a. less frequent acute kidney injury, but
no difference in mortality). study
• Oedemata are very frequent in patients with sep- "Rivers" study
sis and mostly no signs for hyperhydration. They are
caused by:
-- „capillary leak“
Early Goal-Directed Therapy in the Treatment of Severe
-- ventilation: decreased venous return to the right Sepsis and Septic Shock
heart → decreased filling of the left atrium → incre- Rivers et al, N Engl J 2001
ased ADH release (diuresis ↓, oedemata!)
• The preload can be increased by adding volume. In • monocentric study
this way (in hypovolemic patients) myocardial pre- • 263 patients with severe sepsis / septic shock in the
stretching (Frank Starling mechanism) increases the emergency department
stroke volume and thus the cardiac output (fluid res- • 6 hour early goal directed therapy versus standard of
ponsiveness). care prior to transferral to ICU
• targets („goals“):
-- CVP: 8-12 mmHg
septic shock: initially high fluid -- MAP > 65 mmHg
requirement, but after stabilizati- -- ScvO2 > 70% (i.a. „Rivers RCC indication“ in the first
on (48h) rather restrictive fluid 6 hours, if ScvO2 < 70% + haematocrit < 30% despite
administration (cave hypervole- sufficient fluid administration and support with dobut-
mia!) amine)
• significantly lower hospital mortality (30.5% versus
46.5%; reduction in mortality by 16%!)
Early goal directed therapy (EGDT)
• according to Rivers et al, N Engl J 2001 (see box): start
early, i.e. already in the emergency department!
• targets („goals“):
-- CVP: 8-12 mmHg (according to; no more orientation
to CVP recommended nowadays)
-- MAP > 65 mmHg
-- ScvO2 (central venous oxygen saturation) > 70%
• negative studies for EGDT (see infobox):
-- ProCESS (USA)
-- ARISE (Australia, New Zealand)
-- ProMISe (UK)
• All of the three published trials concerning EGDT
were negative, i.e. the advantages of EGDT could not
have been confirmed. Nevertheless, the concept of
early therapy should certainly not be overruled. The
studies were (probably) negative because everybody
has learnt from the Rivers study that early action is
pivotal. Mortality was already significantly lower in all

846 Infectiology
 ProCESS study
A randomized trial of protocol-based care for early septic
shock
The ProCESS-Investigators, N Engl J 2014
• ProCESS: protocolized care for early septic shock
• multicenter study (31 emergency departments in the
USA)
• 1341 patients with septic shock; randomly assigned to
3 groups:
-- protocol- based EGDT (early goal directed therapy;
as mentioned in the Rivers study [i.a. always place-
ment of a central venous catheter and additional mea-
surement of CVP and ScvO2 as well as generous ad-
ministration of red cells concetrates])
-- protocol- based standard therapy (i.a. central venous
catheter insertion only in case of inadequate periphe-
ral venous access)
-- usual treatment (at the physician's discretion; without
protocol)
• results:
-- primary endpoint (60-day mortality): no difference bet-
ween the 3 groups
-- secondary endpoints (i.a. 90-day mortality, 1-year
mortality, necessity of organ replacement therapy): no
difference between the 3 groups
ARISE study
Goal-directed resuscitation for patients with early septic
shock
The ARISE-Investigators, N Engl J 2014
• ARISE (australian resuscitation in sepsis evaluation)
• multicenter study (51 emergency departments in Austra-
lia and New Zealand)
• 1600 patients with septic shock:
-- EGDT (early goal directed therapy)
-- standard therapy
• results:
-- primary endpoint (90-day mortality): no difference
-- secondary endpoints (i.a. hospital mortality, length of
hospital stay, necessity of organ replacement thera-
py): no difference
Types (volume therapy)
• crystalloids
• colloids
ProMISe study
Trial of early goal-directed resuscitation for septic shock
Mouncey et al, N Engl J 2015
• ProMISe (protocolized Management of sepsis)
• multicenter study (51 emergency departments in the UK)
• 1260 patients with septic shock:
-- EGDT (early goal directed therapy)
-- standard therapy
• results:
-- primary endpoint (90-day mortality): no difference
-- secondary endpoints (i.a. hospital mortality, length of
hospital stay, necessity of organ replacement thera-
py): no difference
PRISM study
Early, Goal-Directed Therapy for Septic Shock - A Patient-
Level Meta-Analysis
The PRISM Investigators, N Engl J 2017
• PRISM: Protocolized Resuscitation in Sepsis Meta-
Analysis
• meta-analysis (3 studies [ProCESS, ARISE, ProMISe]):
3723 patients with septic shock
-- EGDT (early goal directed therapy)
-- standard therapy
• results (EGDT):
-- no difference in mortality (after 90d)
-- higher costs
Quick and early therapy in
patients with sepsis is crucial
(“door-to-action-time”, “The early
bird catches the worm!”).
severe sepsis → possibly measure-
ment of the central venous oxygen
saturation (ScvO2)! a good surrogate
parameter for cardiac output (but never
consider it isolated)
Infectiology 847
It has been discussed for a long period of time whether
crystalloids or colloids should be used as fluid therapy
in patients with sepsis. In the VISEP study (see infobox)
an increased rate of renal failure was shown when using
HES (however HES 10% instead of HES 6% just like it’s
currently customary). As a result of this study which is
called for some comments (see infobox) a highly emotio-
nal discussion about the significance of hydroxyl ethylic
starch in sepsis arose. According to the published 6S
study (the most important study on this subject; see in-
fobox) the use of HES 6% resulted in an increased mor-
tality so that the administration of hydroxyl ethylic starch
in sepsis should no longer be performed. Hence in the
SSC guidelines 2012 and 2016 synthetic colloids such
as hydroxyl ethylic starch are no longer recommended
as volume therapy.
VISEP study (SepNet)
Intensive Insulin Therapy and Pentastarch Resuscitation
in Severe Sepsis
Brunkhorst et al, N Engl J 2008
• German multicenter study (17 intensive care units)
• funded by the Federal Ministry of Education and Re-
search (BMBF)
• 537 patients with severe sepsis / septic shock
• 2 arms:
-- volume therapy
◦◦ crystalloids (Ringer's lactate [Sterofundin]; 275 pa-
tients)
◦◦ colloids (HES 10% 200/0.5; 262 patients)
-- insulin therapy
◦◦ intensive (target blood glucose: 80-110 mg/dl)
◦◦ conventional (target blood glucose: 180-200 mg/dl)
• endpoints
-- primary
◦◦ mortality (after 28 and 90 days)
◦◦ morbidity (decrease in SOFA score)
-- sekundary (i.a. rate in acute kidney failure)
VISEP study
results 1st arm
(volume therapy)
• results: HES 10% 200/0.5
-- was not superior to crystalloids
-- but led to a significantly higher rate of acute kidney in-
jury (12%) and necessity of renal replacement therapy
(doubled rate of acute kidney injury requiring RRT)
-- conclusion: no more HES in sepsis?
848 Infectiology
VISEP study
annotations
• HES 10% 200/0.5 (then standard; nowadays HES 6%
almost exclusively used)
• contraindication: creatinine > 2.0 mg/dl (> 3.6mg/dl in
the VISEP study, 25% had a creatinine > 2.0 mg/dl)
• highest recommended dose for HES: 20 ml/kg/day (ex-
ceeded in 38% of patients
• Patients werde included within the first 24 hours of sep-
sis. In 60% of patients colloids have been administered
prior to inclusion. in the control group the central venous
oxygen saturation was 75% compared to 74% in the in-
tervention group meaning that sufficient volume therapy
was administered even prior to inclusion.
meta-analysis
Hydroxyethyl starch (HES) versus other fluid therapies: ef-
fects on kidney function
Dart et al, Cochrane Collaboration 2010
• meta-analysis of 34 studies (2607 patients)
• volume therapy
-- hydroxyethyl starch
-- crystalloids
• hydroxyethyl starch → significantly more RRT (renal
replacement therapy; especially in patients with sepsis)
6S study
Hydroxyethyl Starch 130/0.4 versus Ringer’s Acetate in
Severe Sepsis
Perner et al, N Engl J 2012
• 6S: scandinavian starch for severe sepsis / septic shock
• multicenter randomized controlled trial
• 798 patients with severe sepsis
-- HES 6% 130/0.4
-- Ringer’s acetate
• results: HES 6% 130/0.4
-- combined primary endpoint (mortality and dialysis-
dependent renal insufficiency after 90 days): signifi-
cantly increased
-- mortality after 90 days: significantly increased
-- dialysis-dependent renal insufficiency: not significant-
ly increased
-- cumulative volume: no difference
Kolloids
• synthetic colloids: HES 10% not recommended (VI-
SEP study, S2k guideline 2010); SSC guideline 2012
+ 2016 and S3 guideline Sepsis 2018: HES regard-
less of whether 6% or 10%) no longer recommended
in sepsis
• natural colloids
-- human albumin (see chapter "circulatory therapie"
[page 249])
◦◦ not superior to crystalloids but more expensive
◦◦ SSC guideline 2012 + 2016: possibly in addition to
crystalloids (if a large amount of volume of crystal-
loids has already been administered)
◦◦ S3 guideline 2018: weak recommendation for pa-
tients with septic shock who cannot be adequately
stabilized with crystalloids. Human albumin (alter-
natively gelatin) can additionally be administered
here.
-- red cell concetrates (see chapter blood products
[page 1173]; also with sepsis only from an hemo-
globin value < 7 g/dl [TRISS study; see page 1176])
Catecholamine therapy
commonest error regarding circulato-
ry therapy in sepsis: not enough
volume, initiation of catecholamines
too early! Catecholamines only after
exclusion of hypovolaemia! Ca-
techolamines are obscuring a
volume depletion!
study
Effect of Heart Rate Control With Esmolol on Hemodyna-
mic and Clinical Outcomes in Patients With Septic Shock
Morelli et al, JAMA 2013
• randomized monocenter open phase-II study (University
Hospital Rome)
• 154 patients with septic shock (i.a. high-dose noradre-
naline perfusor) and heart rate > 95/min
-- esmolol
-- placebo
• results: Esmolol
-- primary endpoint (reduction in heart rate): reached
-- secondary endpoints:
◦◦ MAP: no difference
◦◦ significantly lower 28-day mortality
◦◦ significantly shorter ICU stay (by 5 days)
• note: no general recommendation (phase-II study only)

• Premise is an adequate volume therapy (normo-
volaemia)!
• types:
-- vasopressor of choice: noradrenaline, possibly va-
sopressin
-- inotropics of choice: dobutamine (note: However,
there is still no randomized controlled trial that would
have proven a benefit here.), possibly levosimendan
(LeoPARDS study [see box]: no benefit; S3 guideli-
ne sepsis 2018: not recommenden)
• no more striving for supranormal values(Shoemaker
1988; abandoned)
• generously advanced hemodynamic monitoring (e.g.
PiCCO) in septic shock (especially if there is no im-
provement after initial volume administration and an-
tibiosis)
DO NOT BLOCK!
β-blocker & catecholamines: no
general recommendation (either
"accelerate" or "brake" [but not both
at the same time])
in case of tachyarrhythmia absoluta:
digitalis; in case of sinus tachycardia:
do not treat (demand tachycardia)
CATS study
Norepinephrine plus dobutamine versus epinephrine alone
for management of septic shock: a randomized trial
Annane et al, Lancet 2007
• prospective randomized multicenter study
• 330 patients with septic shock
-- noradrenaline + dobutamine
-- adrenaline
• no difference in mortality (both regimens were equally
poor!)

Infectiology 849

LeoPARDS study
Levosimendan for Prevention of Acute Organ Dysfunction
in Sepsis
Gordon et al, N Engl J 2016
• multicenter randomized controlled study
• 516 patients with septic shock who had been treated
with vasopressors for > 4h:
-- levosimendan
-- placebo
• results: levosimendan
-- primary endpoint (SOFA score): no difference
-- sekundary endpoints: i.a.
◦◦ mortality: no difference
◦◦ less fequent successful weaning (longer duration of
ventilation)
◦◦ more frequent arrhythmia (supraventricular tachy-
cardia)
• note: The majority of patients had no septic cardiomyo-
pathy, and exactly for those levosimendan would have
made sense to increase inotropy. Therefore in my opi-
nion levosimendan is still an alternative to dobutamine
in patients with septic shock and septic cardiomyopathy.
0.3 μg/kg/min [corresponds to 1.3 mg/h with a body
weight of 72kg], early [within 6 hours after initiation
of noradrenaline])
-- national:
◦◦ S2k guideline 2010: not recommended
◦◦ S3 guideline 2018: weak recommendation in the-
rapy-refractory cases in addition to noradrenaline
• We administer argipressin (empressin) in the rare ca-
ses of a severe therapy-refractory vasodilatory (mostly
septic) shock, in which despite high-dose (p.d.> 1.3
mg/h) noradrenaline and hydrocortisone, there is still
a massively reduced systemic vascular resistance
(SVR).
• other vasopressin analogues
-- terlipressin (glycylpressin): not recommended be-
cause it mainly causes selective vasoconstriction
only in the splanchnic area and not systemically (fur-
thermore no benefit proven [Liu et al, Intensive Care
Med 2018; see box])
-- selepressin (a selective vasopressin V1a-receptor
agonist): no effect in septic shock (SEPSIS-ACT stu-
dy [Laterre et al, JAMA 2019])

Vasopressin (Pitressin)
• a hormone (syn.: ADH [antidiuretic hormone])
• as an alternative vasopressor to noradrenaline (e.g. in Fig. 1100  empressin (1 amp. = 2ml = 40 IE)
case of massively reduced SVR and severe acidosis
where noradrenaline is less effective)
• maybe as rescue medication (ultima ratio)
• reduced vasopressin levels in sepsis VASST study
• vasopressin analogue: argipressin (Empressin)
-- approved since 2015 in Germany for the therapy of
catecholamine refractory septic shock
-- dosage: Vasopressin versus Norepinephrine Infusion in Patients
◦◦ 1 Amp. = 2ml = 40 IE with Septic Shock
Russell et al, N Engl J 2008
◦◦ perfusor: 1 ampoule a 2ml + 48ml NaCl 0.9% →
0.8 IE/ml • multicenter randomized controlled study
◦◦ initially 0.6 IE/h (0.75 ml/h), then every 15min in- • 778 patients with septic shock; vasopressor:
crease if necessary to 1.2 IE/h (1.50 ml/h) up to a -- noradrenaline
maximum of 1.8 IE/h (2.25 ml/h) -- vasopressin
-- pulmonary artery pressure (PAP) ↓, pulmonary vas- • result: vasopressin → no difference in mortality (neit-
cular resistance (PVR) ↓ her after 28 nor after 90 days); note: In a posthoc ana-
• studies: lysis of the subgroup of patients with only mild septic
shock (i.e. noradrenaline 5-15 µg/kg/min), however, va-
-- VASST (see box)
sopressin showed a reduction in mortality.
-- VANISH (see box)
-- VANCS (in postoperative cardioplegic syndrome in
cardiac thoracic surgery [see page 406])
-- meta-analysis (Polito et al, Intensiv Care Med 2012):
no reduction in mortality
• recommendations:
-- international (SSC guideline2016): recommended
(but only weakly) in therapy-refractory cases in ad-
dition to noradrenaline (note: from noradrenaline >

850 Infectiology

VANISH study
Effect of Early Vasopressin vs Norepinephrine on Kidney
Failure in Patients With Septic Shock
Gordon et al, JAMA 2016
• multicenter randomized controlled study
• 409 patients with septic shock; vasopressor:
-- noradrenaline
-- vasopressin
• results:
-- primary endpoint (number of kidney failure–free
days): no difference
-- secondary endpoints: i.a.
◦◦ mortality: no difference
◦◦ rate of RRT (renal replacement therapy): signifi-
cantly lower in the vasopressin group
study
Terlipressin versus norepinephrine as infusion in patients
with septic shock
Liu et al, Intensive Care Med 2018
• multicenter randomized controlled study
• 526 patients with septic shock; vasopressor:
-- noradrenaline
-- terlipressin (a vasopressin analogue)
• result: terlipressin → no difference in mortality (after
28 days) with increased side effects (especially digital
ischemia, diarrhea); study was stopped prematurely
va-ECMO (septic shock)
• no randomized controlled studies (only retrospective
analyses)
• only useful for a special phenotype of septic shock, in
fact only with severe septic cardiomyopathy, especially
with:
-- low cardiac index (CI < 2.0 l/min/m2)
-- low ejection fraction (EF < 25%)
-- high systemic vascular resistance (SVR > 2400 dyn
x sec x cm-5 x m-2)
• This special phenotype of septic shock is ultimately a
cardiogenic shock due to septic cardiomyopathy.
• not useful with hyperdynamic circulation (i.e. high car-
diac index and low systemic vascular resistance), be-
cause the necessary blood flows would be much too
high here
• survival rate (hospital) in patients with refractory septic
shock and left ventricular dysfunction under va-ECMO:
90% (Falk et al, Crit Care Med 2019 [however only a
retrospective monocentric observational study])
• if necessary combination with Impella (va-ECMO + Im-
pella = ECmella): The rationale is that the va-ECMO
increases the afterload even further. The afterload can
be reduced again by the Impella. The impella pumps
the blood out of the left ventricle and thus relieves it
(venting, LV-unloading)
Adjunctive therapy
• intensive insulin therapy (IIT)
• glucocorticoids (hydrocortisone)
• rhAPC (rekombinantes aktiviertes Protein C, Xigris)
• coagulation therapiy
• nutrition
• immunoglobulines
• statines:
-- They also have an anti-inflammatory effect (pleiotro-
pic effects).
-- A pre-existing therapy with statins should be conti-
nued and not interrupted in septic patients. Howe-
ver, starting a de novo statin therapy has no benefit
(ASEPSIS study: Patel et al, Crit Care 2012; Kruger
et al, Am J Resp Crit Care Med 2013; Wan et al,
Crit Care 2014). If a patient is mechanically ventila-
ted statin therapy should be discontinued due to an
increased risk for the development of critical illness
polyneuropathy.
• metabolic resuscitation
Fig. 1101  summary of adjunctive sepsis therapy “waiting for
a miracle” (unfortunately still!)
Infectiology 851
Intensive insulin therapy (IIT)
Definition
It is known for a long time that hyperglycaemia with blood
glucose levels > 180mg/dl is harmful in sepsis and incre-
ases mortality (i.a. Falciglia et al, Crit Care Med 2009).
This still applies today. Greet van den Berghe compared
two therapeutic regimens: conventional versus intensive
insulin therapy in which the blood glucose level was ad-
justed from 80-110mg/dl via a perfusor with insulin (sohrt
acting). The results of her first study in surgical critically
ill patients performed in 2001 (see info box) were surpri-
sing: Ultimately in almost every aspect an advantage in
favour of intensive insulin therapy could be shown. There
was a great sense of euphoria: Finally the “magic bullet”
in the treatment of sepsis appeared to have been found,
and also so simple! Hence intensive insulin therapy
(syn.: TGC [tight glycaemic control], i.e. strict control of
blood sugar using insulin) has been the standard of care
for a long time. Blood glucose levels were controlled
using a short-acting insulin via a pump (e.g.. Actrapid 50
IE/50ml). The median demand of insulin in the van-den-
Berghe study in 2001 was relatively high (59 IU per day;
50 IU of short-acting insulin/50ml; infusion rate 2-3ml/h).
In case of elevated blood sugar levels insulin infusion
rate was increased, calorie restriction should not be
performed. Glucose infusion should not be reduced ac-
cording to the previous recommendation. After the initial
enthusiasm the first disillusionment had to be accepted
5 years later when, again, Greet van den Berghe inves-
tigated the intensive insulin therapy in medical critically
ill patients in 2006: Here no survival benefit was shown.
Hypoglycaemia is the main risk.
Blood glucose measurements in the intensive care unit
may only be performed with the blood gas analysis de-
vice and not (as usually done on the general ward) by
using the strip test device due to imprecise results (Blood
glucose levels are usually overestimated in critically ill
patients.). Blood sugar in arterial blood is approximately
10 mg/dl (0.6 mmol/l) higher than in venous blood and 5
mg/dl (0.3 mmol/l) higher than in capillary blood.
Over time the amount of studies without a positive effect
was increasing.
852 Infectiology
van den Berghe study I
Intensive Insulin Therapy in Critically ill Patients
van den Berghe et al, N Engl J 2001
• monocenter (Leuven University Hospital / Belgium) ran-
domized controlled study
• 1548 patients with SIRS (predominantly postoperative
surgical [mostly cardiac surgery] patients); insulin the-
rapy:
-- intensive insulin therapy (target blood glucose: 80-110
mg/dl)
-- conventional insulin therapy (180-200 mg/dl)
• results: intensive insulin therapy
-- significantly less infections, acute kidney injury, shor-
ter duration of mechanical ventilation, less CIP, shor-
ter ICU length of stay
-- significantly reduced mortality in
◦◦ reduction in ICU mortality by 43%
◦◦ reduction in hospital mortality by 34%
◦◦ especially in patients with multi organ failure
van den Berghe study II
Intensive Insulin in Medical ICU
van den Berghe et al, N Engl J 2006
• monocenter (Leuven University Hospital / Belgium) ran-
domized controlled study
• 1200 medical critically ill patients; insulin therapy:
-- intensive insulin therapy (target blood glucose: 80-110
mg/dl)
-- conventional insulin therapy
• overall no significant reduction in mortality (neither
ICU nor after 90 days)
• subgroups: intensive insulin therapy
-- length of stay ≥ 3 days: decreased mortality (survival
benefit):
◦◦ decrease of ICU mortality from 38.1% to 31.3%
◦◦ decrease of hospital mortality from 52.5% auf 43%
◦◦ shorter duration of ventilation, less acute kidney
failure
-- length of stay < 3 days: increased ICU mortality
 Mayo Clin Proc 2010).
• possibly continuous blood glucose monitoring (sub-
cutaneous, intravenous, intraarterial; i.a. Holzinger et
meta-analysis al, Diabetes Care 2010, Brunner et al, Crit Care 2012:
reliably applicable in ICU patients, significantly less
frequent severe hypoglycaemia), e.g. EIRUS system
(Pulsion); already firmly established in the outpatient
Benefits and risk of tight glucose control in critically ill area (especially self-measurement of blood sugar in
adults type 1 diabetics with CGM devices (CGM: continuous
Wiener et al, JAMA 2008 glucose monitoring)
• In case of ascertained hypoglycaemia blood glu-
• meta-analysis of 29 randomized studies (8432 patients)
cose level should not be raised too rapidly (initially to
• insulin therapy
a maximum of 90mg/dl, 8g glucose usually sufficient
-- conventional
[cave reperfusion damage due to an increased activity
-- intensive → no reduction in mortality
of NADPH oxidase])
• Sometimes it happens that during the morning interdis-
ciplinary visit, which often takes place without a nurse,
it is decided that another measure (e.g. EGD, TEE)
meta-analysis should take place on the same day, for which the pati-
ent should be sober. The intensive care physician then
immediately stops the enteral nutrition without knowing
that the insulin perfusor is still running, so that severe
Intensive insulin therapy and mortality among critically ill hypoglycemia can result, which often manifests itself in
patients a ventilated patient as a seizure or cardiac arrest. If the
Griesdale et al, CMAJ 2009 enteral nutrition is stopped, the insulin perfusor should
also be stopped or at least reduced.
• meta-analysis of 26 randomized studies (13567 pati-
ents)
• insulin therapy
-- conventional VISEP study
-- intensive results 2nd arm
◦◦ no reduction in mortality (insulin therapy)
◦◦ significantly increased rate of hyperglycaemia
• premature cancellation of the intensive insulin therapy
arm after inclusion of 488 patients due to an unjustifiably
Hypoglycaemia high rate of hyperglycaemia (17.6%)
• the main problem of intensive insulin therapy • no difference in 28- and 90-day mortality
• per definition blood glucose level < 40 mg/dl (SI- units:
< 2.2 mmol/l)
The final stab in the back for the intensified insulin thera-
• increased risk in sepsis per se (due to diminished ac-
py was ultimately the NICE-SUGAR study (see box), the
tivity of the enzyme PEPCK [phopsphoenolpyruvate-
results of which were absolutely "bitter sweet: Intensive
carboxykinase])
insulin therapy here even led to an increased mortality!
• symptoms
Finally the magic of the intensive insulin therapy evapo-
-- hypoglycaemic coma rated. Intensive insulin therapy is also definitely no longer
-- often unnoticed due to analgosedation (almost no recommended in the current guidelines. However, a mo-
warning symptoms) derate insulin therapy (blood glucose controll; i.e. blood
-- seizures glucose < 150 mg/dl [SI-units: 8.3 mmol/l; S2k guideline]
• initially blood glucose monitoring every hour (not every sepscively < 180 mg/dl [SI-units: 10mmol/l; SSC 2012 +
4 hours) 2016] and S3 guideline 2018) should still be performed,
• training of medical staff (physicians, nurses) because hyperglycemia is harmful and leads to increa-
• frequency during intensive insulin therapy: sed mortality. Probably intensive insulin therapy will ex-
perience a renaissance provided that continuous blood
-- van den Berghe
glucose monitoring will be available.
◦◦ study 2001: blood glucose < 40 mg/dl in 5.1%
◦◦ study 2006: blood glucose < 40 mg/dl in 18.7% Intensive insulin therapy was also investigated in critically
-- VISEP: 17.6% ill children (CHiP study 2014 [see box]) without showing
any benefit, solely there was more hyperglycaemia.
• VISEP studie (Brunkhorst et al, N Engl J 2008): prema-
ture cancellation of the intensive insulin therapy arm
• Hypoglycaemia is associated with an increased mor-
tality (i.a. GluControl study [Preiser et al, Int Care Med
2009]; Hermanides et al, Crit Care Med 2010; Egi et al,

Infectiology 853

NICE-SUGAR study
Intensive versus Conventional Glucose Control in Critically
Ill Patients
The NICE-SUGAR Study Investigators
Finfer et al, N Engl J 2009
• NICE-SUGAR (normoglycemia in intensive care evalua-
tion survival using glucose algorithm regulation)
• multicenter prospective randomized study
• 6,104 ICU patients (one of the largest studies ever!); in-
sulin therapy:
-- conventional (target blood glucose < 180 mg/dl)
-- intensive (target blood glucose: 81-108 mg/dl)
• results ("bitter sweet"): intensive insulin therapy
-- in 6.8% severe hypoglycaemia (blood glucose < 40
mg/dl)
-- significantly increased mortality (90-day mortality
27.5% versus 24.9%)
-- applied to medical as well as to surgical ICU patients
CHiP study
A randomized Trial of Hyperglycemic Control in Pediatric
Intensive Care
Macrae et al, N Engl J 2014
• CHiP: Control of Hyperglycemia in Paediatric Intensive
Care
• multicenter randomized controlled study
• 1369 critically ill children (without diabetes mellitus; 60%
after cardiac surgery); insulin therapy:
-- intensive (target blood glucose: 72-126 mg/dl)
-- conventional
• results: intensive insulin therapy
-- results: primary endpoint (survived ventilator-free
days within the first 30 days): no difference
-- secondary endpoints: i.a. more hyperglycaemia
(blood gucose < 36 mg/dl)
Guidelines (SSC [since 2012], S2k 2010 + S3
2018)
• intensive insulin therapy (target blood glucose: 80-
110 mg/dl): not recommended (level of recommendati-
on A, level of evidence Ia)
• A moderate insulin therapy (target blood glucose < 150
mg/dl) can be considered, but a target blood glucose <
180 mg/dl should be achieved to in any case!
• increased blood glucose levels → initial reduction of
the amount of parenteral administration of glucose
(and increase of the amount of lipid consecutively) and
possibly reduction of steroid therapy, only then increa-
se of insulin therapy
854 Infectiology
intensive insulin therapy (IIT): no
longer recommended!
target blood glucose nowadays:
150-180 mg/dl (only glucose control)
maybe IIT in the future: continuous
blood glucose monitoring!
Hydrocortisone
Definition
• syn.: cortisol
• effect: increase in catecholamine sensibility of the vas-
cular smooth muscle cell → haemodynamic stabiliza-
tion, reduction of catecholamine requirement in septic
shock
• In sepsis a (relative) adrenocortical insufficiency (CIR-
CI: critical illness-related corticosteroid insufficiency
[according to Marik et al, Crit Care Med 2008]) is quite
common: On the one hand this is a result of reduced
perfusion during septic shock, on the other hand com-
plement factor C5 is being activated in the course of
sepsis leading to an inhibition of corticosteroid synthe-
sis in the adrenal cortex and furthermore to adrenocor-
tical insufficiency.
• Infection defense is preserved under low dose hydro-
cortisone (In fact this has even an anti-inflammatory
effect.).
• according to former guidelines (S2 guideline) recom-
mended in all patients with septic shock (former! no
longer valid!)
• application
-- boluswise 4 x 50 mg or
-- continuous (better because of less side effects) via
perfusor (100 mg a 20ml + 30 ml NaCl 0.9% → 2 mg/
ml, infusion rate: 10 mg/h → 5 ml/h)
• low-dose: 200 mg/Tag („stress dose“)
• duration: for 7 days or until the patient ist haemodyna-
mically stable
• tapering (recommended) every 2 days
-- perfusor 5 mg/h
-- perfusor 2.5 mg/h
-- 20-0-20 mg
-- 20-0-0 mg
• daily costs: only about 10 €
• side effects:
-- possibly increased rate of infections ­
-- increased rate of critical illness polyneuro- / myopa-
thy (CIP, CIM) ­
-- hyperglycaemia
-- hypernatraemia (due to the mineralocorticoid ef-
fect; if sodium levels increase > 150mmol/l, hydro-
cortisone should be stopped!)
-- hypokalaemia
ACTH test
• for the detection of adrenocortical insufficiency
• administration of 250 μg ACTH (cortikotropine, Synac-
then) i.v., measurement of basal cortisol and after 60
minutes
• Adrenocortical insufficiency is proven if increase in cor-
tisol is less than 9 µg/dl (non-responder).
• limitations:
-- The threshold level of 9 µg/dl has only poor sensitivi-
ty and specifity for adrenocortical insufficiency.
-- measurement of cortisol
◦◦ depending on the assay used
◦◦ Immunoassays are very variable in septic shock.
• regimen
-- perform ACTH test, then start with hydrocortisone 4
x 50 mg/d and fludrocortisone 1 x 50 mg
◦◦ ACTH test negative → stop
◦◦ ACTH test positive → continue for a total of 7 days
• SSC guideline 2008. 2012 and 2016: not recom-
mended
Studies
• Annane et al, JAMA 2002 (see box): significant reduc-
tion in mortality from 61% to 55%
• COITTS study (see box)
• CORTICUS study (see box)
• ADRENAL study (see box)
• APROCCHSS study (see box)
• HYPRESS study (see box): hydrocortisone for the pre-
vention of septic shock → no benefit
study
"Annane" study
Effect of Treatment With Low Doses of Hydrocortisone and
Fludrocortisone on Mortality in Patients With Septic Shock
Annane et al, JAMA 2002
• French multicenter study
• 300 patients with septic shock
-- 150 patients: hydrocortisone 6 x 50 mg i.v. boluswise
+ fludrocortisone p.o. 50 μg/d for 7 days
-- 150 patients: placebo
• ACTH test
-- responder (25%): increase of cortisol > 9 μg/dl → no
relative adrenocortical insufficiency
-- non-responder (75%): increase of cortisol < 9 μg/dl →
relative adrenocortical insufficiency
• primary endpoint: mortality (28d)
• result: non-responder (75%) → significant reduction
in mortality from (from 63% to 53%)
Annotations
• In everyday clinical practice, an ACTH test is usually not
carried out and the guidelines do not recommend it at all.
• all patients together (responder + non-responder) → no
mortality advantage
• responder in ACTHt est (i.e. no adrenocortical insuffici-
ency) → even increased mortality!
COIITSS study
Corticosteroid Treatment and Intensive Insulin Therapy for
Septic Shock in Adults - a randomized controlled trial
The COIITSS-Study Investigators (u.a. Annane), JAMA
2010
• multicenter (11 intensive care units in France) rando-
mized controlled study
• 509 patients with septic shock and therapy with hydro-
cortisone (50mg i.v. every 6 hours)
• 2 x 2 design
-- intensive versus conventional insulin therapy →
no reduction in mortality
-- with / wothout fludrocortisone (50μg p.o.) → no
reduction in mortality
Infectiology 855
 CORTICUS study
Hydrocortisone Therapy for Patients with Septic Shock
Sprung et al, N Engl J 2008
• multicenter (52 centres) double-blinded prospective ran-
domized controlled study
• founded by the European Union
• designed to confirm the results of the Annane study
• 500 patients with septic shock
-- hydrocortisone 50 mg i.v. 4 x daily (no fludrocortisone)
-- placebo
• results: hydrocortisone
-- significantly earlier cessation of vasopressor therapy
-- significantly shorter length of ICU stay
-- no influence on 28-day mortality (not even in the
subgroup with adrenocortical insufficiency)
-- increased occurrence of
◦◦ infections (statistically non-significant )
◦◦ hyperglycaemia
ADRENAL study
Adjunctive Glucocorticoid Therapy in Patients with Septic
Shock
Venkatesh et al, N Engl J 2018
• ADRENAL: ADjunctive coRticosteroid trEatment iN criti-
cAlly ilL Patients With Septic Shock
• multicenter randomized controlled study (especially
Australia, New Zealand)
• 3,800 patients with septic shock
-- hydrocortisone 200mg/24h (continuously) i.v. for 7
days or until discharge from ICU
-- placebo
• results: hydrocortisone
-- primary endpoint (mortality after 90d): no diffe-
rence
-- secondary endpoints:
◦◦ mortality after 28d: no difference
◦◦ length of ICU stay: no difference
◦◦ duration of invasive ventilation / RRT: no difference
◦◦ bacteremia / fungemia: no difference
◦◦ significantly faster decrease in shock (after 3
versus 4 days)
◦◦ significantly fewer blood transfusions
◦◦ increased side effects (especially hyperglycemia,
hypernatremia)
856 Infectiology
APROCCHSS study
Hydrocortisone plus Fludrocortisone for Adults with Septic
Shock
Annane et al, N Engl J 2018
• multicentre randomized controlled study (France)
• 1241 patients with therapy refractory septic shock (nor-
adrenaline > 1 mg/h)
-- hydrocortisone (4 x daily 50mg boluswise i.v.) + flud-
rocortisone (1 x 50μg via gastric tube)
-- placebo
• results: hydrocortisone +fludrocortisone
-- primary endpoint (mortality after 90d): significantly
reduced (relatively effective with an NNT of only 18!)
-- secondary endpoints:
◦◦ significantly more vasopressor-free days
◦◦ significantly more organ failure-free days
◦◦ increased rate of hyperglycemia
HYPRESS study
Effect of Hydrocortisone on Development of Shock Among
Patients With Severe Sepsis
Keh et al, JAMA 2016
• multicenter randomized controlled study
• 380 patients with severe sepsis (without septic shock)
-- hydrocortisone (200mg daily as a continuous infusion
over 5 days)
-- placebo
• results:
◦◦ primary endpoint (occurrence of septic shock): no
difference
◦◦ secondary endpoints (i.a. mortality, infections,
length of ICU / hospital stay, weaning failure, hy-
perglycaemia, hypernatremia, CIP / CIM): no diffe-
rence
Recommendation
• SSC guideline 2012 und 2016
-- hydrocortisone in septic shock only in patients
„poorly responsive to fluid or vasopressor therapy“
(2C [weak recommendation])
-- therapy refractory septic shock
• S2k guideline 2010 + S3 guideline 2018
-- low-dose hydrocortisone in septic shock: no lon-
ger recommended
-- can be considered in therapy refractory septic shock
• In patients with long-term steroid therapy hydrocortiso-
ne should always be administered in case of a critical
illness due to frequent occurrence of adrenocortical
insufficiency.

septic shock and high-dose noradrena-
line demand (i.e. > 1 mg/h) → hydro-
cortisone
Activated protein C (Xigris)
Definition
• recombinant human activated protein C (rhAPC) = dro-
trecogin α
• effects:
-- anticoagulant
-- anti-inflammatory
• studies:
-- PROWESS study (see box): significant reduction in
mortality of patients with severe sepsis
-- ADDRESS stud (Abraham et al, N Engl J 2005):
premature termination because there was no advan-
tage versus placebo (no effect in patients with low
risk, i.e. single organ failure at most)
-- PROWESS-SHOCK study (se box; no effect)
• dosage: 24 μg/kg/h for 96 hours
• European approval was initially granted for severe
sepsis and multi organ failure (2 or more organs) and
APACHE II score > 25 (level of recommendation A, le-
vel of evidence Ib)
• contraindications: i.a.
-- platelets < 30000/μl, INR > 3
-- neurosurgical intervention / major operation < 12
hours ago
• Thrombosis prophylaxis with heparin should be conti-
nued during therapy with drotrecogin α.
• costs
-- ampoule with 5mg: 260 €, with20mg: 980 €
-- 4-day-therapy in a patient with 70kg: 7900 € (rela-
tively aggressive marketing and high price strategy
of the manufacturer at that time)
• Due to negative results of the PROWESS-SHOCK
study in 2011 the company (Lilly) has removed Xigris
from the market.
Recommendation
• SSC guideline
-- 2008:
◦◦ consideration in patients with sepsis induced or-
gan dysfunction and high mortality risk (APACHE
II > 25 or multi-organ failure), if there are no cont-
raindications (2B, 2C)
◦◦ no use in severe sepsis and low mortality risk
(APACHE II < 20 or single organ failure) (1A)
-- 2012 and 2016: no more recommended
• S2k guideline 2010:
-- recommended for patients with severe sepsis / sep-
tic shock and high mortality risk (APACHE-II > 25), if
there are no contraindications (C/Ic)
-- nor recommended patients with severe sepsis / sep-
tic shock and low mortality risk (APACHE II < 25 or
single organ failure) (A/Ia)
The recommendations go back to the period before the
PROWESS-SHOCK study from 2011. Due to the nega-
tive results of this study the Lilly company has removed
Xigris from the market, the product has been completely
erased from new recommendations. One single indica-
tion remains in the therapy of purpura fulminans (see
page 829), where there is an underlying protein C de-
ficiency. Production is already cancelled, some depots
with remainders are still existing in Germany.
PROWESS study
Efficacy and Safety of Recombinant Human Activated Pro-
tein C for Severe Sepsis
Bernard et al, N Engl J 2001
• multicenter randomized controlled phase III study
• 1,690 patients with severe sepsis
-- 850 patients: drotrecogin α 24 μg/kg/h over 96 hours
-- 840 patients: placebo
• results: drotrecogin α
-- significantly reduced 28-day mortality (24.7% versus
30.8%); risk reduction:
◦◦ relatively (RRR): by 19.4%
◦◦ absolutely (ARR): by 6.1% (in case of manifest DIC
and multi organ failure even 18.1%)
-- tendency towards increased rate of haemorrhage (3.5
versus 2 percent, especially SAH) without reaching
statistical significance
• point of criticism: Shortly after initiation of the study the
inclusion criteria were subsequently changed!
PROWESS-SHOCK
study
Drotrecogin alfa (activated) in adults with septic shock
Ranieri et al, N Engl J 2012
• multicenter, double-blind, randomized controlled study
• 1697 patients with septic shock
-- drotrecogin α (Xigris)
-- placebo
• results: drotrecogin α
-- no difference in mortality (after 28 days)
-- no difference in bleeding rate
drotrecogin α (Xigris):
completely out!
Infectiology 857
Coagulation therapy
• heparin
-- significantly increased risk of venous thromboembo-
lism (VTE) in critically ill patients in the intensive care
unit (i.a. risk of pulmonary embolism: 3%)
-- application:
◦◦ mostly LMWH (low molecular weight heparin)
s.c. (meta-analysis Beitland et al, Intensive Care
Med 2015: with LMWH significantly less frequent
thrombosis compared to UFH [unfractionated
heparin] without increasing the bleeding rate →
Therefore in the SSC guideline 2016 LMWH are
recommended over UFH [however, in the S3 gui-
deline sepsis 2018 equal])
◦◦ in septic shock generously i.v. (UFH) via perfusor
(In patients with septic shock and high noradre-
naline requirement [> 1 mg/h], heparin should not
be administered as LMWH s.c., but as UFH i.v.
via perfusor, because one does not know how the
subcutaneously administered heparin is even ab-
sorbed in shock [centralization] and high-dose va-
sopressor therapy.); dosage (without PTT control):
▪▪ heparin 400 E/h
▪▪ platelets < 50000/μl → 200 E/h
• In case of contraindications for pharmacological
thrombosis prophylaxis (e.g. active bleeding, severe
coagulopathy), mechanical thrombosis prophylaxis
(intermittent pneumatic compression [IPC]) should be
performed. Mechanical thrombosis prophylaxis in ad-
dition to pharmacological thrombosis prophylaxis did
not show any further advantages (PREVENT study
(Arabi et al, N Engl J 2019; no reduction in VTE inci-
dence or mortality).
• FFP if necessary (no cosmetic improvement in labo-
ratory parameters! indicated only in haemorrhage or
surgery)
• platelet concentrates - indications:
-- without haemorrhage: < 10000/μl
-- with haemorrhage: < 20000/μl
• no use of AT III (i.a. KyberSept study 2001 [see page
1184]; SSC guideline 2016: no recommendation)
• thrombomodulin: not recommended (i.a. S3 guideline-
sepsis 2018)
858 Infectiology
Nutrition
• enteral instead of parenteral (if possible; nearly always
possible in medical critically ill patients)
• not full caloric in the first week (only hypocaloric! [SSC
guidelines 2012 + 2016])
• selen (Selenase)
• immunonutrition (syn.: pharmaconutrition)
-- arginine (e.g. Impact): not recommended (i.a. SSC
guideline 2016; even increased mortality!)
-- omega-3 fatty acids:
◦◦ OxEPA formerly recommended in case of additi-
onal ARDS
◦◦ Eden-Omega study: no benefit; Omega study
(Rice et al, JAMA 2011: even negative effects!)
◦◦ SSC guideline 2016: no longer recommended
-- glutamine (Dipeptamin; see esp. page 269):
◦◦ recommended during long-term total parenteral
nutrition (from day 5 onwards if nourished totally
parenteral previously)
◦◦ no recommendation for shock and multi organ fai-
lure
◦◦ SSC guideline 2016: no longer recommended
Selen
• pathophysiology:
-- pathophysiology → increased formation of free radi-
cals → organ damage
-- selen: essential trace mineral, antioxidant, radical
catcher
• studies:
-- SIC study (see box)
-- meta-analyseses:
◦◦ Kong et al, Am J Emerg Med 2013 (5 studies, 530
patients): no reduction in mortality
◦◦ Alhazzani et al, Crit Care Med 2013 (9 studies,
792 patients): no reduction in mortality
-- SIGNET studiy (Andrews et al, BMJ 2011): less
infectious complications but no influence on organ
failure and mortality
-- SIS-PCT study (SepNet; Bloos et al, JAMA Intern
Med 2016; see box): no reduction in mortality
• indications (former): severe sepsis, septic shock
• dosage:
-- Selenase (sodium selenite) 1 amp. = 20ml = 1000 μg
-- 2000 μg as loading-dose in 30 min, then 1000 μg/
day for a total of 14 days (high-dose therapy)
 -- costs: approx. 130 €/14 days
• guidelines: no longer recommended
-- international: SSC guidelines 2012 + 2016
-- national (Germany)
SIS-PCT study
◦◦ S2k guideline of the German Society for Nutritio-
nal Medicine DGEM ("Clinical Nutrition in Intensi-
ve Care Medicine") 2018
Effect of Sodium Selenite Administration and Procalcitonin-
◦◦ S3 guideline Sepsis 2018
Guided Therapy on Mortality in Patients With Severe Sep-
sis or Septic Shock
Bloos et al, JAMA Intern Med 2016

• SISPCT: Placebo-Controlled Trial of Sodium Selenite

Fig. 1102  Selenase 1 amp. = 20ml = 1000 μg
Selen: not longer recommended
and Procalcitonin Guided Antimicrobial Therapy in Se-
vere Sepsis
• multicenter randomized (2 x 2 factorial) controlled study
• 1,089 patients with severe sepsis or septic shock
-- with / without Selenase (1000μg loading-dose, then
1000μg daily for max. 21 days)
-- with / without PCT control (PCT: Procalcitonin)
• results:
-- primary endpoint (mortality after 28d): no difference
-- secondary endpoints (i.a. mortality after 90d, infec-
tions, antibiotic costs): no difference

SIC study Immunoglobulines

Selenium in Intensive Care (SIC): results of a prospective

randomized, placebo-controlled, multiple-center study in
patients with severe systemic inflammatory response syn-
drome, sepsis and septic shock
Angstwurm et al, Crit Care Med 2007

• multicenter randomized controlled study

• 189 (after „per protocol analysis“) patients mit with SIRS/
sepsis/ septic shock and APACHE-III score > 70
-- 92 patients: sodium selenite (Selenase) 1000 μg/d
for 14 days
-- 97 patients: placebo
• result: sodium selenite (Selenase) → significant reduc-
tion of the 28-day mortality from 56.7% to 42.4% (abso-
lute risk reduction [ARR] by 14.3% [septic shock + DIC
sogar even by 26%])
• „SIC for all the SICK?“

• rationale: diminished serum levels of IgG and IgM in

sepsis
• types:
-- ivIgG (only IgG)
-- ivIgGMA (IgG + IgM + IgA; e.g. Pentaglobin: infusion
solution with 5g/100ml → dosage 5ml/kg = 0.25g/kg
i.v. daily for 3 days; costs: approx. 1000€ daily)
• Exclusion of an IgA deficiency is mandatory prior to
application, otherwise an allergic reaction is possible.
• meta-analysis (Kreymann et al, Crit Care Med 2007)
-- significant reduction in mortality
-- ivIgGMA more efficient than ivIgG
• prospective randomized controlled studies (regarding

Infectiology 859
 sepsis): no reduction in mortality
-- adults: SBITS study (Werdan et al, Crit Care Med
2007)
-- neonates: INIS study (Brocklehurst et al, N Engl J
2011)
• possible indications in sepsis:
-- meningococcal sepsis (Waterhouse-Friderichsen
syndrome)
-- streptococcal toxic shock syndrome
• expensive (Pentaglobin: approx. 1000€/day)
• Concerning immunoglobulins large randomized con-
trolled studies would be necessary, there are more
meta-analyses than studies!
• CIGMA studiy (phase II study, Welte et al, Intensive
Care Med 2018; see box): also no advantage in severe
(requiring mechanical ventilation) pneumonia
• guidelines: not recommenden
-- international (SSC guidelines 2012 and 2016):
-- national (Germany: S3 guidelines sepsis 2018)
CIGMA study
Efficacy and safety of trimodulin, a novel polyclonal anti-
body preparation, in patients with severe community-ac-
quired pneumonia
Welte et al, ICM 2018
• multicenter randomized controlled study (phase II)
• 160 patients with severe (requiring mechanical ventilati-
on) community-aquired pneumonia
-- Trimodulin (preparation that contains IgG, IgM and
IgA similar to Pentaglobin, with the difference that the
IgM content is twice as high) each 42 mg/kg IgM i.v.
over 5 days
-- placebo
• results: Trimodulin
-- ventilator-free days (primary endpoint): no difference
-- mortality: no difference (subgroup of patients with
CRP > 7 mg/dl and IgM deficiency [IgM < 0.8 g/l]: si-
gnificant reduction in mortality [only hypothesizing])
Metabolic Resuscitation
• definition: administration of hydrocortisone + vitamin C
(1/3 of all sepsis patients have vitamin C deficiency
[< 11 µmol/l; Carr et al, Critical Care 2017].) + thiamin
• ACTS study (see box): no benefit
• currently ongoing studies: ORANGES, HYVCTTSSS,
VITAMINS
860 Infectiology
CITRIS-ALI study
Effect of Vitamin C Infusion on Organ Failure and Biomar-
kers of Inflammation and Vascular Injury in Patients With
Sepsis and Severe Acute Respiratory Failure
Fowler et al, JAMA 2019
• multicenter randomized placebo-controlled study (phase
II)
• 167 patients with sepsis and ARDS (requiring ventila-
tion)
-- high-dose vitamin C infusion 50 mg/kg 4 x daily over
4 days
-- placebo
• results: vitamin C
-- primary endpoints (organ failure, decline in bio-
markers for inflammation [CRP] and vascular injury
[thrombomodulin]): no difference
-- secondary endpoints:
◦◦ mortality after 28d: significantly reduced
◦◦ length of ICU stay: significantly reduced
◦◦ length of hospital stay: significantly reduced
◦◦ all other secondary endpoints (i.a. oxygenation in-
dex, creatinine, vasopressor therapy): no difference
• note: The study had 49 endpoints, 46 of which were
negative.
ACTS study
Effect of Ascorbic Acid, Corticosteroids, and Thiamine on
Organ Injury in Septic Shock
Moskowitz et al, JAMA 2020
• ACTS: Ascorbic Acid, Corticosteroids and Thiamine in
Sepsis
• multicenter randomized placebo-controlled study
• 200 patients with septic shock
-- over 4 days 4 x daily i.v. each vitamin C (ascorbic acid)
1500mg, thiamin 100mg and hydrocortisone 50mg
-- placebo
• results:
-- primary endpoint (decrease in SOFA score, i.e. impro-
vement of organ dysfunction): no difference
-- secondary endpoints: especially
◦◦ mortality after 30d: no difference
◦◦ kidney failure after 30d: no difference
 anti-
se- throm- ALERT study
len bin gluta-
mine

hydro-
cortisone drotreco- The use of an early alert system to improve compliance
intensive gin with sepsis bundles and to assess impact on mortality
insulin (Xigris) La Rosa et al, Crit Care Res Pract 2012
therapy
immuno-
• study from Beth Israel Medical Center (New York);
globulines
• A specified checklist with several parameters (body
temperature > 38.3°C or < 36°C, tachycardia > 90/min,
tachypnoea > 20/min, acute alteration in mental status,
leukocytes > 12000/µl or < 4000/µl, differential blood
count > 10% banded neutrophils [immature granulocy-
tes]) was used.
Fig. 1103  The cemetery of adjunctive sepsis therapy: All of • Once the limit values were exceeded a so-called SMART
this meanwhile is buried here! team (sepsis management alert response team) was ac-
tivated.
• In-hospital mortality was 29%in the control group and
9% in the SMART- group.
study

The Surviving Sepsis Campaign: results of an international
guideline-based performance improvement program tar-
geting severe sepsis
Levy et al, Crit Care Med 2010
• therapeutic bundles (SSC 2004)
-- resuscitation bundles (< 6h)
-- management-Bundles (6-24h)
• 15002 patients, 165 intensive care units, 30 countries
• implementation in only 31%
study
Improvement in Process of Care and Outcome After a Mul-
ticenter Severe Sepsis Educational Program in Spain
Ferrer et al, JAMA 2008
• training of 59 intensive care units in Spain in sepsis
therapy according to the SSC guidelines (average 10.5
hours)
• result: significant reduction in mortality
Prognosis
• mortality
-- according to the old sepsis definition:
◦◦ sepsis: 16%
◦◦ severe sepsis: 20%
◦◦ septic shock: 50% (In former times cardiogenic
shock was thought to be the most lethal type of
shock, nowadays it’s septic shock! It is also the
most common form of shock. Therapy has, howe-
ver, improved significantly in recent years so that
mortality has decreased. In the three negative stu-
dies on EGDT (ProCESS 2014, ARISE 2015, Pro-
MISe 2015), in which one obviously learned from
the Rivers study, the mortality of septic shock was
"only" 30%.)
-- according to the new sepsis definition:
◦◦ sepsis: 10%
◦◦ septic shock: 40%
• In Australia and New Zealand a decreasing in-hospi-
tal mortality of patients with severe sepsis and septic
shock is being reported (Kaukonen et al, JAMA 2014).
Nevertheless this is only based upon the analysis of
administrative routine data.
• main causes of death:
-- No.1: heart failure (septic cardiomyopathy with
cardiogenic shock [most common cause of death in
intensive care units!])
-- No.2: encephalopathy
-- No.3: DIC
• after surviving sepsis in the long-term course:
-- mortality twice as high after two years as patients
with an otherwise comparable state of health without
sepsis (Prescott et al, BMJ 2016)
-- 5-fold increased risk of epilepsy (Reznik et al, Neu-
rology 2017; possibly as a result of septic encepha-
lopathy)

Infectiology 861
 -- 5-fold increased risk of myocardial infarction and Scores
stroke in the first 4 weeks after hospital discharge
(Lai et al, CMAJ 2018)
SOFA score (Sepsis-related Organ Failure
The shock form with the highest Assessment)
mortality today is no longer the parame-
cardiogenic but septic shock organ ters 1 2 3 4
(mortality 50%)! Septic shock is 200-100 < 100
also the most common shock with with
form! paO2/FiO2 400- 300- ventila- ventila-
lung mmHg      300 200 tion tion
creatinine 1.2
(mg/dl) -2.0 2.0
Multi-organ failure kidney
diure-
sis (l/d)
nor-
mal
- 3.5
normal
3.5 - 5.0
< 500
> 5.0
< 200
(MOF) bilirubin  1.2 - 2.0 - 6.0 -
liver (mg/dl) 2.0 6.0 12.0 >12.0
BB cate- catecho- cate-
heart/ (mmHg) chola- lamines chola-
circu- catechola- MAP mines mode- mines
lation mines < 70 low rate high
platelets
blood per nl < 150 < 100 < 50 < 20
CNS GCS 14-13 12-10 9-6 <6

SOFA score: 0P. → mortality 1%, 1P. → mortality 3%, 2P.

→ mortality 8-10%, 3P. → mortality > 20%

new sepsis definition (Sepsis-3):

i.a. SOFA score ≥ 2P. (or increase
≥ 2P.)

Definition
• syn.: MODS (multiple organ dysfunction syndrome)
• first described in 1973 by Kinkley
• traditionally associated with sepsis
• failure of at least two organ systems
• mortality (MOF)
-- in case of failure of two organ systems: 60%
-- in case of three or more failing organ systems: 80-
100%
The SOFA score is meanwhile a central component in
the new sepsis definition (sepsis-3 definition). However,
since no one can remember the score, it makes sense
to implement it in the PDMS (patient data management
system) in the intensive care unit.
A quick SOFA score (qSOFA; see infobox) was also in-
troduced as part of the sepsis-3 definition (Seymour et
al, JAMA 2016): This is especially recommended as a
screening tool for the preclinical, emergency department
and normal ward, since here the use of the classic SOFA
score is not as widespread and common as in the inten-
sive care unit.

862 Infectiology
 Marshall-Score (modified)
organ parameter 0 1 2 3 4
paO2/FiO2 > 400- 300- 200-
lung (mmHg)      400 300 200 100 < 100
creatinin < 1.4- 1.8- 3.6-
kidney (mg/dl) 1.4 1.8 3.6 4.9 > 4.9
heart/ < 90 < 90
circula- SBP > < 90 < 90 pH < pH <
tion (mmHg) 90 vol+ vol- 7.3 7.2
vol+: volume responsive, vol-: not volume responsive
score ≥ 2P.: respective organ failure

Gastrointestinal organ failure

SIRS criteriea: high sensitivity, low

specificity
qSOFA: low sensitivity, high • stomach / oesophagus:
specificity -- upper gastrointestinal bleeding
◦◦ No.1: erosions (erosive gastritis),
◦◦ No.2: oesophagitis
MOF-score according to Goris ◦◦ No.3: ulcer (mostly stress ulcers)
0 1 2
-- ischaemic gastropathy, possibly necrosis (I.a. in
post-resuscitation care nearly every patient has
ventilation ventilation haemorrhagic necrosis due to ischaemia in the
lung with FiO2 < with FiO2 >
EGD.)
failure no ventilation 0.40 0.40
• intestine (bowel):
heart / circu- BB normo- BB normoton requiring
lation ton without with fluid ad- catecholami- -- small intestine:
failure support ministration nes ◦◦ necrotizing enterocolitis (NEC)
kidney creatinin < 2 creatinin > 2 RRT ◦◦ NOMI (nonocclusive mesenteric ischaemia [see
failure mg/dl mg/dl (CVVH, HD) page 892])
bilirubin < 2 bilirubin 2-6 bilirubin > 6 -- large intestine:
liver mg/dl, GOT mg/dl, GOT mg/dl, GOT ◦◦ colonic pseudo-obstruction (Ogilvie syndrome
failure < 25 U/l 25-50 U/l > 50 U/l [see page 830])
◦◦ ischaemic colitis (see page 895)
coagulation platelets platelets hemorrhagic • pancreas: exocrine pancreatic insufficiency
failure normal < 50/nl diathesis
-- frequency: in 90% in septic shock [Tribl et al, Crit
Care Med 2000]), up to 50% of all critically ill patients
slightly limi- severely limi- (regardless of the presence of a pancreatic disease)
CNS ted responsi- ted responsi-
-- genesis: decreased perfusion in the context of shock
failure none veness veness
-- diagnosis: pancreatic elastase in faeces (decreased,
Stress ulcer
i.e. . < 200 µg/g faeces)
bleeding,
NEC, -- therapy
gastrointes- pancreatitis, ◦◦ substitution of pancreatic enzymes (Kreon; with
tinal cholecystitis, perforation of consequent gastric acid suppression [but only
failure normal stress ulcer gall bladder necessary if the pancreatic enzymes have to be
administered via a gastric tube: In this situation the
enzymes would be degraded by the gastric acid.])

Infectiology 863
 ◦◦ low molecular tube feeding (chemically defined
diets [CDD]; here the components are already
much more splitted)
• gall bladder: acalculous cholecystitis
-- definition: inflammation of the gall bladder without
detection of a gall stone
-- “stress cholecystitis”, “stress gall bladder”
-- vascular disorder of the gall bladder wall
-- possibly perforation of the gall bladder
-- therapy:
◦◦ cholecystectomy
◦◦ option in critically ill patients: percutaneous punc-
ture of the gall bladder (ultrasound guided) and
consecutive drainage (transhepatic, trocar or Sel-
dinger technique, insertion of a 8F-pigtail draina-
ge; relatively simple!)
• biliary tract: ischaemic cholangiopathy (see also page
442)
-- caused by a diminished perfusion of the bile ducts
(Bile ducts are not supplied by arteries and portal
veins like the rest of the liver, but only by arteries.)
-- biliary-cast syndrome: The bile ducts get grouted
with clots (casts).
-- secondary sclerosing cholangitis (see page 870)
• liver: shock liver (hypoxic hepatitis [see page 442])
• abdominal cavity: intra-abdominal compartment syn-
drome (IACS)

Fig. 1104  ischaemic gastropathy: extensive necrosis in the

stomach of a patient with septic shock (caused by reduced
perfusion in the context of shock)

864 Infectiology
 Fig. 1107  acalculous cholecystitis (enlarged gall bladder,
Fig. 1105  Gastroscopy: In almost every resuscitated patient wall thickening and triple-layer aspect, no gall stones)
there is haemorrhagic necrosis due to ischemia.

Fig. 1106  abdominal CT of a patient with septic shock (uro-

sepsis) and high-dose noradrenaline infusion: There is
gas in the colonic wall (intestinal pneumatosis; arrows) as
a consequence of a severe ischemic colitis necessitating
colectomy.

Infectiology 865

Fig. 1108  A very good and simple option in acalculous
cholecystitis (especially in critically ill patients) is percu-
taneous drainage. Hereby we use the Hydroplus-drainage
catheter (for images of the catheter see page 817). Punc-
ture is performed from the right intercostal direction under
sonographic control. Dreggy putrid bile is discharging.
IACS (intra-abdominal compartment
syndrome )
Definition
• intra-abdominal pressure (IAP) > 20mmHg (IAH: intra-
abdominal hypertension) plus new organ dysfunctions:
-- intestinal (splanchnic hypoperfusion → motility ↓,
bacterial translocation, ischemiae)
-- renal (renal perfusion ↓ → kidney failure)
-- hepatic (hepatic perfusion ↓ → hypoxic hepatitis,
liver failure)
-- pulmonary (diaphragmatic elevation; extrathoracical
restriction; increased ventilation pressures required)
-- cardiac (intrathoracic pressure ↑­ → preload ↓, after-
load ↑)
-- cerebral (intracranial pressure ↑­)
• intra-abdominal hypertension (IAH): IAP (intraabdomi-
nal pressure) > 12 mmHg
• a frequent complication in critically ill patients
• frequency in intensive care units (Malbrain et al, Crit
Care Med 2005):
-- IAH (intra-abdominal hypertension): 50%
-- IACS (intra-abdominal compartment syndrome): 8%
• incidene ↓ (Bologh et al, Arch Surg 2011)
IACS: common in intensive care
units and unfortunately also very
commonly overseen!
Etiology
• primary IACS
-- pancreatitis
-- peritonitis
-- intestinal ischemia
-- ileus
-- Ogilvie syndrome
-- aszites
866 Infectiology
-- tumors (cancer)
-- abdominal trauma
-- haemorrhage, retroperitoneal haematoma
-- obesity (especially when performing prone positio-
ning in the course of ARDS: In patients with (espe-
cially abdominal) obesity the IAP is already elevated.
Due to prone positioning the IAP continues to raise
causing manifest intra-abdominal compartment syn-
drome with corresponding organ failure. In a study
(Weig et al, J Crit Care 2014) it was shown that
patients with abdominal obesity who were prone-
positioned due to ARDS suffered significantly more
frequently from acute kidney injury and hypoxic he-
patitis. The longer prone position was performed the
higher the mortality was.
• secondary IACS
-- surgery of aortic aneurysm (abdominal aorta)
-- forced abdominal wall closure
-- hernia surgery
-- carbon dioxide peritoneum (laparoscopy)
-- burns (scarring of the skin and thus a reduction in
abdominal compliance)
-- sepsis with capillary leak
-- hyperhydration (over-watering)
An increased IAP can be the
cause of a multi-organ failure!
Intraabdominal pressure (IAP)
Definition
• pressure in the abdominal cavity
• breath dependent
• highly significant correlation between IAP and mortali-
ty (Delius et al, Intensivmed 2009; especially in acute
pancreatitis)
• The higher the intraabdominal pressure (IAP), the lo-
wer the abdominal perfusion pressure (APP; analo-
gous to the cerebral perfusion pressure [CPP])
-- APP = MAP - IAP
-- Norm APP > 60mmHg
Measurement
• direct (percutaneously via paracentesis; no standard)
• indirect:
-- via urinary bladder (bladder pressure; standard)
◦◦ special catheter (Foley catheter)
◦◦ The bladder incorporates abdominal pressure as a
passive reservoir.
◦◦ The intra-vesical pressure is measured and equa-
ted to the intra-abdominal pressure.
◦◦ methodaccording to Cheatham and Safcsak
◦◦ distal clamping of the urinary catheter followed by
instillation of 25ml NaCl 0.9%
◦◦ endexpiratory measurement (IAP depends on
breathing) in complete supine position with the
transducer zeroed in the mid-axillary line at the le-
vel of the iliac crest (calibration)
 -- via stomach: CiMON system (Pulsion company)
◦◦ continuous measurement of the intra-abdominal
pressure
◦◦ similar principle with the probe lying in the sto-
mach (not measurement of the intra-vesical, but of
the intra-gastric pressure; due to the larger volume
in the stomach this measurement is more failure-
prone)
◦◦ contraindications: burst abdomen, ileus

connection to the pressure

measurement system

instillation syringe
Fig. 1110  CiMON system: continuous measurement of intra-
abdominal pressure indirectly by measuring the intra-gas-
tric pressure [30]

generous measurement of IAP in ICU

(especially in case of unclear organ
connection to the
urinary catheter failure)!
connection to the urine
drainage system Degrees of severity
connection to the flush bag
degrees of severity IAP (intra-abdominal pressure)
I 12-15 mmHg
II 16-20 mmHg
III 21-25 mmHg
IV > 25 mmHg

Fig. 1109  measurement of the intra-abdominal pressure
(IAP) indirectly by measuring the intra-vesical pressure
(22mmHg in this case): The urinary catheter was previously
distally clamped and then 25ml of physiological saline so-
lution was instilled (Here the system AbViser AutoValve IAP
Monitoring Device is demonstrated.).
Therapy
• conservative: i.a.
-- prokinetic agents, rectal enema, if necessary de-
compression probe
-- reduction or abandonment of enteral nutrition
-- flat positioning
◦◦ This improves the compliance of the abdominal
wal.
◦◦ Elevation of the upper body is contraindicated
here because the flexion in the hip joint can incre-
ase the intra-abdominal pressure.
◦◦ Alternatively, anti-Trendelenburg positioning can
be used for these patients.
-- removal of tight abdominal bandage (after abdomi-
nal surgery)
-- sufficient analgosedation (A pain-related increased
tone of abdominal muscles increases the intra-abdo-
minal pressure.)
-- possibly ascites puncture (if present)
-- The higher the IAP the higher the PEEP level during
mechanical ventilation should be set (extrathoracic
restriction!).
• surgical (in refractory cases): surgical decompression
(decompressive laparotomy) followed by temporary
abdominal closure (TAC; standard today in VAWCM
technique ([vacuum assisted wound closure and mesh
mediated fascial traction])

Infectiology 867
Septic cardiomyopathy Pathophysiology
• disturbance of contractility caused by myocardial de-
pressant factor (MDF)
• Endotoxins (i.a. lipopolysaccharid [LPS]) and cytokins
(i.a. TNF-α, Il-1) lead to an activation of the endotoxin-
NO-cGMP cascade, which has a negative inotropic
effect.
• intramyocardial haemorrhage
• damage to the cardiomyocytes caused by cytokines
and toxins (i.a. LPS, α-toxin)
• microcirculatory disorder of the myocardium
• Coronary arteries are not stenosed but mostly even di-
lated in the course of systemic vasodilation!

Dysfunction
Definition
• term inaugurated by Schuster in 1989 Mechanic dysfunction
• a secondary cardiomyopathy
• systolic
• insufficiently increased or even decreased cardiac out-
-- global
put relative to the distinctly reduced systemic vascular
resistance SVR (“vasoplegia”) ◦◦ left ventricular (moderately reduced ejection frac-
tion in 20% of patients with severe sepsis); often
• Often, septic cardiomyopathy is not diagnosed be-
also dilated left ventricle (LVEDD [left ventricular
cause the cardiac output, which is often still normal, is
end-diastolic diameter] ↑)
considered in isolation without the SVR. However, in
relation to the massively decreased systemic vascular ◦◦ right ventricular (in 30%; i.a. with ARDS [pulmona-
resistance (SVR; afterload) it is far too low. Therefo- ry hypertension] or ventilation with high PEEP →
re cardiac output has always to be set in relation to right ventricular decompensation)
the reduced afterload (SVR; afterload-related cardiac -- regional
output). • diastolic ( even more often than systolic dysfunction
-- ACP (afterload-related cardiac performance): [in 50%])
◦◦ In the study of Werdan et al (Septic cardiomyopa-
thy: hemodynamic quantification, occurrence, and Electrical dysfunction (arrhythmias)
prognostic implications; Clin Res Cardiol 2011) • atrial fibrillation (paroxysmal)
the measured cardiac output was set in relation to -- in 30% of all patients with sepsis
normal cardiac output (for a distinct SVR in each -- often no (persistent) success of cardioversion (rea-
case). This quotient was designated ACP (after- sons: catecholamine perfusors, increased endoge-
load-related cardiac performance; unit: percenta- nous sympathetic tone)
ge of the normal value).
-- poor prognosis (3-fold increased mortality; i.a. Wal-
◦◦ ACP = COmeasured / COnormal key et al, JAMA 2011)
◦◦ COnormal = 560.68 x SVR-0.64 • ventricular fibrillation, ventricular flutter, ventricular ta-
◦◦ With ACP < 80% there is septic cardiomyopathy. chycardia: very rare (unusual!)
◦◦ The lower the ACP, the higher the mortality (i.a. • autonomic dysfunction with excessive reduction of
ACP 60-80% → mortality 36%, ACP 40-60% → heart rate variability (poor prognosis!)
mortality 67%). • inadequately high heart rate due to hypersensitivity of
-- In the clinical routine we like to use the product of the β-receptors caused by interaction of endotoxins
CO and SVR respectively (related to the body sur- (especially LPS) with the If channel (f: funny; inhibition
face) CI x SVRI. The product of cardiac index (unit: of the If channel with ivabradine → no benefit [Nuding
l/min/m2) and systemic vascular resistance index et al, SHOCK 2018])
SVRI (unit: dyn x sec x cm-5 x m-2) CI x SVRI / 60
should be > 100 l x dyn x cm-5 x m-4. If the product
of CI x SVRI / 60 undershoots this threshold, septic
cardiomyopathy is present (annotation: own experi-
ence value useful in daily practice, no scientific evi-
dence for this).
• commonest cause of death in sepsis: cardiogenic
shock caused by septic cardiomyopathy
• anyway the commonest cause of death in ICU!
• maybe daily ECG (unspecific signs of ischemia) and
troponin (note: not very helpful)
• almost reversible

868 Infectiology
Septic liver failure
Definition
• acute liver failure in the course of sepsis
• „pneumonia biliosa“ (Garvin, 1896)
• almost no proceedings, liver as “traditionally forgotten
organ” in intensive care medicine
• triad:
-- jaundice "(ICU jaundice")
-- coagulopathy (INR > 1.5)
-- hepatic encephalopathy
• pattern of damage (Kohashi et al, Hepatol Res 2013):
-- 50% cholestatic (AP ↑)
-- 50% hepatotoxic (GPT [= ALT] ↑)
Among all organ failures, liver
failure is the organ failure with the
worst prognosis!
Epidemiology
• occurrence mostly in the late phase of sepsis
• severe sepsis → in 20% liver function disorder
• commonest cause of slightly elevated transaminases:
drugs (usually harmless unless bilirubin is elevated
[Hy's law])
study
Incidence and prognosis of early hepatic dysfunction in
critically ill patients - A prospective multicenter study
Kramer et al, Crit Care Med 2007
• Austrian multicenter propective cohort study
• 38036 critically ill patients
• in 11% early liver dysfunction
• liver failure as the strongest prognostic parameter
(among all organ failures)
Pathophysiology
• hypoxic induced liver damage (hypoxic = ischemic he-
patitis; shock liver)
• sepsis (sepsis induced cholestasis or cholestatic
dysfunction), ischaemia → disturbance in energy de-
pendent transportation processes (ischaemic cholan-
giopathy) → excretion of bile acids ↓ → secondary
sclerosing cholangitis (typical)
• drug toxicity (especially antibiotics such as amoxicillin/
clavulanic acid)
• right ventricular decompensation (septic cardiomyopa-
thy)
• ventilation with high PEEP
• total parenteral nutrition (causes cholestasis)
Shock liver
Definition
• syn.: hypoxic (= ischemic) hepatitis
• caused by hypoxia (decreased oxygen delivery, mostly
cardiac)
• commonest cause of massively elevated transami-
nases in ICU
• common (10% of all patients in medical ICU [Fuhr-
mann et al, Int Care Med 2009])
Causes
• shock
-- cardiogenic shock (No.1; 18% of all patients with
cardiogenic shock, 7% of all patients after [out-of-
hospital] cardiac arrest [Jung et al, Clin Res Cardiol
2016])
-- septic shock
• respiratory insufficiency
Diagnostics
• laboratory:
-- transaminases ↑↑ (increase > 20-times of the norm;
GOT > GPT, i.e. de-Ritis quotient [= GOT/GPT] > 1;
note: GOT = AST, GPT = ALT; in contrast to acute
viral hepatitis, in which the de-Ritis quotient is < 1)
-- LDH ↑↑ (typically very high LDH!), quotient GPT
/ LDH < 1.5 (in contrast to acute viral hepatitis, in
which the quotient is > 1.5)
-- possibly NH3 (ammonia) ↑
-- possibly Quick ↓ resp. INR ↑
-- blood glucose ↓ (cave spontaneous hypoglyce-
mia!)
-- bilirubin (only elevated in 30%; mostly non-cholesta-
tic liver function disorder)
• sonography:
-- mostly (especially if caused by cardiac dysfunction
[the commonest reason]) dilated hepatic veins and
inferior vena cava with reduced respiratory variation
-- also to exclude portal vein thrombosis and Budd-
Chiari syndrome
• histology (however, liver biopsy not mandatory): diffu-
se centrilobular liver cell necrosis
Infectiology 869
Therapy
• causal (therapy of shock)
• supportive
-- In cardiac decompensation (commonest cause of
shock liver) negative fluid balance (with the aid of
loop diuretics or renal replacement therapy in case
of anuria respectively) is the pivotal therapeutic step!
Low blood pressure is not a contraindication for the
administration of diuretics and not an indication for
fluid supply here. One should focus on cardiac out-
put instead of blood pressure. Positive fluid balance
would be catastrophic here and similar to execution!
-- Liver transplantation is not indicated in case of a
shock liver.
-- Statins are protective due to their pleiotropic effect
so that preexisting statin therapy should be continu-
ed (Drolz et al, J Hepatol 2014). Nevertheless there
is no recommendation for the initiation of de novo
statin for therapy of shock liver.

Prognosis
• The prognosis of hypoxic hepatitis is very poor!
• in 30% acute liver failure
• ICU mortality: 50%
• 1-year survival rate: 25%

Secondary sclerosing cholangitis (SSC)

Definition
• syn.:
-- SC-CIP (sclerosing cholangitis in critically ill pati-
ents)
-- biliary-cast syndrome (Casts are formed [poured out
lumps in the biliary tract].)
• ischaemic cholangiopathy caused by reduced perfusi-
on of bile ducts
-- Bile ducts are not supplied by arteries and portal ve-
ins like the rest of the liver, but only by arteries.
-- most common location: middle part of the common
bile duct (DHC: ductus hepatocholedochus), bran-
ching in to the right and left hepatic duct
• often shows similarity to severe end-stage primary sc-
lerosing cholangitis (PSC)

ERCP
• typical peripheral rarefied ducts ("defoliated tree")
• with papillotomy
• ERCP can be used to remove the casts from the larger
bile ducts, but not from the smaller bile ducts, so that
this is usually only a cosmetic procedure.
• always draw bile secretion for microbiology during
ERCP!

Fig. 1111  ERCP: A typical picture of secondary sclerosing

cholangitis can be seen. The common bile duct is not dila-
ted, the peripheral bile ducts are segmentally dilated like a
pearl string and segmentally stenosed.

870 Infectiology
Fig. 1112  endosonography: biliary-cast syndrome (a lump
in the common bile duct can be recognized; no acoustic
shadowing as in cholecystolithiasis)

Fig. 1113  ERCP: The typical picture of a biliary-cast syndro-

me with poured out lumps in the bile ducts can be seen.
Some of these casts could at least be removed from the
common bile duct (DHC; see arrow). However, they still re-
main in the small bile ducts, so that the endoscopic removal
of these lumps is usually only a purely cosmetic measure.

Differential diagnoses
• primary sclerosing cholangitis (PSC)
-- most common in patients with ulcerative colitis
-- laboratory: pANCA ↑
• IgG4 associated sclerosing cholangitis (can immitae
exactly the same picture and ican be treated with ste-
roids very effeticely; therefore always determine IgG4
levels in the serum)

Therapy
• ursodesoxycholic acid (10-15 mg/kg p.o.)
• antibiosis in case of infection
• liver transplantation if necessary

Prognosis
• mortalitity: 50% (Voigtländer et al, Endoscopy 2012)
• median survival time: 13 months (Ruemmele; Nat Rev
Gastroenterol Hepatol 2009)

Infectiology 871
Diagnostics ICG clearance
• sonography: i.a. resistance index (RI; syn.: Pourcelot • indocyanine green:
index) in the hepatic artery (vsys - vdias) / vsys > 0.8 indi- -- anionic dye
cates reduced liver perfusion -- strict hepatic clearance
• laboratory -- no enterohepatic recirculation
• norm: ICG clearance > 16%
• an early marker of liver dysfunction
• correlation with mortality in sepsis (i.a. Malbrain et al,
Int Care Med 2006)
• The lower the ICG clearance, the higher the mortality
(e.g. ICG clearance 8% → mortality 80%).
• Kortgen et al, Shock 2009: significantly higher sensiti-
vity and specificity for septic liver failure than bilirubin
• systems
-- LiMON system (Pulsion company)
-- PiCCO 2 monitor (from software version 3.x, availa-
ble since 2009; the ICG module is inserted instead
of the module for central venous oxygen saturation)

Fig. 1114  determination of the resistance index RI (syn.:

Pourcelot index) in the hepatic artery by determination of
the maximum systolic velocity and the end-diastolic velo-
city; RI = (vsys - vdias) / vsys; RI > 0.8 indicates a reduced liver
perfusion

Laboratory
• static tests:
-- bilirubin
◦◦ pragmatic p.d. liver dysfunction from bilirubin
> 4 mg/dl (septic cholestasis; note: An increase in
liver function tests [transaminases, µGT] can be
found relatively frequently in ICU. This is usually
due to drug-toxicity [mainly due to antibiotics]. As
rule of thumb for the clinical everyday life with an
increase of liver function tests one can remember:
If bilirubin is not elevated, it is usually harmless
[Hy's law]).
◦◦ Typically the direct (conjugated) bilirubin is in-
creased. The conjugation still works, but energy-
dependent excretion and transport processes no
longer work (typically intrahepatic cholestasis!).
-- GOT (= AST), GPT (= ALT)
-- parameters of liver synthesis
◦◦ Quick < 50% resp. INR > 1.5 Fig. 1115  ICG: indocyanide green [30]
◦◦ albumin ↓ (half-life 19 days → reacts only very LiMON system
slowly → subordinated significance in acute liver
failure) • ICG 0.25 mg/kg i.v. / measurement (e.g. once daily)
◦◦ cholinesterase ↓ (half-life 14 days → reacts only -- 1 dry powder ampoule = 50mg, dissolve with 10ml
very slowly → subordinated significance in acute Aqua (5 mg/ml)
liver failure) -- max. 5 mg/kg daily
◦◦ factor V (activity) ↓ -- application via peripheral access possible (no central
• dynamic tests: venous catheter and no PiCCO artery necessary)
-- ICG clearance -- side effects: i.a. allergic reaction (cave especially
with iodine allergy)
-- LiMAx test
-- contraindications (ICG contains iodine!):
-- MEGX test
◦◦ iodine allergy
◦◦ manifest hyperthyroidism
• With the new PiCCO models, the software is already

872 Infectiology
 integrated in the device itself: The LiMON module is
plugged into the place where the CeVOX module (for
the central venous oxygen saturation) would otherwise
be plugged in.
• measurement
-- plasma disappearance rate (PDR) of ICG (norm:
ICG-PDR > 16%)
-- non-invasive (sensor on earlobe, finger clip)
-- principle: spectrometric
-- duration: 15min
• Critically one can surely ask the question, which the-
rapeutic consequence the diagnosis of a liver failure Fig. 1117  LiMON system for ICG clearance measurement
has at all. Extracorporeal liver replacement procedu- [30]
res have at least today no longer any significance at
all. On the one hand, however, the early diagnosis of
liver failure can certainly lead to the discontinuation
of potentially hepatotoxic drugs and, if necessary, to
a reduction of PEEP. The higher the PEEP, the hig-
her the intra-abdominal pressure and therefore the
lower the liver perfusion. Furthermore, the diagnosis
of septic liver failure has been confirmed and thera-
peutic measures that are discussed again and again
due to uncertainty (e.g. laparoscopic cholecystectomy
for questionable cholecystitis, ERCP for questionable
choledocholithiasis), which would only endanger the
patients, can be waived. On the other hand, among
all organ failures in sepsis, liver failure represents the
organ failure with the worst prognosis. If a septic liver
failure has now been diagnosed, it may help as one of
many components in the question of limitation or dis-
continuation of therapy.

Fig. 1118  ICG measurement (PDR: plasma disappearance

rate) using LiMON system; meanwhile the software is alrea-
dy integrated in the device itself

Fig. 1116  non-invasive spectrophotometric measurement

of ICG clearance (usually performed by using a finger clip)
[30].

Infectiology 873

Fig. 1119  ICG measurement: The PDR (plasma disappea-
rance rate) and thus the liver function is very low at 2.2%.
This can (together with many other factors, of course)
serve as a component for establishing a possible therapy
limitation or discontinuation.
LiMAx test
• maximal liver function capacity based on 13C-methace-
tin (MA) kinetics
• i.v. application of 13C-labelled methacetine
• Methacetine is degraded in the liver by the enzyme cyt
p450 1A2 into paracetamol and CO2.
• measurement of 13C-CO2 in exhaled air (by infrared
spectrometry) via a respiratory mask
• The higher the measured concentration of 13C-CO2 in
the exhaled air, the better the liver function.
Fig. 1120  LiMAx test [13]
MEGX test
• MEGX
-- monoethylglycinxylidide
-- main metabolite to which lidocaine is degraded in
the liver via cytochrome p450
• determination before and 15 min after lidocaine (xylo-
caine) administration (1 mg/kg bw i.v. over 2min)
874 Infectiology
• contraindications:
-- lidocaine allergy
-- high-grade AV block (Lidocaine acts as a class IB
antiarrhythmic negative chronotropic.)
-- severe heart failure (Lidocaine acts as a class IB an-
tiarrhythmic negative inotropic.)
• interpretation:
-- > 90 µg/l: good liver function
-- < 90 µg/l: impaired liver function
◦◦ 50-90 µg/l: slight
◦◦ 10-50 µg/l: moderate
◦◦ < 10 µg/l: severe (possibly liver transplant)
• only of minor importance (e.g. due to induction of cyto-
chrome p450 by numerous intensive-care drugs)
Therapy
• discontinuation of hepatotoxic drugs
• possibly high-dose N-ACC (e.g. 6 x 600mg i.v.)
• extracorporeal liver replacement procedures (e.g.
MARS, Prometheus)
-- indications (optional):
◦◦ bilirubin > 10 mg/dl
◦◦ ICG clearance (PDR) < 8-14%
◦◦ hepatic encephalopathy grade III / IV
-- significant improvement in liver function, but no ef-
fect on mortality
-- no general recommendation (no significance)
• possibly plasmapheresis (very efficient in acute liver
failure; EMPET study Larsen et al, J Hepatol 2015 [see
page 881])
• ventilation: The lowest possible ventilation pressures
should be used. Especially the PEEP should be set as
low as possible!
• ERCP: It is often performed in ignorance of the exis-
tence of the disease of septic liver failure. In septic liver
failure the direct (= conjugated) bilirubin is also incre-
ased. Ultrasound quality is often also not sufficient in
order to judge the commen bile duct (DHC) sufficiently
well. ERCP is associated with a very high expenditure
(transport of a ventilated patient in an X-ray system
[on-site imaging on the intensive care unit with the C-
arm does not provide sufficient image quality at all - at
least in our clinic], patient must be turned into prone
position) and is almost never effective! Often only a
(hardly comprehensible) microlith is removed, which
only the examiner has seen by himself. Tip for every-
day clinical use: It is much less complex to accomplish
an endosonography at the patient bed on the intensi-
ve care unit: Endosonography can certainly rule out a
concrement in the common bile duct (DHC). Only in
rare cases in which a concrement appears in endoso-
nography, an ERCP has to be performed afterwards.
septic liver failure: ERCP rarely
useful! tip: Endosonography should
be used first!

septic liver failure: no indication for
an extracorporeal liver replacement
procedure!
Septic encephalopathy
Definition
• acute, principally reversible and generalized cerebral
function impairment in sepsis
• an (also with intensive care physicians) often relatively
unknown clinical picture
• Hippocrates of Kos (400 BC), who introduced the term
sepsis (Greek: putrefaction), wrote in his work about
sepsis: "If delirium and dyspnea are added to fever,
then the patient is lost".
• 25% of all patients with sepsis (Young et al, Clin Invest
Med 1990; according to Chanques et al, Lancet Resp
Med 2017 even 50% of all patients with sepsis!)
• the most common encephalopathy in ICU
• an early symptom of sepsis
• always an exclusion diagnosis
• genesis: multifactorial (i.a. reduced cerebral perfusion,
cytokines, disturbance of the blood-brain barrier, neu-
rotransmitter imbalance
Symptoms
• already very early in sepsis (often the first sign of sep-
sis!)
• classically fluctuating course
• disturbance of consciousness:
-- qualitative (delir)
-- quantitative (somnolence, coma)
• personality change
• confusion, restlessness
• hallucinations
• apathy
• agitation, aggressiveness
• tremor, myoclonia, possibly seizures (rare)
• rigor
• pareses (symmetrical)
• But focal neurological deficits are completely atypical!
The most severe septic encepha-
lopathy is typically found in
endocarditis!
Diagnostics
• anamnesis, clinical (especially neurological) examina-
tion
• CCT, possibly MRT
• lumbar puncture (cerebrospinal fluid [CSF], liquor)
-- normal cell count (in contrast to meningitis, which
can also lead to sepsis), small protein increase (up
to 900 mg/l) is possible
-- Lumbar puncture is mainly performed to exclude
meningoencephalitis, but is usually not necessary.
It is usually only performed if meningoencephalitis is
suspected as the cause of sepsis, otherwise it is dis-
pensable for the diagnosis of septic encephalopathy.
• EEG (electroencephalogram; most sensitive)
-- frequency deceleration (predominant delta rhythm
up to burst suppression pattern)
-- The extent of EEG changes correlates very well with
the severity and prognosis of septic encephalopathy.
• possibly neuroelectrophysiology
-- SEP (sensory evoked potentials)
-- NCV (nerve conduction velocity)
-- EMG (electromyogram)
septic encephalopathy: always an
exclusion diagnosis!
Therapy
• no specific therapy
• therapy of sepsis
Infectiology 875
Prognosis
• The occurrence of septic encephalopathy during sep-
sis leads to increased mortality!
• Sepsis patients with septic encephalopathy have a hig-
her mortality than sepsis patients without septic ence-
phalopathy (60% versus 26%).
• prognostic factors
-- GCS (Glasgow Coma Scale)
◦◦ GCS 15: mortality 16%
◦◦ GCS 13-14: mortality 20%
◦◦ GCS 9-12: mortality 50%
◦◦ GCS 3-8: mortality 63%
-- EEG findings
◦◦ delta pattern: mortality 36%
◦◦ triphasic waves: mortality 50%
◦◦ burst suppression pattern: mortality 67%
• reversible (in principle)

876 Infectiology
 ◦◦ foreign body → retention pneumonia
PneumoniA ◦◦ immobility, bedriddenness → hypostatic pneumo-
nia
◦◦ swallowing disorder → aspiration pneumonia (fre-
quently anaerobes)
◦◦ bronchiectases
◦◦ immunosuppression (e.g. HIV infection) → pneu-
mocystis pneumonia
◦◦ mucoviscidosis, influenza infection → bacterial su-
perinfection
• according to lokalization:
-- wirh regard to the tissue:
◦◦ alveolar pneumonia
◦◦ interstitial pneumonia
-- wirh regard to the site:
◦◦ central pneumonia (10% [A central pneumonia is
relatively rare, so that one should think of a tumor
rather than an infiltrate in case of a central mass!])
◦◦ peripheral pneumonia (90%)
• according to chest X-ray:
-- lobar pneumonia (shading of a lobe)
Classification -- lobular pneumonia (= focal pneumonia [many small
• according to etiology: foci], bronchopneumonia [the pathogens are bron-
-- infectious (pneumonia in the narrower sense) chogenically distributed in different parts of the
-- allergic (alveolitis, e.g. exogenous-allergic) lungs]: shading of a segment)
-- physical (pneumonitis)
-- toxic bedside
-- autoimmund
• according to location:
-- community acquired pneumonia (CAP)
-- nosocomial pneumonia
• according to clinic:
-- typical pneumonia (typical clinic with high fever, pro-
ductive cough, dyspnea, increased inflammatory
markers
-- atypical pneumonia (atypical clinic; especially myco-
bacteria, legionella, chlamydia, viruses)
• according to course:
-- acute pneumonia
-- chronic pneumonia (e.g. tuberculosis)
• according to severity:
-- mild pneumonia
-- severe pneumonia
• according to germ:
-- bacterial pneumonia
-- virus pneumonia (see infobox)
-- fungal pneumonia
-- protozoan pneumonia
• according to the persence of a predisposing disease:
-- primary pneumonia (without predisposing disease)
-- secondary pneumonia (with coexisting predisposing
disease); examples:
◦◦ pulmonary embolism → infarction pneumonia
◦◦ decompensated congestive heart failure → con-
gestion pneumonia
◦◦ lung cancer (bronchial carcinoma) → retention
pneumonia

Infectiology 877
Fig. 1121  Example of a secondary pneumonia (retention
pneumonia caused by a foreign body): Here the patient had
unnoticedly aspirated a loose dental crown, which led to
severe pneumonia. The crown could finally be salvaged
bronchoscopically.

878 Infectiology

Fig. 1122  Chickenpox (varicella) are usually a harmless
childhood illness (first two pictures [with many thanks
to my little daughter Lena]). In adults, however, unlike in
children, they often show a severe course. Mainly affected
are immunocompromised patients. As here in the chest x-
ray, a varicella pneumonia can occur. Other complications
include meningoencephalitis, myelitis, hepatitis, nephritis,
and myocarditis. On the one hand, the rash can be seen
here, on the other hand, the typical juxtaposition of fresh
and healed blisters in different stages and crusts ("starry
sky"). The therapy of choice here is the high-dose adminis-
tration of acyclovir i.v. (3 x 10 mg/kg). They are highly con-
tagious (transmission through aerosols ["flying disease"]).
Infectivity already exists 1 day before the vesicles appear
and until all vesicles are crusted (usually 5-7 days after the
appearance of the rash [exanthem]).
Fig. 1123  Measles (not a harmless childhood disease!) with
the typical maculopapular and sometimes confluent exan-
them, which should not be confused with an allergy (The
most important distinguishing feature are the large raised
and palpable papules, which are usually not present in an
allergy.)
COMMUNITY ACQUIRED
PNEUMONIA (CAP)
Definition
• acute microbial infection of the lung parenchyma
• acquired in the domestic environment, i.e. outside hos-
pitals and healthcare facilities
Epidemiology
• most common infectious disease worldwide
• most frequent fatal infectious disease in industria-
lised countries
• mortality (hospitalized patients): 14% (if requiring in-
tensive care: 33%; unfortunately often underestimated
in its importance: For example, the mortality of a hospi-
talized patient with community-acquired pneumonia is
higher than that of ahospitalized patient with STEMI!)
• incidence: 750/100000
• 400000-600000 cases per year in Germany, thereof
approx. 200000 inpatient treatments per year (Compe-
tence Network CAPNETZ)
Infectiology 879
Pathogenesis • p rotozoa
• mostly microaspiration of germs from oropharynx and • i n 25% no germ identifiable
nasopharynx
• most frequent pathogen (germ): pneumococcus
Risk factors
for pseudomonas
Guidelines
• international: Diagnosis and Treatment of Adults with
Community-acquired Pneumonia. An Official Clinical
Practice Guideline of the American Thoracic Socie-
ty (ATS) and Infectious Diseases Society of America
(ISDA) 2019
• national (German) S3 Guideline 2016: Epidemiology,
Diagnostics, antimicrobial Therapy and Management
of Adult Patients with Outpatient Acquired Lower Re-
spiratory Tract Infections and Outpatient Acquired
Pneumonia (Paul Ehrlich Society for Chemotherapy,
German Society for Pneumology and Respiratory Me-
dicine, German Society for Infectious Diseases, Com-
petence Network CAPNETZ)

Germs Symptoms
• bacteria • malaise
-- pneumococcus (50%, No.1) • dyspnea
◦◦ syn.: streptococcus pneumoniae • tachypnea (specify respiratory rate!)
◦◦ gram-positive diplococci • cough with purulent expectoration
◦◦ antibiotic agent of choice: Penicillin G • disturbance of consciousness
◦◦ resistance • hypotension, tachycardia
▪▪ penicillin G: only 1% in Germany (99% of pneu- • myalgia, arthralgia, headache
mococci are penicillin sensitive; increased peni-
cillin resistance however in Spain and France)
▪▪ macrolides: 18%
▪▪ ciprofloxacin: ineffective!
-- hemophilus influenzae (8%; No.2)
-- mycoplasma pneumoniae (No.3)
◦◦ especially in younger patients (8%)
◦◦ increasing macrolide resistance especially in Ja-
pan, China and Taiwan (Spuesens et al, J Infect
2014); in Germany only 3.6%.
-- legionella pneumophila (4%)
-- chlamydia pneumoniae (very rare)
-- moraxella catarrhalis
-- staphylococcus aureus
-- klebsiella pneumoniae (Friedländer´s pneumonia:
shading typically in both upper lobes; often space-
consuming and necrotizing)
-- pseudomonas aeruginosa
◦◦ rare pathogen of a community acquired pneumo-
nia (in contrast to nosocomial pneumonia: here
second most frequent pathogen
◦◦ risk factors for pseudomonas → see infobox
-- anaerobic bacteria (especially in aspiration pneumo-
nia)
-- mycobacterium tuberculosis (TBC; typically in the
upper lobe, mostly on the right)
• viruses (15%; RSV, adenoviruses, influenza viruses
[including H1N1], parainfluenza viruses, enteroviru-
ses, coronaviruses [especially SARS-CoV-2])
• fungi

880 Infectiology
Diagnostics
• anamnesis, physical examination (e.g. respiratory rate
> 30/min, dull percussion sound, reduced respiratory
noise, bronchial respiration)
• laboratory (e.g. blood count [classical: leukocytosis],
differential blood count [left shift], electrolytes, creatini-
ne, urea, transaminases, CRP, possibly procalcitonin)
• BGA
• microbiology
• chest X-ray
-- 2 views
-- evidence of a reduction in transparency, a positive
bronchopneumogram or an infiltrate (Note: Accor-
ding to recent radiological recommendations opaci-
ties are no longer referred to as infiltrations, but as
consolidations.)
-- differentiation lobar- versus bronchopneumonia
-- Radiological follow-up checks are frequently perfor-
med in everyday clinical practice. As a rule, this is
not indicated: The course of the disease is mainly
evaluated clinically and laboratory, but not radiologi-
cally. The infiltrates often persist for a longer period
of time, so that a follow-up makes only sense at the
earliest after 4 weeks (e.g. to exclude malignancy)!
The S3 guidelines recommend an X-ray control (to
exclude a non-infectious infiltrate) at the earliest 2
weeks after completion of the antibiotic therapy and
only in smokers, patients aged > 65 years or with Fig. 1124  Chest X-ray: right-sided pneumonia (different ex-
severe concomitant diseases. amples)
• possibly thoracic sonography:
-- in pleuropneumonia, evidence of a pleural effusion
-- An infiltrate close to the pleura can be recognized
as a "hepatized" lung, i.e. you can see tissue in the
thorax that looks like liver. Pneumonia displaces the
air from the lungs so that it is visible and, with the
appropriate expertise, also recognizable in the ult-
rasound. Typically, you can still see some remaining
air in the consolidation (air reflexes), in contrast to a
tumor in which the air reflexes are missing
• possibly chest CT
• possibly bronchoscopy

Infectiology 881
 Fig. 1127  Chest CT: left-sided pneumonia (The positive
bronchopneumogram is clearly visible.)

Fig. 1125  Chest x-ray: lobar pneumonia right-sided

bedside

Fig. 1128  chest CT: pronounced lobar pneumonia in the

right upper lobe (here even evidence of pneumococci in the
blood culture)

Fig. 1129  chest CT: lobar pneumonia in the right lower lobe
(The positive bronchopneumogram can also be clearly
Fig. 1126  Chest X-ray: right-sided pneumonia with positive seen here.)
bronchopneumogram (arrows; various examples)

882 Infectiology
 DD total shading of a lung:
no routine radiological follow-up of
mediastinum displaced to the
pneumonia!!
healthy side (contralateral): pleural
effusion (sonography) → puncture
mediastinum displaced to the sick
side (ipsilateral): atelectasis →
bronchoscopy

Microbiology
• sputum (not saliva; sample with > 25 granulocytes
and < 10 squamous epithelial cells per visual field at
100-fold magnification meets the quality criteria of a
sputum)
• blood culture (2 x 2 pairs)
• urine (quick tests):
-- legionella antigen
◦◦ ELISA test
◦◦ detection of serogroup 1
◦◦ evaluation: specificity 99% (proving), sensitivity
80% (A negative test does not exclude Legionella!)
◦◦ S3 guidelines: recommended
Fig. 1130  Chest X-ray: There is a total shading of the left -- pneumococcal antigen
lung. Possible differential diagnoses are an extensive pleu-
◦◦ immunochromatographic membrane test
ral effusion and a total alectasis of the left main bronchus
(e.g. by a mucus plug). The pleural effusion can easily be ◦◦ detection of pneumococcal cell wall polysacchari-
detected or excluded with sonography. The distortion of de (also positive for streptococcus mitis and oralis)
the mediastinum to the ispilateral (i.e. sick) side with a cor- ◦◦ result within 15 minutes
responding reduction in volume on the left is indicative for
◦◦ positive even under antibiotisis
an atelectasis. In this case a bronchoscopy is necessary.
A not uncommon cause in invasively ventilated patients is ◦◦ evaluation:
unilateral intubation (i.e. endobronchial instead of endotra- ▪▪ sensitivity 75%, specificity 90%
cheal; mostly on the right): Here you only need to retract ▪▪ positive predictive value 91%, negative predic-
the tube. tive value 83%
◦◦ S3 guidelines: not recommended (pneumococci
always have to be covered by the initial calcula-
ted antibiotic anyway!); however, this is carried
out in many places because it is possible to de-
escalate the antibiotic therapy during the course
of the treatment and, last but not least, because
the DRG- reimbursement ("germs bring money")
increases in the case of a proven germ.
• possibly mycoplasma serology (antibodies [especially
IgM])
• if necessary pleural puncture (gram staining, culture;
pH, protein, LDH); Tip: For microbiological dia-
gnostics, it is best to inoculate blood culture bottles
with the puncture specimen in addition to the standard
sample tubes (considerably higher yield)!
• if necessary bronchoscopy

Bronchoscopy
• indications:
Fig. 1131  Chest X-ray: There is also a total shading of the -- immunosuppressed patients
left lung. Possible differential diagnoses here are again
-- suspected bronchial stenosis
pronounced pleural effusion and total atelectasis of the left
main bronchus. The distortion of the mediastinum to the -- suspected tuberculosis (especially with infiltrates in
contralateral (i.e. healthy) side is indicative of a pleural ef- the upper lobe)
fusion. The pleural effusion can easily be recognized sono- -- infiltrate in the middle lobe (right-sided; often tumor
graphically. A pleural puncture is necessary here. as cause of retention pneumonia)
-- therapy failure
• secretion collection

Infectiology 883
 -- bronchial secretion; possibly BAL (bronchoalveolar
lavage
◦◦ site: usually (generally) in the area of the lingula
(left) or, in the case of pneumonia, in the area of
the focal point in the chest X-ray
◦◦ procedure: repetitive rinsing with 100ml saline so-
lution in total and subsequent suction, recovery of
50-100ml
◦◦ contraindications:
▪▪ severe respiratory insufficiency with a Horovitz
quotienten < 100mmHg
▪▪ absceding pneumonia (due to the potential
spread of germs)
-- PSB (protected specimen brush)
• The more severe the pneumonia, the earlier the bron-
choscopy for the isolation of germs should be perfor-
med.
• If the patient still breathes spontaneously, but is alrea-
dy borderline with the gas exchange, so that one fears
that endotracheal intubation could become necessary
due to the sedation required during bronchoscopy, the
options are as follows:
-- bronchoscopy via the side holes of the oxygen mask
(oxygen flow 15 l/min)
-- insertion of a transnasal probe in the throat, through
which oxygen is then applied during bronchoscopy
-- non-invasive ventilation: NIV is performed during
bronchoscopy, which is performed using an angle
adapter. However, this is often not easy due to the
angle and the standoff distance.
• The obtained samples must be at the microbiologist's Differential diagnoses
within 4 hours (no storage if possible [if not otherwise
• tuberculosis
possible in the refrigerator and not at room tempera-
ture], otherwise nothing grows! Pneumococci can only -- typically in the upper lobe
be detected for up to two hours! That is why it is al- -- for standard therapy see infobox (including S2k gui-
most always the case in everyday clinical practice that deline tuberculosis in adulthood 2017)
pneumococci are never detected in the endotracheal • bronchial carcinoma (retention pneumonia)
secretion, although they are actually the most common • pulmonary embolism (infarction pneumonia [typically
pneumonia pathogen triangular with the base facing peripherally])
• There are numerous germs whose detection in bron- • COP (cryptogenic organizing pneumonia; very good
chial secretion / BAL is usually only a colonisation and response to steroids)
no infection and therefore no indication for antibiotic • exogenous allergic alveolitis (EAA)
treatment (see infobox). • allergic bronchopulmonary aspergillosis (ABPA; asth-
ma, eosinophilia, IgE ↑)
• diffuse alveolar hemorrhage (DAH; see page 717)

884 Infectiology
 Fig. 1133  Chest x-ray: tuberculosis with a cavern in the
right upper lobe

bedside

Fig. 1132  Chest X-ray If opacities affect the upper lobe (va-
rious examples here) one should always think of tubercu-
losis!

Fig. 1134  Cavern in the left upper lobe (in the first image
the chest X-ray, in the second image the chest CT)

Infectiology 885
Fig. 1135  Chest CT: tuberculosis in the left upper lobe
Fig. 1138  Chest CT: miliary tuberculosis (here after BCG
instillation in the case of bladder cancer)

Fig. 1136  Chest CT: cavern of the right upper lobe

Fig. 1137  Chest CT in extensively florid tuberculosis

886 Infectiology

Therapy
• antibiotics
-- calculated
-- after antibiogram (after receiving the microbiologi-
cal results incl. antibiogram [mostly on day 2 or 3]
change of antibiotic): i.a.
◦◦ pneumococci: means of choice Penicillin G (Note:
Macrolides are administered in pneumonia be-
cause of their immunomodulatory effect. This is
most important in the first three days, so macroli-
des are given for three days. The pathogen detec-
tion including antibiogram is usually only obtained
after 2-3 days, so that if pneumococcal pneumonia
is confirmed then no combination with a macrolide
is necessary.)
◦◦ legionella: means of choice fluoroquinolones (es-
pecially levofloxacin; no longer macrolides), pos-
sibly combination therapy with rifampicin
• thrombosis prophylaxis, early mobilization
• respiratory therapy (breathing training)
• mucolytics
-- ACC 600mg p.o./i.v. 1-0-1 (more interactions)
-- Ambroxol 15mg p.o./i.v. 1-1-1 (less interactions)
• if necessary oxygen supply
• if necessary ventilation
-- non-invasive ventilation (however, high failure rate of
30%; no general recommendation); very good opti-
on: HFNOT (high-flow nasal oxygen therapy)
-- invasive ventilation
• possibly steroids
-- advantages described in STEP study (see box]), in a
further RCT (Torres et al, JAMA 2015) and in a me-
ta-analyses (Siemieniuk et al, Ann Intern Med 2015)
and in patients with septic shock (Tagami et al, Eur
Respir J 2014)
-- but no general recommendation yet
-- currently ongoing: ESCAPE study
-- only indicated with additional obstruction (e.g. COPD
exacerbated by pneumonia) or with COP (cryptoge-
nic organizing pneumonia [very good response])
• immunoglobulins: no recommendation (i.a. CIGMA
study [Phase II study, Welte et al, Intensive Care Med
2018; see page 860]: no advantage in severe [requi-
ring ventilation] pneumonia)
• REMAP-CAP study (Randomized, Embedded, Mul-
tifactorial Adaptive Platform Trial for Community-Ac-
quired Pneumonia): currently ongoing (planned 4000
patients) and EU-funded study with several questions:
-- antibiotic (ceftriaxone, piperacillin / tazobactam,
moxifloxacin)
-- steroids yes / no
-- macrolides short-term / long-term
-- ventilation (i.a. tidal volume [6 ml/kg], extracorporeal
CO2 removal, APRV [airway pressure release ven-
tilation])
• therapy of complications:
-- pleural effusion (parapneumonic)
-- pleural empyema
-- lung abscess
STEP study
Adjunct prednisone therapy for patients with community
acquired pneumonia: a multicenter double-blind rando-
mised placebo-controlled trial
Blum et al, Lancet 2015
• multicenter double-blind randomised placebo-controlled
study
• 785 patients with community acquired pneumonia and
antibiotic therapy
-- with prednisone (50mg daily for 7 days)
-- ohne Prednison
• results: prednisone
-- primary endpoint (time to clinical stability [i.e. SpO2 >
90%, paO2 > 60mmHg, SBP > 90mmHg, HR < 100/
min, T < 37.8°C, respiratory rate < 24/min]): signifi-
cantly reduced (by 1.4 days)
-- secondary endpoints:
◦◦ hospital length of stay: significantly shortened
◦◦ pneumonia related complications: no difference (no
increased rate)
◦◦ insulin-dependent hyperglycemia: significantly
more frequent
Antibiotics (calculated)
• outpatient therapy (therapy duration: 5-7 days):
-- without risk factors (see infobox):
◦◦ amoxicillin (means of choice; < 70kg: 3 x 0.750g,
> 70kg: 3 x 1g) p.o.
◦◦ alternative:
▪▪ newer macrolide p.o. (azithromycin [Zithromax]
1 x 500mg, clarithromycin [Klacid; only 20%
of oral dose is absorbed, therefore for severe
pneumonia i.v.-administration] 2 x 500mg, roxi-
thromycin [Rulid; high resorption if administered
p.o] 1 x 300mg)
▪▪ doxycycline (1 x 200mg, then > 70kg: 1 x 200mg,
< 70kg 1 x 100mg)
-- with risk factors (see infobox):
◦◦ amoxicillin / clavulanic acid (Augmentan; means of
Infectiology 887
 choice; 2 x 875/125mg) p.o.
◦◦ alternative: pneumococcus-active fluoroquinolone community acquired pneumonia:
p.o. generous combination therapy!
▪▪ moxifloxacin (Avalox) 1 x 400mg
▪▪ levofloxacin (Tavanic) 2 x 500mg In a meta-analysis (Vardakas et al, Eur J Clin Invest), the
▪▪ not ciprofloxacin (Ciprobay): no activity against combination therapy with a beta-lactam and a macrolide
pneumococci! showed a lower mortality than monotherapy with a beta-
-- note: no oral cephalosporins lactam. In the CAP-START study (Antibiotic treatment
• inpatient therapy: strategies for community-acquired pneumonia in adults;
Postma et al, N Engl J 2015), monotherapy with a beta-
-- normal ward (therapy duration: 5-7 days):
lactam was not inferior to the combination therapy of a
◦◦ amino-penicillin + β-lactamase inhibitor in com- beta-lactam and a macrolide with regard to the mortality
bination with a macrolide (especially due to their after 90 days, so that the combination with a macrolide is
immunomodulating effects; for 3 days; e.g. clari- only optional for mild and moderate CAP, but mandatory
thromycin [Klazid] 2 x 500mg p.o. [only 20% of oral for severe CAP!
dose is absorbed, therefore for severe pneumonia With severe CAP (requiring ICU) and suspected MRSA
i.v.-administration]) (e.g. known MRSA colonization) linezolid should also ad-
▪▪ amoxicillin / clavulanic acid (Augmentan) 3 x ditionally be administered.
2.2g (not 1.2g!) i.v. +
▪▪ ampicillin / sulbactam (Unacid) 3 x 3g i.v.
◦◦ cephalosporin + macrolide
▪▪ ceftriaxone (Rocephin) 1 x 2g i.v.
▪▪ cefuroxime (Zinacef) 3 x 1.5g i.v.
▪▪ cefotaxim (Claforan) 3 x 2g i.v.
◦◦ pneumococcus-active fluoroquinolone (not: cipro-
floxacin [no activity against pneumococci!] )
▪▪ moxifloxacin (Avalox; best activity against
pneumococci among all fluoroquinolones!) 1 x
400mg i.v. (loading dose: 2 x 400mg on day 1
and day 2)
▪▪ levofloxacin (Tavanic) 2 x 500mg i.v. (cave red
hand Letter [warning of risks] in Germany 2012:
QT time extension → prior ECG with determina-
tion of QT interval obligatory!)
-- ICU:
◦◦ without risk factors for pseudomonas (therapie
duration: 8-10 days): always combination with a
macrolide (for 3 days)
▪▪ piperacillin / tazobactam 3 x 4.5g i.v.
▪▪ 3rd generation cephalosporin (ceftriaxone 1 x
2g i.v., cefotaxim 3 x 2g i.v.)
▪▪ alternative: monotherapy with a pneumococcus-
active fluoroquinolone (moxifloxacin, levofloxa-
cin), but only in patients without septic shock
and without ventilation
◦◦ with risk factors for pseudomonas: always in
combination with a pseudomonas-active fluoroqui-
nolone (e.g. ciprofloxacin 3 x 400mg i.v., levoflo-
xacin 2 x 500mg i.v.; nott: moxifloxacin [no activity
against pseudomonas]); therapy duration in case
of detection of pseudomonas: 14 days
▪▪ piperacillin / tazobactam 3 x 4.5g i.v.
▪▪ cefepime (Maxipime) 3 x 2g i.v. (cave severe
neurological side effects [especially encephalo-
pathy] at GFR < 50 ml/min)
▪▪ ceftazidime (Fortum) 3 x 2g (also very effecti-
ve against pseudomonas, but only poorly in the
gram-positive range, i.e. only very poor against
pneumococcus, therefore not as monotherapy)
▪▪ carbapenems (e.g. imipenem 3 x 1g i.v., mero-
penem 3 x 1g i.v.)

888 Infectiology
 • always strive for a diagnostic puncture in the case
cave macrolides: numerous of larger pleural effusions (essential for the decision
drug-interactions on the necessity of thoracic drainage! "The sun must
never set over a parapneumonic effusion!")
• types:
Macrolides are inhibitors of the cytochrome P450 isoen- -- uncomplicated parapneumonic effusion:
zyme 3A4 (CYP3A4). This is especially true for clari- ◦◦ pH > 7.2
thromycin and erythromycin. For azithromycin and roxi-
◦◦ glucose > 40 mg/dl
thromycin, on the other hand, this is almost not the case
(clinically not relevant), so that these two macrolides ◦◦ LDH < 1000 U/l
have significantly fewer interactions. But a cohort study ◦◦ sonography: no septation / chambering
(Zaroff et al, JAMA 2020) also showed a significantly hig- ◦◦ microbiology: negative (no detection of bacteria)
her risk of cardiovascular death for azithromycin compa- -- complicated parapneumonic effusion:
red to a β-lactam (amoxicillin). ◦◦ pH < 7.2
◦◦ glucose < 40 mg/dl
◦◦ LDH > 1000 U/l
study ◦◦ sonography: septation / chambering
◦◦ microbiology: positive (detection of bacteria)
• therapy:
-- uncomplicated parapneumonic effusion: puncture
Use of clarithromycin and roxithromycin and risk of cardiac (repeated if necessary)
death -- complicated parapneumonic effusion: thoracic drai-
Svanström et al, BMJ 2014 nage (possibly CT-controlled), with seperated effusi-
on intrapleural fibrinolysis
• large Danish cohort study in adult patients (160,297 pa-
tients)
• antibiotics:
parapneumonic effusion: always
-- penicillin V puncture (obligatory!)
-- macrolide
◦◦ clarithromycin
◦◦ roxithromycin
• result: compared to penicillin increased risk of cardi- pleural puncture: always also determi-
ac death for clarithromycin ne pH (BGA)! pH < 7.2: thoracic
-- absolutely by 37% drainage obligatory!
-- but only during therapy
-- independent of simultaneous intake of cytochrome P
450 A3 inhibitors Pleural empyema
-- especially in women • frequency:
-- not valid for roxithromycin -- 10% of all patients with a parapneumonic effusion
develop a pleural empyema.
-- 4% of all patients with pneumonia develop a pleural
Complications empyema.
• local: • risk factors:
-- progression of pneumonia (5-10%) -- germs: S. aureus, Klebsiella, E. coli
-- pleural effusion (parapneumonic; 40%) -- patient: i.a. alcoholics, diabetics, i.v.-drug addicts,
-- pleural empyema (4%) bronchial carcinoma, neurologic disease with aspi-
-- lung abscess ration, immunosuppression
• systemic: • air bubbles (gas-forming pathogens) typically in the CT
-- ARDS • puncture fluid:
-- sepsis, septic shock, multiorgan failure ( Pneumo- -- turbid (important DD to chylothorax [chylothorax:
nia is the most common cause of sepsis!) triglycerides > 110 mg/dl])
-- heart failure (ejection fraction ↓) -- such as complicated parapneumonic effusion, in
addition detection of pus (neutrophils in differential
Pleural effusion (parapneumonic) blood count)
• frequency: 40% for pneumonia (pleuropneumonia) • motality: 20%
• exudate according to the Light criteria: • therapy:
-- protein > 3 g/dl or pleura protein / serum protein > -- non-organized pleural empyema: interventional (ho-
0.5 racic drainage [preferably CT-controlled] + intrapleu-
-- LDH > 200 U/l or pleura LDH / serum LDH > 0.6 ral fibrinolysis)
-- organized pleural empyema: surgical (early; inclu-

Infectiology 889
 ding adhesiolysis, removal, decortication of pleural
scar tissue)
◦◦ thoracoscopy (VATS: video-assisted thoracosco-
py)
◦◦ thoracotomy (in 10-20% intraoperative switch from
thoracoscopy to thoracotomy necessary)

complicated parapneumonic
effusion or pleural empyema:
always place thoracic drainage
(obligatory!)

Fig. 1139  Thoracotomy of a patient with pneumococcal

pneumonia and organized pleural empyema: first before,
then after decortication (courtesy of Dr. Heiligensetzer, De-
puty Director of the Clinic for Surgery, Caritas Hospital St.
Josef, Regensburg [Germany])

Intrapleural fibrinolysis
• Urokinase
-- 100000 IE with NaCl 0.9% in 50ml perfusor syrin-
ge, instill locally over the inserted thoracic drainage,
then clamp off for 2h, then again at suction
-- once a day for 4 days
-- further rinsing with 50ml NaCl 0.9% via perfusor sy-
ringe 4 times daily (actively instill and actively suck
off)
-- success rate: 88%
• Varidase
-- 1 amp. Varidase: 125000 IE = 100000 IE streptase +
25000 IE streptodornase
-- Varidase 125000 IE with NaCl 0.9% in 50ml perfu-
sor syringe, instill locally over the inserted thoracic
drainage, then clamp off for 2h, then again at suction
-- further rinsing with 50ml NaCl 0.9% via perfusor sy-
ringe 4 times daily (actively instill and actively suck
off)
• Actilyse (Alteplase, rt-PA): 10mg with NaCl 0.9% in
50ml perfusor syringe, instill locally over the inserted
thoracic drainage, then clamp off for 2h, then again at
suction (Note: Since we can no longer supply Urokina-
se or Varidase, we use Actilyse.)
• note: In some places Granudacyn (hydrochloride so-
lution; 100-200ml) is also given through the thoracic
drainage. This is a wound irrigation solution and is not
officially approved for intrapleural administration

Lung abscess
• DD for pleural empyema using CT (see table)
• always perform bronchoscopy (to exclude bronchial
obstruction)
• therapy:
-- conservative ( heals in 80% under conservative
therapy, mostly sufficient!); antibiosis:
◦◦ amoxicillin / clavulanic acid (also effective against
anaerobic bacteria)
◦◦ cephalosporin (cefuroxime, ceftriaxone, cefotaxi-
me) + clindamycin (3-4 x 600mg i.v.)

890 Infectiology
 -- interventional: relief through CT-guided drainage in-
sertion
-- surgical: rarely necessary

CT morphological differentiation
pleural empyema lung abscess
wall thin thick
vessels presen not present
compression of the
adjacent lung yes no
separation of the yes ("split pleura
pleural leaves sign") np
contrast agent
uptake no yes Fig. 1141  Air bubbles (arrow) in the pleural effusion sug-
gest a pleural empyema. Alternatively, they are also pos-
sible if a pleural puncture has been performed shortly be-
forehand.

Options in therapy failure

• chest CT: to rule out a complication of pneumonia
(pleural empyema, lung abscess)
• bronchoscopy
-- to exclude obstruction / tumor
-- with BAL (incl. viruses [HSV, Infuenza, H1N1, also
SARS-CoV-2 during the pandemic], mycoplasma,
pneumocystis, mycobacterium tuberculosis, nocar-
dia, actinomycetes, fungi
• antibodies against mycoplasma (serology; means of
choice: macrolides)
• exclusion of immunosuppression (HIV test)
• change or extension of anti-infective therapy (additio-
nally cover MRSA or fungi

if no improvement within 72h: do

not immediately change antibiot-
ics, but think of the complications
of pneumonia (e.g. pleural
empyema, abscess) and perform
CT!

Fig. 1140  Chest CT: right-sided lung abscess

Infectiology 891
 be dissolved. The pneumothorax is resolved anyway
by the suction applied afterwards.)
• haematothorax (If the thoracic drainage promotes >
2000 ml/d or > 200 ml/h, surgery should be perfor-
med.)
• ventilated patients with thoracic trauma before planned
transport with the emergency rescue helicopter
• skin emphysema (palpable crepitation; if intubation is
required, prophylactically place a thoracic drainage pri-
or to ventilation if possible, even if no pneumothorax is
visible in the chest X-ray)
• after thoracic surgery
• traumatic cardiovascular arrest (e.g. traffic accident,
fall from great height): A thoracic drainage (at least as
a minimal variant the bilateral relief puncture) should
be applied generously on both sides during resusci-
tation (especially with even the slightest suspicion of
thoracic trauma). Bilateral thoracic drainage improves
the probability of survival (Huber-Wagner et al, Resus-
citation 2007).

Pneumothorax

Fig. 1142  Chest X-ray and chest: CT severe mycoplasma

pneumonia (means of choice: macrolides)

Excursus: Thoracic drainage

Definition
• syn.: chest tube
• plastic catheter in the pleural space for the suction of
air or liquid
• application of a permanent negative pressure (suction)
to unfold the collapsed lung
• physiological negative pressure in the pleural space
(pleural pressure)
-- exspiration: - 4 cmH2O
-- inspiration: - 8 cmH2O
• sizes: 16-32 Ch
Indications
• pneumothorax
• complicated pleural effusion, pleural empyema (Tip for
a chambered or septate pleural effusion: Here it is best
to wait a few minutes before connecting the drainage
with the drainage system, i.e. the patient is allowed to
breathe through the inserted drainage so that a pneu-
mothorax develops. As a result, the glued pleural lea-
ves separate from each another and the chambers can
• indication for the installation of a thoracic drainage
from an extension > 3cm
• Smaller pneumothoraces (mantle pneumothorax, i.e.
< 3cm) usually only have to be observed (if the patient
is not ventilated) with the addition of oxygen (at least 3
l/min continuously without interruption), they often re-
sorb themselves (rationale of oxygen administration:
In the pneumothorax the nitrogen content is relatively
high with 78% according to the inhaled air. If now an in-
haled mixture becomes rich in oxygen and consequent-
ly poorer in nitrogen, the nitrogen diffuses according to
the concentration gradient from the pneumothorax out
into the lungs, i.e. the pneumothorax becomes smaller.
Oxygen has a higher density compared to nitrogen, i.e.
a smaller volume.).
• tension pneumothorax:
-- manifests itself mostly shortly after intubation (practi-
cally only during ventilation; remarkably high ventila-
tion pressure)
-- valve mechanism
-- mediastinal shift to the healthy side
-- upper venous congestion (congested jugular veins

892 Infectiology
 [cave: may be missing in hypovolemia, e.g. in a po-
lytrauma patient], cyanosis), shock, possibly skin
emphysema (palpable crackling
-- auscultation: attenuated breathing sound (after veri-
fication of correct tube position); percussion: hyper-
resonant percussion sound
-- lethal within a few minutes → immediate decom-
pression obligatory
◦◦ relief puncture as a bridging measure (e.g. with
an orange peipheral venous cannula in Monaldi
position); note: It is important that the needle has
a sufficient length! The distance to be overcome
in Monaldi position is 40-50mm, in Bülau position
35-40mm. In the meantime, there are special relief
puncture needles for this purpose
◦◦ placement of a thoracic drainage
• Every pneumothorax (even if < 3cm) in a ventilated pa-
tient (positive pressure ventilation) should always be
relieved immediately!

Fig. 1145  Chest X-ray: complete right-sided pneumothorax

with mediastinal shift (easy to recognize by the trachea [see
arrow]) to the left in the sense of a tension pneumothorax

Fig. 1143  Chest x-ray: left-sided pneumothorax

Fig. 1146  Chest x-ray: On the right side a pleural effusion

can be seen (on the laterally rising Ellis-Damoiseau line
[black arrows]). Furthermore, a horizontal line (level [white
arrow]) is visible. This is evidence for an additional pneu-
mothorax. One speaks here of a seropneumothorax.

Fig. 1144  Chest X-ray: left-sided pneumothorax with medi-

astinal shift to the right in the sense of a tension pneumo-
thorax

Infectiology 893
 bedside

bedside

Fig. 1147  Chest X-ray: The line typical for a pleural effusi-
on, which rises laterally (Ellis-Damoiseau line), is not reco-
gnizable, if the x-ray was taken with the patient lying down Fig. 1149  Chest X-ray: pronounced skin emphysema
("bedside images"). Here, a milky homogeneous reduction
of transparency can be seen due to the leakage of the effu-
sion (here on the right).

Fig. 1150  Chest CT: pneumothorax, mediastinal emphyse-

ma and skin emphysema

bedside

Fig. 1148  Chest X-ray: skin emphysema

894 Infectiology
Fig. 1151  skin emphysema: Air accumulates in the sub-
cutaneous fatty tissue. The patients seem massively bloa- bedside
ted In addition to the neck, thorax, trunk and extremities,
the face (especially the eyelids [it may not be possible to
open the eyes]; the nose is usually left out) and the scro-
tum are particularly affected. Classically, you can palpate
a crackling on the thorax. Although it looks frightening, it
is usually harmless and, if the triggering cause has been
eliminated, usually disappears again quickly. If skin emphy-
sema occurs with an already inlying thoracic drainage, you
should check that the drain is not dislocated: If this slips
out a little, it may be that the side holes of the drainage
are no longer in the pleural space, but in the subcutaneous
fatty tissue and thus cause the skin emphysema. Then you
just have to push the drainage back into the pleural space.

Fig. 1153  pitfall skin fold (here routine chest x-ray after the
implantation of a permanent pacemaker): On the right, the-
re is no pneumothorax, just a skin fold (see arrows). The
line runs over the lung border, furthermore the vessels can
be seen up to the periphery.

bedside
Fig. 1152  pleural sonography for a hemothorax: An orga-
nized hematoma can already be seen.

Fig. 1154  pitfall skin fold: On the right, there is no pneumo-

thorax, but just a skin fold (see arrows). The vessels can be
seen up to the periphery.

Infectiology 895
Fig. 1155  pitfall scapula: This is only the medial edge of the
scapula (shoulder blade) and not a pneumothorax.
bedside

Fig. 1157  pitfall pleural effusion in the interlobar gap: The

patient had a pronounced pleural effusion on the right, so
that pleural puncture was carried out, which was stopped
after 1500 ml to prevent re-expansion edema, so that ul-
timately some pleural effusion remained. After the pleural
puncture, a chest x-ray was carried out to rule out a pneu-
mothorax. There was a line on the right (see arrows) that
can easily be confused with a pneumothorax line. On closer
inspection, however, one can clearly see vessels also late-
rally and apically of the line, so that it cannot be a pneu-
mothorax. Ultimately, it was just a pleural effusion in the
interlobar gap, which the CT thorax was able to show well.

Fig. 1156  pitfall cavern: This is not a pneumothorax, but a

large cavern in a patient with tuberculosis. Thoracic draina-
ge is not indicated here.

896 Infectiology
 Fig. 1159  Meanwhile the are now special needles for relief
puncture in a tension pneumothorax on the market. They
have the advantage over peripheral venous cannulas that
they are longer. In the last picture a Heimlich valve is at-
tached, but this is not absolutely necessary in practice.

Localization
• according to landsmarks:
-- Bülau drainage (named after the German internist
Gotthard Bülau [1835-1900]): 4th ICS, anterior axilla-
ry line ( to be preferred; never below the mamille!)
-- Monaldi drainage (named after the Italian physician
Vincenzo Monaldi [1899-1969]: 2nd ICS, mediocla-
vicular line (only recommended cautiously due to im-
mediate proximity to large vessels; relatively narrow
intercostal space; only suitable for pneumothorax)
• according to imaging:
Fig. 1158  The patient suddenly had a ventilation problem: -- guided by sonography
The respirator couldn't get any more air into the patient, -- guided by CT (good option e.g. for chambered pa-
she had to be ventilated manually by the hand (Ambu bag). rapneumonic effusion or pleural empyema)
The saturation kept falling. Furthermore there was a break-
down of the circulation, the catecholamine perfusors were
turned up massively. During auscultation, the right side
showed a weaker breathing sound compared to the opposi-
te side. Pleural sliding was absent in pleural ultrasound. Im-
mediately the relief puncture was performed with an orange
peripheral venous cannula (14G) in Monaldi position on the
right. As a result, the air hissed out, so that both the ven-
tilation situation and the circulation immediately improved
dramatically. In the further course, a chest x-ray and the
installation of a thoracic drainage wa performed. The cause
of the entire symptomatology was a tension pneumothorax
induced by excessive ventilation pressures (RAP: respira- Fig. 1160  Thoracic drainage catheters (chest tubes) with
tor-associated pneumothorax). trocar in different sizes: black (10Ch), orange (16Ch; mostly
sufficient for pneumothoraces), blue (24Ch; mostly suffici-
ent for pleural effusions), green (28Ch)
If a ventilated patient suddenly
experiences problems in ventilation
("I can't get any more air in") AND in
circulation (hemodynamically
unstable), the most common cause is
a tension pneumothorax! immediate
auscultation + pleural sonography (do
not wait until X-ray), then generous
relief puncture (takes 1 second! no
false restraint!)

Infectiology 897
 skin suture.
◦◦ assessment:
▪▪ The advantage of this procedure is that it is less
invasive.
▪▪ The disadvantage of this procedure is, however,
that the pleural gap cannot be palpated digitally,
which increases the risk of lung injury.
• placement of the drainage (note: In complex cases, it
is often very helpful to place the chest drainage under
fluoroscopy.)
-- pneumothorax: to dorso-apical direction (Air rises
upwards, therefore the thoracic drainage should be
as apical as possible.)
-- pleural effusion: in dorso-basal direction (Water
Fig. 1161  Thoracic drainage catheter with integrated trocar
sinks downwards, so the thoracic drainage should
[32]
be as basal as possible.)
• connection to the thoracic drainage system
Procedure
• protection of the connection points with cable ties (al-
• sterile gown, sterile gloves, mouthguard, hood ternative: 2 x 15cm long medical strips in longitudinal
• local anesthesia (also in analgosedated patients) sub- direction)
costal, peri- and intercostal (generously, e.g. 2 x 10ml • position control:
Xylonest 1%), if necessary analgosedation (e.g. pethi-
-- clinically: Normally, after loosening the clamp, the
dine [Dolantin] 25mg or fentanyl 0.05-0.1mg, midazo-
inner wall of the drainage should be fogged (with
lam [Dormicum] 2-3mg or propofol 50-100mg)
pneumothorax) or filled with fluid (with pleural effu-
• positioning: supine position, abducting the patient's sion) and the fluid level should fluctuate depending
arm behind the head on breathing.
• disinfection (e.g. with Betasiodona) -- radiologically: chest X-ray (should always be perfor-
• masking with sterile wipes med after the placement of the drainage by default)
• techniques:
-- mini thoracotomy (standard):
◦◦ skin incision with scalpel (2-3cm) 1
◦◦ blunt preparation along the finger with the scissors
at the upper edge of the rib
◦◦ piercing the parietal pleura (with the closed scis-
sors or with the finger [mostly only possible in
older patients], in any case not with the trocar!),
palpation of the pleural gap with the finger (impor-
tant to exclude that the lung is in contact with the
thoracic wall!)
◦◦ blunt insertion (without trocar or with trocar in
which the tip was retracted into the plastic sleeve
[only as a guide rod]) of the thoracic drainage so
that only about 10 cm of the drainage are showing,
then clamp off
-- Seldinger technique: An alternative to mini thoraco-
tomy is the insertion of a thoracic drainage via Sel-
2
dinger technique (e.g. Thal-Quick-Thoraxdrainage-
Set, Cook Medical):
◦◦ procedure: After local anaesthesia the puncture
is performed with the puncture cannula. If liquid
(for pleural effusion) or air (for pneumothorax) can
be aspirated, an intrapleural position can be assu-
med. The guidewire is then inserted and the punc-
ture needle removed. The dilators (here 3: small,
medium and large) are then inserted successively
over the guidewire and the access to the pleural
cavity is expanded. The thoracic drainage unit
(consisting of the thoracic drainage catheter and
the integrated stabilizer) is then inserted via the
wire. Finally, the stabilizer and the guide wire are
removed and the thoracic drainage is fixed with a

898 Infectiology
3 6

7
4

8
5

Infectiology 899
9 12

13
10

14
11

900 Infectiology
15 18

Fig. 1162  The individual steps of a thoracic drainage (here

Bülau) via a mini thoracotomy: The arm of the patient is
abducted and attached to the bedside gallows with a gau-
ze bandage (1). The intercostal spaces are thus spread out
and there is more space. After the local anaesthesia (2) the
skin incision (3) is made with a scalpel over 2-3cm. Then
blunt preparation with scissors (not cutting) into the depth
is made (4, 5): The scissors are inserted closed, then pres-
sure is exerted and then the scissores are being opened.
The parietal pleura is now opened with the finger (without
trocar) (6). The drainage is inserted (7, 8), clamped (9) and
firmly sewn (10, 11). Now a purse-string suture (12) is pre-
16 sented and rolled up onto a gauze ball(13): This is then
simply pulled closed later when the drainage is pulled. The
procedure is followed by the bandage (15, 16). Finally, the
clamp is opened and the drainage is connected to the hose
system (16). The connection point is secured with two long
plaster strips (17, 18).

17

Fig. 1163  The trocar has only its place in a flowerpot and
no longer in the thorax of a patient: The pleura is opened
bluntly with the scissors or the finger and no longer with
the trocar, as the risk of injury is far too high here!

Infectiology 901
 Fig. 1165  installation of a thoracic drainage using the Sel-
dinger technique as an alternative to mini-thoracotomy
(here as an example: Thal-Quick-Thorax drainage set, Cook
Medical)

Complications
• Verletzungen:
-- injuries: liver or spleen (cave in unilateral diaphragm
elevation)
-- lung (Therefore feel out the pleural gap before inser-
tion to ensure that the lung does not lie against the
thoracic wall!)
-- diaphragm
• bleeding (i.a. intercostal vessels [They run along the
lower edge of the rib. Therefore the puncture and the
preparation should always be done on the upper edge
of the rib!], internal thoracic artery)
• infection
• air leak (skin emphysema)
• pulmonary edema (in case of too rapid relief [> 1500ml
pleural effusion]; so-called reexpansion pulmonary
edema [especially in patients with heart failure])

Thoracic drainage system

• 3 chambers (closed three-chamber drainage system
almost everywhere standard today):
-- secretion collection chamber (collects the sucked
secretion)
-- water seal chamber
◦◦ It prevents the backflow of air into the pleural ca-
vity and acts as a one-way valve: It allows air to
escape from the pleural cavity, but no longer to
Fig. 1164  left-sided pneumothorax: The fisrt picture shows flow back there ("principle as with blowing through
that the mediastinum has already shifted to the healthy side the straw into a full glass": You can blow air in, but
in the sense of tension pneumothorax. In the second pic- you can only suck off liquid and no more air.)
ture the lung is unfolded again after a Bülau drainage.
◦◦ It should not bubble (If it bubbles, the lung is not
yet fully re-inflated in pneumothorax.)
-- suction control chamber (= manometer)
◦◦ The negative pressure (suction) is set here. It is
regulated by the height of the water column (stan-
dard: - 20 cmH2O). In ventilated patients (over-
pressure) no suction is necessary at all (not even
with pneumothorax)!
◦◦ The level should fluctuate depending on breathing
("backlash of the drainage"). The level fluctuation
directly indicates the degree of lung expansion:

902 Infectiology
 The lower the fluctuations, the further the lung has
expanded.
• preparation:
-- The seal chamber should be filled up with water to
the mark.
-- The suction chamber should be filled up with water
to the mark.
• pneumothorax: 2-3 days suction, then clamp (6-8h are
sufficient, 24h are not necessary), then chest x-ray (in
expiration!); notes:
-- Actually one should not clamp (disconnect) at all,
since this (in rare cases) can lead to a tension pneu-
mothorax. If the patient is not monitored, this can be
lethal! Since this is a closed suction system anyway,
it is completely sufficient to simply remove the suc-
tion. .
-- Thoracic drains should only be drawn in the morning
when the entire team is present, and not in the af-
ternoon or evening when there is only one doctor
on duty!
• pleural effusion: The drainage can be removed if out-
put is less than 100-200ml per day (often irritant effusi-
on due to inserted drainage).
• removal (pulling out) of the drainage at the end of the
inspiration while pulling closed the purse-string suture, Fig. 1166  Thoracic drainage system
possibly sealing with Betaisodona ointment (note:
Actually, it is completely irrelevant for spontaneously
breathing patients whether the drainage is pulled out
during inspiration or expiration, since the intrapleural
pressure [pleural pressure] is always negative anyway!
In ventilated patients, the drainage should not be re-
moved anyway, but should be left for the duration of
the ventilation.)
• In patients with mechanical ventilation, the drainage
should remain in place for the duration of the ventilati-
on if possible.
secretion
• no clamping for transport necessary (it is a closed water seal suction
collection
chamber chamber
system; especially never in ventilated patients → can chamber
be fatal!) Fig. 1167  Three-chamber thoracic drainage system
• When ventilating a patient with pneumothorax, low
ventilation pressures (especially a small pressure diffe-
rence between inspiration pressure and PEEP) should Never clamp thoracic drainage in
be selected (if possible). ventilated patients: lethal!

No suction is necessary with ventila-

ted patients (not even with pneumo-
thorax)!

Infectiology 903
 suction water seal cause -- osteomyelitis of the sternum (especially after cardi-
chamber chabmer othoracic surgery [1-2% after sternotomy])
fluctuation bubbling • secondary
-- traumatic
Pneumothorax is not
yes yes unfolded yet. ◦◦ esophageal rupture
no more pneumo-
▪▪ iatrogenic (most common cause; e.g. perforation
thorax is gone (The during endoscopy; after esophageal resection)
lung is completely ▪▪ spontaneous (Boerhaave syndrome , foreign
no no unfolded.) body, acid/alkaline burns, pregnancy)
air leakage in the ▪▪ pharmacological (drog-induced; especially che-
yes yes system motherapy with angiogenesis inhibitors [e.g.
not yet completely bevacizumab, pazopanib]: frequent perforations
unfolded (mucoid in the gastrointestinal tract)
impaction is very ◦◦ tracheal / bronchus rupture
common → broncho- ▪▪ iatrogenic (e.g. injury during intubation, bron-
yes no scopy!)
choscopy)
▪▪ polytrauma
-- neoplastic (infiltration of an esophageal or bronchial
carcinoma into the mediastinum)

Symptoms
• dyspnea
• chest pain (usually very severe)
• fever, chills
• skin emphysema (palpable crackling, crepitations)
• Hamman's sign: pulse-synchronous crackling during
auscultation over the jugulum

Diagnosis
• chest x-ray (mediastinal emphysema, possibly pneu-
mothorax)
Fig. 1168  In the meantime we have switched to a new tho- • CT chest + CT neck
racic drainage system (Thopaz from Medela) in which the
suction is generated electrically. Here the water seal has
• causal investigation
been replaced by a valve. A constant suction is always -- EGD (often better: barium swallow)
maintained through appropriate digital measurements and -- if necessary bronchoscopy
air leaks are detected and compensated for.

Excursus: Mediastinitis

Definition
• infection of the compartment of the thoracic cavity, lo-
cated between the two pleural sacs
• mostly phlegmonous, mostly necrotizing (formation of
necroses)
• mostly bacterial (mostly gram-positive germs: espe-
cially S. aureus [No.1] and streptococci)
• most common cause: iatrogenic esophageal perfo-
ration (endoscopy)
• main complication: sepsis with multiorgan failure
• incidence ↑
• mortality: 40%

Causes
• primary (per continuitatem) Fig. 1169  A bright line (white arrows) appears to the left of
-- infections from ENT / stomatology area (descending the heart shadow: This sign is relatively little known and
mediastinitis) is absolutely pathognomonic for mediastinal emphysema
(always perform chest CT then). To the right there is a pneu-
-- pneumonia
mothorax (black arrows).
-- pericarditis

904 Infectiology
 Fig. 1172  Chest X-ray: You can see the skin emphysema
especially on the left neck (arrow).

Fig. 1170  Chest X-ray: mediastinal emphysema

Fig. 1171  Chest X-ray: On the one hand free air is visible
under the right diaphragm, on the other hand mediastinal
emphysema (e.g. vertical upward air lines; pronounced pa-
racardial air gap). The cause was a Boerhaave syndrome.

Infectiology 905
Fig. 1173  Chest CT: mediastinal emphysema (various ex-
amples)

Fig. 1175  EGD: esophageal perforation (The hole can easi-

ly be seen!)

Therapy
• conservative
-- circulatory stabilisation
-- broad-spectrum antibiotic (e.g. piperacillin/tazobac-
tam); note:
◦◦ for mediastinitis after cardiac surgery, add vanco-
mycin (S3 guideline "Management of mediastinitis
after cardiac surgery" 2019)
◦◦ in case of a esophageal rupture always add an
antifungal
• interventional (e.g. stent implantation or endoluminal
vacuum therapy [nowadays first choice interventional
therapy before stent implantation; e.g. EndoSponge]
for esophageal rupture)
• surgical
-- drainages for relief
◦◦ thoracic (thoracic drainage)
◦◦ mediastinal (collar mediastinotomy: skin incision
across the jugulum, then blunt preparation with
the finger anterior to the trachea, then insertion of
a drainage)
-- mediastinal debridement (access: postero-lateral
thoracotomy)
-- treatment of the rupture site (e.g. in oesophage-
al rupture oesophageal suture or resection, e.g. in
tracheal/bronchus rupture suture via a right lateral
thoracotomy)
Fig. 1174  EGD: oesophageal tear (here as a complication of
a bolus obstruction; by the way, a "trachealization" ["crepe
paper"] of the esophageal mucosa can be seen, which is
typical for eosinophilic esophagitis [50% of all patients with
bolus obstruction have eosinophilic esophagitis, therefore
you always have to take biopsies as part of EGD. The the-
rapy consists of topical administration of budenoside such
as Jorveza].)

906 Infectiology
 Mediastinal emphysema
• Definition: air in the mediastinum
• syn.: pneumomediastinum
• epidemiology:
-- mean age: 27 years
-- in 75% men
• causes:
-- chest trauma
-- infection
-- hollow organ perforation (especially esophagus [e.g.
in Boerhaave syndrome])
-- spontaneous (especially male, tall juveniles; fre-
quent in asthmatics)
• diagnosis:
-- anamnesis, physical examination (palpable skin em-
physema)
-- chest X-ray
◦◦ typical bright line next to the heart shadow
◦◦ often even better visible in the lateral image (cir-
cular lightening around the pulmonary artery ["ring
around the artery"-sign])
◦◦ in Boerhaave syndrome:
▪▪ V-sign according to Naclerio (in the p.a. image
air in the left lower mediastinum between the
aorta and the diaphragm)
▪▪ usually also left-sided pleural effusion
-- chest CT
-- barium swallow, possibly EGD
-- bronchoscopy
• therapy: conservative (mostly self-limiting!)
-- administration of oxygen
-- avoidance of an intrathoracic pressure increase
-- antibiotics for increased inflammatory parameters
(e.g. piperacillin/tazobactam)

Fig. 1176  supply of an iatrogenic esophageal rupture with a
covered esophageal stent
Fig. 1177  Chest X-ray in Boerhaave syndrome: On the one
hand, you can see the V-sign according to Naclerio (gray).
This is a V-shaped accumulation of air in the lower left me-
diastinum between the aorta and the diaphragm. The eso-
phageal perforation in Boerhaave syndrome almost always
occurs in the lower third of the esophagus and on the left
side. On the other hand, in Boerhaave syndrome one usu-
ally also finds a left-sided pleural effusion (white).

Infectiology 907
Excursus: Thoracic sonography pneu-
mothorax
The domain of pneumothorax diagnostics is usually X-
ray. In the case of a lying patient (the classic intensive
care patient), however, the chest X-ray image has only
a low sensitivity, so that usually only a very pronounced
pneumothorax can be excluded by X-ray. Otherwise an
inconspicuous chest X-ray in a lying patient does not ex-
clude a pneumothorax at all! A chest X-ray is only sui-
table for excluding a pneumothorax in a standing pati-
ent. Especially in a lying patient thoracic sonography is
clearly superior to X-ray: In a meta-analysis (Wilkerson
et al, Academic Emergency Medicine 2010) there could
be shown that sonography (with the same specificity)
has a significantly higher sensitivity in the diagnosis of
a pneumothorax than X-ray. In another meta-analysis
(Alrajhi et al, Chest 2012), sonography showed a sen-
sitivity of 91%, X-ray only of 50%. Thoracic sonography
in the intensive care unit is also explicitly recommended
especially on the question of pneumothorax and infiltra-
tes (International evidence-based recommendations for
point-of-care lung ultrasound; Volpicelli et al, Intensive
Care Med 2012).

Chest X-ray in a lying patient

excludes only a (very) large pneumo-
thorax

In lying patients (typically intensi-

ve care patients), sonography is
superior to X-ray in the diagnosis
of pneumothorax!

A linear transducer (7.5 MHz) is best used for thoracic

sonography. In thoracic sonography, one works with ar-
tifacts: These are desired here, so that all improvement
modes (e.g. THE [tissue harmonic imaging]) that sup-
press artifacts should be switched off on the ultrasound
device. The classical sonographic signs of a pneumo-
thorax are the missing pleural sliding (breath dependent
movement of the pleura [echo rich band]; "like running
ants") and the missing B-ligns ("comet tail", "flashlight" Fig. 1178  Thoracic sonography (first image: cross section
phenomen). If B-lines are shown, a pneumothorax is to rib, second image: longitudinal section to rib): The linear
excluded. Furthermore, in pneumothorax the pulse-syn- transducer is placed at the highest point of the thorax. This
chronous movement of the pleura (lung pulse) is mis- is the sternum in case of a lying patient. For the question of
a left-sided pneumothorax, the transducer is placed paras-
sing. The point where the pleural sliding and the B-ligns
ternally left, for the question of a right-sided pneumotho-
reappear, i.e. where the lung is again closed to the tho- rax, the transducer is placed parasternally right.
racic wall and no pneumothorax is present, is called the
lung point. Air always collects at the highest point in the
thorax, which is the sternum in lying patients. If the pleu-
ral sliding and B-ligns can be detected sonographically
there, a pneumothorax is excluded! The easiest and fas-
test of all is to put the M-mode through the pleura: If the
seasore sign (normal finding) appears, no pneumothorax
is present. If the stratosphere sign appears, a pneumo-
thorax is present.

908 Infectiology
 rib

Fig. 1179  Thoracic sonography (cross section): Pleura

(echo-rich band; see arrows), rib with posterior acoustic
shadowing

Fig. 1181  Thoracic sonography (M-mode): in the first

image Seashore sign (no pneumothorax; normal finding):
Above the pleura (arrow points to the pleura) air-induced
reveberation artifacts are visible, below the pleura a finely
granulated tissue (above waves ["sea”], below granulated
["beach"]; "seashore"; memo: "When you see the sea and
the beach, you are relaxed"); in the second image strato-
spheric sign (pneumothorax): Here the reverberation arti-
facts caused by air can not only be seen above, but also
below the pleura. This is caused by a complete mirror ar-
tifact at the pleura which is no longer adjacent to the wall,
i.e. above the pleura one sees exactly the same as below
the pleura.

Special forms (pneumonia)

Fig. 1180  Thoracic sonography (longitudinal section): If • legionella pneumonia
the sliding of the pleura (see arrows) at the highest point of • swine flu (H1N1)
the thorax (in the case of a lying patient: the sternum) can
• COVID-19
be detected, a pneumothorax is excluded (simply place the
linear transducer to the right or left of the sternum in the • pneumocystis jirovecii pneumonia
longitudinal section).
Legionella pneumonia

Definition
• legionella pneumophila
-- gram-negative, aerobic, non-spore-forming, intracel-
lular rod-shaped bacteria
-- 16 serogroups (most important: serogroup 1)
-- environmental germ in fresh water (especially in

Infectiology 909
 warm water [25-45°C], > 60°C quickly killed [It is
therefore for example advisable to let the shower
run hot in the hotel room before the first shower for
about 5min])
• occurrence mainly in warm water (e.g. air conditioning
systems, whirlpools, hot water systems in hospitals,
shower heads in hotels, humidifiers, inhalers)
• infection caused by inhalation of aerosols, no trans-
mission from person to person (therefore no isolation
measures necessary)
• incubation period:
-- Pontiac fever (named after a city in the USA where
an outbreak occurred in 1968): 1-2 days
-- legionella pneumonia: 2-10 days
• duty to report (only) on proof (§7 Infection Protection
Act in Germany)
• mortality: 15%
Epidemiology
• epidemics:
-- 1976 meeting of the legionnaires (4400 war vete-
rans) in a hotel in Philadelphia, where 181 of them
fell ill with legionella pneumonia (hence the name
"legionnaire's disease") and 28 died
-- 1999 in the Netherlands (in the city of Bovenkars-
pel during a garden show, 231 cases of illness, 21
deaths)
-- 2001 in Spain (in the city of Murcia; 805 cases of
illness, 4 deaths)
-- 2013 in Germany (in the city of Warstein; 160 cases
of illness, 2 deaths)
• 5% of all cases of pneumonia
• in Germany approx. 400 cases / year reported (approx.
20000 pneumonia caused by legionella estimated an-
nually in Germany)
• m > w
Risk factors
• age
• chronic nicotine abuse, alcohol abuse
• diabetes mellitus
• renal insufficiency
• immunosuppression (e.g. organ transplantation, bone
marrow transplantation, long-term steroid therapy)
• leukaemia
-- qualitative (confusion)
-- quantitative (somnolence, coma)
• nausea, vomiting, diarrhea, abdominal pain
• myalgia (especially in the chest area; possibly rhabdo-
myolysis), arthralgia, cephalgia
Diagnostics
• anamnesis (especially travel anamnesis), clinical ex-
amination
• laboratory: i.a.
-- increased liver function parameters (classical: In
case of pneumonia with increased liver function pa-
rameters you should always think of legionella!)
-- hyponatremia (in 50%; SIADH)
-- hypalbuminemia
• detection of legionella:
-- antigen detection (urine; serogroup 1)
◦◦ ELISA test
◦◦ detection of serogroup 1 only (the clinically most
important serogroup)
◦◦ assessment:
▪▪ specificity: 99% (proving)
▪▪ sensitivity: only 80% (A negative legionella test
does not exclude legionellosis! Especially in
the case of seriously ill patients, if the antigen
test is negative, a bronchoscopy should always
be carried out with the removal of bronchial se-
cretions for microbiology with the question of
legionella!)
◦◦ can be false negative in the early stages if the an-
tigen excretion in the urine is too low (Therefore
repetition is advisable if there is clinical suspicion.)
◦◦ remains positive for a long time (no indication of
therapie failure; not suitable for therapy control)
-- antibody detection (serology; titer increase; only ret-
rospective significance)
-- culture (sputum, bronchial secretion, BAL), possibly
PCR
• chest X-ray

Course
• asymptomatic (mostly)
• symptomatic
-- Pontiac fever (90%; flu-like, without pneumonia,
good prognosis, no antibiosis necessary)
-- legionella pneumonia (clinically an atypical pneumo-
nia)

Symptoms
• lever (low [atypical pneumonia])
• cough (dry)
• disturbance of consciousness (frequent) Fig. 1182  Chest X-ray: left-sided legionella pneumonia

910 Infectiology
 H1N1 (swine flu)

Fig. 1183  Chest X-ray: bilateral legionella pneumonia

Definition
Antibiotics • syn.: new flu
• means of choice: fluoroquinolones • subtype of influenza virus A (RNA virus; orthomyxovi-
-- significantly faster defevering, fewer complications ridae)
and shorter hospital length-of-stay with fluoroquino- • isolated for the first time in swine (hence the name
lones compared to macrolides "swine flu", but also occurring in birds and humans)
-- representatives: • incubation period: 2-4 days (contagious until 5 days
◦◦ moxifloxacin (Avalox) 1 x 400mg i.v. (loading dose: after onset of symptoms)
2 x 400mg at day 1 and day 2) • duty to report already in suspicion (§7 Infection Protec-
◦◦ levofloxacin (Tavanic) 2 x 500mg i.v. tion Act in Germany)
• macrolids • mortalitity: 14%
• possibly combination therapy
-- A combination therapy of fluoroquinolones and ma- Epidemiology
crolides does not increase the efficacy on the one • young people (meean age: 39 years)
hand, but on the other hand the risk of side-effects • first detected in Mexico in 2009
(especially QT time prolongation, hearing loss), so • 1918 Spanish flu (22 million deaths)
that today legionella pneumonia is treated as stan-
• 2009 pandemic (also in Germany)
dard with a monotherapy of a fluoroquinolone.
-- with rifampicin (3 x 300mg p.o.)
Suspicious case
◦◦ contraindicated if GOT > 100 U/l
• fever > 39°C
◦◦ however, no clear evidence and therefore also no
recommendation • acute respiratory disease
• therapy duration: at least 14 days (standard: 21 days!) • direct contact with a probable or confirmed case or
death of swine flu virus infection (influenza A/H1N1)
• simultaneous stay in a room with confirmed case of
Standard antibiosis for legionella swine flu
pneumonia: levofloxacin 500mg i.v.
twice dailye Risk factors
• obesity (BMI > 35 kg/m2)
• pregnancy
• COPD, bronchial asthma
• heart failure, CAD
• diabetes mellitus

Infectiology 911
Symptoms
• like conventional influenza
• fever > 39°C, chills
• sudden onset
• (dry) cough, cold
• dyspnea
• nausea, vomiting, diarrhea
• myalgia, arthralgia, cephalalgia, throat pain
• burning eyes, photophobia

Complications
• pneumonia
-- viral (interstitial pneumonia)
-- bacterial (superinfection: pneumococcus, S. aureus,
H. influenzae) Fig. 1184  Chest CT in H1N1 (swine flu): impresses like aty-
• ARDS (frequent; in 50% ECMO necessary) pical pneumonia
• pneumothorax (frequently occurring during ventilation
with H1N1 [similar to SARS-CoV-2 or pneumocystis Therapy
jiroveci])
• paracetamol
• otitis
• neuraminidase inhibitors:
• perimyocarditis
-- p.o.: oseltamivir (Tamiflu) 75mg 2 x daily (capsules;
• myocardial infarction (6-fold increased risk with influ-
liquid suspension [e.g. in ventilated patients via gas-
enza)
tric tube]; in severe cases 2 x 150mg)
• meningitis, encephalitis
◦◦ dose reduction in renal insufficiency; creatinin
• sepsis clearance
▪▪ 30-60 ml/min: 2 x 30mg
Diagnosis ▪▪ 10-20 ml/min: 1 x 30mg
• imaging ▪▪ < 10 ml/min or dialysis required: contraindicated
-- chest X-ray (impresses like an atypical pneumonia) ◦◦ preferably within 48h
-- chest CT ◦◦ therapy duration: 5 days (in critically ill patients
• rapid test (Quick-Vue; influenza A test) better 10 days!)
-- sensitivity for H1N1 < 50% ◦◦ side effects: i.a.
-- positive only until the 4th day ▪▪ nausea (20%), vomiting (10%)
• PCR (should always be performed); types: ▪▪ abdominal pain
-- nasasl oder pharyngeal swab: dry; no saline addi- ◦◦ contraindicated in pregnancy
tive; 2 dry pharyngeal swabs (sterile dry swabs in -- inhalative: zanamivir (Relenza)
glass tubes)
◦◦ 5mg/dose single inhalation, 2 x 2 hubs daily
-- throat rinsing water (10 ml of nasopharyngeal fluid in
◦◦ also i.v. possible (2 x 600mg)
sterile container)
◦◦ side effect: i.a. bronchospasm (cave in bronchial
-- bronchoalveolar lavage (BAL)
asthma / COPD)
◦◦ no dose reduction in kidney or liver insufficiency
• replication inhibitors: baloxavir (Xofluza)
-- inhibition of the cap-dependent endonuclease (CEN)
of the RNA polymerase
-- already approved in the USA
-- CAPSTONE studies
-- dosage:
◦◦ < 80kg: 1 x 40mg p.o.
◦◦ > 80kg: 2 x 40mg p.o.
• steroids: In two studies (Brun-Buisson et al, Am J Resp
Crit Care Med 2011; Kim et al, Am J Resp Crit Care
Med 2011), the administration of steroids in cases of
ARDS by H1N1 led to more nosocomial infections and
increased mortality. The GETGAG study (Moreno et
al, ICM 2018) also showed excess mortality, so that
even if the studies cited are only retrospective cohort
studies, the use of steroids in ADRS caused by H1N1

912 Infectiology
 must be urgently discouraged!
• bacterial superinfection → antibiotics (always in seri-
ously ill patients prophylactically β-lactam + macrolide
[IDSA-Guidelines 2018])
• ventilation (in 65% necessary)
• ECMO (in 50% necessary; very efficient and helpful;
lung shows an extremely high regeneration potential,
especially with H1N1)
• isolation:
-- 7 days after the onset of symptoms, the isolation
may be terminated if the patient is asymptomatic.
-- A small isolation is sufficient.
-- Cohort isolation is generally possible with positive
influenza pathogen detection (PCR), but not with su-
spected cases
• hygiene measures (e.g. FFP-2 mask, protective gown,
gloves, goggles)
• vaccination: H1N1 was included in the current seaso-
nal vaccine (Pandemrix; very rare side effect including
narcolepsy [on average 160 days after vaccination]).

Infectiology 913

COVID-19
Definition
• COVID-19: coronavirus disease 2019 (COVID is the
name for the disease caused by SARS-CoV-2)
• disease caused by the new corona virus (2019-nCoV
[novel Coronavirus; syn: Wuhan-virus, SARS-CoV-2])
• outbreak in China (increased number of pneumonia in
the city of Wuhan [origin: seafood and reptile market]
in the province of Hubei) in December 2019, as a result
of the strong travel movement (approx. 3 billion trips)
around the Chinese New Year celebrations on January
25th then spread throughout China, then finally world-
wide spread (pandemic 2020); i.a. first confirmed case
in Germany: 27/01/2020 (employee of the automotive
supplier Webasto company [branch office in Wuhan;
chain of infection has been broken]; cases in Germany
mainly caused by returnees from skiing holidays in Is-
chgl [Austria ] and South Tyrol [Italy])
• transmission:
-- person-to-person
-- especially by droplet infection (transmissible up to a
distance of 1.5m; also via mucous membranes [e.g.
conjunctiva]) and by smear infections (Coronavirus
can survive on surfaces for up to 5 days.), also pos-
sible by aerosols (albeit of minor importance)
-- no classic aerogenic transmission (i.e. "flying" infec-
tion)
-- no clear fecal-oral transmission (however, it can-
not be excluded with certainty; especially in the la-
ter course of the infection cases of a positive rectal
swab with simultaneous negative nasopharynge-
al swab are described; therefore, fecal microbiota
transplantation [FMT; e.g. in the case of clostridia]
should currently be avoided according to the Ger-
man Federal Institute for Pharmaceuticals and Medi-
cal Products [BfArM]!)
-- no vertical transmission from mother to child
• often asymptomatic
• key symptoms: fever + cough
• phases
-- according to spread (in the body):
914 Infectiology
◦◦ first week: upper respiratory tract
◦◦ second week: lower respiratory tract
-- according to pathophysiology:
◦◦ first phase (early phase): viremia (virus replication)
◦◦ second phase (late phase): hyperinflammation
(cytokine release syndrome [CRS])
• incubation period: median 5.7 days (range: 2-14 days)
• suspected case: symptoms (especially fever, cough,
dyspnea) + up to 14 days before the onset of symp-
toms
-- stay in a risk area (note: Due to the increasing num-
bers in Germany, the RKI [Robert Koch Institute] left
the concept of risk areas on 25.03.2020.) or
-- close contact (distance < 2 meters) to a patient with
confirmed COVID-19
• duty for notification according to §6 of the German
Infection Protection Act to the health department, es-
pecially in case of suspected or confirmed illness and
death
• most important differential diagnosis: influenza (Also a
co-infection is possible!)
-- therefore always take an influenza smear during the
influenza season
-- The following symptoms speak more for influenza
and rather less for COVID: tiredness (fatigue), hea-
dache, body aches, sudden onset (suddenly; with
COVID gradually [creeping])
-- The 2020 influenza season is over since April!
• course:
-- 80% mild (upper respiratory infection only)
-- 20% severe (5% requiring intensive care)
• treatment (in Germany):
-- outpatient: 85%
-- inpatient (hospital): 15% (mean hospital stay: 21
days)
• mortality of all hospitalized patients (in Germany): 22%
(observation study Karaggianidis et al, Lancet Resp
Med 2020)
• average age of deceased patients:
-- worldwide: 79 years
-- in Germany: 81 years
• A autopsy series of 65 deceased COVID patients in
Hamburg (Germany) showed that all patients had co-
morbidities (Püschel et al, Dtsch Arztebl Int 2020)
• main cause of death: ARDS (Mostly it is a mono-organ
failure of the lung!)
• infectiousness (contagious risk): 2 days before to
10 days after the onset of symptoms (maximum on the
day of symptom onset)
SARS-CoV-2 2 receptors than SARS-CoV-1 and also causes an
upregulation of the receptors!
-- In contrast to SARS-CoV-1, SARS-CoV-2 not only
docks on the ACE-2 receptors of the lungs, but also
on those on the nose with consecutive replication,
which is why the risk of infection and thus the num-
ber of infections with SARS-CoV-2 is significantly
higher.
-- When the viruses are aspirated from the nasopha-
rynx, pneumonia occurs (typically bilaterally).
-- excessive reaction of the own immune system (cy-
• family: coronaviruses (Latin "corona": wreath [visible in tokine release syndrome [CRS], hyperinflammation,
the electron microscope) "cytokine storm", macrophage activation syndrome
• genus: β-coronaviruses [MAS]; note: This is nothing new and typical for
• classification of human corona viruses (HCoV [H: hu- SARS-Co-V-2 at all, but a fundamental pathomecha-
man]; in total 6): see infobox nism of sepsis!)
• designation: Both the SARS pandemic 2002/2003 ◦◦ mostly in the late phase
(SARS: severe acute respiratory distress syndrome; ◦◦ massive release of proinflammatory cytokines
number of infections: approx. 8000; mortality: 10%; such as interleukin 1 and 6, TNFα, IP-10 (inducible
reservoir: Sneak cats; since 2004 no more proven ca- protein), MCP-1 (monocyte chemoattractant pro-
ses) in China (was almost not in Europe [only a few tein), MIP-1α (macrophage inflammatory protein)
cases]) and the MERS epidemic 2012 (MERS: middle ◦◦ typically recognizable by very high ferritin values
east respiratory syndrome; number of infections: ap- ◦◦ in children: PIMS (pediatric inflammatory multisys-
prox. 2500; mortality: 35%; reservoir: camels) in the tem syndrome; similar to Kawasaki syndrom)
Near East (Arabian Peninsula; especially Saudi Ara- -- excessive coagulation activation (hypercoagulabili-
bia [90%]) were caudes by coronaviruses (SARS-CoV ty; CIC: COVID-19 associated coagulopathy)
respectively MERS-CoV). The current COVID pande-
◦◦ recognizable by increased D-dimers
mic 2020 is caused by a different and previously unk-
nown coronavirus (new variant), which is why the term ◦◦ formation of macro- and microthrombi (i.a. also
"novel" corona virus ( 2019-nCoV) was introduced. pulmonary: PIC [pulmonary intravascular coagu-
The coronavirus that caused the SARS epidemic in lopathy])
2002/2003 is now referred to retrospectively as SARS- ◦◦ Every third patient suffers from a thrombotic com-
CoV-1, the corona virus that caused the COVID pan- plication!
demic 2020 as SARS-CoV-2. In addition, there are four -- endothelial cell infiltration with consecutive endothe-
harmless ("endemic") coronaviruses (OC43, HKU1, litis (an important pathomechanism!)
229E, NL63) with which we become infected every two -- damage especially of the lung (diffuse alveolar da-
years on average and which cause a harmless respi- mage [DAD])
ratory infection (15% of all colds).
• a zoonosis:
-- SARS-CoV-1: passed from sneak cats to humans
-- SARS-CoV-2: passed from bats to humans
• nucleic acid: a RNA virus, single-stranded genome,
high genetic variability
• size: relatively large (120-160nm)
• envelope: present (lipid envelope; viruses with an
envelope such as SARS-CoV are much easier to in-
activate [e.g. by alcoholic hand disinfection] as non-
enveloped viruses [e.g. norovirus])
• groups: 4 main groups, 10 sub-groups (viral diversity;
Chen et al, MedRxiv 2020)
• mutations already described (e.g. D614G with increa-
sed infectivity)
• thermolabile (Coronaviruses are killed at temperatures
above 70°C.)
• pathophysiology (both SARS viruses):
-- docking via the virus spice protein (S protein) to the
ACE-2 receptors (ACE: angiotensin converting en-
zym; an aminopeptidase) of the epithelial cells of the
respiratory system (highest concentration of ACE-2
receptors: nasal) and then invasion into the cell
-- SARS-CoV-2 has a much higher affinity to the ACE-

Infectiology 915

Fig. 1185  structure of the corona virus (SARS-CoV-2): In the
center is a single-stranded RNA (genome). The genome is
enveloped by the N protein (N: nukleocapsid). The virus
has a lipid envelope with 4 membrane proteins: S protein
(S: spike; via this the virus docks onto the ACE-2 recep-
tor; the spikes visible in the electron microscope also gave
the name ["corona"]), E protein (E: envelope), M protein (M:
membran), HE-Protein (HE: hemagglutinin esterase)
Epidemiology
• classified as pandemic by the WHO on March 11, 2020
• for comparison, the number of deaths during the in-
fluenza epidemic (often trivialized as "flu wave") in
Germany 2017/2018: 25100 (although vaccination is
possible)
• mean age: 50 years (intensive care patients: 63 ye-
ars); note: The average age in Germany has dropped
significantly to 30 years since August 2020 (return from
travels [vacation]; "party people" [with almost negligib-
916 Infectiology
le mortality]).
• m > f (55% male, 45% female)
• Children become infected just as often as adults, but
usually have a very mild course (in contrast to influ-
enza): The virus has only recently spread to humans
(from bats). The main responsibility for the damage in
the body is the own immune system, which is not yet
fully developed in children. They play infectiously an
important role especially as an asymptomatic source
of infection ("silent spreaders"; i.a. Yonker et al, J Ped
2020).
• number of second infections from a case (basic repro-
duction number R0): 2.4-3.3 (at influenza only 1.3)
• country with the most infections: initially China (foloo-
wed by Italy, USA, Spain and Germany); since March
27, 2020 USA (especially New York) the country with
the most infections (followed by [as of 08/05/2020]
Spain, Italy, UK, Russia, France and Germany); as of
28/07/2020: USA, Brazil, India, Russia, South Afrika;
as of 02/10/2020: USA, India, Brazil, Russia, Colom-
bia, Peru
• country with the most deaths
-- absolutely: Italy (esp. Lombardy; as of 22/04/2020:
24648), since 13/04/2020 USA (as of 27/07/2020:
146935)
-- relatively (country with the highest percentage of de-
ceased; deaths per 1 million inhabitants):
◦◦ No.1: Belgium (633)
◦◦ No.2: Spain (510)
• heterogeneous distribution (e.g. in Germany especially
Bavaria, Baden-Wuerttemberg and Hamburg; counties
with the highest number of cases per inhabitant: Tir-
schenreuth [result of a strong beer festival], Heinsberg
[result of a carnival session])
• The number of unreported cases is estimated to be
about six times higher than the officially reported num-
ber of cases.
• lethality (fatality rate)
-- infection fatality rate (IFR): 1.4% (according to a
WHO bulletin [Ioannidis et al] of 14.10.2020: only
0.27%)
◦◦ proportion of infected people who dies
◦◦ The number of infected people is only estimated
and is naturally significantly higher than the num-
ber of actually confirmed cases.
◦◦ This applies to Germany. In Italy for example the
mortality is 4%. This is mainly because in Germa-
ny it is tested very frequently and generously.
◦◦ in comparison to the influenza pandemics 1968
und 1957: 0.5%
-- case fatility rate (CFR): 4.4% (according to RKI
on 04.09.2020: 3.8%, on 30.10.2020: 2,0%, on
07.11.2020: 1,7%)
◦◦ proportion of confirmed cases who dies
◦◦ The number of actually confirmed cases is signifi-
cantly lower than the estimated number of infected
people. That is why the case fatility rate (CFR) is
higher than the infection fatality rate (IFR).
• no excess mortality in Germany during the first
wave: In a study (Stang et al, J Infect 2020) the num-
 ber of expected deaths (estimated; SMR [standardized filled with water up to the top stand and you drowned
mortality ratio]) was set in relation to the number of yourself if you couldn't free yourself by then.
observed deaths in Germany between the 10th and 23rd
calendar week 2020. If demographic changes are ta- Numbers (Johns Hopkins University USA)
ken into account (including an increase in people > 80
• 18/03/2020:
years of age by 17.5% from 2016 to 2020), there was
-- worldwide:
no excess mortality. There was even an reduced mor-
tality rate (4926 fewer deaths than expected). ◦◦ number of infections: 190,124
• more than one million deaths worldwide since ◦◦ number of deaths: 7,516
30/09/2020 and than one million cases of infection in -- Germany:
Germany sonce 26/11/2020 ◦◦ number of infections: 8.604
• pandemic waves in Germany: ◦◦ number of deaths: 23
-- first wave: from beginning of March to beginning of • 17/04/2020:
June 2020 -- worldwide:
-- second wave: from the beginning of September 2020 ◦◦ number of infections: 2,165,500
◦◦ significantly stronger than the first wave: higher ◦◦ number of deaths: 145,705
number of new infections (mainly due to more -- Germany:
tests), deaths and occupied intensive care beds ◦◦ number of infections: 138,135
(first wave 2,680 beds [out of a total of 30,000],
◦◦ number of deaths: 4,093
second wave 3,299 beds [as of 13/11/2020])
• 27/05/2020:
◦◦ initially due to returning travelers (summer vaca-
tion) -- worldwide:
◦◦ average age: 41 years ◦◦ number of infections: 5,604,461
◦◦ inpatient treatment: only in 5% ◦◦ number of deaths: 350,862
• The main problem with viral infections is not the linear, -- Germany:
but exponential growth: This is dangerous and risky as ◦◦ number of infections: 181,293
it can lead to an overload of the health system extre- ◦◦ number of deaths: 8,386
mely quickly. The exponential growth should be illust- • 18/06/2020:
rated by two examples: -- worldwide:
-- wheat grain legend: The Brahame Sissa Ibn Dahir ◦◦ number of infections: 8,391,551
(India) invented a new game for his king Shihram ◦◦ number of deaths: 449,898
(tyrant) in the 4th century AD: chess. In return he had -- Germany:
one wish: He wanted grains of wheat, namely 1 grain
◦◦ number of infections: 189,512
on the 1st field of the chessboard (64 fields in total)
and then double the amount of the previous field on ◦◦ number of deaths: 8,869
the next field (i.e. on the 2nd field 2 grains, on the 3rd • 28/07/2020:
field 4 grains etc.). The king accepted this wish and -- worldwide:
was angry about his modesty. The mathematicians ◦◦ number of infections: 16,407,310
at the court checked and came to the conclusion that ◦◦ number of deaths: 652,459
this wish could not be fulfilled: 18.5 trillion grains of -- Germany:
wheat (1500 times the worldwide annual wheat har-
◦◦ number of infections: 207,112
vest). Nowadays one would need 104 billion trucks
◦◦ number of deaths: 9,125
for the transport: If the trucks were put bumper to
bumper one behind the other, the distance would be • 04/10/2020:
793 million km (20,000 times around the world). -- worldwide:
-- thought experiment of the US physicist Dr. Albert ◦◦ number of infections: 34,909,703
Bartlett (1923-2013; "The greatest shortcoming of ◦◦ number of deaths: 1,033,249
the human race is our inability to understand the ex- -- Germany:
ponential function."): A drop of water (magic drop) ◦◦ number of infections: 300,285
is dispensed with a pipette into a stadium (Fenway ◦◦ number of deaths: 9,533
Park [baseball stadium] in Boston / USA [one of the
• 18/10/2020:
largest baseball stadiums in the world]). The special
thing about the drop is that after every minute it is -- worldwide:
twice as large as before. The stadium is watertight. ◦◦ number of infections: 39,698,835
You yourself are handcuffed to one of the very high- ◦◦ number of deaths: 1,110,226
est bleacher seats. The drop will be released in the -- Germany:
middle of the field at 12:00. At 12:44 only 7% of the ◦◦ number of infections: 364,664
entire stadium is filled with water (height of the water ◦◦ number of deaths: 9,785
level on the field: 1.5m), i.e. 93% of the stadium is • 01/11/2020:
still empty, so you feel safe. But just 5 minutes later
-- worldwide:
(at 12:49) the entire stadium is completely (100%)
◦◦ number of infections: 46,071,388

Infectiology 917
 ◦◦ number of deaths: 1,195,408 of a severe course [Clift et al, Ann Intern Med 2020])
-- Germany: -- immunosuppression (e.g. HIV [especially with a
◦◦ number of infections: 539,530 numberof CD-4 cells < 200/µl; Dandachi et al, Clin
◦◦ number of deaths: 10,504 Infect Dis 2020])
• 15/11/2020: • obesity (BMI > 35 kg/m2; as with influenza; i.a. Lighter
-- worldwide: et al, Clinical Infectious Diseases 2020: 7-fold increa-
sed risk of the need for invasive ventilation)
◦◦ number of infections: 53,970,228
• laboratory:
◦◦ number of deaths: 1,311,832
-- LDH > 400 U/ml
-- Germany:
-- lymphopenia (lymphocytes < 800/µl; i.e. a differential
◦◦ number of infections: 799,733
blood count is necessary)
◦◦ number of deaths: 12,511
-- leukocytosis
• 23/11/2020:
-- neutrophil-lymphocyte ratio (NLR) > 3
-- worldwide:
-- thrombopenia (platelets < 100000/µl)
◦◦ number of infections: 58,563,459
-- D-dimers > 1 µg/ml (18-fold increased mortality risk
◦◦ number of deaths: 1,386,465 [Zhou et al, Lancet 2020])
-- Germany: -- CRP > 10 mg/dl
◦◦ number of infections: 932,111 -- ferritin > 300 μg/l
◦◦ number of deaths: 14,091 -- troponin ↑ (i.a. Lippi et al, Prog Cardiovasc Dis 2020)
• 01/12/2020: -- bilirubin ↑ (especially direct bilirubin; i.a. Paliogian-
-- worldwide: nis et al, Liver International; meta-analysis Wang et
◦◦ number of infections: 62,192,543 al, JCLA 2020; meta-analysis Kumar et al, Indian J
◦◦ number of deaths: 1,467,174 Gastroenterol 2020)
-- Germany: • blood group (note: However, this is of little relevance
◦◦ number of infections: 1069,912 for everyday clinical practice.):
◦◦ number of deaths: 16,694 -- Patients with blood group A have a 1.45 times higher
risk of severe course than patients with blood group
Non-A (Ellinghaus et al, N Engl J 2020).
Risk factors
-- Blood group 0 is even protective.
• age > 60 years ( the most important rick factor);
• CT - In addition to the extent of the changes, the fol-
mortality according to age:
lowing types of changes are indicative for a severe
-- 10-40 years: 0.2% course: consolidation (instead of ground glass opaci-
-- 40-50 years: 0.4% ty), bronchial wall thickening, crazy paven sign
-- 50-60 years: 1.3% • pregnant: For a long time it was believed that pregnant
-- 60-70 years: 3.6% women had no increased risk of a severe course (in
-- 70-80 years: 8.0% contrast to influenza). A multicentre case-control study
-- > 80 years: 14.8% (Badr et al, AJOG [American Journal of Obstetrics and
• male gender Gynecology] 2020), however, showed that pregnant
women have a clearly higher risk of a severe disease
-- doubled risk of a severe course
than non-pregnant women. This applies especially to
-- The data come from China, where a lot more men
pregnant women with diabetes mellitus (Ellington et al,
smoke than women.
CDC Morb Mortal Wkly Rep 2020). In a meta-analysis
• smokers (2.4-fold increased risk of severe course [Var- (Allotey et al, BMJ 2020), compared to non-pregnant
davas et al, Tob Induc Dis 2020]) women, pregnant women had a 62% higher risk of
• comorbidities: being transferred to an intensive care unit and an 88%
-- CHD higher risk of mechanical ventilation.
-- heart failure
-- arterial hypertension Risk scores
-- COPD (note: Bronchial asthma is not a risk factor • COVID-GRAM
[Williamson et al, Nature 2020]; only with long-term • 4C-Score
systemic OCS therapy [oral glucocorticosteroids]) • BAS2IC-Score
-- obstructive sleep apnoea (Miller et al, Sleep Med
Rev 2020)
-- diabetes mellitus (Strictly speaking, only an increa-
sed blood sugar when hospitalized, which can have
various reasons, is associated with a severe course,
but not an increased HbA1c.)
-- liver cirrhosis
-- malignancies
-- trisomy 21 (Down syndrome; 10-fold increased risk

918 Infectiology
COVID-GRAM 4C-Score

Infectiology 919

BAS2IC-Score
Symptoms
• fever (in 88%; i.e. in 12% but also without a fever; in
Germany according to RKI (Robert Koch Institute) only
fever in 40%, i.e. in 60% without fever)
• cough (usually dry; in Germany according to RKI only
in 54%)
• rhinorrhea (However, a runny nose is relatively atypical
for COVID and speaks more for a harmless cold).
• dyspnea
-- usually only after 7 days
-- There is often a discrepancy between condition (no
or only slight dyspnea) and the finding (pronounced
hypoxemia in the BGA [„silent hypoxemia“]: This of-
ten only becomes clinically manifest through tachyp-
nea, which is a surrogate parameter for increased
work of breathing and thus an early indication of an
impending respiratory decompensation!).
• athralgia, myalgia
• sore throat
• headache
• tiredness (fatigue)
• inappetence
• nausea, vomiting, diarrhea (frequent), possibly ab-
dominal pain
• disturbance of the sense of smell and taste (anos-
mia; frequent; in 75% [but not surprising: The most
common cause for a disturbance of the sense of smell
and taste are viral infections!]; often persistent for
920 Infectiology
weeks)
• dermatological: chilblains-like changes on the toes and
fingers ("COVID toe"; i.a. Landa et al, International
Journal of Dermatology 2020)
-- reddish-purple discoloration and swelling
-- painful
-- mostly self-limiting (harmless; no therapy necessary)
• dermatological (skin changes in 20% of all hospitalized
[Hay et al, Br J Dermatol 2020]):
-- chilblains-like changes on the toes and fingers
("COVID toe"; i.a. Landa et al, International Journal
of Dermatology 2020)
◦◦ reddish-purple discoloration and swelling
◦◦ painful
◦◦ especially children and adolencents
◦◦ especially in (with regard to the classic COVID
symptoms) asymptomatic patients (in 41% SARS-
CoV-2 positive [Galvan et al, Br J Dermatol 2020])
◦◦ mostly self-limiting (harmless; no therapy neces-
sary)
-- exanthema (erythematous, maculopapular)
-- urticaria (wheals)
-- vesicular eruptions (vesicles like chickenpox)
-- scaling (desquamation)
-- livedo racemosa, necrosis
Complications
• lung:
-- pneumonia (atypical, interstitial; on average 4 days
after the onset of symptoms)
-- ARDS
◦◦ on average 8 days after the onset of symptoms
◦◦ in 15% of all hospitalized patients (Sun et al, J
Med Virol 2020)
◦◦ main cause of death
-- pneumothorax (generally increased incidence in all
viral pneumonia, especially with COVID-19 in 1%
[Martinelli et al, Eur Resp J 2020]), formation of bul-
lae, mediastinal emphysema
• heart:
-- myocarditis (i.a. increased troponin: In a cohort [Shi
et al, JAMA Cardiol 2020] of 419 hospitalized COVID
patients, 20% had an increased troponin. Mortality
in this group was significantly increased at 50%! In
a meta-analysis [Li et al, Crit Care 2020], 37% of all
intensive care COVID patients showed an increased
troponin.)
-- cardiomyopathy with cardiogenic shock
-- arrhythmias (i.a. atrial fibrillation in 27.5% of all in-
tensive care patients [Colon et al, JACC Clinical
Electrophysiology 2020])
-- frequently right heart failure
◦◦ causes: ARDS with pulmonary hypertension,
ventilation with high PEEP, pulmonary embolism,
maybe isolated right heart myocarditis
◦◦ dilated right ventricle in 39% (Szekely et al, Circu-
lation 2020)
-- acute myocardial infarction
 ◦◦ as a thrombotic complication due to excessive ac- mon with 27% venous [venous thromboembolism;
tivation of coagulation from this most often with 80% pulmonary embolism],
◦◦ STEMI with COVID significantly more severe than in 4% arterial)
STEMI without COVID (Little et al, Open Heart -- Cui et al, J Thromb Haemost 2020: venous throm-
2020 [retrospective analysis]: more pronounced boembolism in every fourth intensive care patient
coronary thromboses, more frequently requiring -- In an autopsy study (Wichmann et al, Ann Intern Med
intensive care [33% instead of 9%], increased 2020), in 58% of the deceased patients a previously
mortality [22% instead of 9%]) unknown deep vein thrombosis could be detected
-- Kawasaki syndrome (children; as part of the PIMS and in 30% a pulmonary embolism.
[pediatric inflammatory multisystem syndrome]) -- In an observational study (Middledorp et al, J Thromb
-- pericarditis with pericardial effusion (up to pericardial Haemost 2020), venous thrombo-embolism occur-
tamponade) red in 9% of patients in normal ward and in 59% in
-- the second leading cause of death with 10% patients in ICU in spite of phamacological thrombo-
• kidney: sis prophylaxis with LMWH.
-- acute kidney injury (in 7%, with severe sourse even • orchitis (with testicular pain; only case reports)
in 80%; i.a. Argenziano et al, BMJ 2020: acute kid- • fatigue (following the survived infection; in 52% [Town-
ney injury in 78% of all intensive care patients [renal send et al, PLoS One 2020])
replacement therapy necessary in 35%])
-- in 25% proteinuria (according to a meta-analysis
[Yang et al, Crit Care 2020] even in 57%; therefore
always determination of the albumin / creatinine quo-
tient in spontaneous urine [i.a. also recommended
in the S2k guideline of the DGIIN from 23.11.2020];
possibly development of a nephrotic syndrome [i.a.
with hypalbuminemia; cave AT III deficiency → pul-
monary embolism])
• nervous system (overall, however, rarely neurologi-
cally relevant participation in COVID-19; SARS-CoV-2
is not a neurotropic virus [like herpes virus]):
-- CNS (transfer from the nose to the brain via the ol-
factory nerve):
◦◦ meningitis, encephalitis (especially hippocampus)
◦◦ stroke (as a thrombotic complication due to exces-
sive activation of coagulation; i.a. Oxley et al, N
Engl J 2020)
-- PNS:
◦◦ Guillain-Barré syndrome (GBS)
◦◦ myasthenia gravis
• gastrointestinal tract:
-- mesenteric ischemia
◦◦ occlusive (due to the excessive activation of co-
agulation [hypercoagulability]): increased inci-
dence in intensive care patients with COVID-19
(Moheb et al, JAMA 2020)
◦◦ non-occlusive (NOMI; with 10% significantly in-
creased incidence in intensive care patients with
COVID-19 [Wiesner et al, Internist 2020]) Diagnosis
-- ileus • anamnesis (medical history), physical examination
• sepsis (only in 5%), septic shock (with bacterial su- (i.a. auscultation: The mostly bilateral pneumonia can
perinfection) be heard very well with the stethoscope [cave, howe-
• hemophagocytosis syndrome (typically trinary cytope- ver, increased risk of infection]!)
nia, hyperferritinemia [ferritin > 10000 μg/l almost pro- • virus detection
ving], hypertriglyceridemia, hypofibrinogenemia; see • imaging
page 829)
• laboratory
• DIC
• thrombotic complications Virus detection
-- Klok et al, Thrombosis Research 2020: every
• direct (PCR)
third patient (thrombotic complications [pulmonary
• indirect: detection of antibodies (serology)
embolism, deep vein thrombosis, myocardial infarc-
tion, stroke, systemic embolism] in 31%, most com-

Infectiology 921
PCR (direct virus detection)
• locations of sample collection:
-- upper respiratory tract (Rule: The smear must be
uncomfortable for the patient, otherwise it will not be
effective.):
◦◦ nasopharynx (first choice)
▪▪ introducing the swab through a nostril parallel
to the nasal floor in the direction of the earlobe
until resistance is felt; then leave the swab there
for 3-4 seconds and turn it (to remove secretion)
▪▪ It is important that the sample is taken from
the back of the throat, because here is the high-
est virus concentration and not from the front
area of the nasal cavity. 3/4 of the swab must be
in the patient!)
◦◦ oropharynx (as an alternative; deep throat smear
or throat rinsing water [e.g. with 10ml NaCl 0.9%])
-- lower respiratory tract (cave increased risk of infec-
tion):
◦◦ sputum (for productive cough [rarely the case])
◦◦ endotracheal secretion
◦◦ bronchoalveolar lavage (BAL) by bronchoscopy
(not absolutely necessary since there are no ad-
vantages over the endotracheal secretion)
• assessment:
-- specifity: very high (nearly 100%), i.e. almost no
false positive results, no cross-reactions with other
(harmless ["endemic"]) coronaviruses (A positive
test proves SARS-CoV-2!)
-- sensitivity:
◦◦ only 75% (Therefore, if the test is negative and
there is an urgent suspicion, another test should
follow!); note: The tests have improved significant-
ly, so that the sensitivity is meanwhile 98% (with
correct preanalytics).
◦◦ The test from the upper respiratory tract can be
false negative in the second week because the vi-
ruses have already migrated from the upper to the
lower respiratory tract. In contrast, the test from
the lower respiratory tract can be false negative
in the first week because the viruses have not yet
migrated from the upper to the lower respiratory
tract. For this reason, samples from the lower re-
spiratory tract (endotracheal secretion sufficient)
should always be taken from intubated patients
(if the test is negative from the upper respiratory
tract)!
• transport: in a UTM tube (universal transport medium),
does not have to be cooled (only necessary in case of
longer storage at 4°C)
• virus load (indirectly proportional to the cycle threshold
[Ct]; quantification):
-- low: Ct S-gen > 30 (from here on it can no longer
be grown in cell culture [amount of RNA < 250 co-
pies / 5µl RNA eluate; swab is resuspended in 1ml
liquid, 140µL of which is extracted with the QIAamp
Viral RNA Mini Kit and the RNA is eluted in 60µl] and
therefore no longer infectious)
-- moderate: Ct S-gen 20-30
-- high: Ct S-gen < 20 (i.a. < 5: highly infectious ["su-
922 Infectiology
perspreader"])
• duration of the test: 3h (In the meantime there are also
rapid tests [POCT: point-of-care-testing; e.g. GeneX-
pert, IDNow], with which the result is finished much
faster.)
• cost per test (medically validated): 100-150 € (in Ger-
many)
• For self protection, the samples should only ever be
taken with protective clothing (especially FFP-2 mask,
safety glasses, gloves)!
• According to the S2k guideline of the DGIIN of
23.11.2020 a PCR test should be carried out in the
context of the pandemic situation for every patient who
is admitted to the hospital (strong recommendation).
The most common cause of a false
negative test is incorrect sampling
(error in preanalytics)!
Fig. 1186  PCR rapid test: here as an example the GeneXpert
system of the company Cepheid from our emergency de-
partment, with which you can test as POCT not only for in-
fluenza, RSV, MRSA, A streptococci, Mycobacterium tuber-
culosis and Clostridium difficile, but also for SARS-CoV-2:
The result is available within 45 minutes. Since this is also
a PCR test, the specificity and sensitivity are comparable to
the conventional test.
Serology (indirect virus detection)
• detection of antibodies against the S protein (spike; the
decisive antibody for virus elimination)
• unsuitable for the question of an acute infection, since
seroconversion only occurs in the second week of ill-
ness (on average on day 10)
• well suited to the question of a past infection (but ear-
liest useful after 14 days)
• Immunosuppressed patients often cannot form antibo-
dies at all, so that no seroconversion occurs at all.
• Furthermore, cross-reactions against the harmless
("endemic") coronaviruses, against which most people
have high antibody titers anyway, may be seen.
• study Li et al, J Med Virol 2020: detection of antibodies
against the S protein
-- sensitivity: 89%
-- specifity: 91%
• i.a. EUROIMMUN test currently approved
• However, the currently available tests are not yet so
 reliable, so that, based on the current status, the de-
tection of antibodies should not lead to the conclusion
that one is supposedly protected and no longer has to
wear protective clothing.
• rapid antigen tests
-- strip assays according to the "lateral flow" principle
(analogous to the pregnancy test)
-- result: within 15-30min
-- price: 10 €
-- list of the BfArM (Federal Institute for Drugs and Me-
dical Devices in Germany) with approx. 70 validated
tests (as of October 31, 2020)
-- assessment:
◦◦ high specificity (97%): However, a positive rapid
antigen test should always be confirmed by a PCR
test.
◦◦ low sensitivity (75%)
▪▪ strongly dependent on the virus concentration:
usually only positive from a high virus concent-
ration in the throat (> 106/ml, Ct [cycle threshold]
< 5 ["superspreader"]), from a Ct > 30 strong
drop in sensitivity (with a low virus concentrati-
on [especially in the early and late phase] often
false negative)
▪▪ therefore explicitly not recommended for symp-
tomatic patients (Gold standard here is still the
PCR!)
-- optional (especially for the prophylaxis of overloa-
ding the PCR test capacities; meanwhile also part of
the corona test strategy of October 14th, 2020 of the
Federal Ministry of Health in Germany) for asympto-
matic patients (e.g. as screening for hospital admis-
sion), visitors (e.g. from nursing homes), staff (e.g.
for series tests)
Fig. 1187  Rapid antigen test
Imaging
• chest x-ray (specifity 86%, sensitivity 59% [both apply
only to patients with positive PCR]): often bilateral and
multiple
• chest CT (specifity 97%, sensitivity 86% [both apply
only to patients with positive PCR])
-- findings: initial ground glass opacity (GGO; patchy
screen-like cloudiness), later consolidation (infiltra-
tes)
• often bilateral
-- often multiple lesions (not solitary)
-- especially peripherally localized (not centrally)
-- especially localized in the lower lobes (basal)
-- positive bronchopneumogram
-- crazy paving (paving stone pattern, tile pattern; map-
like ground glass opacities with overlaid thickened
interlobular septa; also in cases with alveolar pro-
teinosis)
-- reticular pattern
-- subpleural lines
-- thickening of the pleura ("crescent")
-- not suitable: cavern, nodules, lymphadenopathy,
bronchial wall thickening, pleural effusion (only per-
sent in 5% with COVID)
-- In addition to the extent of the changes, the following
types of changes indicate a severe course (risk fac-
tors for a poor prognosis; Lin et al, The Clinical and
Chest CT Features Associated with Severe and Cri-
tical COVID-19 Pneumonia; Investigative Radiology
2020):
◦◦ consolidation (instead of ground glass opacity)
◦◦ bronchial wall thickening (i.e. also involvement of
the bronchi)
◦◦ crazy paven sign
-- COV-RADS-scheme (RADS: reporting and data sys-
tem)
◦◦ 1: normal lung finding
◦◦ 2: striking lung findings, but atypical for COVID-19
◦◦ 3: COVID-19 possible
◦◦ 4: COVID-19 suspicious
◦◦ 5: COVID-19 typical
-- COBRA study (Schulze-Hagen et al, Dtsch Arztebl
Int 2020): low-dose chest CT (without contrast agent)
◦◦ sensitivity: 94.7%, specifity: 91.4%
◦◦ positive predictive value: 87.7%, negative predic-
tive value: 96.4%
• possibly lung ultrasound (POCUS [point-of-care-ul-
trasound] of the lung (increased detection of B-lines
["comet's tail" artifacts, "flashlight" phenomenon] as an
indication of pulmonary edema)
Infectiology 923
Fig. 1188  Chest X-ray at COVID-19 (SARS-CoV-2; various
examples): You can see bilateral and peripheral infiltrates.

Fig. 1190  Chest CT ("the classic") at COVID-19 (SARS-

CoV-2): Typically multiple and especially peripherally loca-
lized infiltrates can be recognized. Futhermore the typical
crazy paving sign can be seen.

Fig. 1189  Chest X-ray at COVID-19 (SARS-CoV-2): At first

glance, you might think that the patient was fluid overloa-
ded (in the sense of cardiac decompensation). However,
this was excluded sonographically. Ultimately, these were
pronounced bilateral infiltrates.

924 Infectiology
 ↑ [meta-analysis Kumar et al, Indian J Gastroenterol
2020])
• procalcitonin: not increased (usually only increases
with bacterial superinfection; in a small study [Garrido
et al, AJEM 2020], however, procalcitonin turned out
to be useless as a marker for bacterial superinfection
in COVID)
• possibly measurement of interleukin 6 (norm: < 5,9 pg/
ml)
• for differential diagnosis: influenza smear, urine on le-
gionella and pneumococcal antigen, blood cultures (2
pairs)

Fig. 1191  Chest CT at COVID-19 (SARS-CoV-2)

study
at suspicion of COVID: generous and
early chest CT (native and low-dose
sufficient)!
The Characteristics of 50 Hospitalized COVID-19 Patients
With and Without ARDS
Annotation: There are not few clinics that perform a CT Dreher et al, Dtsch Arztebl Int 2020
scan on every patient with a confirmed SARS-CoV-2. CT
can certainly be helpful in diagnostics (especially to the • observation study of 50 hospilized COVID patients (case
question of whether a new test should be carried out if series) at the University Hospital Aachen (near the dis-
trict of Heinsberg [one of the hotspots in Germany])
the PCR test is initially negative) and also in prognostics.
• mean age: 65 years
On the other hand, CT is not specific for COVID! The first
• gender:
choice of diagnostics is PCR and not CT! One should not
-- female: 34%
ignore the risk of infection (especially for the X-ray staff
-- male: 66%
and subsequent patients), so that a CT should only be
• comorbidities present at all patients
carried out if there is a clear consequence (e.g. to exclu-
de pulmonary embolism)! • median time from onset of symptoms to hospital admis-
sion: 4 days
• course:
Laboratory
-- 24 patients with ARDS (invasive ventilation in ICU)
◦◦ compared to the patients without ARDS:
▪▪ increased rate of pre-existing respiratory disea-
ses and obesity
▪▪ significantly higher levels ​​of leukocytes, CRP,
LDH, D-dimers, creatin kinase und interleukin 6
▪▪ no difference in viral load
◦◦ antibiotics: in 83%
◦◦ ECMO: in 33%
• blood count changes:
◦◦ hemodialysis: in 46%
-- leukopenia (33%; leukocytosis is a risk factor for a
◦◦ 3 patients died.
severe course)
-- 26 patients without ARDS (requireing oxygen in the
-- lymphopenia (80%; due to apoptosis; lymphocytes normal ward; 4 patients died [therapy limitation])
< 1100/µl [< 800/µl → severe course]; the lower the
lymphocytes, the higher the mortality)
-- thrombopenia (40%)
• LDH ↑ (in 40%; > 400 U/ml → severe course)
• CRP ↑↑
-- typically very high for viral infection
-- The level of CRP correlates with the severity of the
disease (Guan et al, N Engl J 2020).
-- CRP > 10 mg/dl → severe course
• D-dimers ↑ (40%; > 1 µg/ml → severe course)
• often excessive activation of coagulation)
• ferritin ↑ (as a typical sign of hyperinflammation)
• liver parameters ↑ (male > female; very often mild he-
patitis; in 25% transaminases ↑, in 9% also bilirubin

Infectiology 925

study
Case characteristics, resource use, and outcomes of
10 021 patients with COVID-19 admitted to 920 German
hospitals
Karagiannidis et al, Lancet Respir Med 2020
• restospective observational study
• 10021 hospitalized patients (920 hospitals) with COVID
in Germany
• mean age: 72 yeras
• gender: m = w (with mechanical ventilation however m:
w = 2: 1, but no difference in mortality)
• likelihood of needing ventilation:
-- men: 22%
-- women: 12%
• mechanical ventilation: in 17%
-- non-invasive ventilation: in 24%
-- invasive ventilation: in 76%
• mean duration of ventilation: 13.5 days (in 23% longer
than 21 days)
• mean duration of hospital stay: 14 days
-- without ventilation: 12 days
-- with ventilation: 25 days
• comorbidities:
-- arterial hypertension (56%)
-- diabetes mellitus (28%)
-- cardiac arrhythmias(27%)
-- renal failure (23%)
-- heart failure (20%)
-- chronic pulmonary disease (14%)
-- obesity (6%)
• procedures
-- dialysis: in 6% (in ventilated patients in 27%)
-- ECMO: in 1.2% (in ventilated patients in 7%)
-- tracheotomy: in 4.4% (in ventilated patients in 26%)
• mortality (hospital) of all hospitalized patients:
-- according to gender:
◦◦ men: 25%
◦◦ women: 19%
-- according to need of ventilation:
◦◦ without ventilation: 16%
◦◦ with ventilation: 53%
▪▪ according to age: < 60 years 28%, 60-70J ye-
ars 46%, 70-80 years 63%, > 80 years seven
72%
▪▪ if additionally acute kidney injury requiring dialy-
sis (of all ventilated patients): 73%
Guidelines
• national (Germany; DGIIN, DIVI, DGP, DGI and DGA):
-- S1 guideline "Recommendations for intensive care
treatment for patients with COVID-19"
◦◦ 1st version from 09.03.202
◦◦ 2nd version from 19.06.2020 (update)
◦◦ 3rd version from 21.07.2020 (update)
926 Infectiology
-- S2k guideline (23.11.2020): "Recommendations for
hospitalized therapy for patients with COVID-19";
-- 3 levels of recommendation:
◦◦ strong recommendation
◦◦ weak recommendation
◦◦ open recommendation
• international:
-- Surviving Sepsis Campaign (SSC) - Guide­lines on
the Management of Critically Ill Adults with Coronavi-
rus Disease (COVID-19) 2020 (dates back to March
2020 and has not been renewed since)
-- Infectious Diseases Society of America (ISAA) Gui-
delines on the Treatment and Management of Pati-
ents with COVID-19 2020
Therapy
• causal
-- still under testing (currently approx. 300 ongoing
trials), i.e. still purely experimental and (except for
remdesivir) off-lable (This should also be pointed out
to the patients or their representatives.)
-- Only Remdisivir is currently officially approved in Eu-
rope (as of 03.07.2020).
-- however already performed in many hospitals (indi-
vidual decision; preferably in the context of clinical
trials)
-- If antiviral therapy is performed, then it should be
performed early (at best before the patients requi-
res intensive care). If the lungs are completely de-
stroyed by diffuse alveolar damage, then antiviral
substances don´t help much anymore! Furthermore
antiviral therapy should inhibit virus replication and
this takes place in the early and no longer in the late
phase of the disease!
-- studies:
◦◦ SOLIDARITY (see box on page 932): meanwhile
completed worldwide multicenter international stu-
dy pf the WHO on the efficacy of hydroxychloro-
quine, lopinavir / ritonavir, interferon-β (alone or
22% in combination with lopinavir / ritonavir) and rem-
desivir (especially for Europe: DISCOVERY) → no
advantage (especially with regard to mortality) at
for any substance
◦◦ RECOVERY (see page 934): currently still ongo-
ing (and the largest worldwide) study in England
by the NHS (National Health Service) on the ef-
fectiveness of hydroxychloroquine (already com-
pleted: no benefit), lopinavir / ritonavir (already
completed: no benefit), azithromycin, tocilizumab,
immuntherapy with convalescence plasma and
dexamethasone (already completed: significant
reduction in mortality)
• supportive
Causal therapy
• antiviral therapy (useful in the early phase)
• antiinflammatory therapy (useful in the late phase)
Antiviral therapy
• fusion inhibitors: chloroquine resp. hydroxychloroquine
• protease inhibitors:
-- lopinavir / ritonavir
-- Camostat (Foipan; inhibition of the serine protease
TMPRSS2; i.a. used in Japan for treatment of acute
pancreatitis)
• RNA polymerase inhibitors (exactly: RdRP [RNA-de-
pendent RNA polymerase])
-- remdesivir
-- favipiravir (Avigan):
◦◦ previous indication: influenza
◦◦ company: Fujifilm Toyama Chemical
◦◦ study: Cai et al, Elsevier 2019 (see box)
• neuraminidase inhibitors (e.g. oseltamavir, zanamivir):
not effective against SARS viruses
• interferon-β (SOLIDARITY study [see page 932]: no
benefit)
• possibly application of zinc (no randomized controlled
data):
-- Zinc inhibits the virus replication by inhibiting the
RNA polymerase (exactly: RdRP [RNA-dependent
RNA polymerase]; Aartjan et al, PLos Pathogens
2020).
-- application: 3 x 30mg daily
◦◦ parenteral: unizinc (Zinkaspartat)
◦◦ enteral: zincorotate
-- A zinc deficiency (normal value for zinc level: 0.70-
1.20 mg/l) should be made up.
-- In a retrospective observational study (Carlucci et al,
MedRxiv 2020), the additional application of zinc (to
hydroxychloroquine and azithromycin) showed no
benefits.
• possibly immun therapy
-- passive, i.e. with antibodies from already recovered
COVID patients (plasma donation from convale-
scents; convalescent plasma)
-- a relatively old method
-- typical side effect: hypersensitivity reaction
-- no clinical benefit so far in the studies (e.g. Li et al,
JAMA 2020; Shen et al, JAMA 2020; Liu et al, med-
RXiv 2020; Valk et al, Cochrane Database Syst Rev
2020)
-- In a propensity score analysis (Salazar et al, Ameri-
can Journal of Pathology 2020) from Houston / USA,
it could be shown that plasma therapy is successful
and also leads to a reduction in mortality if it is car-
ried out early (< 72h) and if there is sufficient antibo-
dy titer (≥ 1: 1350) in the donor plasma.
-- In a retrospective single-center case-control study
(Liu et al, Nat Med 2020), plasma therapy showed
a reduction in mortality in patients with severe CO-
VID-19.
-- currently ongoing studies in Germany: CAPSID, RE-
COVER
-- approved by the FDA
-- S2k guideline of the DGIIN (23.11.2020): use out-
side of clinical studies not recommended
• possibly colchicine (GRECCO-19 study [Deftereos et
al, JAMA 2020]: In this randomized, controlled study in
105 patients with COVID-19, with colchicine [1.5 mg as
loading dose, then 0.5 mg after 60min, then 0.5 mg twi-
ce a day over 3 weeks] significantly less often a severe
course was seen compared to placebo.)
• possibly human recombinant soluble ACE-2 (hr-
sACE-2; e.g. APN01)
• possibly aviptadil (RLF-100): VIP (vasoactive intestinal
peptide)
-- binding to VIP receptors (VPAC; glycoprotein cou-
pled)
◦◦ VPAC type 1
◦◦ VPAC type 2
-- protective pulmonary effect by binding to the VPAC
type 2 receptor of the alveolar cells type II
-- In a prospective, externally controlled study (Yous-
sef et al, preprint at SSRN [Social Science Research
Network] 2020), aviptadil (3 infusions each over 12
hours at a dose of 50, then 100 and then 150 pmol/
kg/h ) showed a 9-fold lower mortality in critically ill
COVID patients compared to placebo.
study
Experimental Treatment with Favipiravir for COVID-19: An
Open-Label Control Study
Cai et al, Elvesier 2019
• randomized controlled study
• 80 patients with COVID:
-- favipiravir (d1 2 x 1600mg, d2-14 2 x 600mg) +
interferon-β (inhalativ; 5 millions IU twice daily)
-- lopinavir / ritonavir
• results (favipiravir + interferon-β):
-- faster virus elimination (already after 4 instead of 11
days)
-- more frequent improvement of chest CT findings (in
91% instead of 62%)
Chloroquine
• chloroquine (Resochin; no more on the market since
2016) or hydroxychloroquine (Quensyl, Praquenil; a
less toxic and better tolerable metabolite [an additional
hydroxyl group] of chloroquine)
• previous indications:
-- malaria ( antimalarial drug [already since 1934])
-- systemic lupus erythematosus (SLE; the basic drug
here)
-- Q-fever (Q: query; coxiella burnetii)
-- Whipple´s disease (tropheryma whipplei)
• effects:
-- blockage of the ACE-2 receptor of the respiratory
epithelial cells, via which SARS viruses dock and
enter the cell (inhibition of fusion)
-- immunosuppressive effect
• studies: overall only little validated data for use in CO-
VID
Infectiology 927
 -- In an experimental study (Wang et al, Cell Research
2020), infection with SARS-CoV-2 was prevented in
cell cultures (in vitro).
-- A clinical study (Chen et al, MedRxiv 2020; see box)
showed a faster improvement in symptoms, the CT
findings and less often a severe course.
-- CloroCovid-19 study (Borba et al, MedRxiv 2020):
premature termination due to increased QT time
extension and an increased number deaths (in the
high-dose group [1200 mg/d])
-- retrospective observational study in the United Sta-
tes (Magagnoli et al, MedRxiv 2020; evaluation of all
hospilized patients in the veterinary clinics [i.e. only
men]): 2.6-fold increased mortality compared to pla-
cebo
-- An international registry study (Mehra et al, Lancet
2020) showed an increased rate of ventricular ar-
rhythmias and increased mortality! However, the re-
sults of the study were withdrawn due to errors (fake
news).
-- meta-analysis (11 studies; Chacko et al, MedRxiv
2020): no reduction in mortality
-- In the largest worldwide therapy study RECOVERY
(see page 934), there was no effect at all on hyd-
roxychloroquine, so that it can now be regarded as
obsolete.
-- also no effect in patients treated out-of-hospital with
mild infections (Skipper et al, Ann Intern Med 2020)
-- Covid-19 Brazil I study (Cavalcanti et al, N Engl J
2020; an RCT): no clinical improvement due to hyd-
roxychloroquine in mild and moderate COVID infec-
tion (not even in combination with azithromycin)
• dosage (relatively high doses here, therefore often
side effects): hydroxychloroquine 2 x 500mg or 3 x 200
daily p.o. for 10 days; alternatively: 2 x 400mg at day 1,
then 2 x 200mg for 4 days; not i.v. available
• side effects:
-- QT interval ↑ (especially in combination with a ma-
crolide [e.g. azithromycin; therefore generous ecg
monitoring when combined with azithromycin]; pos-
sibly torsade de pointes)
-- retinopathy
-- central deafness
-- hypoglycemia
-- agranulozytosis
-- nausea, vomiting
-- cerebellar dysfunction
• contraindications:
-- Glucose-6-phosphate dehydrogenase deficiency
(G6PDD; but no general screening usefule with CO-
VID-19 because it takes too long until you get the
result)
-- retinopathy (e.g. macular degeneration)
-- epilepsy (seizures)
-- myasthenia gravis
-- psoriasis
-- porphyria
• also possible in pregnancy
• The antidote for chloroquine intoxication is diazepam
928 Infectiology
in a very high dosage (1 mg/kg i.v.; intubation readi-
ness).
• possibly combination with azithromycin (d1 500mg,
dann d2-5 250mg): Combination therapy over 5 days
showed faster virus elimination on day 6 than with
monotherapy with hydroxychloroquine over 5 days
(Gautret et al, International Journal of  Antimicrobi-
al Agent 2020).
• COVID guideline of SSC 2020: Neither a recommen-
dation for it nor against it can be given.
• was approved by the FDA for the treatment of SARS-
CoV-2 ("emergency authorization") for a short time, but
after the results of the RECOVERY study the permis-
sion to use it outside of clinical studies was withdrawn
• SOLIDARITY study (see page 932): no benefit
• also no longer recommended by the WHO
study
Efficacy of hydroxychloroquine in patients with COVID-19:
results of a randomized clinical trial
Chen et al, MedRxiv (preprint-server) 2020
• monocentric (Wuhan University Clinic) randomized con-
trolled clinical trial
• 62 patients with COVID:
-- hydroxychloroquine 400mg p.o. daily ober 5 days
-- placebo
• results (hydroxychloroquine):
-- significantly faster regression of fever and cough
-- more frequent improvement of chest CT findings
-- significantly less often severe course (in 4 patients in
the placebo and in no patient in the nocebo group!)
Lopinavir / Ritonavir (Kaletra)
• a protease inhibitor (from HIV therapy; Ritonavir inhi-
bits the breakdown of lopinavir.)
• dosage: 2 x 400mg/100mg daily p.o. for 10-14 days
• studies:
-- Cao et al, N Engl J 2020 (RCT; see box)
-- currently ongoing study (MIRACLE study): lopinavir/
ritonavir in combination with interferon-β in Saudi
Arabia with MERS-CoV
• interactions: Ritonavir is the most potent inhibitor of
the cytochrome P450 enzyme CYP3A4. The following
drugs are also inhibitors of the cytochrome P450 enzy-
me CYP3A4 and must therefore not or only carefully
(after appropriate risk-benefit assessment) be given
in combination with ritonavir: ticagrelor, clarithromy-
cin, verapamil, amiodaron, fluconacole, voriconacole,
isavuconacole, opioids, midazolam (Ritonavir poten-
tiates midazolam, so the dose should be reduced.),
ergotamine-containing drugs (cave ergotism) such as
migraine drugs (ergotamine, dihydroergotamine) or
Parkinson drugs (bromocriptine, cabargoline, lisuride,
pergolide, dihydroergotriptine)
• side effects: especially gastrointestinal
 -- nausea, vomiting, diarrhea
-- hepatopathy
-- acute pancreatitis
• In the largest worldwide therapy study RECOVERY
(see page 934), there was no benefit for ritonavir /
lopinavir.
• SOLIDARITY study (see page 932): no benefit
• recommendations:
-- international (COVID guideline off SSC 2020): not
recommended
-- national (S2k guideline of the DGIIN [23.11.2020]):
not recommended
study
A Trial of Lopinavir-Ritonavir in Adults Hospitalized with
Severe COVID-19
Cao et al, N Engl J 2020
• randomized controlled study (open-label)
• 199 hospitalized patients with proven SARS-CoV-2 in-
fection with respiratory insufficiency (SpO2 < 94% or Ho-
rovitz quotient < 300 mmHg)
-- lopinavir / ritonavir 2 x 400mg/100mg daily p.o. for 14
days
-- placebo
• results: lopinavir / ritonavir
-- primary endpoint: time to clinical improvement → no
difference (no clinical benefit)
-- secondary endpoints: i.a.
◦◦ mortality: no difference
◦◦ viral load: no difference
◦◦ more frequent gastrointestinal side effects
• note: However, the patients in this study were already
seriously ill and all had already alung damage, so that
the drug might have been given too late. They were in-
cluded on average only 13 days after the onset of sym-
ptoms.)
study
Triple combination of interferon beta-1b, lopinavir–ritonavir,
and ribavirin in the treatment of patients admitted to hospi-
tal with COVID-19
Hung et al, Lancet 2020
• multicenter randomized controlled study (open-label)
• 127 hospitalized patients with proven SARS-CoV-2 in-
fection; lopinavir / ritonavir 2 x 400mg/100mg daily p.o.
for 14 days; in addition:
-- ribavirin 400mg 2 x daily + (if duration of disease <
7 days) interferon-β up to max. 3 x 8 millions IU s.c.
every 2 days
-- placebo
• results: triple therapy
-- significantly faster virus elimination (by 5 days)
-- significant reduction in duration of the disease (was
halved)
Remdesivir
• a nucleotide analog (inhibition of the RNA polymerase;
exactly: RdRP [RNA-dependent RNA polymerase])
• trade name: Veklury
• was actually developed for the therapy of the Ebola
and Marburg viruses, but was not effective here; in
animal experimental studies, however, well effective
against MERS-CoV and in vitro also against SARS-
CoV (Wang et al, Cell Research 2020)
• dosage: d1 200mg i.v., then 100mg i.v. for 5-10 days
(SIMPLE Severe study [Goldman et al, N Engl J 2020]:
no difference between 5 or 10 days; Spinner et al,
JAMA 2020: Only the administration over 5 days show-
ed a significant clinical improvement, but not the admi-
nistration over 10 days.); note: dosage for children: d1
5mg/kg, then 2.5mg/kg (but only approved for those
aged > 12 years and body weight > 40kg)
• was not commercially available for a long time, but as
"Compassionate Use" (use of a not yet approved drug
in particularly serious cases of illnesses) via the Gi-
lead company (prerequisites: invasive ventilation, no
catecholamines, GFR > 30 ml/min, transaminases <
5-fold of the norm; special approval in the USA since
03/05/2020); "Compassionate Use" program has me-
anwhile ended and the substance is also commercially
available (also for non-intubated patients)
• contraindications:
-- renal failure with a GFR < 30 ml/min
-- transaminases (GOT or GPT) > 5-fold of the norm
• side effects (rare [a relatively safe drug]): especially
-- vomiting, diarrhea
-- hepatopathy (transaminases ↑)
-- renal dysfunction
-- hypotension
• studies:
-- in the first randomized controlled trial (Wang et al,
Infectiology 929
 Lancet 2020; see box) no clinical benefit demonst-
rated
-- ACCT-1 study (Beigel et al, N Engl J 2020; see box):
faster clinical improvement but no reduction in mor- study
tality (note: Patients with moderate disease benefi-
ted most. However, this is only a subgroup analy-
sis.); overall only marginal effectiveness
-- currently two ongoing phase-III studies (RCT) Compassionate Use of Remdesivir for Patients with Se-
vere Covid-19
-- SOLIDARITY study (see page 932; but only Grein et al, N Engl J 2020
preprint and has not been peer-reviewed): no benefit
at all (no reduction in mortality, in the rate of requi- • cohort study (observational study); evaluation of the
ring ventilation or in the length of hospital stay) Compassionate Use program (no comparison cohort)
• officially approved in the EU since 03.07.2020 for CO- • 53 patients with proven SARS-CoV-2 infection, SpO2 <
VID patients older than 12 years and body weight > 94% or application of oxygen → remdesivir
40kg with pneumonia requiring additional oxygen • i.a. invasive ventilation in 57%, ECMO in 8%
• results:
• recommendations
-- clinical improvement (decrease in oxygen demand):
-- IDSA (Infectious Diseases Society of America) for in 68%
patients with COVID requiring additional oxygen (i.e. -- discharge from hospital: in 47%
early administration) for 5 days (if no improvement:
-- mortality:
for 10 days) in combination with dexamethasone
◦◦ without ventilation: 5%
-- STAKOB (permanent working group of the compe- ◦◦ with ventilation: 18%
tence and treatment centers for diseases caused by • excluding criteria:
highly pathogenic pathogens) and the S2k guideline -- renal failure with a GFR < 30 ml/min
of the DGIIN (23.11.2020): open recommendation -- transaminases (GOT or GPT) > 5-fold of the norm
("can") if requiring additional oxygen and radiogra-
phic evidence of an infiltrate (duration: 5 days); but
not recommended for:
◦◦ invasively ventilated patients
◦◦ renal insufficiency with a GFR < 30 ml/min study
◦◦ transaminases ↑ 5-times the norm
-- WHO (20.11.2020): no longer recommended
guideline development group); WHO recommends
against the use of remdesivir in COVID-19 patients Remdesivir in adults with severe COVID-19: a randomized,
double-blind, placebo-controlled, multicenter trial
Wang et al, Lancet 2020

• multicenter randomized controlled study

• 237 patients with proven SARS-CoV-2 infection with res-
piratory insufficiency (SpO2 < 94% or Horovitz quotient <
300mmHg) and radiologically proven pneumonia
-- 158 patients: remdesevir (d1 200mg i.v., d2-d10
100mg i.v.)
-- 79 patients: placebo
• results:
-- primary endpoint: time to clinical improvement → no
Fig. 1192  Remdesivir (storage in the refrigerator) difference (no clinical benefit)
-- secondary endpoints: i.a.
◦◦ mortality: no difference
◦◦ viral load: no difference

930 Infectiology

ACCT-1 study
Remdesivir for Treatment of COVID-19: preliminary report
Beigel et al, N Engl J 2020
• multicenter randomized controlled study
• ACTT: Adaptive COVID-19 Treatment Trial
• 1063 patients with proven SARS-CoV-2 infection and
evidence of lower respiratory tract involvement
-- Remdesevir (d1 200mg i.v., d2-d10 100mg i.v.)
-- Placebo
• results:
-- time to clinical improvement (primary endpoint):
significantly reduced (11 versus 15 days); rate ratio of
recovery: all in all 1.32; subgroups:
◦◦ without additional oxygen: 1.38
◦◦ with additional oxygen 1.47 (benefited the most)
◦◦ with HFNOT / non-invasive ventilation: 1.20
◦◦ with invasive ventilation / ECMO: 0.95 (benefited
the least [no benefit at all here])
-- mortality: no difference
Remdesivir: no longer recommended
(WHO)
Antiinflammatory therapy
• against interleukins:
-- against interleukin-6:
◦◦ tocilizumab (RoActemra)
◦◦ sarilumab (Kerzara; phase III study: no benefit)
-- against interleukin-1: anakinra (Kineret)
• against Janus kinase: baricitinib (Olumiant): a Janus
kinase inhibitor (previous indication: rheumatoid arth-
ritis)
• immunoglobulines i.v.: not recommended (COVID gui-
deline of the SSC 2020)
• possibly extracorporeal cytokine removal (especially
in a proneounced CRS [cytokine release syndrome];
e.g. with massively increased Il-6 levels [> 1000 pg/
ml]) using special filters (i.a. CytoSorb, oXiris), which
are integrated into the cycle of an ongoing renal repla-
cement therapy (CVVH); no general recommendation
• possibly fluvoxamine (an SSRI): In a randomized cont-
rolled study (Lenze et al, JAMA 2020), outpatients with
COVID treated with fluvoxamine showed less clinical
deterioration than placebo. Fluvoxamine is also an
α1-agonist (S1R [sigma-1 receptor]) and may thereby
have an immunomodulating effect.
Tocilizumab (RoActemra)
• a monoclonal antibody against interleukin-6
• usefull only with CRS (cytokine release syndrome)
with increased Il-6 levels (> 170 pg/ml; should be mea-
sured beforehand!)
• previous indication: rheumatoid arthritis, Still's disease
(systemic juvenile idiopathic arthritis)
• dosage: 8 mg/kg (maximum 800mg) as a short infu-
sion over 60min (usually only a single dose); if there
is no clinical deterioration after administration, up to 3
administrations at least 8 hours apart are still possible
• Tocilizumab suppresses CRP synthesis.
• contraindications: bacterial superinfection, increased
transaminases > 5-fold of the norm, neutropenia (<
500/µl), thrombopenia (< 50000/µl), hepatitis B (HBs-
Ag, anti-HBc-IgM, anti-HBs-Ag), tuberculosis (Quanti-
feron test)
• side effects: especially
-- increased risk of bacterial infections
-- leukopenia (esp. neutropenia)
-- hepatopathy
• studies:
-- COVACTA study (a phase III study): Tocilizumab did
not show any reduction in mortality or ventilation-free
days in hospitalized patients with severe COVID-19
pneumonia compared to placebo.
-- EMPACTA 2020 study (a phase III study): Tocili-
zumab showed a reduction in the primary endpoint
of requiring mechanical ventilation and death in hos-
pitalized patients with COVID-19 pneumonia.
-- BACC study (Stone et al, N Engl 2020; see box): no
benefit
-- Hermine et al, JAMA 2020 (siehe box): no benefit
• S2k guideline of the DGIIN (23.11.2020): use outside
of clinical studies inot recommended
BACC study
Efficacy of Tocilizumab in Patients Hospitalized with Co-
vid-19
Stone et al, N Engl J 2020
• multicenter randomized controlled study
• BACC: Boston Area COVID-19 Consortium
• 243 patients with proven SARS-CoV-2 infection, hyper-
inflammatory status (at least one of the following criteria:
CRP > 5 mg/dl, ferritin > 500 ng/ml, D-dimers > 1 µg/ml
or LDH > 250 U/ l) and at least 2 of the following criteria:
fever > 38 °C, pulmonary infiltrates or SpO2 < 92% (i.e.
additional administration of oxygen required)
-- tocilizumab (singe dose 8 mg/kg i.v.)
-- placebo
• results: tocilizumab
-- primary endpoint (time to need for intubation and me-
chanical ventilation or to death): no difference
-- secondary endpoints: i.a.
◦◦ time to clinical deterioration: no difference
◦◦ time until no additional administration of oxygen
was necessary: ​​no difference
◦◦ duration of invasive ventilation: no difference
Infectiology 931

study
Effect of Tocilizumab vs Usual Care in Adults Hospitalized
With COVID-19 and Moderate or Severe Pneumonia
Hermine et al, JAMA 2020
• multicenter randomized controlled study
• 130 hospitalized patients with COVID-19 and at least
moderate (p.d. at least 3 l/min additional oxygen requi-
red) pneumonia
-- tocilizumab (8 mg/kg i.v. at day 1 and if clinically ne-
cessary again at day 3)
-- placebo
• results: tocilizumab
-- primary endpoints: no difference
◦◦ WHO-CPS score (CPS: Clinical Progression Scale;
score with 10 points) at day 4
◦◦ survival without requiring ventilation
-- secondary endpoints: no difference; i.a.
◦◦ time until no additional administration of oxygen
was necessary
◦◦ time to discharge from hospital
◦◦ mortality
Anakinra (Kineret)
• a monoclonal antibody against interleukin-1
• usefull only with CRS (cytokine release syndrome)
with increased Il-1 levels (> 5 pg/ml; should be mea-
sured beforehand!)
• previous indication: rheumatoid arthritis, inflammatory
bowel disease
• S2k guideline of the DGIIN (23.11.2020): use outside
of clinical studies not recommended
SOLIDARITY study
Public health emergency SOLIDARITY trial of treatments
for COVID-19 infection in hospitalized patients
WHO Solidarity Trial Consortium, medRxiv 2020
• worldwide international (30 countries) multicenter (405
hospitals) randomized controlled study of the WHO
• 11,266 hospitalizd with COVID-19
• 4 substudies: each versus placebo (4088 patients)
-- hydroxychloroquin (954 patients)
-- lopinavir / ritonavir (1411 patients)
-- remdesivir (2750 patients [ the largest group])
-- interferon β (2063 patients; in 32% with and in 68%
without lopinavir / ritonavir)
• results: for each of the 4 substances
-- no reduction in mortality (total 12%; if ventilated: 39%)
-- no reduction in the rate of requiring ventilation
-- no reduction in the length of hospital stay
932 Infectiology
currently (still) no evidence for a
causal, i.e. antiviral or anti-inflamm-
atory therapy!
Supportive therapy
• if necessary admission to ICU (intensive care unit)
-- 5% of all patients require intensive care.
-- 20% of all patients admitted to hospital require inten-
sive care in the further course.
-- admission to ICU: typically on average 10 days
after onset of symptoms
-- indication (according to the S1 guideline):
◦◦ dyspnea + tachypnea (respiratory rate > 25-30/
min) + SpO2 < 90% despite administration of oxy-
gen (up to 4 litres / minute); note: according to the
S2k guideline of the DGIIN (23.11.2020) the only
criterion
◦◦ SBP < 100 mmHg
◦◦ increased lactate
-- invasive ventilation: in 50% of all patients admitted
to ICU (i.a. Grasseli et al, JAMA 2020; Richardson
et al, JAMA 2020)
-- length of ICU stay: on average 9 days (in invasive
ventilation: 18 days)
-- mortality:
◦◦ if requiring intensive care: 50% [Meng et al,
Anesthesiology 2020]; analogue ICNARC report
2020 [UK]; laut RKI [Robert Koch Institute] and
DIVI registry in Germany: 33% [as of November
2020: 22%])
◦◦ if requiring intubation and invasive ventilation:
66% (ICNARC report 2020 [Intensive Care Nati-
onal Audit and Research Center; UK]); according
to Namendys-Silva et al, Lancet Resp Med 2020
even 86%, according to Zhou et al, Lancet 2020
even 97%!); according to an observation study in
Germany (Karaggianidis et al, Lancet Resp Med
2020): 53%
• hygienic measures
• respiratory insufficieny:
-- oxygen administration (usually sufficient in mild to
moderate cases; close control of saturation [target
SpO2 > 90%])
-- if necessary ventilation
-- in obstruction (e.g. by SARS-CoV-2 infect exacerba-
ted COPD): nebulization (e.g. Berodual 10gtt + 5ml
NaCl 0.9% 4 x daily)
◦◦ The staff should wear the appropriate protective
equipment (especially FFP-2 masks) due to the
increased risk of aerosol formation.
◦◦ However, there was no evidence of a significant-
ly increased delivery of infectious aerosols under
nebulization (jet nebulizer) compared to sponta-
neously breathing patients, neither in vitro nor in
vivo. Under nebulization with sodium chloride the
excretion of aerosols was even reduced (due to a
reduced surface tension)!
◦◦ One should therefore not withhold this therapy
 from the patient out of fear of infection!
• angibiotic therapy (antibiosis) for bacterial superinfec-
tion (e.g. ampicillin / sulbactam, piperacillin / tazobac-
tam)
-- no prophylactic administration recommended (nati-
onal S1 + S2k guideline); note: In the international
COVID guideline of the SSC 2020 antibiosis is re-
commended as soon as the patient is ventilated in-
vasively [but only a weak recommendation]!)
-- Bacterial coinfection is rare overall (only in 6.9% of
all COVID patients [of which already at admission
in 3.5% and later in the further course in 14.3%],
especially in the intensive care unit in 8.1% [meta-
analysis Langford et al, Clinical Microbiology and
Infection 2020).
• antifungal therapy (especially voriconazole) for invasi-
ve aspergillosis:
-- significantly increased incidence of invasive as-
pergillosis in COVID (co-infection; CAPA: coronavi-
rus-associated pulmonary aspergillosis); Bartoletti et
al, Clin Infect Dis 2020: 27.7% of all mechanically
ventilated COVID patients; after 4 days on average;
significantly increased mortality (74% versus 26%)
-- In case of an unclear pulmonary deterioration in ven-
tilated patients, also think of aspergillosis!
• restrictive fluid administration (fluid overload should be
avoided because it worsens oxygenation; exception:
sepsis [however, with 5% rare])
• in the case of hemodynamic instability (overall rare),
generously advanced hemodynamic monitoring (i.a.
echocardiography, PiCCO)
• steroids
• thrombosis prophylaxis with LMWH in at least prophyl-
actic dosage ( if D-dimers > 1,5 µg/ml even in halve-
therapeutic dosage weight adapted [syn.: intensified
thrombosis prophylaxis; e.g. 80kg patient → dalteparin
2 x 4000 IE s.c.] due to the excessive activation of co-
agulation! In a retrospective analysis, systemic antico-
agulation in hospitalized COVID patients was associa-
ted with a higher probability of survival [Paranjpe et al,
JACC 2020]. In two other retrospective studies [Motta
et al, medRxiv 2020; Lynn et al, Thrombosis Research
2020], therapeutic anticoagulation [full anticoagulation]
in hospitalized COVID patients showed no advantages
over prophylactic anticoagulation.)
• if necessary renal replacement therapy for refractory
acute kidney injury (in 15% of all patients requring in-
tensive care)
• antipyretic therapy:
-- metamizole (Novalgin)
-- acetaminophen (paracetamol)
-- cave NSAR (e.g. ibuprofen [initially advised against
by the WHO, but the warning was then withdrawn]:
detorioration of the disease has been described in
individual cases; up-regulation of the ACE-2 recep-
tors via which SARS viruses enter the cells; howe-
ver, the data situation is inconsistent)
• A pre-existing immunosuppressive therapy (e.g. aza-
thioprin, calcineurin inhibitor, mycophenolate-mofetile)
should be reduced or even discontinued in the case of
severe infection (especially with lymphocytopenia [es-
pecially if lymphocytes < 800/µl])!
• if hemophagocytosis syndrome is detected, immuno-
suppressive therapy (see page 829)
Steroids
• guidelines (previous recommendations regarding ste-
roids in ARDS):
-- national (S1 guideline DGIIN 2020 [1st and 2nd ver-
sion]): not recommended (explicitly); except hydro-
cortison 200mg/day with therapy-refractory septic
shock or with proven adrenocortical insufficiency or
prednisolon 1 x 40mg p.o. over 5 days in exacerba-
ted COPD
-- international (COVID guideline of the SSC 2020):
recommended (but only weakly with very little evi-
dence); note: However, if there is only pneumonia
without ARDS, steroids are clearly not recommen-
ded here either.
• studies: There are no randomized controlled trials here
for a long time. The recommendations were mainly
derived from the analogy to influenza. In a retrospec-
tive analysis (Wu et al, JAMA Intern Med 2020) of 221
patients with COVID-19 pneumonia methylprednisolo-
ne (Urbason) showed a lower mortality compared to
placebo. In the worldwide largest therapy study RE-
COVERY low-dose administration of dexamethasone
(Fortecortin; 6mg once a day p.o. or i.v. for 10 days;
dosage in children: 0.2 mg/kg [max. 6mg/d]; note:
6mg dexamethasone corresponds to 45mg predniso-
lone [conversion factor: 7.5].) showed a significant re-
duction in mortality, so that it is now (by the NHS and
WHO) regarded as the therapy standard! Dexametha-
sone is also recommended in the position paper of the
German Society for Pneumology (DPG) as soon as
there is an indication for the administration of oxygen.
It is also clearly recommended as a standard in the 3rd
version of the S1 and the S2K guideline of DGIIN and
by the IDSA (Infectious Diseases Society of America).
Alternatively, another glucocorticoid (e.g. hydrocortiso-
ne 3 x 50mg i.v.) is also possible.
• recommendation (i.a. WHO, ISDA, DGP [German So-
ciety for Pulmonology]): COVID infection as soon as
the additional administration of oxygen is necessary
(i.e. SpO2 breathing room air < 94% [S2k guideline
DGIIN: only < 90%])
Infectiology 933
 RECOVERY study
Randomized Evaluation of COVid-19 thERapY
Hobry et al, N Engl J 2020
• RECOVERY: Randomized Evaluation of COVid-19 thE-
RapY
• therapy study of the NHS (National Health Service) in
the UK (175 hospitals)
• largest worldwide (11500 patients) clinical trial for the
treatment of COVID-19
• 6 substudies:
-- hydroxychloroquine (1542 patients) versus placebo
(3132 patients) → no significant reduction in 28-
day mortality (also no effect on length of hospital stay
or other outcome parameters)
-- lopinavir / ritonavir (1596 patients) versus placebo
(3367 patients) → no significant reduction in 28-
day mortality
-- azithromycin: still ongoing
-- tocilizumab: still ongoing
-- immuntherapy with convalescent plasma: still ongoing
-- dexamethasone (2104 patients; low-dose: 6mg p.o. /
i.v. for 10 days) versus placebo (4321 patients) →
significant reduction in 28-day mortality (in mechani-
cally ventilated patients by 35% [NNT only 8!], in pati-
ents with additional O2 application by 20%; in patients
with additional O2 application no effect)
CODEX study
Effect of Dexamethasone on Days Alive and Ventilator-
Free in Patients With Moderate or Severe Acute Respira-
tory Distress Syndrome and COVID-19
Tomazini et al, JAMA 2020
• multicenter (41 ICU in Brazil) randomized controlled stu-
dy
• 299 patients with proven SARS-CoV-2 infection and at
least moderate (Horovitz quotient <200 mmHg) ARDS
-- dexamethasone i.v. (for 5 days 1 x 20mg daily, then
for another 5 days 1 x 10mg)
-- placebo
• results: dexamethasone
-- primary endpoint (ventilator-free days after 28
days) → significantly increased
-- secondary endpoints
◦◦ SOFA score (severity of disease): significantly re-
duced
◦◦ secondary infection: significantly reduced (despite
steroids!)
◦◦ mortality: no difference
◦◦ duration of mechanical ventilation: no difference
934 Infectiology
meta-analysis
Association Between Administration of Systemic Cortico-
steroids and Mortality Among Critically Ill Patients With
COVID-19
The WHO Rapid Evidence Appraisal for COVID-19 Thera-
pies (REACT) Working Group, JAMA 2020
• meta-analysis (7 RCT [incl. RECOVERY study])
• 1703 critically ill patients with COVID-19
-- steroids (dexamethasone, hydrocortisone or methyl-
prednisolone)
-- placebo
• result: steroids → significant reduction in mortality (after
28 days)
as soon as additional oxygen is
required: dexamethasone 6mg p.o. /
i.v. for 10 days (the only drug to date,
for which a reduction in mortality in
COVID is proven!)
Hygienic measures
• isolation
-- single room (preferably in a room with negative pres-
sure [recommended in the COVID guideline of the
SSC 2020] and with lock and anteroom)
-- also cohort isolation possible with high patient volu-
me (of patients with proven SARS-CoV-2)
-- The following patients cannot be "free tested" i.e.
they always have to be isolated for 14 days (a nega-
tive test result has no effect on the isolation, so that
a test is not necessary here.):
◦◦ contact persons of category I
◦◦ patients from a risk area abroad (e.g. according
to RKI)
• basic hygiene, i.a. hygienic hand disinfection (Alcoho-
lic hand disinfection is very effective with SARS-CoV
and much more effective than hand washing), con-
ventional wiping disinfection (e.g. stethoscopes, ultra-
sound devices)
• personal protective equipment (PPE):
-- with patient contact (and explicitly especially always
with aerosol-generating procedures [AGP: esp. tn-
tubation, open suctioning, disconnection from the
ventilator, bag mask ventilation, non-invasive ven-
tilation, high-flow nasal oxygen therapy, nebulizati-
on, broncho­scopy, tracheotomy, resuscitation] also
personal protective equipment: close-fitting [cave
beard → shave] mask (at least FFP-2 [Europe; see
infobox] or N95 [USA]; cave: do not use self-made
masks in the hospital), long-sleeved water-resistant
gown, protection goggles (or face shield), disposa-
ble gloves
 -- If no aerosol-generating procedures take place,
a FFP-2 or N95 mask is not absolutely necessary
for patient contact according to the SSC's COVID
guideline. A face mask (surgical mask) is sufficient
here, which should be considered in terms of limited
resources.
-- In a meta-analysis (Martinez et al, Antimicrob Agents
Chemother 2020), respiratory masks were not su-
perior to mouth-nose masks in terms of infection by
medical staff.
-- cave infection of the medical staff (In Italy, for ex-
ample, 11% of medical staff got infected, in Germany
according to RKI 5.8%. However, it is unclear whe-
ther they got infected while working on COVID-posi-
tive patients or outside the hospital.)
• Spontaneously SARS-CoV-2 positive breathing (awa-
ke) patients should always wear a mouth and nose
mask (surgical mask). They should not wear a respi-
ratory mask (like FFP-2 [especially no FFP-2 masks
with exhalation valve), as this will blow the virus out of
the mask
• regular window ventilation (very effective to prevent
aerosol-related transmission to the staff)
• The following is considered to be non-infectious: blood
(SARS-CoV-2 viruses almost never occur in the blood,
viremia is a rarity!), urine and stool of the patient (virus
RNA detected here, but ultimately usually not infec- Fig. 1193  PPE (personal protective equipment; with cour-
tious ["dead" viruses]) tesy of Dr. Florian Eisner, senior physician at Graz Univer-
sity Hospital [Austria])

Infectiology 935
Ventilation
• invasive:
• non-invasive: NIV (non-invasive ventilation) and HF-
NOT (high-flow nasal oxygen therapy) are aerosol-
generating procedures, so that the risk of infection for
the staff is significantly increased! The risk of infection
with NIV with a ventilation helmet may be lower. How-
ever, the COVID guideline of the SSC 2020 does not
make an explicit recommendation for the helmet. A
mouth-nose mask or a full face mask is also possible.
You should definitely use closed systems (non-vented
masks). Leakages should be kept to a minimum. Fur-
thermore, a filter with virus protection should be used
at NIV. It is best to use systems with a double-barrel
hose system (i.e. in addition to an inspiratory hose the-
re is also an expiratory hose): This is the case with
almost all intensive care respirators, only turbine de-
vices have only one hose (for inspiration). A filter with
virus protection should then be attached to the exha-
lation valve here. The staff has to wear the appropri-
ate personal protective equipment (especially FFP-2
masks) during NIV or HFNOT. Patients with HFNOT
should wear a mouth and nose mask over the nasal
cannula: This reduces the expiratory cloud (Leonard
et al, Chest 2020). HFNOT is very effective on the one
hand in patients with hypoxemic respiratory failure
such as COVID, but on the other hand it is also asso-
ciated with a high risk of infection due to the high flow
(up to 60 l/min) in the nose and pharynx. Up to a flow
of 30 l/min, the risk of infection under HFNOT seems
to be justifiable. However, there was no evidence of a
significantly increased delivery of infectious aerosols
in vitro or in vivo under HFNOT compared to sponta-
neously breathing patients without HFNOT (i.a. Hui et
al, Chest 2006 und 2009; Hui et al, European Resp J
2019). According to the position paper on the practical
implementation of the differential therapy of acute re-
spiratory failure in COVID-19 by the German Society
for Pneumology (DPG), both HFNOT and NIV can be
carried out without an increased risk of infection, if the
personal protective equipment is worn. The fear of a
possible infection must not be a reason to withhold HF-
NOT or NIV from the patient and therefore to perform a
hasty and premature intubation: The risk of infection is
significantly higher here! In the COVID guideline of the
SSC 2020, both NIV and HFNOT are primarily recom-
mended (but only weakly), HFNOT, however, is favor-
ed, since on the one hand the failure rate is significant-
936 Infectiology
ly increased (70%) under NIV in hypoxemic respiratory
failure in pneumonia and on the other hand the aerosol
formation is more proneounced under NIV than under
HFNOT. NIV would only be an option in hypercapnic
respiratory failure (e.g. infect exacerbated COPD as a
result of SARS-CoV-2 infection). Furthermore, the use
of HFNOT leads to a conservation of the resource of
ventilators. HFNOT is also clearly recommended in the
national guideline of the DGIIN (S1 guideline, S2k gui-
deline [23.11.2020])!
-- intubation and ventilation if Horovitz quotient paO2/
FiO2 < 200 mmHg (according to the 1st version of
the S1 guideline of DGIIN 2020; since the 2nd versi-
on: only if paO2/FiO2 < 150 mmHg); note: conversion
with spontaneous breathing: FiO2 = 0.21 + 0.03 x
liter O2 per minute
-- cave high risk of infection (therefore always RSI [ra-
pid sequence induction; i.e. always with muscle rela-
xation and without bag mask ventilation] and always
only by a very experienced physician)
-- use of a introducer guide for intubation
-- Intubation is best performed with a video laryngo-
scope, since the distance to the patient can be in-
creased.
-- It is best to check the correct tube position using
capnography (not by auscultation, as cases of trans-
mission are described here).
-- cuff pressure: keep highly normal (30-32 cmH2O)
-- HEPA filter (hydrophobic; pore ​​size: 0.2-0.3 µm) bet-
ween tube and Y-piece (HEPA: high efficiency parti-
culate air; a very effective air filter)
-- A closed suctioning should be used.
-- Disconnections should be avoided (if necessary,
then disconnect the tube and set the ventilator to
"stand by" mode).
-- mean duration of invasive ventilation: 9 days (accor-
ding to an observation study in Germany [Karaggia-
nidis et al, Lancet Resp Med 2020] median 10 days,
on average 14 days)
-- on principle use a higher PEEP (high PEEP table)
and a low pressure difference (Lung compliance is
usually still maintained, i.e. > 50 ml/mbar!)
-- prone positioning if Horovitz quotient paO2/FiO2 <
150 mmHg (basic measure in the ARDS!)
◦◦ in case of cardiovascular arrest in prone position:
CPR difficult, but possible (i.a. recommendations
ILCOR and ERC for CPR in patients with CO-
VID-19 2020)
▪▪ pressure point: between the shoulder blades
▪▪ turn back in the supine position only if no DBP >
25 mmHg can be achieved
▪▪ defibrillation: anterior / posterior or biaxillär
◦◦ maybe also in awake patients with spontaneous
breathing ("awake proning"; especially under HF-
NOT; good option for cooperative patients practi-
ced in many hospitals; i.a. Coppo et al, Lancet
2020; Thompson et al, JAMA Intern Med 2020;
Ferrando et al, Crit Care 2020)
-- mostly high need for sedation (often very difficult to
 sedate!)
-- if necessary vv-ECMO
◦◦ for therapy-refractory hypoxemia
◦◦ in 5% of all patients requiring intensive care
◦◦ mostly extremely long runtime (support time): on
average 36 days (otherwise only 8 days on ave-
rage)
◦◦ mortality after 90 days: 37.4% (ELSO registry data
[Barbaro et al, Lancet 2020])
Therapy COVID-19:
if requiring oxygen (i.e. SpO2 < 94%
breathing room air): dexamethasone)
halve therapeutic anticoagulation with
LMWH
Other
• RAAS inhibitors (ACE inhibitors, AT-II blockers):
-- A severe course may occur frequently among them,
so that they should be discontinued (e.g. in arterial
hypertension) and replaced by calcium antagonists
if necessary. However, the data situation is incon-
sistent.
-- They may lead to up-regulation of the ACE-2 recep-
tors through which SARS viruses enter the cells.
However, this is only a hypothesis.
-- But especially in patients with heart failure, who are
already high-risk patients for a severe course of a
COVID infection, a general discontinuation of the
ACE inhibitor, which has prognostic relevance in
heart failure, is to be seen as rather critical. With
systolic heart failure (HFREF) calcium antagonists
(non-dihydropyridines) are contraindicated anyway
because of their negative inotropic effect.
-- However, neither in a retrospective study (Li et al,
JAMA Cardiology 2020) in 1178 inpatient COVID
patients nor in a meta-analysis (Baral et al, Curr
Atheroscler Rep 2020) with 28,872 patients a con-
nection could be shown between the medication with
an ACE -inhibitors and the severity and prognosis of
the disease.
• A discharge from the hospital without further isolation
measures is possible (Otherwise, hospital discharge
into domestic isolation is also possible.), if:
-- at least 10 days from the onset of symptoms and
-- > 48h no more symptoms and
-- 2 negative PCR tests (deep throat swab or throat
rinsing water)
◦◦ In the previous recommendations of the RKI (Ro-
bert Koch Institute), a gap of 24 hours was requi-
red between the two tests. According to the new
recommendations, the two tests can be taken at
the same time (simultaneously).
◦◦ The tests are only necessary for hospilized pati-
ents (inpatients) with a severe course (requiring
additional oxygen) or for residents of nursing ho-
mes. In hospilized patients (inpatients) with a mild
course (not requiring additional oxygen) or outpa-
tients no tests are necessary to discontinue iso-
lation.
◦◦ Alternatively, if the PCR test is positive, discharge
from the hospital can be carried out without further
isolation measures if the viral load is low (Ct va-
lue> 30 [RNA amount < 250 copies / 5µl RNA elu-
ate]; loss of cultivability, i.e. no longer infectious)
• in mild cases also outpatient treatment (in 85% in Ger-
many) possible (under quarantine), if the following re-
quirements are met:
-- no risk factors (especially chronic underlying disea-
ses, immunosuppression, higher age)
-- no pregnancy
-- existing compliance
-- accommodation in a well-ventilated single room
-- outpatient care by a physician
-- possibility to get help at any time in case of deteri-
oration
• If an employee of the medical staff becomes infected in
the course of his professional activity, COVID-19 can
be recognized as an occupational disease in Germany
(BK number 3101).
• dealing with the deceased: The corpses are conside-
red infectious (but not highly contagious). "Infectious"
should be marked on the death certificate, which then
entails appropriate measures according to the fune-
ral decree. Appropriate protective equipment must be
worn (e.g. also from relatives who say goodbye; i.e.
water-resistant apron or gown, mouth-nose and eye
protection). Wearing an FFP-2 mask is only necessary
for procedures with the risk of aerosol formation (e.g.
embalming).
Prophylaxis
• vaccination
-- not yet possible (in contrast to influenza)
-- currently (as of 12/11/2020) 51 vaccines in clinical
testing, 11 of which are already in phase III (mostly
mRNA, but also recombinant adenovirus vector; es-
pecially against the S protein [spike]), not expected
before mid 2021 (one already appoved ["Sputnik V";
Logunov et al, Lancet 2020 [see box]; but only on
Russia])
-- however, influenza (available from the beginning of
October) and pneumococcal vaccination (especially
for patients with COPD and age > 65 years; influen-
za also for medical staff!) usefull and recommended
• An infection that has gone through leaves an immunity
(however unclear how long; at least for 3-6 month). At
least one is protected for life from reinfection with a
severe course.
• Even without detectable (neutralizing) antibodies, a
certain immunity remains due to the "immunological
memory".
• Herd immunization occurs from a contamination of 60-
70% of the people.
• hygienic measures: washing hands, hand disinfection
(High-proof ethanol destroys the virus!), don't touch
the face ("Fingers away from the face!"), cough and
sneeze label (in the elbow instead of the hands), keep
Infectiology 937
 distance (at least 1.5 meters), avoiding social contacts
("social distancing"), exit restrictions ("lockdown"),
mask requirement in public (for protection of the others;
here, self-made masks are also an option), possob-
ly tracing apps (e.g. Corona warning app in Germany
[16.07.2020: downloaded by 18%]); note: These mea-
sures (especially the "lockdown") are very effective: In
a study (Flaxman et al, Nature 2020) it could be shown
that these measures (from February to May 2020) in
Germany around the lives of half a million people and
in Europe of 3.1 million people could be saved!
• possibly rinseing of the throat with oral antiseptics to
reduce the viral load in the throat and thus the risk of
a severe course for yourself and the risk of infection
for others (including Leisman et al, Lancet Resp Med
2020)
• respiratory protection masks (e.g. FFP-2, N95) for all
risk patients
• To de-escalate the measures, the doubling time should
reach a certain levels, e.g. in Germany at least 14 days:
Then the supply capacity in the hospitals in Germany
is sufficient (doubling time in Germany 09/04/2020: 11
days, am 23/04/2020: 21 days). Furthermore, the re-
production rate Rt should be less than 1 (in Germany
23/04/2020: 0.9; 30/04/2020: 0.76).
• contact person tracking (see infobox); note: It makes
sense to test contact persons after 6 days at the ear-
liest. Before that one often has false negative results.

study

Safety and immunogenicity of an rAd26 and rAd5 vector-

based heterologous prime-boost COVID-19 vaccine in two
formulations
Logunov et al, Lancet 2020

• 2 open non-randomised phase I/II studies (Russia)

• 38 participiants (healthy adults) in each study
• vaccine: recombinant adenovirus vector (containing a
gene from the spike protein) in two formulations (frozen
and lyophilized; [rAd26 and rAd5])
• All produced neutralizing antibodies against the spike
protein.
• side effects: especially
-- pain at injection site (58%)
-- fever (50%)
-- headache (42%)

938 Infectiology
 study

A Phase 1/2/3, placebo-controlled, randomized, observer-

blind, dose-finding study to evaluate the safety, tolerability,
immunogenicity and efficiacy of SARS-CoV-2 RNA vaccine
candidates against COVID-19 in healthy individuals
www.clinicaltrialsregister.eu (10.11.2020)

• multicenter (120 centers) randomized controlled double-

blind study (phase III study)
• 43,538 participants (healthy adults; in phase III also
children> 12 years and patients with chronic diseases
[i.a. hepatitis B / C, HIV]; interim analysis)
-- vaccine BNT162b2 from BioNTech (Germany [Mainz])
and Pfizer (USA); mRNA vaccine; storage at -70°C; 2
injections i.m. at an interval of 21 days
-- placebo
• result: BNT162b2 vaccine → significantly fewer con-
firmed SARS-CoV-2 infections (> 7 days after the 2nd
vaccination; protective effect: 90% [18.11.2020: 95%
for mumps, measles, rubella: 93-99%])

COVE study

A Phase 3, Randomized, Stratified, Observer-Blind, Place-

bo-Controlled Study to Evaluate the Efficacy, Safety, and
Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in
Adults Aged 18 Years and Older
www.clinicaltrials.gov (17.11.2020)

• multicenter (100 centers) randomized controlled double-

blind study (phase III study)
• 30,000 participants (healthy adults; interim analysis)
-- vaccine mRNA-1273 from Moderna (USA); also a
mRNA vaccine; storage only necessary at 2-8°C
(standard refrigerator temperature); 2 injections i.m.
at an interval of 21 days
-- placebo
• results:
-- vaccine mRNA-1273 → significantly fewer confirmed
SARS-CoV-2 infections (> 14 days after the 2nd vacci-
nation; protective effect: 94.5%)
-- side effects: especially
◦◦ pain at injection site (2.7%)
◦◦ myalgia (8.9%), athralgia (5.2%)
◦◦ headache (4.5%)
◦◦ fatigue (9.7%)

A vaccination can prevent COVID-19!

Infectiology 939

nosocomial Pneumonia
Introduction
Johann Peter Frank (German physician and founder of
hygiene; 1745-1821): "Can there probably be a greater
contradiction than a hospital disease? An evil that one
only gets when one thinks of getting rid of one's own?“
Definition
• pneumonia p.d. 48h after hospital admission (mostly
in intensive care unit) or occurring within 3 months of
a hospital stay
• The main risk factor is endotracheal ventilation.
• guidelines / recommendations:
-- national (German)
◦◦ S3 guideline epidemiology, diagnostics and the-
rapy of adult patients with nosocomial pneumonia
2012
◦◦ Recommendations of the Commission for Hospital
Hygiene and Infection Prevention (German: KRIN-
KO) at the Robert Koch Institute for the Prevention
of Nosocomial Ventilator-associated Pneumonia
2013
-- international: Guidelines for the management of
adults with hospital-aquired, ventilator-associated
and healthcare-associated pneumonia 2005 (Ame-
rican Thoracic Society [ATS])
Types
• HAP: hospital aquired pneumonia (in contrast toCAP
[community aquired pneumonia])
• VAP: ventilator-associated pneumonia, tube-associa-
ted pneumonia (TAP; actually the most precise term,
940 Infectiology
since nosocomial pneumonia does not occur frequent-
ly under non-invasive ventilation), ventilation pmeumo-
nia
• HCAP: health care associated pneumonia
-- nursing home, dialysis facilities
-- The term was introduced in 2005 by the American
Thoracic Society (ATS) and the Infectious Diseases
Society of America (IDSA). Ultimately, however, the-
re was no association with an increased risk of multi-
resistant pathogens, so that the term has meanwhile
been abandoned because this also induced consi-
derable overtreatment.
Epidemiology
• 500,000 nosocomial infections in Germany per year
(15000 deaths)
• 64,000 nosocomial infections on intensive care units in
Germany per year (of which one third would be avoi-
dable!)
• 40,000 nosocomial pneumonias in Germany per year
• The prevalence of nosocomial infections is highest in
intensive care units!
• 51% of all ICU patients have infection (No.1 pulmona-
ry, No.2 abdominal [EPIC II study, Vincent et al, JAMA
2009]).
• 120000 cases per year in Germany
• most common nosocomial infection in intensive care
units (KISS study)
• incidence: 5-15 /1000 inpatients
• 90% of nosocomial pneumonia occurs in ventilated pa-
tients, only 10% in spontaneously breathing patients.
• VAP in 17% of all ventilated patients (Safdar et al, Crit
Care Med 2005)
• maximum prevalence: day 5-10
• The incidence rises with increasing ventilation du-
ration by 1% per ventilation day (therefore no uncriti-
cally long ventilation; VAP is the main complication of
invasive ventilation!).
• VAP → extension of ventilation and length of stay by 6
days (average)
• NISS (Nosocomial Infection Surveillance System
2014): 4.2/1000 ventilation days (VAP: 3.6/1000 ven-
tilation days)
• occurrence:
-- 7% of all > 48h ventilated patients
-- 75% of all > 10 days ventilated patients
• additional costs: approx. 4500€ / case (Moller et al, J
Med Econ 2012)
VAP (ventilator-associated
pneumonia) is the main complica-
tion of invasive ventilation!
 3
2 4 7 8
9
1
10

5 6

Fig. 1194  the ten most common transmission pathways

The most common way of transmit-

ting germs in hospitals is through the
hands of the staff

Risk factors
• age
• male gender
• duration of ventilation
• pre-existing conditions (i.a. COPD)
• stress ulcer prophylaxis
• polytrauma
Pathogenesis • disturbance of consciousness
• consequences of ventilation • emergency surgery
-- reduction of the fibronectin protective film in the oral • administration of blood products (especially red cell
mucosa concentrates [Metaanalyse Rohde et al, JAMA 2014])
-- clearance of respiratory secretions ↓
-- reduced humoral and cellular protective functions in
the epithelium Diagnostic
• colonization of the oropharynx with pathogenic germs • clinical examination
• microaspiration (past the blocked tube cuff; "silent" as- -- auscultation
piration) of pathogenic germs colonizing the oropha- -- fever
rynx and gastrointestinal tract -- putrid endotracheal secretion
• loss of gastric acidity due to ulcer prophylaxis (espe- • blood cultures
cially in the case of proton pump inhibitors); in ulcer
-- obtaining of 2 x 1 pair at different puncture sites
prophylaxis, one must always weigh up the results:
The higher the gastric pH is raised, the less stress -- only positive in 10-20%
ulcers occur on one side, but on the other side less • laboratory
germs are killed by the increased gastric pH due to the -- leukocytes, CRP
loss of acidity: These can then colonize the throat and -- procalcitonin
lead to ventilator-associated pneumonia past the blo- • chest X-ray
cked tube cuff . As a compromise, a gastric pH of 3-4 -- new or increasing infiltrate
should therefore be aspired to in ventilated intensive -- bronchopneumogram
care patients.
-- difficult assessment due to bed exposure ("dead
• often polymicrobial angles": upper mediastinum, para- / retrocardiac
• infection mechanism space)
-- endogenous (70%; microaspiration) -- In many places, a chest x-ray is still performed daily
-- exogenous (30%; germ transmission by medical as standard for every ventilated patient. The back-
staff [especially by hands]) ground of this is a recommendation of the ACR
(American College of Radiology) from 1995, which
has since been revised. Several studies (e.g. Heij-
blum et al, Lancet 2009; Oba et al, Radiology 2010)
have shown that a demand-oriented chest X-ray

Infectiology 941
 examination, i.e. an chest X-ray performed only in ◦◦ klebsiella pneumoniae (No.3)
clinical indications, leads neither to an extension of ◦◦ proteus mirabilis
the duration of ventilation nor to an increase in mor- -- pseudomonas aeruginosa (No.2)
tality, so that the dogma that a chest X-ray has to be
-- acinetobacter baumanii (especially late VAP: Among
performed daily for each ventilated patient certainly
all bacterial pathogens of ventilator-associated
no longer applies today.
pneumonia, A. baumannii has the highest mortality
• possibly thoracic sonography with 59%!)
• possibly chest CT • gram-positive germs
• endotracheal secretion (ETA) -- pneumococci
-- staphylococci (S.aureus, No.1; the most common
Endotracheal secretion germ in nosocomial pneumonia)
• techniques: ◦◦ MSSA
-- blind aspiration (initial aspiration of the secretion in ◦◦ MRSA (frequent in nosocomial pneumonias!) )
the tube, then introduction of a new catheter with
connected aspiration trap) Multi-drug resistant organisms (MDRO) are more com-
-- bronchoscopic (targeted) mon in nosocomial pneumonia:
◦◦ bronchoscopic (targeted) BAL (bronchoalveolar • MRSA
lavage; contraindicated i.a. with severe respiratory • ESBL
insufficiency with a Horovitz quotient < 100mmHg • pseudomonas aeruginosa
and abscessing pneumonia due to potential • Acinetobacter baumanii
spread of germs)
• stenotrophomonas maltophilia (mostly colonization)
◦◦ PSB (protected specimen brush)
• Targeted bronchoscopically obtained endotracheal The risk factors for MDRO are summarized in the info-
secretion is not superior to blindly removed endotra- box.
cheal secretion (i.a. Canadian Crit Care Trial Group,
N Eng J 2006)
• airway samples: have to be in the microbiology la- Risk factors
boratory within 4 hours (otherwise: store in refrigerator MDRO
at 4°C)

Diagnostic criteria (according to Jo-

hanson)
• chest X-ray: new, persistent or increasing infiltrate, and
• 2 of the following criteria:
-- fever > 38.3°C or hypothermia < 35°C
-- leukocytosis > 12000/μl or leukopenia < 4000/μl
-- purulent endotracheal secretion

CPIS (Clinical Pulmonary Infection Score)

• CPIS < 6P: VAP unlikely
• CPIS ≥ 6P: VAP likely

0 P. 1 P. 2 P. In contrast to community-acquired pneumonia, atypical

bacteria (mycoplasma, legionella, chlamydia) play vir-
tracheal abundant
tually no role in nosocomial pneumonia. In contrast to
secretion little abundant purulent
community-acquired pneumonia however, pseudomo-
chest X-ray - diffuse llocalized nas aeruginosa plays a very important role in nosocomial
temperature °C 36.5 - 38,5 38.5 - 39 > 39 pneumonia (2nd most frequent pathogen).
< 4 or > < 4 or > 11 +
leukocytes / nl 4-11 11 > bands Types
paO2/FiO2 > 240 > 240 < 240
according to onset
• early nosocomial pneumonia (early onset):
Bacteria -- < 5 days after hospital admission (but p.d. > 48h)
• gram-negative germs (leading overall [60%]) -- even more germs of community acquired pneumo-
-- enterobacteria (the most common family of bacteria nia (pneumococci, H. influenzae) and more easily
in nosocomial pneumonia ["stool flora" in the lung!]) treatable germs
◦◦ E. coli (No.4) -- germs mainly from oropharynx

942 Infectiology
• late nosocomial pneumonia (late onset):
-- > 5 days after hospital admission
-- increased gram-negative and multi-resistant germs
-- germs mainly from stomach
Note: according to recent findings (e.g. Gastmeier et al,
Antimicrob Agents Chemother 2009) no difference in the
pathogen spectrum between early and late nosocomial
pneumonia
according to respiratory situation
• nosocomial pneumonia in non-ventilated patients
(10%)
• nosocomial pneumonia in ventilated patients (90%)
according to infection mechanism
• endogenous (70%; microaspiration; most common
mechanism)
• exogenous (30%; e.g. hands of medical staff)
Antibiosis
Principles
• early (Kumar et al, Crit Care 2006)
• high-dose
• adequate (initially inadequate antibiotic → doubling of
mortality!)
• broad
• duration: 7 days (ProRespII study AJRCCM 2006: an-
tibiosis over 13 days versus 6 days → no difference)
• combination therapy
-- in contrast to community community-acquired pneu-
monia (β-lactam + macrolide) no clear recommen-
dation
-- no combination with aminoglycosides
-- in severe nosocomial pneumonia combination
therapy of a pseudomonas-active β-lactam and a
fluoroquinolone (ciprofloxacin, levofloxacin) or fos-
momycin (note: not with a macrolide) recommended
(PEG)
• For the selection of the antibiotic it is fundamentally
important whether there are risk factors for multi-drug
resistant organisms (MDRO) or not.
study
A randomized trial of diagnostic techniques for ventilator-
assiciated pneumonia, Canadian Critical Care Trial Group
Heyland et al, N Engl J 2006
• multicenter prospective randomized study
• 740 patients with VAP
• 2 x 2 factorial design
-- diagnosis
◦◦ (only) ETA (blimd endotracheal aspiration
◦◦ BAL
-- therapy
◦◦ monotherapy (meropenem 3 x 1g)
◦◦ combination therapy (meropenem 3 x 1g + ciproflo-
xacin 2 x 400mg)
• endpoints
-- primary: mortality after 28 days
-- secondary:
◦◦ duration of ventilation
◦◦ intensiv care and hospital length of stay
• results (BAL, combination therapy)
-- no significant difference
-- significantly delayed start of antibiotic treatment in the
BAL group (but without effect on mortality)
• critical note: Patients with pseudomonas (2nd most com-
mon germ!), MRSA and multimorbid patients were ex-
cluded.
Representatives
• without risk factors for MDRO
• with risk factors for MDRO
Representatives (without risk factors for
MDRO)
• amino penicillin + β-lactamase inhibitor
-- amoxicillin / clavulanic acid (Augmentan) 3 x 2.2g i.v.
-- ampicillin / sulbactam (Unacid) 3 x 3g i.v.
• 3rd generation cephalosporin (IIIa)
Infectiology 943
 -- ceftriaxone (Rocephin) 1 x 2g i.v.
-- cefotaxime (Claforan) 3 x 2g i.v
• fluorchinolon
-- moxifloxacin (Avalox) 1 x 400mg i.v. (loading dose: 2
x 400mg at day 1 and day 2)
-- levofloxacin (Tavanic) 2 x 500mg i.v.
Representatives (with risk factors for MDRO)
• piperacillin 4g + tazobactam 0,5g 3 x i.v. (note: if Pseu-
domonas is detected → 4 x i.v.)
• cephalosporins
-- ceftazidime (IIIb; Fortum; outstandingly effective i.a.
against pseudomonas, but no effect in the gram-
positive range [especially not effective against sta-
phylococci and pneumococci] → therefore never as
monotherapy, only in combination with e.g. with a
fluorochinolon) 3 x 2g i.v.
-- cefepime (IV; Maxipime) 2 x 2g i.v. (cave severe
neurological side effects [especially encephalopa-
thy] with GFR < 50 ml/min)
-- combinations with a β-lactamase inhibitor:
◦◦ ceftolozane + tazobactam (Zerbaxa)
◦◦ ceftazidime + avibactam (Zavicefta)
• carbapenems
-- ertapenem (Invanz) 1 x 1g i.v. (gap in effectiveness:
pseudomonas → unsuitable for nosocomial pneu-
monia)
-- meropenem (Meronem) 3 x 1g i.v.
◦◦ no dose reduction recommended in case of renal
failure or renal replacement procedure any more
◦◦ no uncritical use (Frequently, if piperacillin / tazo-
bactam do not respond, the patient is being swit-
ched to meropenem, which is completely point-
less, as the germ spectrum is not expanded at
all! The disadvantage is that by the uncritical use
of meropenem among others stenotrophomonas
maltophilia is selected!)
-- Zienam (imipenem + cilastatin [Cilastatin is an in-
hibitor of dehydropeptidase in the kidney and thus
prevents renal inactivation; side effect: i.a. lowering
of the seizure threshold]) 3 x 0.5g i.v.
-- doripenem (Doribax) 4 x 500mg i.v.
◦◦ approved since 2008
◦◦ very good against Pseudomonas (almost no resis-
tances)
◦◦ In a multicenter, prospectively randomized study
(Chastre et al, Crit Care Med 2009) in patients with
VAP, doripenem was not inferior to imipenem (sig-
nificantly better in pseudomonas).
◦◦ prolonged infusion (over 3 hours)
◦◦ meanwhile withdrawn from the market
Ceftolozane + Tazobactam (Zerbaxa)
• new group III (IIIc) cephalosporin combined with a
β-lactamase inhibitor
• spectrum of activity:
-- very good effectiveness against pseudomonas (
currently the most effective antibiotic against Pseu-
domonas [v.a. good option against multi-resistant
pseudomonas])
944 Infectiology
-- good effectiveness also against ESBL (although it is
a cephalosporin, against which ESBL are normally
resistant!)
-- poor effectiveness in the gram-positive range (i.a.
staphylococci, streptococci) and against anaerobes
• approvals:
-- complicated intra-abdominal infections and urinary
tract infections (3 x 1.5g [i.e. 1g/0.5g; each over 1h)
-- since 9/2019 now also approved for nosocomial
pneumonia (including VAP; 3 x 3g [i.e. 2g/1g; each
over 1h]; appoval study: ASPECT-NP [Kollef et al,
Lancet Infect Dis 2019])
• dose reduction in renal insufficiency:
-- complicated intra-abdominal infections and urinary
tract infections:
◦◦ GFR 30-50 ml/min: 3 x 500mg/250mg
◦◦ GFR 15-30 ml/min: 3 x 250mg/125mg
◦◦ GFR < 15 ml/min bzw. RRT: initially 1 x
500mg/250mg, then 3 x 100mg/50mg
-- nosocomial pneumonia:
◦◦ GFR 30-50 ml/min: 3 x 1g/0.5g
◦◦ GFR 15-30 ml/min: 3 x 500mg/250mg
◦◦ GFR < 15 ml/min bzw. RRT: initially 1 x 1.5g/0.75g,
then 3 x 300mg/150mg
• no dose reduction in hepatic insufficiency
Ceftazidime + Avibactam (Zavicefta)
• approvals (since 2016):
-- complicated intra-abdominal infections and urinary
tract infections
-- nosocomial pneumonia (including VAP; appoval stu-
dy: REPROVE [Torres et al, Lancet Infect Dis 2018])
-- infections due to aerobic gram-negative bacteria
with limited treatment options (e.g. 4-MRGN)
• avibactam
-- a new β-lactamase inhibitor (substance class:
DABCO [diazabicyclooctane])
-- In contrast to almost all other β-lactamase inhibitors,
avibactam does not induce the enzyme β-lactamase.
-- also very effective against CRE (carbapenem-re-
sistant enterobacteria), so ceftazidime + avibactam
(Zavicefta) is also a good option against CRE! Hoew-
ver, it is not effective against metallo-β-lactamases
(Ambler class B): Here the combination with the mo-
nobactam aztreonam (not available in Germany) is
very effective (Marshall et al, Antibiol Agents Chemo
2017).
• doss age: 3 x 2.5g as short infusion over 2h
• dose reduction in renal insufficiency
-- GFR 30-50 ml/min: 3 x 1g/0.25g
-- GFR 15-30 ml/min: 2 x 1g/0.25g
-- GFR 5-15 ml/min: 1 x 1g/0.25g
-- GFR < 5 ml/min inkl. RRT: 1 x 1g/0.25g every 48h
• no dose reduction in hepatic insufficiency
• side effects: esp. nausea, vomiting, diarrhea, positive
Coombs test

modified according to the S2k guideline of the Paul-
Ehrlich Society (calculated initial parenteral therapy for
bacterial diseases in adults); note: The purpose of the
recommended combination therapy in group III is to pro-
vide double protection against pseudomonas.
Piperacillin / Tazobactam: pseu-
domonas resistance in Germany:
20% (Knowledge of the hospital's
own internal resistance statistics
is crucial!)
MRSA
• S. aureus
-- MSSA: 75%
-- MRSA: 25%
◦◦ MRSA: 25% Spain: 65%, Greece: 80%
◦◦ in intensive care unit or sepsis: 40%
◦◦ additional 2.5-fold increase in mortality
• antibiotics
-- vancomycin +
◦◦ rifampicin
◦◦ fosfomycin (see page 958)
-- oxalidinones
◦◦ linezolid (Zyvoxid; see page 957)
◦◦ tedizolid (Sivextra; seit 2015 approved since 2015
for severe skin and soft tissue infections)
-- Daptomycin (Cubicin; see page 957; inactivation by
surfactant, therefore unsuitable for pneumonia)
-- tigecycline (Tygacil; see page 958)
-- 5th generation cephalosporins (see page 959)
◦◦ ceftobiprole (Zevtera)
◦◦ ceftarolin (Teflaro)
Severe nosocomial pneumonia
(especially invasive ventilation, septic
shock): Combination of Pseudomonas
effective β-lactam (e.g. piperacillin /
tazobactam) + fluoroquinolone (e.g.
ciprofloxacin)
Prognosis
• mortality of nosocomial pneumonia significantly higher
than community-acquired pneumonia (CAP)
• Of all nosocomial infections, nosocomial pneumonia
has the highest mortality.
• mortality: 20% (according to meta-analysis Melsen
et al, Lancet Infect Dis "only" 13%)
• most frequent cause of sepsis in intensive care
units (sepsis: most frequent cause of death in intensi-
ve care units)
• Additional pneumonia in ICU patients increases mor-
tality by a factor of 1.91 (attributable mortality: 33%).
Prophylaxis
VAP is the most frequent cause of
sepsis and thus the most frequent
cause of death (the "killer number
1") in intensive care! Therefore,
the main goal is the prophylaxis
of VAP!
• hygiene measures:
-- hygienic hand disinfection (essential)
-- further hygiene measures: i.a.
◦◦ wearing disposable plastic aprons and gloves du-
ring every bedside activity on the patient
◦◦ disinfection of the stethoscope or ultrasound pro-
be after each examination
• early extubation (short intubation period, early
weaning, possibly early tracheotomy [not recommen-
ded however])
• non-invasive instead of invasive ventilation (NIV
instead of IV [if possible])
• respiratory toilet
• suction of secretion in the oropharynx before extuba-
tion
• avoid raising the gastric pH too high
Infectiology 945
 -- target gastric pH: 3-4
-- The VAP rate among proton pump inhibitors is not
higher than among H2-blockers (meta-analysis Al-
hazzani et al, Crit Care Med 2013).
-- S3 guideline 2017 "Invasive ventilation and use of
extracorporeal procedures in acute respiratory in-
sufficiency" of the DGAI (The German Society of
Anaesthesiology and Intensive Care Medicine): no
routine pharmacological stress ulcer prophylaxis
recommended for invasively ventilated patients, i.e.
neither with proton pump inhibitors nor with H2-blo-
ckers
• upper body elevation
• possibly CLRT (continuous lateral rotation therapy;
e.g. RotoRest; see page 624; studies: Staudinger et
al, Crit Care Med 2010 [see box page 625]; Simonis
et al, Clin Res Cardiol 2012; however, recommended
neither in the PEG nor in the KRINKO guidelines)
• selective decontamination of the digestive tract (SDD)
• early enteral nutrition
• regular control of the cuff pressure
• passive (HME filter [heat moisture exchange; for ima-
ges see page 122]) instead of active humidification
(note: In contrast to previous studies, more recent me-
ta-analyses [Siempos et al, Crit Care Med 2007; Kelly
et al, Cochrane Database 2010; Menegueti et al, BMC
Anesthesiology 2014], however, showed no advantage
for passive humidification, i.e. there was no increased
VAP rate with active humidification.)
• oral antiseptics (administered as a mouthwash)
-- examples: Chlorhexidin, Octenidin (a broad spec-
trum antiseptic; the active ingredient of the wound
disinfectant Octenisept [for the skin]; name of the
mouthwash: Octenidol)
-- 3 times a day as part of oral care
-- Koemann et al, AJRCCM 2006: significant reduction
in VAP rate
-- recommended
• ventilation hoses:
-- no frequent routine change
◦◦ once a week sufficient (recommended by DGKH
[German Society for Hospital Hygiene] and DGAI
[German Societiy of Anaesthesiology and Intensi-
ve Care Medicine])
◦◦ One ventilation hose (and also the bag mask valve
[Ambu bag]) can be used for several patients, you
only have to change the filter (exception: mulire-
sistant germs in the bronchial secretion, airborne
germs such as influenza, mycobacterium tubercu-
losis, measles, SARS-CoV-2).
-- no sterilisation (thermal or chemical disinfection suf-
ficient)
-- Condensation in the ventilation system should be re-
moved without disconnection and aspiration should
avoided.
• closed multiple suction systems (probably) better than
open disposable suction systems (recommended)
• antibiotic prophylaxis after successful resuscitation
and hypothermia (significantly less VAP in the AN-
THARCTIC study [see page 322] by routine two-day
946 Infectiology
intravenous antibiosis with amoxicillin / clavulanic acid
i.v.)
• probiotics
-- definition: living apathogenic microorganisms (stab-
le to gastric and bile acids) with a health-promoting
effect
-- meta-analyses:
◦◦ Siempos et al, Crit Care Med 2010: significant re-
duction in VAP rate, no effect on mortality
◦◦ Gu et al, Chest 2012: no reduction in VAP rate
-- no general recommendation (only recommended in
the Canadian guidelines, not in all other guidelines
because too little data)
-- in no case saccharomyces boulardii (Perocur) be-
cause of an increased rate of candidemia and the
formation of ethanol and CO2
• possibly use of special endotracheal tubes
Hygienic hand disinfection
• essential (basic measure)
• AHD (alcoholic hand disinfection)
• compliance: only 50% (Unfortunately, hygienic
hand disinfection is not carried out in half the cases!)
• history: The Hungarian physician Ignaz Semmelweis
(1818-1875) is considered to be the founder of hand
disinfection. Because the doctors carried out hand dis-
infection with a chlorinated lime solution, the mortality
of child bed fever (puerperal sepsis) was reduced from
18% to 2.5%. ("NNT" of only 7). This was considered
the "savior of mothers". As a reminder, he wrote open
letters to the professors of obstetrics: "The killing must
have an end!" At that time, however, he found no sym-
pathetic ear and finally broke up with it. He died of sui-
cide from a self-inflicted wound infection with conse-
cutive sepsis.
• Joseph Alois Schumpeter (1883-1950; Austrian econo-
mist and politician): "It is not enough to produce satis-
factory soaps, it is also necessary to induce people to
wash!"
• per patient 28 times daily, total 85ml daily
• memo: hygienic hand disinfection even before patient
contact!
• Wearing gloves does not replace hygienic hand disin-
fection!
• Stethoscopes are also a frequently contaminated: In
a study (Molecular analysis of bacterial contamination
on stethoscopes in an intensive care unit; Knecht et al,
Infection Control & Hospital Epidemiology 2019), the
majority of the examined stethoscopes were found to
be contaminated with germs of nosocomial infections
( in descending order: S. aureus, Pseudomonas, Aci-
netobacter, Stenothrophomonas, Enterococci, Clostri-
dia). The membrane of the stethoscope should there-
fore be disinfected after each patient contact.
Fig. 1195  Hygienic hand disinfection must be carried out:
before and after every patient contact, before aseptic acti-
vities, after contact with potentially infectious material and Fig. 1197  The stethoscope should also be disinfected after
after contact with surfaces in the immediate vicinity of the each patient comtact.
patient [8].

hand disinfection: by far the most

important prophylactic measure! is
not carried out in 50%!

Fig. 1198  Ventilation hoses should not be changed too of-

ten: One change once a week is sufficient [32].

Fig. 1199  closed suction system: The risk of ventilator

associated pneumonia can be reduced by using closed
instead of open suction systems.
Fig. 1196  Disposable aprons and gloves must always be
worn and changed after each patient during every activity
at the patient's bedside in the intensive care unit (e.g. as
part aof the routine physical examination in the morning).

Infectiology 947
Upper-body elevation
Definition
• syn.: semi-recumbent position
• 30-45 degrees (The guidelines recommend an upper
body elevation of 45 degrees: This is a relatively steep
angle and often not feasible in practice. Furthermore,
the risk for the development of decubital ulcers is incre-
ased here. An upper body elevation of only 30 degrees
on the other hand showed no benefit in the studies.)
• Upper body elevation should be carried out in eve-
ry intubated patient, provided there are no contraindi-
cations (e.g. shock [upper body elevation → venous
return flow to the heart ↓ → CO ↓], increased intra-
abdominal pressure, open abdomen)!
• standard also with increased intracranial pressure
(even in non-ventilated patients), as the intracranial
pressure (ICP) decreases when the upper body is ele-
vated
• possibly also with prone position (upright prone positi-
on; u.a. Hoste et al, Int Care Med 2005; Richard et al,
Int Care Med 2008); however, the problem here is not
infrequently that the patient slides down on the anti-
decubitus mattress
• In ventilated obese patients or in patients with abdo-
minal diseases, the elevation of the upper body with
the consequent necessary flexion in the hip joint can
lead to an increase in intra-abdominal pressur. There-
fore, these patients should undergo reversed Trende-
lenburg positioning (RTP; see diagram on page 620),
which does not involve flexion of the hip joint.
Studies
• RCT (randomized controlled trials):
-- positive (benefit proven): Drakulovic et al, Lancet
1999 (fewer microaspirations → lower rate of pneu-
monia)
-- negative (no benefit proven):
◦◦ van Nieuwenhoven et al, Crit Care Med 2006
◦◦ Keeley et al, Nurs Crit Care 2007
• meta-analyses:
-- Niel-Weisse et al, Crit Care 2011:no benefit proven
-- Wang et al, Cochrane Database Syst Rev 2016 (see
box): benefit proven (less [clinically suspected] VAP)
948 Infectiology
meta-analysis
Semi-recumbent position versus supine position for the
prevention of ventilator-associated pneumonia in adults
requiring mechanical ventilation
Wang et al, Cochrane Database Syst Rev 2016
• metaanalysis (8 RCT)
• 850 patients with invasive ventilation
-- upper body elevation
-- flat supine position
• results: upper body elevation
-- clinically suspected VAP: significantly reduced
-- no reduction:
◦◦ microbiologically proven VAP
◦◦ mortality
◦◦ duration of ventilation
◦◦ ICU / hospital length of stay
◦◦ antibiotic use
◦◦ pressure ulcers
Guidelines
• S2e guideline for positioning therapy of the DGAI (Ger-
man Society of Anaesthesiology and Intensive Care
Medicine) 2015: upper body elevation clearly recom-
mended
• sepsis guideline of SSC (Surviving Sepsis Campaign)
2016: upper body elevation clearly recommended
• S3 guideline "Invasive ventilation and use of extracor-
poreal procedures in acute respiratory insufficiency"
of the DGAI (German Society of Anaesthesiology and
Intensive Care Medicine) 2017: upper body elevation-
recommended (weak)
• note: no longer recommended by the KRINKO (Com-
mission for Hospital Hygiene and Infection Prevention)
Upper body elevation in every intuba-
ted patient!
Selective decontamination of the di-
gestive tract (SDD)
Implementation
• local: nasooral + gastral mixture of
-- polymyxin meta-analysis
-- aminoglycoside (e.g. tobramycin)
-- amphotericin B
-- example: 4 times daily after nose / mouth care: po-
lymyxin B 50mg + 8ml NaCl 0.9% + 2ml Tobramycin Impact of selective decontamination of the digestive tract
(80mg) in 10ml syringe , 1ml each in both nostrils, on multiple organ dysfunction syndrome: Systematic re-
3ml oral cavity, 5ml gastric tube, distribute ampho- view of randomized controlled trials
tericin B 3ml into the oral cavity using a swab clamp Silvestri et al, Crit Care Med 2010
• systemic: cefotaxime (Claforan) 3 x 2g for 4 days (if not
• meta-analysis (7 studies, 1270 patients)
antibiotic therapy anyway) )
-- SDD
-- control grpip
Assessment • results: SDD
• reduction in rate of pneumonia, but no reduction in -- significantly less multiorgan failure
mortality in controlled studies published until 2009 (i.a. -- mortality: no difference
Stoutenbeek et al, Intensive Care Med 2007)
• Both in the meta-analysis by Silvestri (J Hosp Infect
2007; 51 studies, 8065 ventilated patients) and in the
meta-analysis by Liberati (Cochrane Collaboration
2009, 36 studies, 6914 ventilated patients), the SDD
showed a lower rate of VAP and a lower mortality. study
• disadvantages:
-- possible selection of resistant germs (Helninger et
al, Intensive Care Med 2006: no increase in resis-
tance rate; Ochoa-Ardila et al, Int Care Med 2011: no Decontamination of the Digestive Tract and Oropharynx in
ICU Patients
increase in resistance rate)
de Smet et al, N Engl J 2009
-- high costs
• guidelines: • multicenter cluster randomized prospective study
-- international: SSC (Surviving Sepsis Campaign) • 5,939 patients (largest study to date on SDD ) on 13 ICU
◦◦ 2002: recommendation grade A, evidence grade in the Netherlands with expected ventilation duration >
48h; 3 arms (per ICU each for 6 months):
Ia at expected ventilation > 48h
-- SOD (selective oropharyngeal decontamination; not
◦◦ 2008: not mentioned at all gastral and i.v.; "SDD light")
◦◦ 2012: recommended -- SDD
◦◦ 2016: not mentioned at all -- standard
-- national: German Sepsis Society / DIVI • results (posthoc-analysis [systematic errors in the inclu-
◦◦ S2k guideline 2010: clear recommendation at sion of patients])
expected ventilation > 48h (recommendation gra- -- significant reduction of 28-day mortality (relative
de A, evidence grade Ia) risk reduction) by 11% (SOD) and 13% (SID) respec-
tively
◦◦ S3 guideline 2018: not mentioned at all
-- no increased antibiotic resistance (note: at least
• significant reduction in mortality, especially in necro-
not in the Netherlands, where the study was conduc-
tizing pancreatitis (Luiten et al, Int Care Med 1998; ted)
Wyncoll et al, Int Care Med 1999; but no general re-
commendation in pancreatitis)
• We perform SOD ("SDD light" variant; SOD: selective
oral decontamination; SOD paste 4 times daily 1ml into S2k guideline 2010: SDD / SOD →
the oral cavity) in our clinic for patients who are inva- clear recommendation
sively ventilated for longer than 48 hours. The SOD is
as good as the SDD (Oostdijk et al, JAMA 2014 [see
box]). If the patient is extubated or decannulated, the
administration is terminated.

Infectiology 949
 study

Effects of decontamination of the oropharynx and intestinal

tract on antibiotic resistance in ICU
Oostdijk et al, JAMA 2014

• multicenter cluster randomized prospective study

• 11,998 intensive care patients with an expected length
of stay in intensive care (note: not ventilation duration
here) > 48h
-- SDD (selective decontamination of the digestive tract)
-- SOD (selective orophayrngeal decontamination)
• results:
-- no difference in resistance rate
-- no difference in mortality
-- no difference in duration of intensive care or hospita-
lization study

RGNOSIS study
Decontamination Strategies and Bloodstream Infections
With Antibiotic-Resistant Microorganisms in Ventilated Pa-
tients
Wittekamp et al, JAMA 2018
• multicenter randomized controlled study
• 8665 ventilated (> 24h) intensive care patients in ICU
with a moderate to high risk of antibiotic resistance (i.e.
at least 5% of bloodstream infections caused by ESBL)
-- Chlorhexidine mouthwash
-- SDD (selective decontamination of the digestive tract)
-- SOD (selective orophayrngeal decontamination)
• results:
-- primary endpoint: rate of bloodstream infections with
multi-resistant gram-negative pathogens → no diffe-
rence
-- secondary endpoint: mortality (after 28d) → no diffe-
rence
Standard in our clinic: SOD paste 4
times daily (with invasive ventilation >
48h)
Fig. 1200  SOD paste (content 50g; hydromorphic base gel
DAC/Paraffinum liquidum [60:40] + colistin 1g, amphoteri-
cin B 1g, tobramycin 1.52g; produced by the pharmacy of
the hospital; should be stored in a cool place; 4 times daily
1ml is distributed in the oral cavity
Cuff pressure
• The cuff (like the tube) is made of PVC (polyvinyl chlo-
ride.)
• rationale:
-- If the cuff pressure is too high, necrosis of the trache-
al mucosa occurs. From a cuff pressure of approx.
30-32 cmH2O (corresponds to 23-25 mmHg), the
tracheal mucosa becomes less perfused.
-- If the cuff pressure is too low, the risk of microaspi-
ration increases and ventilator-associated pneumo-
nia occurs. The cuff pressure should be at least 5
cmH2O higher than the inspiratory pressure (IPAP).
• target cuff pressure: 22-32 cmH2O (16-24 mmHg; mi-
nimum 5 cmH2O above set inspiratory pressure, but
maximum 32 cmH2O).
• The cuff pressure decreases again and again so that it
must be measured regularly (once per shift) and read-
justed if necessary.

950 Infectiology
 2011; meta-analysis Mao et al, Crit Care 2016; meta-
analysis Caroff et al, Crit Care 2016)
-- recommendations: for ventilation> 48h
◦◦ S2k guideline sepsis 2010 + S3 guideline 2018:
can be considered
◦◦ S3 guideline 2017 "Invasive ventilation and use of
extracorporeal procedures in acute respiratory in-
sufficiency": weak recommendation
• silver-coated endotracheal tubes
-- silver: antimicrobial effect (inhibition of biofilm forma-
tion)
-- NASCENT study (Kollef et al, JAMA 2008): In this
multicenter randomized controlled study in 1932 pa-
tients (ventilation > 24h), the use of a silver-coated
tube showed a significantly lower VAP rate (4.8%
versus 7.5%) compared to a conventional tube wi-
thout (significant) reduction in mortality.
-- Bewertung: teuer, keine allgemeine Empfehlung
• tubes with ultra-thin polyurethane cuffs
-- The cuffs of these tubes are made of polyurethane
and are only 7μm thick, so the trachea is sealed bet-
ter. The cuffs of conventional tubes are made of po-
lyvinyl and are 50-80μm thick.
-- reduction of the VAP rate (i.a. Lorente et al, Am J
Crit Care Med 2007; Miller et al, J Crit Care 2011)
-- assessment: expensive, no general recommendati-
on
• tubes with a cone-shaped ("tapered") instead of the
usual cylindrical cuff (i.a. Jaillette et al, ICM 2017: no
use; no general recommendation)

Fig. 1202  Evac tube: In addition to the lumen for blocking

(black arrow), it has a lumen for suctioning off the subglot-
tic space (white arrow).

Fig. 1201  The cuff pressure must be checked regularly

(once per shift and after each suction) and should be bet-
PneuX P.Y. system
ween 22-32 cmH2O (= mbar; 16-25 mmHg; rule: 5 cmH2O • Venner Medical Germany GmbH Company
above the inspiration pressure). If it is too low, the risk of • endotracheal tube with 3 irrigation cannulas above the
aspiration is increased. If it is too high, the risk of tracheal cuff for suction of the subglottic space
damage due to pressure necrosis is increased [33].
• special coating to reduce biofilm formation
• tracheal wall pressure monitor that continuously mea-
Special endotracheal tubes sures the cuff pressure, automatically adjusts and
• tubes with an additional lumen for subglottic secretion maintains it constant
suction (CASS: continuous aspiration of subglottic se- • goal: VAP prophylaxis
cretions)
-- i.a. Evac tubes (additional lumen for suction of the
subglottic space; standard in our hospital in the in-
tensive care unit), i.a. PneuX P.Y. system
-- significant reduction in VAP rate (i.a. Smulders et
al, Chest 2002; meta-analysis Dezfulian et al, Am
J Med 2005; Lorente, Am J Respir Crit Care Med
2007; Lacherade et al, Am J Respir Crit Care Med
2010; meta-analysis Muscedere et al, Crit Care Med

Infectiology 951
Fig. 1203  PneuX P.Y. system [12]

study

A multifaceted program to prevent ventilator-associated

pneumonia: Impact on compliance with preventive meas-
ures
Bouadma et al, Crit Care Med 2010

• observational study
• 2-year program to prevent VAP in a 20-bed intensive
care unit
• 8 measures:
-- hygienic hand disinfection
-- use of gloves and smocks
-- bed back straightening (upper body elevation)
-- regular measurement of cuff pressure
-- use of oropharyngeal tubes
-- avoidance of overinflation of the stomach
-- adequate oral hygiene
-- no unnecessary endotracheal suction
• result: By observing these 8 preventive measures the
VAP incidence could be reduced by 51% within two
years!

ALERTS study

• ALERTS study: currently ongoing, Germany's largest

prevention study on hospital infections (started in 2011,
planned for over 4 years, approx. 75,000 patients)
• conducted by IFB (integrated research and treatment
center; funded by the Federal Ministry of Education and
Research) at the University Hospital Jena

952 Infectiology
 die of infectious diseases against which antibiotics are
multi-drug resistant no longer effective (Shrestha et al, Antimicrobial Re-
sistance & Infection Control 2018). In Europe, around
organisms (MDRO) 33,000 patients die every year from multi-resistant
bacteria, in Germany 2,300 (Cassini et al, Lancet In-
fect Dis 2018). That number will still increase! There
is a risk that the feared "post-antibiotic era" is getting
closer and closer.
• The main problem at present and especially in the fu-
ture are not the gram-positive (MRSA: declining; VRE:
no relevant problem in Germany), but the gram-nega-
tive germs (especially the carbapenem-resistant orga-
nisms; "bad bugs - no drugs")!
• The Robert Koch Institute introduced a classification
(see infobox) for Germany for multi-resistant gram-
negative bacteria (MRGN; all of them rods). The clas-
sification is based on resistance to the four most im-
portant antibiotic classes. Internationally, however, the
classification does not exist.

Definition
• almost exclusively bacteria
• germs with increased resistance to antibiotics
• MDR: multi-drug-resistent
• ESCAPE:
-- definition: acronym for a group of pathogens that can
increasingly "escape" the effect of antibiotics, i.e.
with increasing resistance to antibiotics (according
to IDSA [Infectious Diseases Society of America])
-- bacteria:
◦◦ E: Enterobacteria (especially ESBL, CRE)
◦◦ S: Staphylococcus aureus (especially MRSA)
◦◦ C: Clostridium difficile (older classification ESKA-
PE: The K stood for Klebsiella pneumoniae [CRE].
In the newer classification [ESCAPE] klebsiellae
are classified among the enterobacteria.) )
◦◦ A: Acinetobacter baumanii
◦◦ P: Pseudomonas aeruginosa
◦◦ E: Enterokokken (especially VRE)
• Infections with multi-resistant pathogens lead to a sig-
nificant increase in mortality. This is not due to the fact
that the pathogenicity of these germs is so high, but to
the fact that the adequate antibiotic therapy is delayed
and therefore often very late (often inadequate first-
line therapy: e.g. 75% for ESBL, 70% for MRSA, 50%
for pseudomonas, 40% for enterococci).
• There are currently around 700,000 deaths worldwide
annually due to antibiotic resistance, i.e. the patients

Infectiology 953

"bad bugs - no drugs"
Types
• MRSA (No.1)
• ESBL (No.2)
• VRE (No.3)
• multi-drug-resistent (MDR) non-fermenter:
-- multi-drug-resistent pseudomonas aeruginosa
-- stenotrophomonas maltophilia
-- acinetobacter baumanii
• MRSE (methicillin-resistant staphylococcus epidermi-
dis)
Epidemiology
• increase in nosocomial infections (approx. 500000/
year in Germany)
• increase in resistant pathogens
• ECDC (European Center of Disease Control): in Eu-
rope annually
-- approx. 25000 additional deaths
-- approx. 1.5 billion additional costs
Causes
• increasing consumption of antibiotics
-- Most antibiotics are consumed in veterinary medici-
ne (especially in the keeping of stores; approx. 1700
tons per year in Germany) and not in human medici-
ne ("only" approx. 40 tons per year [of which 90% in
the outpatient and only 10% in the inpatient sector]).
-- No.1 in hospitals: cephalosporins
-- Every second intensive care patient in Germany re-
ceives an antibiotic!
• hygienic errors (i.a. hygienic hand disinfection: only
practised in 50%)
• increase in resistances (selection)
• increase in invasive measures
• decrease in therapy options
Prophylaxis
• hygienic hand disinfection
• isolation measures
• regular (once per year) recording and analysis of the
local pathogen and resistance statistics for the respec-
tive intensive care unit (These should be known, as
large regional differences can be observed here!)
• SARI project (Germany):
-- SARI: Surveillance of Antibiotic use and Resistance
situation in Intensive care units
-- funded by the Federal Ministry of Education and Re-
search
-- since 2000
• rational antibiotic therapy :
-- early de-escalation: Initially in sepsis (especially
in septic shock), it should always be started with a
954 Infectiology
broad antibiotic therapy. After three days one usu-
ally receives the antibiogram, then the antibiosis
should be adjusted according to the test. One often
hears the saying "never change a winning team" and
therefore leaves the broad spectrum antibiotic. This
is complete nonsense both with regard to the deve-
lopment of resistance and efficiency: In pneumococ-
cal pneumonia, for example, penicillin G is far (100
times!) more effective than piperacillin / sulbactam
or meropenem!
-- no therapy of colonizations
-- no therapy of fever with antibiotics (Antibiotics are
not antipyretics!)
-- no therapy of increased inflammatory markers ("no
therapy of CRP-itis"!)
-- Rapid onset of antibiotic therapy (according to
the Kumar study [see page 842]) is only required
for severe sepsis and septic shock. In all other ca-
ses, a clean microbiological diagnosis including fo-
cus search should be performed first.
-- In the case of uncomplicated appendicitis, no anti-
biotic treatment is necessary, only surgery (Vons et
al, Lancet 2011). Also in the case of uncomplicated
(mild) diverticulitis, no antibiotic treatment is neces-
sary either (Chalok et al, Br J Surg 2012).
-- antibiotic cycling (rotating antibiotic therapy) to pre-
vent resistance
-- reduction of the use of antibiotics that increase the
selection pressure and thus promote the develop-
ment of resistance (especially cephalosporins and
fluoroquinolones: These antibiotics are particularly
strong MDR selectors!)
• The German government launched the DART pro-
gram (DART: German Antibiotics Resistance Strategy)
in 2008. This includes joint tasks to reduce the deve-
lopment of resistance (e.g. updating of the Infection
Protection Act, introduction of reporting obligations for
multi-resistant pathogens).
• introduction of the so-called Antibiotic Stewardship
programs (ABS: Antibiotic-Stewardship)
infectiological antibiotics-basic rules
for fever:
Antibiotics are not antipyretics!
no antibiotic therapy of CRP-itis!
Fever is not a meropenem-deficiency
disease!
Antibiotic-Stewardship (ABS)
• 30% of all antibiotic prescriptions in the hospital sector
are inadequate (including no indication as there is only
colonization, wrong antibiotic, wrong dosage, therapy
duration too long). This should be improved by the int-
roduction of ABS.
• initially introduced in the USA by the American Society
for Health Epidemiology and Infectious Diseases, now
also widely used in Germany
• meanwhile also explicitly required by the law in Ger-
many
• S3 guideline on antibiotic stewardship "Strategies to
ensure the rational use of antibiotics in hospitals" 2013
(updated 2019)
• structured measures in dealing with antibiotic-resistant
bacteria:
-- establishment of an interdisciplinary ABS team:
◦◦ ABS-trained clinician (ABS courses from the Ger-
man Society for Infectious Diseases; every hospi-
tal department should have a physician with the
appropriate qualification; 1 full-time equivalent] job
per 250 beds), possibly infectiologist
◦◦ microbiologist
◦◦ hygienist
◦◦ pharmacist
-- development and regular updating of an in-house
antibiotics guideline (SOP [standard operating pro-
cedure])
-- regular visits (mainly focused on antibiotics) through
hygiene and microbiology
-- structured reporting on antibiotic consumption and
development of resistance
-- release regulations (special recipes) for reserve an-
tibiotics
-- training / schooling measures
-- IT-supported decision support (CDSS: computerized
clinical decision support systems)
meta-analysis
Effect of antibiotic stewardship on the incidence of infec-
tion and colonisation with antibiotic-resistant bacteria and
Clostridium difficile infection
Baur et al, Lancet Infect Dis
• meta-analysis (32 studies)
• through the introduction of an ABS (Antibiotic Steward-
ship) significant reduction in the infection / colonization
of inpatients in the hospital:
-- MRGN (multi-resistant gram-negative bacteria; by
51%)
-- ESBL (by 43%)
-- MRSA (by 37%)
-- C. difficile ( by 32%)
MRSA (Methicillin-resistant staphy-
lococcus aureus)
Definition
• other designation: multi-resistant staphylococcus au-
reus
• the most common multi-resistant germ
• staphylococcus aureus: in 20% in nasal atria (main re-
servoir) of healthy people
• additional modified penicillin binding protein: PBP2a
(encoded on mecA gene, chromosomally on SCCmec
[staphylococcal cassette chromosome])
• first appeared in 1961
• all betalactam antibiotics (exception: 5th generation ce-
phalosporins) and carbapenems ineffective
• staphylococcus aureus
-- MSSA: 80%
-- MRSA: 20%
◦◦ Spain: 65%, Greece: 80%
◦◦ in intensive care: 40%
• inzidence ↓ (2001: 26%, 2008: 20%, 2014: 13%
[SARI project])
• 1.3 / 100 patients admitted to intensive care (ICU-
NISS)
• increased morbidity, mortality and hospital costs
• The mortality rate in MRSA (as in other multi-resistant
pathogens) is increased not because the pathogenicity
of the MRSA germ is so high, but because adequate
antibiotic therapy is delayed.
• current problems:
-- VISA: vancomycin intermediate resistant staphylo-
coccus aureus (The MIC for vancomycin has increa-
sed in recent years [so-called "vancomycin creep"].
Therefore also the target trough level for the vanco-
mycin therapy was increased to 15-20 μg/nl!)
-- VRSA: cancomycin resistant staphylococcus aure-
us (in Germany not ascertained so far)
-- GISA: glycopeptide intermediate resistant staphy-
lovcoccus aureus (glycopeptides: Vancomycin, tei-
coplanin)
-- LRSA: linezolid resistant staphylococcus aureus
(especially in Spain; e.g. Garcia et al, JAMA 2010;
resistance mechanisms: cfr-bearing plasmids [cfr:
chloramphenicol-florfenicol resistance], chromoso-
mal mutation of ribosomal RNA)
Types
• hMRSA (hospital aquired; the usual MRSA)
• cMRSA (community aquired)
-- toxin: PVL (Panton-Valentine-Leucocidine; first de-
tected in London in 1932 by the scientists Panton
and Valentine)
-- proportion: 2.8%
-- especially in USA (rare in Germany)
-- diseases:
◦◦ abscessing skin and soft tissue infectious disea-
ses (especially recurrent abscesses / boils)
◦◦ severe necrotizing pneumonia
-- means of choice: linezolid
-- frequent transmission within communities (e.g. fami-
ly, prison, contact sports, ship crew)
Infectiology 955
• lMRSA (laMRSA: lifestock associated; in livestock
[especially pigs]; especially in mass livestock farming;
increased risk for humans in contact with animal fat-
tening)
Fig. 1204  Chest CT: severe necrotizing, partially melting
pneumonia on the right by cMRSA
Antibiotics (effective against MRSA)
• clindamycin, trimethoprim-sulfamethoxazole (Bac-
trim), doxycycline (very suitable for less severe MRSA
infections!)
• glycopeptides
-- vancomycin:
◦◦ means of choice for MRSA bacteremia (further op-
tion: daptomycin; linezolid is unsuitable here be-
cause it has only a bacteriostatic effect)
◦◦ always loading-dose 30 mg/kg i.v.
◦◦ therapeutic drug monitoring
▪▪ target level (trough level): 15-20 mg/l (with conti-
nuous administration [perfusor]: 20-25 mg/l)
▪▪ In critically ill intensive care patients, the vanco-
mycin level should be determined daily!);
◦◦ at best continuous administration as perfusor
over 24 hours
▪▪ perfusor: 1g vancomycin in 50ml NaCl 0.9% →
initially 1g as bolus, then infusion rate 2ml/h (i.e.
1g vancomyin per day; then adjustment accor-
ding to the level)
▪▪ equally effective compared to the conventional
bolus application, but significantly lower neph-
rotoxicity (meta-analysis Cataldo et al, J Antimi-
crob Chemother 2012)
956 Infectiology
-- teicoplanin
• rifampicin (the best biofilm-penetrating antibiotic!)
• fosfomycin
• oxalidinones
-- linezolid (Zyvoxid): means choice for MRSA
pneumonia and MRSA skin/soft tissue infections (Li-
nezolid shows a good penetration into the tissue!)
-- torezolid (new name: tedizolid [Sivextro]; in contrast
to linezolid, has a bacteriocidal effect; study for the
treatment of severe skin and soft tissue infections
has been completed [approval studies: ESTAB-
LISH-1/2], since 2015 also approved for this purpose
(1 x 200mg for 6 days); study on nosocomial pneu-
monia currently ongoing [VITAL study]; less throm-
bocytppenias than linezolid)
-- radezolid (study completed for the therapy of skin
and soft tissue infections and community acquired
pneumonia)
• daptomycin (Cubicin)
• tigecyclin (Tigacyl)
• quinupristin-dalsopristin (Synercid; a streptogramine)
• cephalosporins (5th generation; memo: Cephalospo-
rins of the 4th generation are also effective against
anaerobes, cephalosporins of the 5th generation also
against MRSA.)
-- with effectiveness against pseudomonas: ceftobipro-
le (Zevtera)
-- without effectiveness against pseudomonas: cefta-
roline (Zinforo, Teflaro)
• lipoglycopeptides
-- telavancin (Vibativ)
◦◦ approved for nosocomial pneumonia (incl. VAP)
and complicated skin and soft tissue infections,
but only in patients without renal function impair-
ment
◦◦ increased mortality in renal insufficiency (therefore
only if no other alternative is possible)
-- dalbavancin (Xydalba)
◦◦ very long T1/2 (156h), therefore only one administ-
ration (single dose; effect for 14 days)
◦◦ 1500mg i.v. as short infusion ober 30min (in G5%)
◦◦ 1 amp. = 500mg (costs for 1500mg: 2280€ [as of
1/2019])
◦◦ approved for complicated skin soft tissue infec-
tions and catheter-associated infections
◦◦ effect: bactericidal
◦◦ good biofilm penetration
◦◦ effective in the gram-positive range (especially S.
aureus [incl. MRSA])
◦◦ well suited for outpatient parenteral antibiotic the-
rapy or early inpatient (hospital) discharge
◦◦ GFR < 30 ml/min: 1 x 1000mg
-- oritavancin (Orbactiv; very T1/2 [144h], therefore only
a unique administration (single dose [1,2g]; appro-
ved only for complicated skin soft tissue infections
[cSSTI])

MRSA: means of choice for
bloodstream infections vancomy-
cin or daptomycin, for tissue
infections (e.g. lung) linezolid!
in MRSA pneumonia with positive
blood culture (bacteremic pneu-
monia): combination of linezolid
and vancomycin!
Linezolid (Zyvoxid)
• an oxazolidinone (relatively new antibiotic class)
• inhibition of bacterial protein synthesis by specific bin-
ding to the 23S-rRNA of the 50S subunit of the ribo-
somes
• effect: bacteriostatic (Therefore it is relatively ineffec-
tive in case of MRSA bacteremia, here it should not
be used!)
• very good tissue penetration (especially in the lungs),
because it is a small molecule
• only effective in gram-positive range (not e.g. against
ESBL)
• dosage:
-- 2 x 600mg i.v.
-- no dose reduction in kidney or liver insufficiency
• therapy costs: approx. 110 €/d
• very high oral bioavailability (almost 100%)
• no cross-resistances
• side effects (usually only with long-term use [> 14
days]; usually reversible), i.a:
-- thrombocytopenia, anaemia
-- polyneuropathy
-- serotonergic syndrome (Linezolid inhibits the mo-
noaminooxidase [MAO inhibitor]; especially in com-
bination with SSRIs [SSRIs should therefore be
paused during therapy with linezolid!])
• S2k sepsis guideline 2010 + S3 sepsis guideline
2018: first line
-- MRSA pneumonia: linezolid (i.a. also with cMRSA)
significantly better than vancomycin (monotherapy;
i.a. ZEPHYR study 2010 [see box]; therapy duration:
at least 10 days)
-- MRSA skin/soft tissue infections (SSTI; i.a. Itani stu-
dy 2010)
-- VRE
• resistances:
-- LRSA: linezolid resistant S.aureus (e.g. Garcia et al,
JAMA 2010; occured in Spain, not yet in Germany)
-- LRE: linezolid resistant enterococci (significant incre-
ase: in Germany from 0.6% [2008] to 8.8% [2013])
ZEPHYR study
Vancomycin versus linezolid in the treatment of methicillin-
resistant Staphylococcus aureus nosocomial pneumonia
Alaniz et al, Ann Pharmacother 2012
• prospective randomized controlled study
• 348 patients with MRSA pneumonia
-- linezolid
-- vancomycin
• results: linezolid
-- significantly higher clinical success rate
-- comparable adverse event rate
Daptomycin (Cubicin)
• a cyclic lipopeptide (derivative of minocyclin; first
member)
• only effective in the gram-positive range (e.g. good
efficacy against MRSA, VRE [due to the higher MIC
with VRE higher dosage required: 10 mg/kg i.v. once
a day])
• very good tissue penetration, good penetration into
biofilms (means of choice e.g. for MRSA prosthetic in-
fections) )
• effect: bactericidal (the most bactericidal antibiotic af-
ter penicillin!)
• T1/2 = 9h
• indications
-- complicated skin/soft tissue infections (4 mg/kg i.v.
1x/day)
-- S.aureus bacteremia (6 mg/kg i.v. 1x/day; mean-
while 10 mg/kg recommended!)
-- right heart endocarditis by S. aureus (6 mg/kg i.v. 1x/
day; note: For endocarditis a higher dosage is re-
commended in the ESC guidelines 2015: 10mg/kg!)
-- VRE bacteremia (i.a. VRE endocarditis; due to the
higher MIC with VRE, higher dosage here also re-
commended: 10 mg/kg)
• inactivation by surfactant → unsuitable for pulmo-
nary infections (e.g. pneumonia)
Infectiology 957
• does not pass the blood-brain barrier → unsuitable for replacement therapy necessary, no dose reduction in
CNS infections case of liver insufficiency (only in stage Child C: also
• side effects: i.a. loading dose with 100mg , then half dose, i.e. reduc-
-- rhabdomyolysis (increase in CK; especially in com- tion to 2 x 25mg i.v.)
bination with statins; discontinue if necessary if the • also applicable in case of penicillin allergy (but not in
increase is > 5 times the norm), myopathy, polymy- case of tetracycline allergy)
ositis • costs: 98 €
-- eosinophilic pneumonia (i.a. Red-Hand-Letter 2011) • side effects: i.a.
• dose reduction in renal insufficiency -- nausea, vomiting, diarrhea
-- creatinine clearance 50-30 ml/min: 4 mg/kg 1x/day -- fibrinogen ↓
-- creatinine clearance < 30 ml/min: 4 mg/kg 1x every
second day Fosfomycin (InfectoFos)
-- CVVH / haemodialysis: dosage as for creatinin clea- • an epoxy antibiotic
rance < 30 ml/min • effect: bactericidal (inhibition of cell wall synthesis)
• for severe nosocomial pneumonia recommended
Tigecyclin (Tygacil) as a combination partner (alternative to ciprofloxacin
• glycylcycline (first representative; further development or levofloxacin) in the PEG recommendations 2010 +
of tetracyclines) 2018 (renaissance!)
• effect: bacteriostatic • only in combination therapy (not as monotherapy, since
• T1/2 = 8h it alone leads to a rapid development of resistance)
• broad spectrum antibiotic • the smallest antibiotic (very low molecular weight)
-- gram positive (incl. MRSA, VRE) • no protein binding
-- gram-negative (incl. ESBL, acinetobacter bauman- • broad-spectrum antibiotic (incl. MRSA, ESBL, multi-
nii, atypical germs) resistant pseudomonas)
• the only antibiotic that is effective against both mul- • very good tissue penetration
tiresistant gram-positive (MRSA, VRE) and multiresis- • good biofilm penetration
tant gram-negative germs (ESBL, CRE, actinetobac- • no cross allergies / cross resistances
ter) • no cross allergies / cross resistances
• gaps in effectiveness (no activity): -- meropenem + fosfomycin (pneumonia)
-- therefore unsuitable for nosocomial pneumonia -- vancomycin + fosfomycin (MRSA)
(Pseudomonas is the second most common patho- -- ceftriaxone + fosfomycin (meningitis)
gen!)
• dosage
-- proteus
-- moderate infections: 2 x 5g, 3 x 3g
• 1 bottle dry powder a 50mg
-- severe infections: 3 x 5g, 2 x 8g
• indications:
• dose reduction in renal insufficiency
-- complicated skin and soft tissue infections
-- according to GFR:
-- complicated intraabdominal infections (intraabdomi-
◦◦ 40-20 ml/min: 60-80% of the dose
nal abscess, complicated cholecystitis, peritonitis,
ulcer perforation, perforated sigmoid diverticulitis, ◦◦ 20-10 ml/min: 40-60% of the dose
complicated appendicitis) ◦◦ < 10 ml/min: 20-40% der Dosis
-- severe pseudomembranous colitis (clostridium dif- -- according to creatinine:
ficile) ◦◦ 0.8 mg/dl: 3 x 3g
• dosage: 100mg loading-dose, then 2 x 50mg i.v. ◦◦ 2.0 mg/dl: 2 x 3g
• not suitable for: ◦◦ 3.5 mg/dl: 3 x 1.5g
-- sepsis / bacteremia, as it does not reach an ade- ◦◦ 6,0 mg/dl: 2 x 1.5g
quate level in the blood ◦◦ 15 mg/dl: 1 x 1.5g
-- urinary tract infection as it does not reach an ade- -- renal replacement therapy:
quate level in the urine ◦◦ CVVH: 2 x 8g
-- pneumonia, as it is not approved for this (off-label ◦◦ hemodialysis: 2g after each hemodialysis
use) • side effects: especially
◦◦ above all not suitable for nosocomial pneumonia -- hypernatremia: The i.v.-applicable form is a sodium
(because it has no activity against pseudomonas salt (high sodium load).
[second most common pathogen]) -- nausea, vomiting, diarrhea
◦◦ Red-Hand-Letter 2011: increased mortality in -- headache
pneumonia (Freine et al, Diag Microbio Infect Dis
-- vulvovaginitis
2010: Tigecyclin versus Imipenem in ventilator-
• contraindicated in pregnancy
associated pneumonia led to increased mortality!)
• EMA (European Medicines Agency) 3/2020: restric-
• no dose reduction in case of renal insufficiency / renal
tion of use for the i.v. form for cases in which other

958 Infectiology
 antibiotics are not considered suitable (due to the side
effects and the increasing resistance rate)
Ceftobiprole (Zevtera)
• cephalosporin of the 5th generation
• first cephalosporin with efficacy against MRSA (highly
effective against MRSA)
• effect: bactericidal
• the only cephalosporin that is also effective against
enterococci (usually the "enterococcal gap" of cepha-
losporins)
• also effective against pseudomonas
• approvals:
-- pneumonia
◦◦ community acquired pneumonia (but not necessa-
ry for this purpose)
◦◦ nosocomial pneumonia (but not approved for VAP
[ventilator-associated pneumonia], since ceftobi-
prole was inferior to the comparative substance
[ceftazidime and linezolid] in the approval study
[Awad et al, Clin Infect Dis 2014])
-- complicated skin and soft tissue infections (cSSTI;
The approval for this was withdrawn by the FDA.)
• dosage: 3 x 500mg i.v. (better: 3 x 1000mg)
• dose reduction
-- renal insufficiency:
◦◦ GFR 30-50 ml/min: 2 x 500mg i.v.
◦◦ GFR 10-30 ml/min: 2 x 250mg i.v.
◦◦ GFR < 10 ml/min or renal replacement therapy: 1
x 250mg i.v.
-- liver insufficiency: no dose reduction necessary
Ceftaroline (Zinforo)
• cephalosporin of the 5th generation
• also effective against MRSA
• not effective against Pseudomonas, ESBL and non-
fermenters
• effect: bactericidal
• approval received in USA and Europe for (since 2012):
-- complicated skin and soft tissue infections (cSSTI)
-- community acquired pneumonia (i.a. Zhong et al,
Lancet Infect Dis 2015)
-- note: The approval is relatively unfortunate. For the
two diseases for which ceftaroline has now been ap-
proved, we actually do not need it at all. Especially
for the therapy of community acquired pneumonia
no MRSA-effective antibiotic is necessary. It would
have been particularly important for MRSA pneumo-
nia (nosocomial) or for MRSA CNS infections. .
• dosage: 2 x 600mg i.v.
• dose reduction
-- renal insufficiency:
◦◦ GFR 30-50 ml/min: 2 x 400mg i.v.
◦◦ GFR < 30 ml/min: not recommended
-- liver insufficiency: no dose reduction necessary
Prevention
• hygienic hand disinfection
• screening (smear of nose, if necessary of wound) in
case of risk factors (see infobox)
-- PCR (mecA-Gen; rapid test; faster [2-3h], but more
expensive)
-- culture (slower [24-48h], but cheaper)
• isolation
• eradication
• rational use of antibiotics
• staff training
• limitation of intrahopsital transports to the medically
necessary minimum
• Since 2009, MRSA must be reported in Germany if it
has been detected in the blood or CSF (cerebrospinal
fluid).
If a patient is transferred from
another hospital to the intensive
care unit, protective isolation
should be carried out until the
result of MRSA smear is received!
Isolation
• single room (if possible; cohort isolation if necessary)
• gloves, mouthguard, protective gown; note: headgear
no longer necessary
Eradication
• syn.: decolonization
• means:
-- 1st choice: mupirocin nasal ointment (Turixin; an anti-
biotic produced by pseudomonas fluorescens)
-- 2nd choice: PVP iodine
-- 3rd choice: Octenisept
• over 5 days
• removal of isolation if smears are negative 3 times (3
different days; without [staphylococcal effective] anti-
biotics) after the end of antibiotic treatment
• colonisation of intact skin areas (e.g. groin, axilla) →
whole body washing with Octenisept or Chlorhexidine
Infectiology 959
ESBL (extended spectrum betalac-
tamase)
Definition
• enterobacteria (especially klebsiella, E.coli, proteus)
with a beta lactamase, which has an increased activity
against beta lactam antibiotics
• most common betalactamases: CTX-M-15, CTX-M-14,
SHV-12
• dramatic increase (2001: 1.2%, 2008: 19.7% [SARI
project]), tenfold increase in the last 10 years!
• 0.9 / 100 patients admitted to intensive care units (ICU-
NISS)
• ESBL proportion (according to T.E.S.T. [Tigecyclin Eu-
ropean Surveillance Trials], ICAAC 2011) in Germany:
-- E. coli: 15% (no increase; low transmission rate)
-- klebsiella pneumoniae: 16% (2014 in Germany even
20%; significant increase; high transmission rate)
• 3-4 fold increased mortality
• resistance mechanism: horizontal transfer of the point
mutation via plasmids
• typically resistant to 3rd generation cephalosporins
(cefotaxime, ceftriaxone, ceftazidime)
• normally sensitive to carbapenems, now however car-
bapenemase producing enterobacteria (CPE; syn.:
carbapenem-resistant enterobacteria [CRE; see ex-
cursus])
• main reason (for the development of ESBL): oral ce-
phalosporins
• diseases:
-- urinary tract infections
-- nosocomial pneumonia
-- catheter infections
-- intraabdominal infections
-- sepsis
960 Infectiology
study
ESBL colonization and acquisition in a hospital population:
The molecular epidemiology and transmission of resist-
ance genes
Hagel et al, PLOS One 2019
• prospective cohort study (Germany)
• 1334 patients admitted to the hospital
• colonization with ESBL: in 13% (every 8th patient; if co-
ming from a nursing home even in 24%)
• de novo colonization with ESBL during the hospital stay:
in 8%
• ESBL: in 89% E.coli
• infection but only very rarely (0.006%)
Risk factors
• age > 70 years
• previous hospitalization
• transfer from nursing home
• Charlson comorbidity index > 4
• antibiotic pretreatment with betalactams or fluoroqui-
nolones
• permanent catheters
Isolation
• like MRSA
• The isolation of different ESBL (E.coli, Klebsiella) in a
common room is permitted.
Antibiotics
• carbapenems (means of choice!)
-- imipenem
-- meropenem
-- ertapenem
-- doripenem (meanwhile (withdrawn from the market))
• tigecyclin
• fosfomycin
• piperacillin / tazobactam:
-- definitely an option (e.g. urinary tract infection, pneu-
monia) if tested as sensitive (If you only ever use
carbapenems at ESBL, the development of carbape-
nem-resistant organisms [CRO] is promoted!)
-- but definitely not in case of bloodstream infections,
as the mortality is higher here compared to merope-
nem (MERINO study 2018)
• ceftolozan / tazobactam (Zerbaxa):
-- well effective i.a. against Pseudomonas and ESBL
-- dosage: 1g/0.5g i.v. 3x daily (GFR 30-50 ml/min:
0.5g/0.25g 3x daily; GFR 30-15 ml/min: 0.25g/0.125g
3x daily; GFR < 15 ml/min or renal replacement the-
rapy: initially 0.5g/0.25g 1-1-1, then 0.1g/0.05g 3x
daily)
-- indications:
 ◦◦ complicated intra-abdominal infections
◦◦ complicated urinary tract infections, acute pyelo-
nephritis
• Cephalosporins are ineffective in ESBL (even if
"sensitive" in the antibiogram).
ESBL: carbapenem or tigecyclin!
Excursus: Carbapenem-resistant orga-
nisms (CRO)
CRE
Definition
• carbapenem-resistant enterobacteriaceae (especially
K. pneumoniae [most common CRE], E. coli)
• syn.: carbapenemase-producing enterobacteriaceae
(CPE)
• proportion only 2-3% in Germany (more often in
Greece, Italy, Turkey, Malta, Israel, USA, India, Iran,
Iraq, Egypt, China, Thailand, Japan), but a significant
increase in Germany
• They will be the largest problem in the future!
• mortality: 50% (Correa et al, BMC Inf Dis 2013),
4-fold mortality
• especially klebsiella
• carbapenemases (Ambler classifikation [according to
the British molecular biologist Richard Penry Ambler
[1933-2013]):
-- class A: z.B. Klebsiella pneumoniae-Carbape­ne­
mase (KPC)
-- class B
◦◦ VIM (Verona integron encoded metallo-betalacta-
mase; most common)
◦◦ NDM (Neu-Delhi-Carbapenemase)
◦◦ IMP (Imipenemase)
-- class C (e.g. AmpC)
-- classD (e.g. OXA-48 [Oxacillinase])
• Carbapenemasen are β-lactamases:
-- class A, C and D: serin-β-lactamases (SBL)
-- class B: metallo-β-lactamases (MBL)
• the most common carbapenemases in Germany:
OXA-48 (No.1), KPC (No.2), VIM (No.3), NDM (No.4)
Therapy
• polymyxins
-- colistin ( the "backbone" [basis] of CRE therapy!
renaissance! see page 972)
-- polymyxin B
• tigecycline (but not for sepsis or urinary tract infec-
tions, as insufficient levels are achieved; off-lable for
pneumonia)
• fosfomycin
• ceftazidime + avibactam (Zavicefta): The β-latamase
inhibitor avibactam is very effective against CRE (es-
pecially KPC [i.a. CRACKLE study van Duin et al, Clin
Infect Dis 2018] and OXA-48; however, not effective
against metallo-β-lactamases [Ambler class B]: As a
trick, however, one can combine ceftazidime / avibac-
tam with the monobactam aztreonam [not available in
Germany] here [Marshall et al, Antibiol Agents Chemo
2017]).
• carbapenem (e.g. meropenem 3 x 2g) as a combina-
tion partner to colistin or fosfomycin (actually absurd;
also recommended only for MIC <8 mg/l)
• meropenem + vaborbactam (Vabomere)
-- vaborbactam: new β-latamase inhibitor with effec-
tiveness against carbapenemases (especially KPC)
-- already approved in the USA (not yet in Germany)
as a reserve antibiotic for complicated urinary tract
infections (including pyelonephritis) caused by kleb-
siella pneumoniae, escherichia coli or enterobacter
cloacae
-- dosage: 2g/2g 3 x daily. as short infusion over 3h
-- dose reduction in renal insufficiency:
◦◦ GFR 30-50 ml/min: 1g/1g 3 x daily
◦◦ GFR 15-30 ml/min: 1g/1g 2 x daily
◦◦ GFR < 15 ml/min: 0,5g/0,5g 2 x daily
-- approval study: TANGO-1
• Recarbio = imipenem + cilastatin + relebactam
-- cilastatin: an inhibitor of dehydropeptidase in the kid-
ney that prevents the renal inactivation of imipenem
-- relebactam: new β-latamase inhibitor with activity
against carbapenemases of classes A and C (not
active against classes B and D)
-- approvals (FDA since 2019): infections due to ae-
robic gram-negative bacteria with limited treatment
options
◦◦ complicated urinary tract infections
◦◦ complicated intra-abdominal infections
◦◦ nosocomial pneumonia (incl. VAP; not yet appro-
ved; study: RESTORE-IMI 2)
Infectiology 961
• cefiderocol (a siderophore-cephalosporin [new class
of antibiotics]; 3 x 2g i.v. over 3 hours each; already
approved in the USA)
• at best combination therapy (i.a. Dalkos et al, An-
timicrob Agents Chemother 2014; INCREMENT study
[Gutiérrez-Gutiérrez et al, Lancet Inf Dis 2017]) with
colistin as basis (duration: 7-14 days; note: For Citro-
bacter freundii monotherapy with colistin is sufficient.):
e.g. with
-- tigecyclin (Tumbarello et al, Clin Infect Dis 2012)
-- meropenem (but only if MIC < 8 mg/l)
-- ceftazidime + avibactam
means of choice for CRE: combination
therapy with colistin as the basis!
VRE (Vancomycin resistant entero-
cocci)
Enterococci
• physiological intestinal flora
• gram-positive
• low virulence (even if detected in the blood culture only
very rarely septic shock; also applies to VRE)
• relatively little pathogenic, frequent colonisation, usu-
ally not requiring treatment
• especially in stool and urine
• high environmental resistance
• types:
-- E. faecalis (85%; means of choice: ampicillin)
-- E. faecium (15%; means of choice: vancomycin;
VRE resistance therefore mainly concerns E. faeci-
um)
• Enterococci per se already have a relatively high resis-
tance to numerous antibiotics, i.a. a natural resistance
to cephalosporins and fluoroquinolones ("enterococcal
gap").
• sensitivity
-- 85% vancomycin sensitive (VSE)
-- 15% vancomycin resistent (VRE)
• Both the incidence of enterococcal infections and the
incidence of VRE are increasing. The reason for the
increase in enterococcal infections is that more and
more antibiotics with an enterococcal gap (cephalo-
sporines, fluoroquinolones) are used. The reason for
the increase in VRE is the significant increase in the
use of vancomycin as an MRSA antibiotic in recent ye-
ars.
• VRE are now also becoming a significant problem in
Germany. In a European comparison, Germany even
has one of the highest VRE proportion ever (Gastmei-
er et al, J Antimicrob Chemother 2014).
• 8 types of resistance (VanA-VanN); the two most com-
mon are:
-- VanA (No.1): cross-resistance between vancomycin
and teicoplanin
962 Infectiology
-- VanB: resistance to vancomycin, but sensitivity to
teicoplanin
• diseases:
-- peritonitis (especially tumor patients)
-- endocarditis
-- wound infections
-- urinary tract infections
-- CVC infections
-- not pneumonia: Enterococci (including VRE) are
no pneumonia pathogens! Therefore, the detection
of enterococci (including VRE) in endotracheal sec-
retion is always only a colonization and therefore not
an indication for therapy!
Definition
• Infection increases mortality, costs and duration of ill-
ness (Carmeli et al, Arch Intern Med 2002).
• 0.3 / 100 patients admitted to ICU (ICU-NISS)
• cause: i.a. uncontrolled use of antibiotics in agriculture
• colonisation (perianal region, urine): no disease value
(no indication for treatment)
• transmission mostly by smear infection
• isolation like MRSA (however, its effectiveness is con-
troversial)
• screening (anal swab)
-- contact persons
-- VRE in prehistory
Antibiotics
• E. faecalis: good sensitivity to ampicillin (even if
VRE!)
• E. faecium:
-- linezolid (means of choice; however, significant
increase in linezolid-resistant enterococci [LRE] in
Germany from 0.6% [2008] to 8.8% [2013])
-- tigecyclin
-- daptomycin
◦◦ due to the higher MIC with VRE however higher
dosage necessary: 10 mg/kg i.v. 1 x / day
◦◦ in VRE bacteremia (including VRE endocardi-
tis) better (possibly [from pathophysiological con-
siderations]) than linezolid (since daptomycin has
a bactericidal effect and linezolid is only bacterio-
static)
▪▪ but only in the high dose (10 mg/kg), in the nor-
mal dose (6 mg/kg), daptomycin is even worse
than linezolid (Narayanan et al, Ther Adv Infect
Dis 2019)
▪▪ Twilla et al, J Hos Med 2012: no difference bet-
ween daptomycin (6 mg/kg) and linezolid
▪▪ Metaanalyse Balli et al, Antimicrob Agents Che-
mother 2014: even higher mortality with dapto-
mycin (6 mg/kg) than with linezolid
 Epidemiology
Enterococci - therapy:
• one of the most common nosocomial pathogens (no-
VSE:
wadays twice as many nosocomial infections from C.
- E. faecalis: ampicillin
difficile as from MRSA!)
- E. faecium: vancomycin
VRE: linezolid • most common pathogen of nosocomial diarrhoea
• colonisation: 3% of all people (30% of hospital pati-
ents)
• incidence:
Clostridium difficile -- 10.2 / 10000 patient days (Germany)
-- dramatic increase (The number of reported infec-
tions has tripled between 2008 and 2013). 65% of
them were severe [Epi Bull 2014]).
• average age: 76 years
• strains:
-- most common strain in Germany: ribotype 001
-- new strain with high virulence: ribotype 027 (produ-
ces quantitatively more toxins)

Clostridium difficile: dramatic

increase on ICUs!

Definition
• new designation: Clostridioides difficile
• germ:
-- anaerobic gram-positive rod
-- spore forming bacteria (survives outside the colon
in the form of spores that are very resistant to the
environment)
-- toxin producing
• also detectable in 3% in the intestines of healthy peo-
ple
• virulence factor: toxins
-- toxin A (enterotoxin)
-- toxin B (cytotoxin; 1000 times stronger)
• causes:
-- antibiotics (50%)
◦◦ usually 5-10 days after beginning of antibiotic
treatment
◦◦ most common: clindamycin, cephalosporines, flu-
oroquinolones
◦◦ In most cases, however, diarrhoea under antibio-
sis is only an antibiotic-associated diarrhoea (due
to changes in the intestinal flora).
-- transmission (50%; C. difficile is highly contagious!)
• transmission from person (fecal-oral) or from contami-
nated objects to person
• highly infectious (excretion 107-108 pathogens per
gram of stool)
• resistant to alcohol (The alcoholic hand disinfection
does not help here, but washing hands with soap!)
• incubation period: 1-3 days
Diseases
• clostridium difficile associated diarrhoea (CDAD, 50%)
• pseudomembranous colitis (20%)
• toxic megacolon (see infobox; possibly sepsis and per-
foration)
Risk factors
• antibiotic therapy (especially clindamycin, cephalospo-
rines, fluoroquinolones); 4C group (colitogen): Clin-
damycin, Cephalosporins, Chinolons, Clavulanic acid
(in Augmentan)
• ulcus prophylaxis (i.a. Tariq et al, JAMA Int Med 2017;
especially proton pump inhibitors [i.a. Buendgens et al,
Crit Care 2014], but also applies to H2-blocker [i.a. Mac
Laren et al, JAMA Intern Med 2014])
• chronic inflammatory bowel disease (Crohn's disease,
ulcerative colitis)
• hospital stay (especially intensive care unit)
• age > 65 years
• immunosuppression
• tube feeding
• severity of the underlying disease
• chemotherapy
Symptoms
• diarrhea (watery, possibly bloody; note: The sicker the
patient, the more likely it is that there is no diarrhea.)
• typical smell of cresol ("horse stable" smell; could even
be smelled by the dog "Cliff" with a success rate of
86% [Bomers et al, BMJ 2012])
• dehydration
• abdominal pain (especially lower abdomen; cramp-
like)
• fever

Infectiology 963
Diagnosis
• stool sample
-- detection of C. difficile toxin A/B (not antigen [A po- EUCLID study
sitive antigen in negative toxin only means that the
patient has clostridia in his intestine, which is com-
pletely normal and therefore does not constitute a
treatment indication!])
European, multi-centre, prospective bi-annual point preva-
◦◦ by ELISA lence study of Clostridium difficile infection in hospitalised
◦◦ The toxin is extremely environmentally unstable patients with Diarrhoea
(T1/2 only 2h!), so the stool sample should be as Davies et al, Lancet Infect Dis 2014
fresh and chilled as possible.
◦◦ relatively poor sensitivity (because very unstable; • largest study on the epidemiology of C. difficile infections
in Europe (482 hospitals in 20 European countries)
i.a. Crobach et al, Clin Microbiol Infect 2009)
• 3920 stool samples from patients with diarrhoea who
◦◦ toxin gene (molecular biological detection): The were then examined at a centre
toxin gene is now also determined in numerous la- • results:
boratories. Since the toxin is relatively unstable, it -- incidence: 6.6 / 10000 patient days in Europe (in Ger-
can happen that the toxin itself cannot be detected many: 10.2 / 10000 patient days)
anymore because it has been destroyed, for ex- -- Only in 27.4% the correct diagnosis algorithm (i.e.
ample, during a too long transport. However, if the stool sample with detection of C. difficile toxin and
toxin gene is positive, it is repeatedly postulated GLDH antigen test) was performed. .
that, despite negative toxin detection, there is a -- 24.6% of all stool samples were not tested for C. dif-
treatment indication if symptoms are appropriate. ficile at all.
However, a positive antigen, negative toxin (ELI- -- false-negative results (i.e. testing in the center was
SA) and positive toxin gene (PCR) only indicates positive, testing in the hospital was negative): 2.3%
that the patient has clostridia in his intestine which (in Germany: 4.1%)
are potentially able to form the toxin. A prospective
cohort study (Overdiagnosis of C. difficile infec-
tion in the molecular test era; Polage et al, JAMA
2015) showed that molecular biological detection
of the toxin gene often leads to overdiagnosis and
overtherapy. Patients with positive antigen, nega-
tive toxin and positive toxin gene had the same
outcome in this study as patients with positive an-
tigen, negative toxin and negative toxin gene (e.g.
same duration of diarrhoea, no increased Clostri-
dium difficile-associated complications).
-- GLDH antigen test
◦◦ detection of glutamine dehydrogenase (GLDH) di-
stinctive of C. difficile
◦◦ clearly recommended (SHEA/IDSA Guideline
2010)
◦◦ GLDH antigen test negative → C.difficile infec-
tion highly likely to be ruled out (then no further
diagnostics necessary)
-- stool culture: no clinical significance
• endoscopy
-- sigmoidoscopy sufficient, since the rectum and sig-
ma are predominantly affected
-- detection of pseudomembranes (yellow-greenish,
raised, partly confluent plaques)
-- This is the fastest way to diagnosis confirmation!
The result of the stool sample takes much longer!
For sigmoidoscopy, the patient only needs to be pre-
pared for a colonoscopy with a Harris flush and not
as usual.
-- However, the absence of pseudomembranes does
Fig. 1205  Sigmoidoscopy: The typical pseudomembranes
not exclude CDAD.
are recognizable.
-- biopsy if necessary (histology: i.a. "volcano lesions")

964 Infectiology
Guideline
Clinical Practice Guidelines for Clostridium difficile Infec-
tion in Adults and Children: 2017 Update by the Infec-
tious Diseases Society of America (IDSA) and Society for
Healthcare Epidemiology of America (SHEA)
Therapy
• isolation (single room; can be suspended if no diar-
rhoea occurs for 48 hours [no toxin control in stool ne-
cessary!])
• discontinuation of a pre-existing antibiotic therapy
(most important [if possible]! in mild cases often suf-
ficient)
• discontinuation of gastric acid inhibitors (especially
proton pump inhibitors, but also H2-blockers)
• fluid administration, electrolyte compensation
• antibiotics: duration of therapy 10 days
-- metronidazole
◦◦ dosage: 400mg 3 x daily p.o.
◦◦ in the past, means of first choice for mild infec-
tions, not anymore (note: means of first choice
only for children [7.5 mg/kg 3-4 x daily])
◦◦ also i.v.- administration effective
-- vancomycin
◦◦ today means of first choice (regardless of the
severity, i.e. even with a mild infection)
◦◦ dosage: 125mg 4 x daily p.o. (This dosage is
completely sufficient, as it already achieves a con-
centration in the colon that is 1000 times above
the MIC. However, since in Germany the entero-
capsules for vancomycin are only available with
250mg and the ampoules for vancomycin only
with 500mg, for reasons of practicality usually 4 x
250mg or 4 x 500mg are administered. The van-
comycin ampoules with 500mg can be prepared
accordingly to a drinking solution.)
◦◦ i.v.- administration is not effective!
-- severe infection (fulminant colitis, sepsis, toxic
megacolon):
◦◦ metronidazole i.v. (3 x 500mg) and (here always
combination therapy)
◦◦ high dose vancomycin
▪▪ p.o. / via nasogastric tube (4 x 500mg)
▪▪ intracolic (best) because often gastrointes-
tinal atonia (reflexive intestinal paralysis) and
thus the peroral or via gastric tube applied van-
comycin often arrives only insufficiently in the
large intestine; either via a blindly placed intesti-
nal tube or via a colonoscopically placed probe
(just above the left flexure); give 4 times daily
each 500mg in 100ml NaCl 0.9%)
◦◦ tigecyclin i.v. (100mg as loading-dose, then 2 x
50mg)
◦◦ possibly stool transplantation (fecal microbiota
transplantation [FMT]; early [but almost no data
for this])
• loperamide: contraindicated (except immediately after
a stool transplantation)
• toxic megacolon (see infobox; no response under con-
servative therapy within 72h) or perforation → surgery
(subtotal colectomy; in 3.7% of all patients with CDAD
necessary)
• recurrence:
-- first recurrence:
◦◦ if previously treated with metronidazole: vancomy-
cin 125mg 4 x daily p.o
◦◦ if previously treated with vancomycin: vancomycin
interval therapy (or fidaxomicin p.o. 2 x 200mg for
10 days):
▪▪ 1st week: 4 x 125mg
▪▪ 2nd week: 2 x 125mg
▪▪ 3rd week: 1 x 125mg
▪▪ 4th week: 125mg every sedond day
▪▪ 5th week: 125mg every third day
-- second recurrence (and further recurrences):
◦◦ vancomycin interval therapy
◦◦ vancomycin 125mg 4x daily p.o. for 10 days, then
rifaximin (Xifaran; also effective against C. difficile)
400mg 3x daily p.o. for 20 days
◦◦ fidaxomicin 2 x 200mg for 10 days
◦◦ stool transplantation (fecal microbiota transplanta-
tion [FMT])
• probiotics (especially saccharomyces boulardii [Peren-
terol 2 x 250mg]): fewer recurrences in case series,
but the effectiveness could never be proven in clinically
randomized controlled studies (therefore no general
recommendation)
• new C. difficile drugs:
-- fidaxomicin (Dificlir)
◦◦ a non-absorbable macrocycline
◦◦ relatively narrow spectrum of action with good ef-
ficacy against C. difficile (highly selective against
C. difficile)
◦◦ effect predominantly local, almost no systemic ef-
fect
◦◦ already approved by FDA and EMA
◦◦ dosage: 2 x 200mg daily p.o. for 10 days
◦◦ costs: 90€ per pill
◦◦ significantly fewer recurrences (halving the risk of
recurrence) than with (i.a. Louie et al, N Engl J
2011; Cornely et al, Lancet Infect Dis 2012)
◦◦ recommendation (IDSA guideline 2017): already
as an option in the initial therapy (instead of van-
comycin) or from the first recurrence
-- cadazolid
◦◦ a hybrid antibiotic of a fluoroquinolone and an oxa-
zolidinone
◦◦ phase II study (Louie et al, Antimicrob Agents Che-
mother 2015): cure rate comparable to vancomy-
cin with fewer recurrences
◦◦ phase III study ongoing (not yet approved)
-- ridinilazol
◦◦ a "small molecule" antibiotic
◦◦ phase II study (Vickers et al, Lancet Infect Dis
2017): cure rate comparable to vancomycin with
fewer recurrences
-- surotomycin
Infectiology 965
 ◦◦ a cyclic lipopeptide
◦◦ phase III study (Dakey et al, J Antimicrob Chemo-
ther 2017): comparable cure and recurrence rate
as vancomycin
-- nitazoxanide (phase III study ongoing, not yet ap-
proved)
-- ramoplanin (phase III study ongoing, not yet appro-
ved)
-- bezlotoxumab (Zinplava):
◦◦ a human monoclonal antitoxin antibody (against
toxin B so that the toxin is neutralized)
◦◦ MODIFY studies (phase III studies): significant
reduction in the recurrence rate compared to pla-
cebo (In addition to standard therapy with vanco-
mycin, metronidazole or fidoxomicin, the patients
received a single infusion with bezlotoxumab.)
◦◦ approved since 2016 (additive to antibiotic thera-
py)
◦◦ only for the prevention of a recurrence (not for the
therapy of the disease)
◦◦ above all if there is a high risk of recurrence (espe-
cially age > 65 years, status after recurrence, im-
munosuppression, severe infection, ribotype 027)
◦◦ dosage: 1 amp. = 1000mg, single infusion 10 mg/
kg over 1h
◦◦ no dose reduction in renal or hepatic insufficiency
◦◦ costs: approx. 2300€ per ampoulle
◦◦ NUB status since 1/2019
• possibly stool transplantation

severe pseudomembranous
colitis: metronidazole i.v. +
Vancomycin intracolic (insert a
colonoscopic probe)

966 Infectiology
Fig. 1206  X-ray abdomen and CT abdomen (toxic megaco-
lon): One recognizes the clearly dilated colon.

Infectiology 967

Fig. 1207  A 50-year-old patient with severe ulcerative colitis
(images of the colonoscopy performed in the previous hos-
pital stay) who developed a toxic megacolon in the course
of the disease: The first X-ray of the abdomen shows the
clearly dilated colon. In the second X-ray of the abdomen,
a perforation has already occurred as a complication: You
can clearly see free air under the right diaphragm. Surgery
was necessary.
Stool tansplantation
Definition
• syn.: FMT
-- fecal microbiota transplantation
-- fecal microbiome transfer
• rationale: The aim is to restore a normal bacterial in-
testinal flora.
• application a foreign stool (donor stool) duodenally or
colonically (e.g. via a probe or colonoscopy).
• history:
-- already practiced 1700 years ago by the Chinese
physician Ge Hong (283-343 AD) for food poisoning
and severe diarrhea ("yellow soup")
-- Christian Franz Paullini (German physician and
poet; 1643-1712): book from 1697 with the title "The
healing dirt pharmacy" ("how most diseases and da-
mages are happily cured with feces and urine")
• The results of stool transplantation are excellent
(almost complete healing)! In severe pseudomemb-
ranous colitis, stool transplantsation should be carried
968 Infectiology
out generously (at the latest after failure of the stan-
dard therapy after 48 hours)!
• German register "MikroTrans" (Unklinikum Jena)
study
Duodenal Infusion of Donor Feces for Recurrent Clostrid-
ium difficile
Els van Nood, N Engl J 2013
• single center randomized controlled study
• 52 patients with recurrence of C. difficile infection
• 3 treatment groups:
-- infusion of foreign stool (donor stool) via a nasoduo-
denal probe (stool transplantation)
-- vancomycin
-- vancomycin + colonic irrigation
• results:
-- Stool transplantation was best (decrease in diarrhea).
-- healing of infection in 81% in the group of stool trans-
plantation versus 23% and 31% respectively in the
other two groups
-- even premature termination of the study
study
Effect of Fecal Microbiota Transplantation on Recurrence
in Multiply Recurrent Clostridium difficile Infection
Kelly et al, Ann Int Med 2016
• oligocenter (2 centers) randomized controlled study
• 46 patients with at least 3 recurrences of a C. difficile
infection; colonoscopic transfer of stool
-- foreign stool (allogeneic [verum group])
-- own stool (autologous [placebo group])
• results: foreign stool (allogenic)
-- significant increase of the primary endpoint (no more
diarrhoea after 8 weeks) from 62% to 91%
-- If patients who developed a recurrence after applica-
tion of their own stool and then got foreign stool were
also included, the success rate (cure rate) was even
93.5%!
The more severe the pseudomembra-
nous colitis, the earlier the stool
transplantation (FMT)!
Donor
• Relatives are very suitable as donors (do not have to
be relatives).
• In some hospitals there is a permanent team of stool
donors. This has the advantage that you do not always
have to carry out the tests beforehand, so that you
 save money and time (i.a. thereby an emergency stool
transplantion possible). The donated stool can also be
stored refrigerated (deep-frozen at -70 ° C in a carrier
substance), which is very practical for everyday clini-
cal practice. There are no disadvantages compared to
fresh stool (i.a. Le Ch et al, JAMA 2016).
• prerequesites (donor):
-- no antibiotics in the last three months and no gastro-
intestinal infection
-- no major previous gastrointestinal surgery (e.g.
Whipple surgery, colectomy)
-- no i.v. drug abuse
-- donor screening
◦◦ see infobox
◦◦ These examinations must not necessarily be car-
ried out completely in an emergency. However, the
patient should be informed accordingly.
◦◦ The costs for the donor screening amount to ap-
prox. 500-700€ and are not (yet) covered by the
recipient's health insurance.
◦◦ The donor screening examinations may not be
more than 6 weeks old. (Exception: If someone
has repeatedly donated stool, the examinations
should be repeated every 6 months.)
◦◦ After a warning from the FDA 6/2019 that two im-
munosuppressed patients suffered a severe ESBL
infection after a stool transplantion, one of whom
died from it, the donor's stool must now also be ex-
amined for multi-drug resistant organisms (MDRO)
such as ESBL, CRE, MRSA and VRE.
Legal issues
• officially no approval (Patient should also be informed
about it!)
• status of an individual healing attempt according to the
Medicines Act
• os not covered by the Transplantation Act (TPG)
• The preparation and application of the stool suspensi-
on is subject to the Medicines Act in Germany (Section
2 (1), Section 13 (2b) AMG in Germany). The physician
is responsible for the preparation (of the stool suspen-
sion) and implementation. The procedure is notifiab-
le to the local health authorities (locally responsible
district government; notification according to Section
67 (2) of the German Medicines Act for the permis-
sion-free manufacture of medicines by physicians).
This can be done informally and should include the
following: hospital and department (especially rooms,
equipment), list of physicians who carry out the stool
transplantation including certified license to practice
medicine as well as information on production and
application, other personnel involved in production as
well as information on the designation and compositi-
on of the pharmaceuticals produced including applica-
tion route, indication and source of supply of drug. It is
enough to notify this once, i.e. it does not have to be
notified each time for each patient. In many cases, it is
also recommended to obtain prior written approval for
a stool transplantion.
• recommendation of the Federal Institute for Drugs and
Medical Devices (BfArM) 4/2020: In the case of SARS-
CoV-2, faecal-oral transmission cannot be safely ruled
out. Especially in the later course of the infection, ca-
ses of a positive rectal smear with a simultaneous ne-
gative nasopharynx smear were described. Therefore,
stool transplantations should be avoided in the context
of the corona pandemic!
Procedure
• preparation: The donated stool (should be no more
than 6 hours old; refrigerated storage at +2 to +8 de-
grees Celcius possible until application) is put in a uri-
ne collection container, provided with 250-500ml sali-
ne solution and mixed with an electric mixer (medical
device; sterilizable). Then the mixture is filtered via a
conventional coffee filter. One does not need the ex-
crement, but only the liquid with the (healthy) intestinal
flora (suspension). Altogether 250-500ml stool sus-
pension are needed. After our experiences only extre-
mely little liquid could be obtained by several filters, so
that we do not use filters at all.
• patient information obligatory (informed consent; i.a.
off-label, reference to the transmission potential [i.a.
HIV, viral hepatitis, tuberculosis, syphilis, possibly also
allergies and malignancies], character of an individu-
al healing attempt, complications, alternative therapy
options)
• All antibiotics (including those effective against clost-
ridia) are discontinued 48 hours beforehand (and no
longer continued after the stool transplantion).
Applikation
• gastric / duodenal: The administration of foreign stool
via a gastric or duodenal tube is borderline, especially
if the patient vomits; alternative: swallowing of stool
capsules (frozen; i.a. Youngster et al, JAMA 2014; just
as effective as via colonoscopy (Kao et al, JAMA 2017)
• colonic (best): A colonoscopy is performed (usu-
ally up to the transverse colon is sufficient, since the
pseudomembranous colitis usually manifests itself in
the sigmoid; purge as in conventional colonoscopy
Infectiology 969
 to reduce the recipient's own stool flora). Then about -- Of these, 65% suffer a second recurrence (i.a.
50-100ml of the filtered stool suspension is applied McFarland et al, Am J Gastroenterol 2002).
through a catheter (e.g. colonoscopy probe), which
is inserted through the working channel of the colo-
noscope. Alternatively, the stool suspension is injected
directly via a bladder syringe over the working channel.
Then pull back the coloscope by 10cm, give another
50-100ml and repeat the procedure several times un-
til you have reached the anal canal. If before anyway
a probe for the intracolonic application of vancomycin
was inserted, the stool suspension can be given also
over it. Afterwards loperamide is given to extend the
time the suspension remains in the colon. After the
stool transplantation, all antibiotics previously given for
pseudomembranous colitis are discontinued. The ma-
ximum effect usually occurs after 3-4 days. In most ca-
ses a single stool transplantion is sufficient. If a second
stool transplantation is performed, the patient should
only be purged for colonoscopy by means of a Har-
ris flush and not with conventional laxative measures
in order not to miss the previously transplanted stool
flora. The pseumomembranes, which ultimately repre-
sent scars, often perish over a longer period of time,
so that the sole detection of pseudomembranes is not
to be equated with therapy failure. The decisive fac-
tor is the clinical improvement (reduction of diarrhoea,
no more fever). The disgust of stool transplantation is
limited and is not higher than when a colonoscopy is
performed on an inadequately purged patient. It should
be remembered that the only alternative to stool trans-
plantation is often colectomy, which has a high peri-
operative mortality rate in septic patients! Due to the
extremely high success rate of stool transplantation, it
should be used all the sooner, the more sick the patient
is (and not only during recurrence).

Obligation to notify
• normally only non-nominally (§6 section 3 German In-
fection Protection Act [IfSG]) in proven cases
• Since 2007, the German Infection Protection Act (IfSG
Fig. 1208  A tool that is by no means unimportant in stool
transplantation is peppermint oil, which is best put on a
§6 section 1 No.5a) stipulates an obligation to report
face mask. by name for the following:
-- serious cases:
Prognosis ◦◦ necessity of rehospitalisation due to a recurrence
◦◦ admission to intensive care unit
• mortality: 16% (Wiegand et al, J Hosp Infect 2012)
◦◦ colectomy
• estimation of prognosis (mortality) possible using the
ATLAS score (see infobox; according to Miller et al, ◦◦ death within 30 days after diagnosis
BMC Infect Dis 2013) -- ribotype 027
-- A: Age
-- T: Temperature
Multi-resistant Non-Fermenter
-- L: Leukocytosis
-- A: Albumin • multi-resistant pseudomonas aeruginosa
-- S: Systemic therapy with antibiotics • stenotrophomonas maltophilia
• recurrence: • acinetobacter baumanii
-- p.d. another episode within 8 weeks of the end of
therapy
-- in 25%

970 Infectiology
Multi-resistant pseudomonas aerugi-
nosa
Definition
• gram-negative rod
• a MRGN (multi-resistant gram-negative bacterium)
• increasing development of resistance of pseudomonas
aeruginosa
-- currently already in Germany in 20% resistance to
piperacillin / tazobactam! Above all, you should know
your own hospital-internal resistance statistics!
-- increasing resistance also against carbapenems
(Pseudomonas is the most common representative
of the CRO [carbapenem-resistant organisms]!)
• p.d. inefficacy of carbapenems (for multi-resistant
pseudomonas aeruginosa)
Antibiotics
• amikacin (an aminoglycoside)
-- means of choice
-- dosage: 5 mg/kg 3 x daily i.v. (GFR 40-60 ml/min: 2
x daily, GFR 20-40 ml/min: 1 x daily)
• colistin (see infobox)
• ceftolozan + tazobactam (Zerbaxa; good option!)
Stenotrophomonas maltophilia
Definition
• a gram-negative aerobic bacterium (rod)
• an opportunistic pathogen
• only relatively low virulence
• previously assigned to the genus o pseudomonas (for-
mer name: Pseudomonas maltophilia)
• occurence:
-- ubiquitous in nature (i.a. water, ground)
-- commensal flora (colonization) of humans (e.g. res-
piratory tract, urine, wounds)
-- contaminants (e.g. humidifier, dialysis solution, in-
fusion solution, antiseptic solutions [e.g. chlorhexi-
dine])
-- biofilms (e.g. tube, urinary catheter, pacemaker)
• basically multi-resistant (a MRGN; natural resistance
to beta-lactams, aminoglycosides, macrolides)
• is mainly selected by an uncritical use of broad spec-
trum antibiotics (especially carbapenems; selection
pressure)
• but mostly only colonization and therefore no need of
treatment
• infections
-- almost only in (severely) immunosuppressed (espe-
cially haemato-oncological) patients and cystic fib-
rosis
-- mostly nosocomial
-- types:
◦◦ pneumonia (especially VAP)
◦◦ bacteremia (sepsis)
◦◦ urinary tract infection
Antibiotics
• 1st choice: cotrimoxazole (resistance testing recom-
mended)
• 2nd choice (especially with proven resistance to cotri-
moxazole):
-- fluorchinolones (moxifloxacin, levofloxacin)
-- tigecycline
-- ceftriaxone
Stenotrophomonas maltophilia:
infection only in immunosuppressed
patients, otherwise only colonization
and therefore no need for treatment!
Acinetobacter baumanii
Definition
• gram-negative rod
• a typical hospital germ (significant increase)
• a MRGN (multi-resistant gram-negative bacterium)
• intrinsic resistance to penicillins and cephalosporins
• increasing development of resistance (i.a. significant
increase of carbapenem resistance [2014: 46% resis-
tant to meropenem]; A. baumanii is the third most com-
mon representative of CRO [carbapenem-resistant
organisms])
• high environmental resistance (can therefore persist
for a long time on surfaces such as care utensils or
ventilators)
Diseases
• pneumonia (especially nosocomial, especially late
VAP: Of all bacterial pathogens of ventilator-asso-
ciated pneumonia, A. baumannii has the highest mor-
tality with 59%!)
• urinary tract infection
• wound infections
• meningitis
• sepsis
Antibiotics
• colistin (see infobox; means of choice)
-- but always only in a combination therapy (The com-
bination with a carbapenem has a lower mortality
than the combination with tigecycline [Cheng et al,
Crit Care Med 2015].)
-- in therapy refractory cases (e.g. ventilator-associ-
ated pneumonia) also inhalative if necessary (i.a.
Valachis et al, Crit Care Med 2015; for dosage see
infobox)
• tigecycline (but not for sepsis or urinary tract infec-
tions, as insufficient levels are achieved; off-lable for
pneumonia [even increased mortality])
• sulbactam
-- The β-lactamase inhibitor is very effective against
acinetobacter baumanii. Since sulbactam does not
exist as a single substance, ampicillin / sulbactam is
Infectiology 971
 administered for example.
-- dosage: 3g as short infusion over 4h 3 x daily, e.g.
9g ampicillin / sulbactam (i.d. 6g ampicillin + 3g sul-
bactam) 3 x daily
• carbapenems
• rifampicin
• β-lactam + fluorchinolone

means of choice for acinetobacter

baumannii: combination therapy of
colistin + tigecycline + carbapenem
(e.g. meropenem)

972 Infectiology
 -- infected diabetic foot
SKIN AND SOFT TISSUE • severe infection ("rapidly progressive"): immediately
surgical
INFECTIONS (SSTI) -- necrotizing fasciitis
-- gas gangrene

according to FDA (food and drug administrati-

on)
• uncomplicated SSTI
• complicated SSTI
-- deeper tissue layers affected (fascia, musculature)
-- severe underlying disease (e.g. bacteremia, diabe-
tes mellitus, steroid therapy, liver cirrhosis Child B/C,
neutropenia, organ transplantation, immunosup-
pression, alcoholism, malnutrition)

Risk factors
• skin lesion
• surgical wound
• edema (especially lymphedema)
• chronic venous insufficiency (CVI)
• PAD
• diabetes mellitus
Definition • immunosuppression
• bacterial infection of the skin and soft tissues • obesity
• especially gram-positive bacteria (streptococci, sta-
phylococci, clostridia)
Symptoms
• frequently polymicrobial
• extreme local pain
• mortality: 30%
-- microthromboses of the vessels → ischemia of the
fascia
Epidemiology -- "pain out of proportion"
• third most common cause of sepsis (25%) • erythema, livid discoloration, possibly bleeding
• incidence: 2/100000 • blistering (bullae)
• edema
If you have sepsis with an unclear
focus, don't forget to think of the
SSTI! SSTI are the 3rd most leading symptom of SSTI: extreme
common cause of sepsis! local pain (often still without visible
changes!) typical discrepancy between
clinical findings and symptoms!
Types
• erysipelas
Diagnosis
• phlegmone
• anamnesis, clinical examination
• necrotizing fasciitis (special form: Fournier gangrene)
• laboratory (e.g. leukocytes, CRP, procalcitonin, CK)
• streptococcal myositis
• imaging (especially to evaluate the depth of infection)
• gas gangrene (myonecrosis)
-- sonography
-- CT
Classification
-- MRI (the most sensitive imaging)
according to urgency (according to Kingston) • if necessary biopsy (in uncertain cases)
• mild infection ("slow progressive"): conservative
-- erysipelas suspected (severe) SSTI: emer-
-- furunculosis gency MRI!
-- impetigo
• moderate infection: urgently surgical
-- abscess
-- phlegmone

Infectiology 973
Therapy
• conservative
• surgical

Conservative Therapy
• antibiotics
• wound treatment (phase-adapted; initially keep moist,
hydrocolloid dressings, possibly vacuum-sealing Fig. 1209  A severe ascending necrotizing fasciitis deve-
[VAC]) loped from an infection of a pilonidal sinus. Radical sub-
• Sepsistherapie fascial necrosectomy was performed sacral, lumbar and
thoracic (courtesy of Dr. Hanzlick, former senior physician
• sepsis therapy
of the Clinic for Surgery, Caritas Hopsital St. Josef, Regens-
• hyperbaric oxygen therapy if necessary (HBO [hyper- burg [Germany]).
baric oxygenation]; hyperbaric chamber)

Antibiotis
• cefuroxime / cetriaxone + metronidazole
• piperacillin / tazobactam
• carbapenems
-- meropenem
-- imipenem
• MRSA:
-- linezolid (means of choice)
-- daptomycin
-- tigecycline
-- tedizolid
-- vancomycin + rifampicin

always combination mit clindamy- Fig. 1210  severe necrotizing fasciitis of the abdominal wall
cin 3 x 900mg i.v. (courtesy of Mr. Peter Reiser, Nursing Director of the In-
tensive Care Unit, Caritas Hopsital St. Josef, Regensburg
[Germany])

Surgical therapy
• debridement: early and radical; programmed re-debri- Erysipelas
dement (after approx. 24h)
• amputation if necessary (usually the only life-saving Definition
measure in gas gangrene)
• syn.: rosen
• incidence: 100/100000
• bacteria
-- streptococci (group A)
-- staphylococci (rare
• via the portal of entry spread via the lymphatic vessels
• predilection points
-- lower leg (most common)
-- face

Predisposition
• lymphedema (Erysipelas are the most common com-
plications of lymphedema! Erysipelas are also a fre-
quent cause of lymphedema!)
• obesity
• PAD
• chronic venous insufficiency (stasis dermatitis)
• dermatoses, tinea pedis

974 Infectiology
Symptoms • mortality: 33% (one of the few dermatological
• sharply limited (≠ phlegmone: blurred) redness (over- emergencies!)
heated, painful
• possibly regional lymphadenitis (e.g. Cloquet's node in Types (according to Giuliano)
groin) • type I: mixed infection
• fever • type II: streptococcus group A

Symptoms
• extreme local pain („pain out of proportion“)
• livid discoloration (map-like)
• edema, swelling
• blisters, skin detachment
• bluish-black bleeding
• superficial (cutaneous) anaesthesia (through nerve in-
volvement)
• crepitation (due to gas formation)
• fever

Diagnosis
• anamnesis, clinical examination
• laboratory (e.g. leukocytes, CRP, procalcitonin, CK)
• imaging
-- sonography (linear transducer)
Fig. 1211  Erysipelas on the lower leg: The typically sharply
defined redness can be seen.
◦◦ hypoechoic seam over the fascia
◦◦ feathering of the muscles
Complications ◦◦ STAFF (mnemonic): subcutaneous thickening, air,
fascial fluid
• Erysipela bullosum, gangraenosum, migrans
◦◦ tip: always display in right-left comparison
• necrotizing erysipelas
-- CT
• lymphedema
◦◦ native sufficient (no contrast agent required)
• poststreptococcal glomerulonephiritis
◦◦ most quickly available
-- MRI (best)
Therapy • if necessary biopsy
• antibiotics
-- penicillin G (means of choice; 3 x 10 Mega i.v., in
case of renal insufficiency [creatinine > 2 mg/dl] 3 x
5 Mega; possibly continuously via perfusor)
-- cefotaxime (Claforan)
-- clindamycin (Sobelin)
• immobilisation, cooling, dressing (e.g. Retterspitz)
• rehabilitation of the portal of entry (e.g. antifungal the-
rapy for tinea pedis)
• in case of frequent relapses prophylaxis with long-term
penicillin

Necrotizing fasciitis

Definition
• bacterial infection of the fascia with consecutive necro-
sis of the cutis and subcutis
• inzcidence: 0.4/100000
• most common pathogen: streptococci (group A)
• most common severe SSTI
• mostly lower extremity
• mostly severe sepsis
Fig. 1212  necrotizing fasciitis of the right lower leg

Infectiology 975
 In case of SSTI, if the CK (creatine
kinase) is increased in addition to
the CRP, there is a high suspicion
of necrotizing fasciitis!

Fig. 1213  sonography (necrotizing fasciitis): The edema-

tous loosened subcutis, the hypoechoic border above the
fascia as well as the typical feathering of the musculature
can be recognized.

Fig. 1214  CT: severe necrotizing fasciitis

976 Infectiology
 Fournier gangrene
• special form of necrotizing fasciitis (necrotizing fasciitis
of the pelvic fascia)
• named after the French physician Jean-Alfred Fournier
(1832-1914)
• especially men (genital area)
• especially after urological surgery
• therapy
-- antibiosis: combination therapy of
◦◦ piperacillin 4g / tazobactam 0.5g 1-1-1 i.v. +
◦◦ clindamycin 900mg 1-1-1 i.v. +
◦◦ penicillin G 10 millions 1-1-1-1-1-1 i.v.
-- immediate surgery
-- possibly hyperbaric oxygen therapy (HBO [hyperba-
ric oxygenation]; hyperbaric chamber)

Fig. 1215  MRI: necrotizing fasciitis of the lower leg (The

pronounced subcutaneous and epifascial fluid deposition
on the left can be seen compared to the healthy side on
the right.)

Therapy
• antibiosis: combination therapy of
-- piperacillin: 4g / tazobactam 0.5 g 1-1-1 i.v. +
-- clindamycin 900mg 1-1-1 i.v. +
-- penicillin G 10 millions 1-1-1-1-1-1 i.v.
• surgical: radical necrosectomy; note: in case of doubt
always surgical exploration!

Infectiology 977
 Fig. 1217  gas gangrene (worst smelling)
Fig. 1216  Fournier gangrene (courtesy of Prof. Denzinger,
senior physician at the Clinic for Urology, Caritas Hospital
St. Josef, Regensburg [Germany]) Diagnosis
• anamnesis, clinical examination
• laboratory
Gas gangrene • imaging
-- X-ray (feathering of the musculature)
Definition -- CT, MRI
• infection by clostridia (gram-positive anaerobic spore • swab (microbiological pathogen detection)
formers)
-- clostridium perfringens Therapy
-- clostridium histolyticum • antibiosis: combination therapy of
-- clostridium septicum -- piperacillin 4g / tazobactam 0.5g 1-1-1 i.v. +
• syn.: clostridial myonecrosis -- clindamycin 900mg 1-1-1 i.v. +
• classic wound infection -- penicillin G 10 millions 1-1-1-1-1-1 i.v.
• mortality: 50% • HBO (hyperbaric oxygenation; hyperbaric chamber;
reduces mortality from 50% to 22%)
Symptoms • surgical (debridement, amputation)
• extreme pain in the area of the wound
• skin emphysema (crepitation, crackling)
• drainages (after surgery): bloody, foamy, foul-smelling
secretion
• mostly full picture of a severe sepsis or septic shock

978 Infectiology
 FUNGAL INFECTIONS
(MYCOSES)
Arten
• candida (yeast / sprout fungus; No.1 [80%])
• aspergillus (mold; No.2 [15%])
• rare fungi (5%; see infobox at the end of the chapter
[page 923])
Candida
• C. albicans (60%; No.1)
• non-albicans species (40%):
-- C. glabrata (19%; No.2)
◦◦ especially in elderly patients
◦◦ long incubation period (results usually only after
6-7 days!)
◦◦ Infections with C. glabrata have a higher mortality
than infections with C. albicans.
◦◦ worst prognosis among all candida infections
(therefore also in stable patients no fluconazole,
but echinocandin)
◦◦ increasing resistance to fluconazole (therefore
therapy only with echinocandins)
-- C. parapsilosis (9%; No.3)
◦◦ especially in children (frequent in neonatology)
and adolescents
◦◦ best prognosis among all candida infections
◦◦ Echinocandins are not effective here (gap in ef-
fectiveness), so that azoles here are means of
choice!
-- C. tropicalis (2%; No.4)
-- C. krusei
-- C. kefyr
-- newly described: C. auris (high mortality [60%], re-
sistant to most antifungals, several outbreaks alrea-
dy documented, difficult to identify with conventional
laboratory methods [often misinterpreted as candida
haemulonii or saccharomyces cerevisiae])
Fig. 1218  schematic representation of candida (yeast / sp-
rout fungus)
Aspergillus
• occurrence: classically in immunosuppression (Asper-
gillus spores occur ubiquitously and are inhaled daily
by humans. In a functional immune system, inhalation
of the spores usually does not lead to disease.)
• transmission: aerogenic (inhalation of spores; no hu-
man-to-human transmission)
• sources:
-- air conditioners with inadequate filtration
-- potting soil (Therefore no potted plants should be
placed in the patient´s room in the hospital or on the
ward.)
-- renovation / demolition work
-- whirling up of rotten leaves
• types:
-- A. fumigatus (most common)
-- A. flavus
-- A. niger
-- A. nidulans
-- A. terreus
-- A. parasiticus
-- A. repens
• diseases:
-- allergic bronchopulmonary aspergillosis (ABPA)
-- aspergilloma (detection in a preformed cave)
-- invasive aspergillus tracheobronchitis
-- invasive pulmonary aspergillosis (mortality: 70%)
-- disseminated invasive aspergillosis (especially
brain; mortality: almost 100%)
Fig. 1219  schematic representation of aspergillus (mold)
Infectiology 979
Epidemiology
• pathogen No.4 in bloodstream infections
• 17.8 % of all sepsis cases (German prevalence stu-
dy Sepsis [Engel et al, Int Care Med 2007])
• In the MAXSEP study (Brunkhorst et al, JAMA 2012),
which included patients with severe sepsis or septic
shock, 2.3% of patients showed candidemia.
• mortality:
-- candidemia: 50%
-- aspergillosis: 70%
• increase in invasive myocoses (e.g. Lortholary et al,
JCM 2014), due to the increasing number of immuno-
suppressed patients on the intensive care unit and in-
creasing life expectancy
• Invasive mycoses in the intensive care unit are (al-
most) exclusively nosocomial infections.
• severe infections that typically do not respond to
broad-spectrum antibiotics
Risk factors
Risk factors (candida)
• protracted antibiotic therapy (especially broad-spect-
rum antibiosis; especially ciprofloxacin [increased inci-
dence of candidemias; i.a. Hebert et al, Scand J Infect
Dis 2010])
• total parenteral nutrition (TPN)
• malnutrition
• long-term ICU stay
• abdominal surgery (especially hollow organ perfora-
tions [e.g. small intestine → in 35% abdominal can-
didiasis, upper gastrointestinal tract → in 41% abdo-
minal candidiasis; therefore always antifungals here],
anastomosis insufficiency)
• necrotizing pancreatitis (Pancreatic necrosis are a risk
factor for candida! especially in the long-term course
[after 1-2 months] often [in 50%] candida!)
• diabetes mellitus
• CVC
• renal replacement therapy
• ventilation
• severity of disease (APACHE II score > 20P.)
• immunosuppression:
-- AIDS
-- organ transplantation, graft-versus-host disease
(acute / chronic) after allogeneic hematopoietic stem
cell transplantation
-- neutropenia
-- systemic steroid therapy (especially COPD)
-- liver cirrhosis
• colonization
• barrier disorder (e.g. intestinal ischemia, ileus)
• COPD
• premature infants with birth weight < 1000g
• hemato-oncological disease (e.g. acute leukemia), tu-
mors
980 Infectiology
Risk factors (aspergillus)
• immunosuppression:
-- organ transplantation (At the highest risk are ha-
emato-oncological patients after allogeneic stem cell
transplantation [especially in acute myeloid leuke-
mia; therefore always prophylaxis with posaconazo-
le] and patients after lung transplantation.), rejection
reactions
-- neutropenia
-- systemic steroid therapy (especially COPD)
-- calcineurin inhibitors, OKT3
-- liver cirrhosis
• CMV
• diabetes mellitus
• COPD (especially with inhaled corticosteroids
[ICS])
• long-term ICU stay (> 21 days)
• renal replacement therapy
• splenectomy
• viral pneumonia: especially
-- influenza (increased incidence of invasive asper-
gillosis in influenza [co-infection; IAPA: influenza-
associated pulmonary aspergillosis]; i.a. Martin-Lo-
chens et al, ICM 2016; Schauwvlieghe et al, Lancet
Respir Med 2018 [19% of all intensive care patients
with influenza, with additional immunosuppression
even in 32%; after 3 days on average])
-- COVID (increased incidence of invasive asper-
gillosis in COVID [co-Infektion; CAPA: coronavirus-
associated pulmonary aspergillosis]; Bartoletti et
al, Clin Infect Dis 2020: 27.7% of all machanically
ventilated COVID patients; after 4 days on average;
significantly increased mortality [74% versus 26%])
Risk factors for aspergillosis: 3C
- COPD
- Corticosteroids
- Cirrhosis
Diagnostics
Diagnostics candidosis
• tracheal/ bronchial secretion
• laboratory: Procalcitonin > 5.5 pg/ml (Charles et al,
Intensive Care Med 2006) almost certainly excludes
candidemia. Candida inhibits the synthesis of procal-
citonin!
• blood culture
-- means of choice
-- sensitivity only 30% (so draw at least 2-3 pairs!)
-- possibly even special fungal culture bottles (e.g.
BACTEC Mycosis-IC/F bottles; result after 3 instead
of 7 days)
• fundoscopy (mycotic uveitis)
• serology (i.a. recommended in the SSC guidelines
 2012 + 2016; high negative predictive value [helpful
especially for discontinuing an unnecessary, calcula- indication for antifungal therapy:
ted antifungal therapy]) invasive candidiasis (p.d. detection in
-- β-D-glucan (Fungitell) sterile material [blood, pleura, perito-
◦◦ highly specific for candida (but also positive for neum, cerebrospinal fluid])
pneumocystis jirovecii [meanwhile classified as classic indication in internal intensive
a fungus]: Here the test has a very high negative medicine: candida-positive blood
predictive value, i.e. a negative test largely rules culture (candidemia)
out pneumocystis jirovecii pneumonia.)
◦◦ cut-off value in serum: 80 pg/ml
◦◦ i.a. FUNGINOS study (Tissot et al, Am J Respir
Crit Care Med 2013)
◦◦ almost not yet widespread in Germany, however
-- anti-mannan antibodies (less specific for candida
[also positive for aspergillus or fusarium])
• PCR: not yet widely established (no recommendation
yet for general use)
• histology (gold standard)
-- The detection in the biopsy shows the invasive
growth and thus proves the infection.
-- The hyphae can be detected by PAS or Grocott stai-
ning.
-- In case of suspected intraabdominal invasive can-
didiasis in particular, not only peritoneal lavage but
also histology should be performed!

Fig. 1220  candida peritonitis (courtesy of Prof. Eckmann,

Tracheal/ bronchial secretion Peine [Germany] and Prof. Kujath, Lübeck [Germany])
• ICU stay > 7 days → in 60% colonization (Leon et al,
Europ J Clin Microbiol Dis 2009)
• almost always only colonization (exception: immu-
nosuppressed patients)
• There is no (primary) candida pneumonia (at most
secondary; Candida is not a respiratory pathogen!).
• CANTREAT study (Albert et al, ICM 2014): no benefit
of antimyotic therapy in suspected VAP and detection
of candida in tracheal secretion

study

Significance of the isolation of Candida species from air-

way samples in critically ill patients: a prospective, autopsy
study
Meersseman et al, Int Care Med 2009

• autopsy study: 232 intensive care patients

• of which 135 patients with pneumonia
• of which 77 patients with positive findings of candida in
tracheal/ bronchial secretion → in no single case his-
topathological evidence of candida (not a single candida
pneumonia!)

Infectiology 981

Candida
Colonization / Infection
no empirical antifungal therapy (in
non-neutropenic, non-immunosup-
pressed patients with stable circulato-
ry system without risk factors)!
However, if the patient is (still) circulatory unstable despi-
te broad-spectrum antibiotics and there is no other ex-
planation for the fever or the high inflammatory markers
(typically high CRP and low procalcitonin) and there are
risk factors for candidemia, then an empirical (calcula-
ted) antifungal therapy should be generously initiated.
circulatory unstable patient with broad
spectrum antibiosis with high CRP and
low PCT: urgent suspicion of candida-
emia!
Diagnostics aspergillosis
• imaging
-- chest X-ray
-- chest CT, especially HR-CT (HR: high resolution;
best: Angio-HR-CT)
◦◦ generously perform also cranial CT (cerebral as-
pergillosis)
◦◦ An inconspicuous chest CT (possibly including
cranial CT) rules out invasive aspergillosis with a
high degree of probability.
◦◦ signs:
▪▪ Halo sign (ground glass density increase around
982 Infectiology
a pulmonary focus)
▪▪ air crescent sign (air-containing gap in the area
of the mass)
▪▪ cavern (DD to cavern in tuberculosis: In tubercu-
losis, the cavern is classically calcified.)
• tracheal / bronchial secretion: A positive detection of
aspergillus must never be ignored (quite in contrast to
candida) as a harmless colonisation, since in 50% of
cases (AspICU study [Taccone et al, Crit Care 2015])
an infection in the sense of invasive aspergillosis is
present (in neutropenia even in 70%). In case of posi-
tive detection, an antifungal therapy should always be
initiated immediately. The therapy will be continued if:
-- HR-CT (chest) positive or
-- galactomannan test (blood or BAL [perform broncho-
scopy!]) positive
• bronchoscopy (i.a. typical grey membranes which can-
not be washed away; if necessary with biopsy)
• galactomannan test (syn.: aspergillus antigen test)
-- Galactomannan is a cell wall component released by
the aspergillus hyphae during tissue infiltration.
-- antigen detection
-- material
◦◦ serum (sensitivity only 42%, therefore only recom-
mended for patients with neutropenia)
◦◦ bronchoalveolar lavage (BAL; sensitivity 88%
[best!]; BAL is best drawn where the correspon-
ding correlate is found in the imaging)
◦◦ CSF (cerebrospinal fluid)
-- Platelia-ELISA
-- also recommended (serum) for screening of risk pa-
tients (AML / MDS with neutropenia < 500/μl over 10
days, after stem cell transplantation)
-- cave: often false positive with
◦◦ some antibiotics:
▪▪ piperacillin / tazobactam (And this is very
common in everyday clinical practice that pa-
tients were treated in advance with this broad-
spectrum antibiotic.), amoxicillin / clavulanic
acid
▪▪ These antibiotics contain cross-reactive penicil-
lium antigens.
▪▪ Therefore, it is best to take the sample before
administering the antibiotic.
▪▪ less false-positive findings if the cut-off is increa-
sed to 0.7 ng/ml (With a value > 1 ng/ml one can
almost always assume an invasive aspergillosis
[Schröder et al, Crit Care 2016; de Heer et al,
Cochrane Database Syst Rev 2019]!)
◦◦ some chemotherapeutics (e.g. cyclophosphamid)
◦◦ immunoglobulins
• blood culture
-- almost always negative (molds almost never grow in
blood cultures; sensitivity only 5%)
-- if positive: almost 100% mortality
 Galactomannan test (serum,
BAL): often false positive for
piperacillin / tazobactam (often in
in everyday clinical practice)!

Fig. 1224  Bronchoscopy in aspergillosis: The typical

whitish-grey membranes are visible.

Fig. 1221  Chest X-ray: aspergillus pneumonia

Fig. 1222  Chest CT: aspergillosis (melting infiltrate on the

right)

Fig. 1223  Chest CT: aspergillosis Fig. 1225  Bronchoscopy in aspergillosis: One recognizes
the typical grey membranes.

Infectiology 983
 Antifungals
Aspergillus: if there is positive
evidence of aspergillus in the
endotracheal secretion, always start
therapy (never ignore it)!

Therapy
• principles
• antifungals

Principles
• eliminate risk factors (e.g. antibiosis [discontinue if
possible!], steroids, discontinue hydrocortisone if pos-
sible)
• candidemia → always "plastic change", i.e. change of
all accesses (e.g. CVC [if still needed; no over-the-wire
exchange, but new installation!], shaldon catheter, ar-
terial line, urinary catheter)
• candidemia → search for organ participation, i.a.
-- TEE (generously on the question of endocarditis [if
confirmed, always indication for surgery!])
-- fundoscopy (ophthalmologic consultation [if availab-
le in the hopsital])
◦◦ on the question chorioretinitis (most common; eve-
ry 6th patient with candidemia) or endophthalmitis
◦◦ in previously neutropenic patients again after the
leukocytes have increased, as the pus can often
only then be produced in the eye
◦◦ recommended, but often not practicable
◦◦ Azole or liposomal amphotericin B are better than
echinocandins for the treatment of candida chori-
oretinitis / endophthalmitis. Therefore, one of the
two substances is added to the echinocandin. Sur-
gery (vitrectomy) is useless.
• regular blood culture controls (initially daily, then every
two days until the blood culture is negative)
• duration of therapy: up to 14 days after the first nega-
tive blood culture (i.e. again draw blood culture after
start of therapy daily until it is negative; applies to Can-
dida [at least 4 weeks for aspergillus])

With the detection of candidemia one

now has a sufficient reason for
sepsis, i.e. now the antibiotics have
to be discontinued, which unfortuna-
tely one often doesn't dare to do!
Azoles
Fluconazole (Diflucan)
• azole of the 1st generation
• spectrum: candida (C. albicans resistant in 10%)
• effect: fungistatic (not fungicidal)
• gaps in effectiveness:
-- C. krusei, C. tropicalis
-- increasing resistance in C. glabrata, frequently sig-
nificantly increased MIC for C. glabrata (According
to current recommendations, C. glabrata should no
longer be treated with fluconazole, but with echino-

984 Infectiology
 candin, even in patients with circulatory stability.)
-- all aspergillus species
• dosage: d1 800 mg (loading-dose), then 400 mg/d (in
case of severe infection or candida glabrata: 800 mg
per day [note: In case of C. glabrata prefer echinocan-
din!)
• enhancement of the effect of:
-- coumarins
-- sulphonylureas
-- theophylline
-- phenytoin
• dose adjustment for renal insufficiency
-- creatinine clearance < 50 ml/min: ½ dose
-- renal replacement therapy:
◦◦ CVVH: 1 x 10 mg/kg or doubling of dose (800 mg/
day)
◦◦ HD (hemodialysis): 100 mg after each HD
• prophylactically also recommended after gastrointesti-
nal perforation or anastomosis insufficiency
• side effects
-- leucopenia, thrombocytopenia
-- diarrhea
-- LFT­ ↑ (hepatotoxicity)
-- QT interval ↑
• IDSA guideline 2013 (Infectious Diseases Society
of America): no longer recommended as initial therapy
for seriously ill patients with candidemia (e.g. intensive
care patients)! Echinocandin should be used immedi-
ately!
Voriconazole (Vfend)
• azole of the 2nd generation (in contrast to fluconazole
also effective against aspergillus)
• indications:
-- means of choice for aspergillosis (compared to
amphotericin B significantly better response and sig-
nificantly lower mortality [i.a. Herbrecht et al, N Engl
J 2002]); first line (gold standard; therapy duration at
least 4 weeks [best 6 weeks]) )
-- severe (fluconazole-resistant, incl. C. krusei) can-
didoses (without neutropenia): equally effective,
but better tolerated than amphotericin-fluconazole
follow-up therapy
-- candida parapsilosis
-- severe infection with hyalohyphomycetes (fusarium,
scedosporium): also here the means of choice
-- prophylaxis (both primary and secondary prophy-
laxis) of invasive myocoses after allogeneic stem
cell transplantation (approved for this purpose since
2014)
• gap in effectiveness: zygomycetes
• dosage:
-- i.v.: first day 6 mg/kg 1-0-1 (loading dose), then 4
mg/kg 1-0-1
-- p.o.: first day 400 mg 1-0-1 (loading-dose), then 200
mg 1-0-1
-- no dose reduction in renal (with oral administration),
but in liver failure (still normal loading dose, but then
only half the maintenance dose)
-- higher dosages for cerebral aspergillosis
• The parenteral form contains a solubilizer (a cyclodex-
trin vehicle [SBECD: sulphobutyl ester cyclodextrin]),
since voriconazole (applies analogously to posacona-
zole) is extremely lipophilic. This may accumulate in
renal insufficiency. Therefore, at least according to the
official drug information, oral therapy should be admi-
nistered if possible at GFR < 50 ml/min. However, after
a risk-benefit analysis (mortality of aspergillosis: 70%!)
a parenteral therapy can definitely take place here as
well. Due to the extremely high mortality of invasive
aspergillosis, we usually also carry out parenteral the-
rapy in cases of renal insufficiency. The nephrotoxicity
in second-line therapy with liposomal amphotericin B
is still much higher! As a practical rule of thumb for
the maximum duration of the i.v. therapy in order to
avoid accumulation of the solubilizer, the following ap-
plies: GFR / 5 = duration of therapy (e.g. GFR 25 ml/
min → i.v.-therapy for 5 days, then oralize). Renal re-
placement therapy (both CVVH and hemodialysis) eli-
minates SBECD sufficiently and quickly, so that there
is no risk of accumulation here either (Kiser et al, Crit
Care 2015).
• side effects:
-- fever (frequent), chills
-- headache
-- nausea, vomiting, diarrhea
-- edema
-- skin rashes
-- visual disturbances (blurred / color vision in 30%;
reversible; cause is a concentration-dependent re-
versible inhibition of acetylcholine receptors in the
ciliary ganglion), photosensitivity (2%)
-- hepatotoxicity
◦◦ transaminases ↑­, cholestasis parameters ­↑
◦◦ hepatitis, rarely even acute liver failure
• cyt p450 induction → no simultaneous administration
(contraindicated!) of:
-- rifampicin
-- carbamazepine
-- phenobarbital
-- quinidine
-- ergotamine
-- sirolimus
-- Also be careful with the simultaneous administra-
tion of NOAC: Here voriconazole massively increa-
ses the level and thus the risk of bleeding.
• therapeutic drug monitoring (TDM) obligatory
-- often fluctuations of the level: Metabolism depends
on the respective cytochrome genotype. Every se-
cond patient does not have a sufficient level under
the standard dosage of voriconazole (i.a. Hoenigl et
al, Antimicrobial Agents and Chemotherapy 2013: In
56% the levels were too low!)
-- The mortality rate of invasive aspergillosis is 70%: To
carry out a voriconazole therapy today without the-
rapeutic drug monitoring is therefore a malpractice!
-- target trough level: 1.5-5.0 μg/ml
-- The trough level should be adjusted once a week
Infectiology 985
 (therapy duration at least 4 weeks).
-- If the level is too low, the therapy is ineffective. Then
the dose (increased single doses 2 x daily) must be
increased. If the level is too high, the main problem
is hepatotoxicity.
• price:
-- i.v.: approx 400 €/d
-- p.o. or via nasogastric tube: 75 €/d (96% bioavaila-
bility)
-- note: Since 2016 however the patent protection has
fallen, so that Voriconazol costs only about a tenth of
the original price.
Voriconazole: means of choice for
aspergillosis
Voriconazole: level determinati-
ons (TDM) obligatory!
Posaconazole (Noxafil)
• azole of the 2nd generation
• For a long time posaconazole was only available as
a juice, which made it relatively uninteresting for in-
tensive care medicine. It has also been available as a
parenteral since 2014.
• broadest effect spectrum of all antifungals
• dosage:
-- p.o.
◦◦ juice: 3 x 200mg daily (preferably taken with a fatty
meal)
◦◦ pill (1 pill: 100mg): d1 2 x 300mg, then 1x 300mg
(ingestion independent of food)
-- i.v.: d1 2 x 300mg, then 1x 300mg (CVC obligatory,
because the solution has a low pH-value)
• indications:
-- invasive aspergillosis
-- mucorales (older name: zygomycetes)
-- coccidioides
-- used in hematology mainly for the prophylaxis of in-
vasive mycoses in hematological high-risk patients
(e.g. after allogeneic stem cell transplantation in
acute leukemia); note: Note: If invasive aspergillo-
sis occurs in patients who were under posaconazole
prophylaxis, azoles (neithoer voriconazole nor posa-
conazole) should no longer be used, but it should be
switched to another substance class (e.g. caspofun-
gin or liposomal amphotericin B).
• liver insufficiency: no dose reduction
• renal insufficiency:
-- p.o: no dose reduction
-- i.v.: The parenteral form contains a sobulizer
(SBECD: sulphobutyl ester cyclodextrin) because
posaconazole (applies also to voriconazole) is extre-
mely lipophilic. It can accumulate in renal insufficien-
cy. Therefore, according to official drug information,
oral therapy should be administered at GFR < 50 ml/
986 Infectiology
min if possible.
• side effects: i.a. nausea, vomiting, diarrhoea, LFT ↑
• less level fluctuations than with voriconazole, but also
therapeutic drug-monitoring (TDM) recommended (tar-
get trough level: 0.5-2.5 μg/ml)
• interactions:
-- inhibitor of the enzyme CYP3A4 →
◦◦ no simultaneous administration of lovastatin, ator-
vastatin, ergotamine, cisapride, quinidine
◦◦ dose reduction necessary for ciclosporin, siroli-
mus, tacrolimus
-- no interactions with proton pump inhibitors, H2-bloc-
kers, antacids or MCP
• NUB application (new testing and treating methods
Isavuconazole (Cresemba)
• azole of the 2nd generation
• a triazole
• approvals (since 2015): :
-- invasive aspergillosis (approval study: SECURE
[Maertens et al, Lancet 2015])
-- mucormycoses (if amphotericin B is not possible;
approval study: VITAL [Marty et al, Lancet Infect Di-
seases 2016])
• dosage:
-- p.o. (1 pill = 100mg; same dosage as i.v.; high oral
bioavailability)
-- i.v.. for 2 days 3 x 200mg, then 1 x 200mg
• less hepatotoxic compared to voriconazole (50% less
hepatobiliary side effects)
• in contrast to voriconazole and posaconazole hydro-
philic (water-soluble) and not lipophilic (since no solu-
bilizer such as the cyclodextrin vehicle SBECD, which
could accumulate in renal insufficiency, is required)
• no dose reduction in renal or liver insufficiency
• therapeutic drug monitoring (TDM):
-- target trough level: 1.0-5.5 μg/ml
-- not generally recommended (by the company) as the
level is relatively constant (in 90% level > 1 µg/ml)
-- only recommended for:
◦◦ severe cases of aspergillosis (note: With a mor-
tality of 70%, however, invasive aspergillosis is
always severe, so TDM should be carried out ge-
nerously!)
◦◦ mucormycosos
• interactions: inhibitor of the enzyme CYP3A4 → no si-
multaneous administration of rifampicin, carbamazepi-
ne, ritonavir, phenytoin, phenobarbital, St. John's wort
• ESCMID guidelines 2018 (Ullmann et al, Clin Micribiol
Infect 2018): isavuconazole recommended as a first-
line therapy for aspergillosis equivalent to voriconazole
(but only applies to haemato-oncological patients with
neutropenia)
Amphotericin B
• a polyene antifungal
• spectrum:
-- candida (gap of effectiveness: candida lusitaniae)
 -- aspergillus fever)
-- cryptococcus • no dose reduction necessary in renal, but in liver insuf-
• dosage: initially 0.25 mg/kg over 6h, then increase ficiency (dose reduction to 35mg)
within 2 days to 1 mg/kg • CVVH / hemodialysis: dose constant (non-dialysable)
• no combination with azoles (antagonism!) • price: at 50mg approx. 300 €, at 70mg 420-450 €/ bot-
• side effects: tle (but: extra charge); however, since 2017 patent pro-
-- leucopenia, thrombocytopenia tection has fallen (generic) and therefore cheaper
-- transaminases­ ↑ • side effects (rare):
-- allergic reaction (frequent) -- fever
-- hypokalemia -- phlebitis
-- renal diabetes insipidus -- hemolysis
-- nephrotoxicity
◦◦ classic: acute kidney failure due to amphotericin
Anidulafungin (Ecalta)
B (in exaggerated terms, amphotericin B can be • echinocandin of the 2nd generation
used to perform a "conventional nephrectomy"!) • approval: invasive candidiasis / candidaemia (formerly
◦◦ but no dose reduction necessary for renal insuf- only in non-neutropenic patients, i.e. not for neutrope-
ficiency; CVVH: 1 x 1.5 mg/kg; HD: 1 x 1.5 mg/kg nia; but since 2014 also approved for neutropenia)
◦◦ reduction of nephrotoxicity possible by: • dosage:
▪▪ lifting of sodium > 140 mmol/l -- single dose
▪▪ pentoxifylline administration (Trental, 5-10 mg/ -- day 1 200 mg i.v., then 100 mg/d
kg) -- independent of body weight
▪▪ application in lipid solution (Lipodundin) -- no dose adjustment in renal insufficiency (also not in
▪▪ as liposome: liposomal amphotericin B (Am- haemodialysis, CVVH) / liver insufficiency (also not
Bisome): ampoulle containing 50mg; dosage: in Child C)
3-10 mg/kg (3 mg/kg is sufficient [In a compara- • duration of therapy: at least 14 days
tive study with invasive mycoses, the dosage of • no degradation via cytochrom p450 → no interactions,
10 mg/kg was not better than 3 mg/kg at all, but relatively good tolerability (e.g. significantly less incre-
associated with a significantly higher nephotoxi- ase of transaminases compared to fluconazole)
city.]) for 1-2h in G5%, expensive, only stable for • side effects:
6 hours; acute kidney failure still in 10% -- coagulopathy
-- seizures
conventional amphotericin B: -- headache
abandoned! -- hypokalemia
-- exanthema, pruritus
-- transaminases ↑, AP ↑
Echinocandins -- atrial fibrillation
-- diarrhea
Caspofungin (Cancidas) -- BP ↓
• echinocandin of the 1st generation -- alcohol content of the solvent
• broad-spectrum antifungal • no more NUB (new testing and treatment method), but
additional payment after KHEntG § 7
• spectrum:
-- candida (incl. non-albicans species)
-- aspergillus (second line)
-- gaps in effectiveness: cryptococci, fusarium, candi- study
da parapsilosis
• duration of therapy: at least 14 days
• dosage: loading dose 70mg, then 50mg (weight <
80kg) or 70mg (weight > 80kg) 1 x daily i.v. over 1h Anidulafungin versus Fluconazole for Invasive Candidiasis
(single dose) Reboli et al, N Engl J 2007
• cytochrom p450 inducers: increased clearance of
• approval study (double-blind non-inferiority study)
caspofungin in comedication with rifampicin, rifabutin,
• 245 patients with invasive candidiasis (97% non-neutro-
nelfinavir, efavirenz, nevirapin, dexamethasone, carb- penic
amazepine, phenytoin
-- anidulafungin i.v.
• formerly the only echinocandin approved for neutrope-
-- fluconazole i.v.
nia (now also anidulafungin approved for this purpose)
• result: anidulafungin → significantly better clinical
• the only echinocandin that is also approved for empi- and microbiological response
rical therapy ("if suspected"; but only for neutropenic

Infectiology 987
 Antifungal
ICE study
therapy

Anidulafungin for the treatment of candidaemia/invasive

candidiasis in selected critically ill patients
Ruhnke et al, Clin Microbiol Infect 2012

• Invasive Candidiasis Intensive Care study (ICE)

• prospective observational study
• 216 patients with candidaemia / invasive candidiasis
• results
-- clinical success rate of anidulafungin: 69.5%
-- survival rate (90 days): 53.8%
-- Blood cultures were median negative already on day
2!

study

Efficacy of Anidulafungin in Patients with Invasive Candidi-

asis: Focus on non-Albicans Candida spp.
Conte et al, ICAAC 2012

• 504 patients with invasive candidiasis

• global response to anidulafungin:
The European guideline (ESCMID guidelines for the
-- C. albicans: 76%
diagnosis and management of Candida diseases 2012:
-- non-albicans species: i.a.
non-neutropenic adult patients; Cornelly et al, Clinical
◦◦ C. krusei: 73% (data on this for the first time, as C.
Microbiology and Infection) also recommends echino-
krusei was excluded from the approval study)
candins as the highest grade (recommendation grade
◦◦ C. parapsilosis (78%; very good response des-
A) for candidemia or invasive candidiasis (not only for
pite higher MIC! To date the following opinion was
valid: no echinocandins in C. parapsilosis)
unstable but also for stable patients), while only a grade
C recommendation is still available for fluconazole.

Micafungin (Mycamine) no more therapy of candidemia in

• echinocandin of the 2nd generation critically ill patients with fluconazole
• broad-spectrum echinocandin (only fungistatic)! means of choice:
• approved for prophylaxis (e.g. after stem cell trans- echinocandins (fungicide)! Here one
plantation with neutropenia) and therapy of candida must do things in a big way (mortality
infections (systemic candidiasis, candida esophagitis) 50%)!
• the only echinocandin that is also approved for pro-
phylaxis
• on the market since 2009
Candida → echinocandin
• dosage (as short infusion):
Aspergillus → voriconazole
-- prophylaxis: 50 mg 1 x daily
-- therapy:
◦◦ systemic candidiasis: 100 mg 1x daily
◦◦ candida esophagitis: 150 mg 1x daily duration of therapy in invasive
• no dose reduction in renal or liver insufficiency aspergillosis: at least 4 weeks!
• restriction of approval according to official drug in-
formation and EMEA due to warnings regarding liver
damage (including liver tumors) in cases where other
antimycotics are not effective ("last line")
• Physician is liable.

988 Infectiology
 study

Combination antifugal therapy for invasive aspergillosis

Marr et al, Ann Int Med 2015

• prospective randomized placebo-controlled double-blind

study
• 454 patients with (suspected or proven [galactomannan
test]) invasive aspergillosis
-- voriconazole (monotherapy)
-- voriconazole + anidulafungin (combination therapy)
• result: combination therapy → mortality (after 6 weeks)
-- patients with suspected or proven aspergillosis: no
reduction
-- only patients with proven aspergillosis: significant
reduction (only subgroup analysis, so routine antifun-
gal combination therapy for aspergillosis cannot be
recommended)

Infectiology 989

Malaria
Definition
• infectious disease caused by plasmodia
• syn.:
-- alternating fever (because the fever changes again
and again [periodically])
-- swamp fever
-- black water fever (The hemolysis that occurs in ma-
laria results in dark to black urine).
• Latin: „malus aer“ / old Italian: „mala aria“ = bad air
• transmission:
-- most: by the anopheles mosquito (female forms only;
note: The animals that kill most people worldwide
are not sharks or lions, but anopheles mosquitoes.)
-- rare:
◦◦ "airport malaria" or "baggage malaria" (introduced
infected anopheles mosquitoes)
◦◦ transmission by infected blood products, trans-
plantation
◦◦ connatal
◦◦ laboratory exposure
• no direct transmission from human to human (not con-
tagious)
• diseases with resistance to malaria:
-- glucose-6-phosphate dehydrogenase deficiency
-- sickle-cell disease
• S1 guideline 2016 "Diagnostics and therapy of mala-
ria" of the German Society for Tropical Medicine and
International Health (DTG)
990 Infectiology
Epidemiology
• 2nd most common infectious disease in the world (one
of the three "major killing diseases of the world"; No.
1: tuberculosis)
• 500 million new cases per year
• widespread in almost all tropical and subtropical coun-
tries (but not above 2500 masl resp. at the equator not
above 1500 masl)
• main malaria area: Africa (mainly Kenya)
• 1.2 million people die of malaria every year (mainly
in Africa; especially children < 5 years [every 30sec a
child dies of malaria in Africa]).
• However, since the turn of the millennium, prevalence
and mortality worldwide have fortunately been decli-
ning significantly (WHO World Malaria Report 2014):
In 2000, 839.000 people died of malaria, in 2014 "only"
430.000 people (decrease by half).
• in Germany approx. 1000 (reported) imported cases
per year (mostly tropical malaria); travellers returning
(90% from Africa [especially Nigeria], 10% from Asia
[especially India, Pakistan]); number of imported cases
has increased significantly (previously 500-600 cases)
• 75% of all imported malaria cases are tropical malaria.
• also migrants after a home leave (VFR: "visiting friends
and relatives")
• In 90%, the disease begins in the first month after re-
turn.
• increasing resistance of plasmodium falciparum to
chloroquine
• obligation to report if there is evidence (§7 Infection
Protection Act in Germany; not by name; applies to the
laboratory)
• In our house we see about 2-3 malaria cases (mostly
tropical malaria) every year.
major killer diseases of the world:
AIDS, tuberculosis, malaria
Malaria areas
• especially Africa (No.1: Kenya); especially sub-Saha-
ran Africa
• Southeast Asia (e.g. Indonesia, Thailand)
• Central / South America
• South Pacific
• There is no (autochthonous) malaria in:
-- Europe
-- North America
-- Australia
Pathogens
• plasmodium falciparum
• plasmodium malariae
• plasmodium vivax
• plasmodium ovale
• plasmodium knowlesi
-- iinitially discovered in macaques (Javanese mon-
 keys) in Singapore; transferable to humans
-- named after the malaria researcher Robert Knowles
(1883-1936)
-- especially in Southeast Asia (especially in Malaysia:
Plasmodium knowlesi is already the most common
malaria pathogen there!)
-- frequently severe courses (fulminant!)
-- difficult to differentiate microscopically from other
plasmodia species (mostly only molecular biologi-
cally, i.e. by PCR
-- therapy like tropical malaria (artesunate also the first
choice for the complicated form)
Types
• benign forms (1/3):
-- quartan malaria (plasmodium malariae)
-- Tertian malaria (plasmodium vivax / ovale)
• malignant form (2/3): tropical malaria (plasmodium fal-
ciparum)
Incubation periods
• tropical malaria: 12 days
• tertian malaria: 12-18 days
• quartan malaria: 3-6 weeks (longest incubation period)
• notes:
-- A feverish disease < 7 days after return is usually
not malaria (minimum incubation period of malaria 1
week, mean incubation period 1 month).
-- but also incubation period over several months →
stays abroad in malaria areas up to 2 years back
still relevant!
Pathogenesis
• Humans and anopheles mosquitoes are the only re-
servoir of pathogens.
-- mosquito: end host (here sexual phase [= gamogo-
ny])
-- human: intermediate host (here asexual phase [=
schizogony])
• Anopheles mosquitoes (female form) use their sali-
va to transmit the sickle germs (sporozoites) into the
blood of humans during bites.
• first infestation of the liver (short liver phase [5-8 days];
liver schizont), then infestation of the erythrocytes (ery-
throcytic phase)
• in erythrocytes multiplication and maturation (schi-
zogony; blood schizont) → bursting of erythrocytes
(hemolysis) and release (merozoites) → infestation of
further erythrocytes and multiplication
• synchronization of intraerythrocytic parasitic growth →
fever attacks every two (tertian malaria) or three days
(quartan malaria)
• After some cycles, the sexual forms develop (sex form
= gametocyte) → infection of the anopheles mosquito
• in synchronization (not the case with plasmodium falci-
parum) of parasite development: fever
• In tertian malaria (plasmodium vivax and plasmodium
ovale), resting forms in the liver (hypnozoites) can re-
main asymptomatic for years and then lead to relap-
ses. Therefore a final therapy with primaquine is ne-
cessary!
• In tropical malaria there are no liver forms, therefore
relapses are not possible in this type of malaria!
• special property of plasmodium falciparum: alteration
of the erythrocyte surface (e.g. production of PfEMP1:
plasmodium falciparum infected erythrocyte membra-
ne protein 1) → "bonding" of erythrocytes (sequestra-
tion)
Fig. 1226  Life cycle of plasmodia (malaria cycle): Asexual
reproduction (schizogony) takes place in human: First the
hepatocytes (exoerythrocytic phase) and then the erythro-
cytes (erythrocytic phase) are infected. Sexual reproduc-
tion (gamogony) takes place in the anopheles mosquito.
After the mosquito bite, the sporocytes (infectious form of
the pathogen) get from the saliva of the mosquito into the
human blood. There they multiply in the liver (liver schi-
zonts) and in the erythrocytes (blood schizonts). The liver
schizonts disintegrate into numerous merozoites, which
then infect the erythrocytes. Finally, gametocytes (immatu-
re germ cells) develop, which are ingested by the anophe-
les mosquito when it bites (blood meal). In the gut of the
mosquito, these then mature into gametes (mature germ
cells). The female (macrogamete) and male (microgamete)
gametes fuse to form the ookinet, from which the sporocy-
tes then develop (sporogony).
Symptoms
• fever (remember this even up to 2 years after your stay
in the tropics)
-- quartan malaria: 1 day fever, 2 days no fever
-- tertian malaria: 1 day fever, 1 day no fever
-- tropical malaria: fever irregular
• chills
• headache (typically severe!)
• back pain
• limb pain
• myalgia
• hepatosplenomegaly, pain in the right upper abdomen
(liver capsule tension)
• jaundice (due to hemolysis)
• nausea, vomiting
• diarrhea (frequent misdiagnosis: travel diarrhea)
• cough
Infectiology 991

Fig. 1227  sonography abdomen: pronounced splenomega-
ly
Fig. 1228  CT abdomen: pronounced hepatosplenomegaly
Complications
• microcirculation disorders:
-- cerebral
◦◦ encephalopathy (cerebral malaria)
◦◦ most common cause of death
◦◦ only in plasmodium falciparum
◦◦ symptoms: disorientation, seizures (mostly gene-
ralized), paralysis, confusion, coma
◦◦ above all in unclear cases of children, generous
lumbar puncture for CSF (cerebrospinal fluid) to
exclude bacterial meningitis
-- cardiac (shock [so-called algid form of malaria wit-
hout fever])
-- pulmonary (especially pulmonary edema, ARDS)
-- renal (acute kidney failure; i.a. immune complex
glomerulonephritis caused by plasmodium malariae
[typ.: nephrotic syndrome in quartan malaria, "mala-
rianephrosis"])
• severe (hemolytic) anaemia, hemolytic crisis
• rhabdomyolysis
• DIC
• spleen rupture (the main complication of benign forms);
therefore also be careful with palpation or sonography)
• co-infections (bacterial; in 25%):
-- Patients die more frequently from co-infections as
from the primary infection malaria!
-- therefore with the slightest suspicion generous an-
tibiosis
992 Infectiology
Laboratory
• CRP ↑
• leukopenia (Leukocytosis is completely untypical for
malaria!)
• thrombocytopenia (60%; the lower the thrombocytes,
the more severe the malaria)
• anemia
• procalcitonin (PCT)
-- typically increased in malaria
-- PCT > 25 ng/ml is indicative for a poor prognosis.
PCT is a prognosis factor for malaria!
• signs of hemolysis: bilirubin (indirect) ↑, LDH ↑, hapto-
globin ↓ (note: Haptoglobin is an acute phase protein
and can therefore be false normal in inflammation.)
• LFT ↑
• hypoglycemia
• possibly creatinine ↑, urea ↑
• possibly signs of nephrotic syndrome (typical for quar-
tan disease [malaria nephrosis!]):
-- hypoproteinemia
-- proteinuria
-- edemas
-- hypercholesterinemia
Diagnostics
• rapid test (e.g. MalaQuick)
• blood smear / film
-- thin (not enriched [note: This is the normal conventi-
onal blood smear.])
-- thick (enriched)
• PCR (detection of plasmodium-specific DNA; rarely in-
dicated [e.g. suspected plasmodium knowlesi, for spe-
cies differentiation at low parasite density])
• serology
Rapid tests
• RDT (rapid diagnostic tests)
• antigen detection:
-- PfHRP-2 (plasmodium falciparum histidine rich pro-
tein 2)
-- pLDH (parasite-specific lactate dehydrogenase)
• also differentiates between the individual types of plas-
modia
• sensitivity and specificity comparable to the thick blood
film
• mistakes:
-- false-positive if rheumatoid factor is present
-- false-negative possible despite high number of para-
sites in the blood (prozone phenomenon)
Blood smear
• Giemsa staining
• Here morphological differentiation (see infobox) is best
possible (better than in a thick blood film).
• cave: More than one type of plasmodia is also possi-
ble. One speaks of the so-called "multiple infection":
The patient has two types of "malaria" related to the
 erythrocytes. However, only one parasite "lives" in the
erythrocyte. The finding of a "multiple infestation" is ab-
solutely pathognomonic for tropical malaria! In case of
ambiguities one should consult the laboratory.
• parasite density
-- percentage of erythrocytes infected by parasites
-- important for plasmodium falciparum and plasmodi-
um knowlesi
-- from > 5%: severe malaria
-- However, parasite density may be low during the se-
questration phase of a synchronized tropical mala-
ria, although a severe infection is present.
-- In the benign forms, max. 2% are infested.
• if initially negative → blood smear again after 6h; re-
peat examination several times if necessary (every
8-12h)
Fig. 1229  Blood smear plasmodium falciparum: The hor-
seshoe shape with the typical piston-like ends can be seen
(courtesy of PD Dr. Drobnik, Medical Director of MVZ Syn-
lab Regensburg [Germany]).

Fig. 1230  Blood smear plasmodium malariae (courtesy of

PD Dr. Drobnik, Medical Director of the MVZ Synlab Re-
gensburg [Germany])

Infectiology 993
 Therapy
• causal (antimalarial drugs)
• symptomatic

Fig. 1231  Blood smear plasmodium vivax: The dot-shaped

stippling can be seen (courtesy of PD Dr. Drobnik, Medical
Director of MVZ Synlab Regensburg [Germany]).

Thick blood film

• syn.: thick blood smear
• a special blood smear: an enrichment procedure (One
can only see the plasmodia in the conventional blood
smear [thin blood film] from a certain parasite density.
With the thick blood film one can already detect very
small amounts [already from an infestation > 0.0002%;
10-fold increased sensitivity].)
• The parasite density per high power field is 10-20
times higher than with a conventional (i.e. thin blood
film) blood smear.
• preparation:
-- put one droplet of capillary blood (or EDTA blood) on
a slide, mixed with the corner of the slide to form a Causal therapy
spot of approx. 1cm2 • benign forms (outpatient treatment possible):
-- let dry (20min) -- Chloroquine is the means of choice (almost no
-- Giemsa staining chloroquine resistance in plasmodium vivax / ovale;
• A morphological differentiation is not possible in the exception: Southeast Asia / Pacific region → meflo-
thick as opposed to the thin blood film. This requires a quine)
conventional blood smear. -- For tertian malaria, primaquine is additionally nee-
ded for 2 weeks after the treatment in order to de-
Serology stroy also the liver forms (previously exclusion of
glucose-6-phosphate dehydrogenase deficiency).
• detection of malaria antibodies
• malignant form: tropical malaria (inpatient treatment
• no significance in acute diagnostics (even described
necessary)
as superfluous in the guidelines)
-- uncomplicated tropical malaria (normal ward)
• retrospectively for the detection of a previous infection
-- complicated tropical malaria (intensive care unit)

994 Infectiology
 Therapy of complicated tropical malaria
• antimalarial drugs (duration of therapy: 7 days)
-- artesunate (Artesun, Guilin): today means of first
choice
-- quinine i.v.
◦◦ only if artesunate is not available
◦◦ cave: increased quinine resistance in Southeast
Asia
◦◦ always combination with doxycycline (3 mg/kg,
e.g. 100mg i.v. 2 x daily) or clindamycin (600mg
i.v. 4 x daily; especially in pregnant women and
children)
• antibiotic prophylaxis: To cover a possible bacterial
co-infection (in 25%), we also give a broad spectrum
antibiotic (e.g. piperacillin / tazobactam) as standard.
• intensive care unit (ICU)
• Here one should certainly consult a tropical physici-
an as a consultant or transfer the patient immediately
to an infectiological centre with corresponding experi-
ence.
• exchange transfusions from parasitemia > 20%
• In case of severe courses, the possibility of bacterial
coinfection should always be considered!

complicated tropical malaria with

complicated tropical malaria: parasitemia > 10% or relevant
intensive care unit (ICU) cardiac comorbidities: artesuna-
te; otherwise quinine

Therapy of uncomplicated tropical malaria

• areas without chloroquine resistance (rare; current- Antimalarial drugs
ly only Central America, Haiti, Dominican Republic):
chloroquine
• areas with chloroquine resistance:
-- mefloquin (Lariam)
◦◦ agent with most side effects
◦◦ not if from Thailand, Vietnam, Laos, Cambodia,
Myanmar → increased mefloquine resistance • chloroquine
-- dihydroartemisinin / piperaquine (Euratesim) • mefloquine
-- atovaquone / proguanil (Malarone) • primaquine
-- artemether / lumefantrine (Riamet; best) • quinine
• Malarone (atovaquon + proguanil)
• Riamet (artemether + lumefantrine)
• Euratesim (dihydroartemisinin + piperaquine)
• halofantrine

Chloroquine (Resochin, Nivaquine)

• indication: therapy of quartan malaria
• 1 tablet = 250mg
• first dose: 4 tablets, then after 6h, 24h and 48h each
2 tablets
• side effects:
-- retinopathy
-- nausea, vomiting
-- cerebellar dysfunction
-- hypoglycemia
• contraindications:
-- psoriasis

Infectiology 995
 -- porphyria
-- retinopathy (e.g. macular degeneration)
• also possible during pregnancy
• The antidote for chloroquine intoxication is diazepam
in a very high dosage (1 mg/kg i.v.; intubation readi-
ness).
• note: Chloroquine (in use since 1934) itself has not
been on the market since 2016 (is no longer marketed
by Bayer). There is only its metabolite hydroxychloro-
quine (Quensyl, Praquenil): It has an additional hyd-
roxyl group and is less toxic and more tolerable than
chloroquine. dosage: 1 tablet = 200mg (initially 800mg,
then after 8h 400mg, then on each of the following two
days 1 x 200mg [a total of 2g hydroxychloroquine])
Mefloquine (Lariam)
• indication: therapy of uncomplicated tropical ma-
laria
• 1 tablet = 250mg
• first 3 tablets, after 8h 2 tablets, after further 8h 1 tablet
• increased mefloquin resistance of plasmodium falcipa-
rum in Southeast Asia (e.g. Thailand, Vietnam, Laos,
Cambodia, Myanmar) → in this case not means of first
choice (better: Malarone or Riamet)
• side effects (frequent!):
-- nausea, vomiting
-- balance disorders
-- tremor
-- confusion, psychosis
-- sinus bradycardia (cave with simultaneous adminis-
tration of e.g. β-blockers, calcium antagonists of the
verapamil-type or digitalis)
• contraindications:
-- epilepsy
-- psychosis
-- renal insufficiency
-- hepatic insufficiency
-- simultaneous intake of β-blockers, calcium antago-
nists of the verapamil-type or digitalis
-- pregnancy (first trimester)
• no longer approved in Germany since 2016
Primaquine (Primaquine)
• In contrast to all other drugs primaquine not only acts
schizonto-, but also gametozid.
• indication: only for the final treatment of tertian malaria
(for the eradication of hypnozoites in the liver)
• 1 tablet a 15 mg per day for 2 weeks
• always take with food
• always before exclusion of glucose-6-phosphate dehy-
drogenase deficiency (EDTA blood; otherwise severe
hemolytic anaemia!)
• contraindicated in pregnancy and lactation (no final
treatment)
Quinine (Chinimax)
• alkaloid from the bark of the china tree (cinchona pu-
bescens; not to be confused with quinidine: Quinidine
is chemically only the isomer of quinine, but pharmaco-
996 Infectiology
logically a completely different agent: Quinidine is used
as a class IA antiarrhythmic.)
• indication: therapy of complicated tropical malaria
• loading-dose:
-- initial loading-dose 20 mg/kg over 4h, then mainte-
nance dose 3 x 10 mg/kg daily i.v.
-- also loading dose in case of renal failure (creatinine
clearance < 10 ml/min) or hemodialysis
-- no loading-dose if mefloquine was given in the last
two weeks
• always as prolonged infusion (over 2-4h) via perfu-
sor or infusomat (otherwise pronounced drop in blood
pressure!)
• cave: often quinine resistance in Southeast Asia!
• i.v.-preparation in Germany no longer on the market,
therefore stocking or contact with a centre makes sen-
se (optional production of the pharmacy of the hospital)
• maximum dose: 1800 mg/d
• always combination with doxycycline (3 mg/kg, e.g. 2
x 100mg i.v. daily) or clindamycin (4 x 600mg i.v. dai-
ly; especially in pregnant women and children) over 7
days
• oralize as early as possible (1 tablet = 250 mg)
• dose reduction
-- in renal insufficiency (creatinine clearance < 10 ml/
min or hemodialysis: loading-dose 20 mg/kg, but
then only 50% of the maintainance dose), but no
dose reduction in renal replacement therapy (CVVH
or hemodialysis; if possible, determination of quinine
levels)
-- severe hepatic insufficiency: reduction of the main-
tainance dose by 30% (if possible, determination of
quinine levels)
• duration of therapy (complicated tropical malaria): 7-10
days
• contraindicated in pregnancy because it is teratogenic
(crosses the placenta; leads to blindness and deaf-
ness in fetus) and promotes uterine contraction and
can thus trigger labor (note: This is also the reason
why pregnant women should not drink bitter lemon or
tonic water, as these drinks contain quinine!)
• side effects:
-- hemolysis (in glucose-6-phosphate dehydrogenase
deficiency)
-- thrombocytopenia, possibly trigger of thrombotic mi-
croangiopathy (TMA)
-- hypoglycemia (due to hyperinsulinemia)
-- accustic disorder (especially tinnitus)
-- visual disorder (damage to the optic nerve; annular
scotoma, disorders of color vision)
-- dizziness ("quinine ecstasy")
-- mydriasis (with intoxication often rigid without a light
reaction)
-- hepatotoxicity (e.g. granulomatous hepatitis)
-- drop in blood pressure (Quinine blocks the α-receptor
and causes vasodilation; especially if infusion is too
fast; therefore always apply as prolonged infusion
over 2-4h) )
-- cardiac arrhythmias (Quinine acts as a sodium chan-
 nel blocker like its isomer quinidine, which is used as
a class IA antiarrhythmic.):
◦◦ sinus bradycardia
◦◦ extrasystoles (SVES, VES)
◦◦ QT interval prolongation (then dose reduction by
50%), possibly torsade de pointes
◦◦ QRS widening (especially in the case of intoxica-
tion)
◦◦ ventricular tachycardia
Fig. 1232  Quinine: indicated for the complicated tropical
malaria
Excursus: Quinine intoxication
• occurrence: Quinine is not only used as an antimalarial
drug, but also a flu remedy and under the trade name
Limptar N also for the therapy of nocturnal calf cramps
(i.a. as part of a restless legs syndrome) or with con-
genital myotonia. It is also contained in bitter lemon
and tonic water, where it causes the typical bitter taste.
• note: The intoxication with quinidine (an isomer of qui-
nine; used as a class IA antiarrhythmic) is analogous
to the intoxication with quinine (including the therapy).
In the case of quinine, the ocular toxic effect is more
in the foreground, in the case of quinidine more the
cardiotoxic effect.
• dose:
-- toxic from 4g
-- lethal from 8g (in children from 1g)
• level:
-- therapeutic: 2-8 mg/l
-- toxic: ab > 10 mg/l
• symptoms:
-- analogous to the side effects (only in aggregated
form)
-- in addition: seizures, impaired consciousness (quan-
titative [somnolence, coma], qualitative [delirium]),
respiratory insufficiency, circulatory insufficiency (va-
sodilation due to blockade of α-receptors), ventricu-
lar tachycardia / ventricular fibrillation, acute kidney
failure
-- cinchonism: syndrome of nausea, vomiting, diarrhea,
hypacusis, tinnitus, impaired vision, dizziness, head-
ache, sweating, rash
-- possibly trigger of thrombotic microangiopathy
(TMA)
-- The main problem is the cardio- and oculotoxic ef-
fect. Above all complete blindness is feared! The
scotomas usually last forever.
• therapy:
-- poison elimination
◦◦ primary
▪▪ gastric lavage (if ingestion <1h)
▪▪ charcoal (here repeated application indicated
[MDAC: multi-dose activated charcoal])
◦◦ secondary (especially hemodialysis, possibly he-
moperfusion)
-- sodium bicarbonate (especially with QRS widening;
analogous to intoxication with tricyclic antidepres-
sants [also a sodium channel blockers])
-- electrolyte balancing (especially balancing hypo-
kalaemia)
-- no class IA antiarrhythmics (They are all sodium
channel blockers and would aggravate the intoxica-
tion!)
-- possibly hyperbaric oxygenation (especially in the
case of visual disorders for prophylaxis of blindness
[i.a. Wolff et al, Ocular quinine toxicity treated with
hyperbaric oxygen; Undersea and Hyperbaric Medi-
cine 1997])
-- fundoscopy (for visual disorders; by an ophthalmo-
logist): If there is an arterial vasoconstriction, which
among other things is held responsible for the ocular
toxicity, the i.v. administration of nitrates is recom-
mended. In refractory cases, sympathetic denerva-
tion by means of a stellate blockade can be consi-
dered.
cave quinine intoxication: espe-
cially cardiac and ocular toxicity!
Artesunate (Artesun, Guilin)
• indication: therapy of complicated tropical malaria
• an artesimin (mugwort)
• obtainable from Guilin Pharmaceutical Factory (Gu-
angxi, China) or ACE-Pharmaceuticals BV (Nether-
lands)
• dosage: 2.4 mg/kg as bolus (over 5min) i.v. (also i.m.
possible) at the beginning, then after 12h and 24h,
then on the following day once daily, then if possible
switch to p.o. 2 mg/kg once daily for a total (parente-
ral and oral) of 7 days (however, artesunate must be
given parenterally for at least 48h; if p.o. not available:
Riamet p.o. over 3 days [start 4h after the last i.v. ad-
ministration of artesunate])
• 1 amp.: 60 mg/ml (available as powder, must be dissol-
ved with 1ml sodium bicarbonate 5% [included in the
Infectiology 997
 package; the solution must be clear], for application
this solution is diluted again with 5ml of glucose 5%)
• no dose reduction
-- renal insufficiency (not even with CVVH or hemodi- AQUAMAT study
alysis)
-- hepatic insufficiency
• In the SEQUAMAT study (see box) the complicated
Artesunate versus quinine in the treatment of severe falci-
tropical malaria showed a significantly lower mortality
parum malaria in African children (AQUAMAT): an open-
due to the therapy with artesunate than under the pre- label, randomised trial
vious standard therapy with quinine, so that meanwhile Dondorp et al, Lancet 2010
a paradigm shift in the therapy of the complicated tropi-
cal malaria away from quinine towards artesunate has • multicenter randomized controlled study (Africa)
occurred. Accordingly, the WHO has now recommen- • 5425 children (<15 years) with complicated tropical ma-
ded artesunate as the first choice. In the AQUAMAT laria
study (see box) this was also confirmed in children. -- quinine i.v.
Accordingly, the WHO has now recommended artesu- -- artesunate i.v.
nate as the first choice. • result: Artesunate showed a significantly lower mor-
• With a parasitemia > 10% or relevant cardiac co- tality than quinine (8% versus 11%).
morbidities, artesunate (and no longer quinine) is the
absolute first choice in the therapy of the complicated
tropical malaria!
means of choice today for the
• not yet approved in Europe (off-label)
complicated tropical malaria: artesu-
• very rapid reduction of parasite density nate
• effect on all forms (unlike quinine, which only works on
older forms)
• side effects:
-- almost none (much less than quinine, especially no
cardiotoxicity)
-- main side effects: hemolysis and neutropenia (often
late after 14-28 days)
-- also: fever, nausea, vomiting, diarrhea
• pregnancy: in the 2nd and 3rd trimester means of choice,
in the 1st trimester quinine (not artesunate)

SEQUAMAT study

Artesunate versus quinine for treatment of severe falcipa-

rum malaria: a randomised trial
Dondorp et al, Lancet 2005

• multicenter randomized controlled study (Southeast
Asia)
• 1461 patients with complicated tropical malaria
-- qhinine i.v.
-- artesunate i.v.
• result: Artesunate showed a significantly lower mor-
tality than quinine (15% versus 22%).
• note: Mortality reduction was only achieved in patients
with a parasite density > 10%.
Fig. 1233  Artesunate: means of the first choice today for
the complicated tropical malaria (should be kept in stock
in the intensive care unit: If you have a complicated tro-
pica malaria you have to hurry! Here you shouldn't waste
any more time by ordering medication [preferably from ab-
road]!)
Malarone
• = atovaquone + proguanil
• indication: therapy of uncomplicated tropical mala-
ria and tertian malaria
• 1 tablet = 250mg atovaquone + 100mg proguanil
• daily 4 tablets over total 3 days
• side effects:
-- nausea, vomiting, diarrhea, abdominal pain
-- cough
-- transaminases ↑

998 Infectiology
• interactions (reduction of the atovaquone level)
-- MCP (metoclopramide)
-- rifampicin
-- doxycycline
• contraindicated in creatinine clearance < 30 ml/min

Riamet
• = artemether + lumefantrine
• indication: therapy of uncomplicated tropical mala-
ria and tertian malaria
• 1 tablet = 20mg artemether + 120mg lumefantrine
• dosage: 4 tablets each at the beginning, then after 8h,
24h, 36h, 48h and 60h (i.e. 24 tablets in total)
• taking with a high-fat meal (e.g. with a glass of milk)
• side effects:
-- headache (often very severe; Note: Headaches are
a classic side effect of Riamet. Nevertheless, we ge-
nerously carry out a CCT for patients with thrombo-
penia to reliably rule out intracranial hemorrhage.)
-- QT interval prolongation
-- dizziness
-- insomnia
-- abdominal pain
• interactions (especially tricyclic antidepressants, neu-
roleptics, macrolides, fluoroquinolones, metoprolol,
class IA and III antiarrhythmics): inhibition of cytochro-
me CYP2D6, which degrades artemether

Always take Riamet tablets with a

glass of milk!

Euratesim
• = dihydroartemisinin + piperaquine
• indication: therapy of uncomplicated tropical malaria
• 1 tablet = 40mg dihydroartemisinin + 320mg pipera-
quine
Symptomatic Therapy
• dosage: for 3 days • fever → fever reduction:
-- < 75kg: 3 tablets per day -- physical
-- > 75kg: 4 tablets per day -- pharmacological
• taking: fasted ◦◦ e.g. paracetamol, ibuprofen
• side effects: ◦◦ no ASA (inhibition of thrombocyte aggregation in
anaway increased risk of bleeding)
-- QT interval prolongation
• hypoglycemia (frequent [due to the parasitic consump-
-- headaches
tion]; therefore tight glycemic control) → glucose infu-
-- anemia
sions
-- asthenia
• anemia → red cell concentrate transfusions only re-
-- fever strictive, since the microcirculation disorders can be
-- abdominal pain intensified!
-- seizure • fluid administration rather restrictive (danger of pulmo-
-- transaminases ↑ nary edema; up to max. 1000ml/d or CVP < 5 cmH20
[optional])
Halofantrine (Halfan) • acute renal failure → renal replacement therapy
• reserve agent for the therapy of tropical malaria in • acute respiratory failure → intubation and mechanical
WHO zone B/C ventilation
• 1 tablet = 250mg; 6 tablets (1500mg) at the beginning, • seizures → benzodiazepinen (Phenytoin is contraindi-
then after 6h and again after 12h, repetition after one cated during therapy with in quinine.)
week • parasitemia > 20% → exchange transfusions (very ra-
• cave: QT interval prolongation (ECG controls)

Infectiology 999
 rely performed; no data on whether they are useful at
all)
• no full anticoagulation with heparin (despite microcir-
culation disorder; frequent error)
• daily ECG to detect cardiac arrhythmias (i.a. QT inter-
val prolongation)
• antibiosis in co-infections (bacterial; in 25%; patients
die more frequently from this as from primary malaria
infection! therefore, with the slightest suspicion, ge-
nerously antibiosis)

most frequent mistake in the suppor-

tive therapy of malaria: over-watering
(hyperhydration)!

Prognosis
• mortality of imported tropical malaria: 0.5-1%
• mortality of complicated tropical malaria:
-- without therapy: 30%
-- with therapy: 5%
• quartan / tertian malaria: Almost all heal after two years
even without therapy.
• estimation of the prognosis based on CAM score (see
infobox; according to Hanson et al, Clin Infect Dis
2010) Prophylaxis
• most common cause of death: encephalopathy (cere- • exposure prophylaxis
bral malaria) • chemoprophylaxis
• The following factors are indicative for an unfavourable
(poor) prognosis in tropical malaria: Exposure prophylaxis
-- procalcitonin > 25 ng/ml • more important and effective than chemoprophylaxis
-- high LDH, high reticulocyte count (indicative of se- • Anopheles mosquitoes are nocturnally active, so don't
vere hemolysis) stay outside in the corresponding areas at sunset or
-- hyperparasitemia (> 5% of erythrocytes infected) at night!
-- detection of schizonts • sleeping with a mosquito net
• windows / doors with mosquito nets
• Autan spray

1000 Infectiology
Chemoprophylaxis
• drugs:
-- chloroquine
◦◦ 2 tablets / week
◦◦ 1 week before to 4 weeks after (i.e. 5 weeks in
total)
-- mefloquine (Lariam)
◦◦ 1 tablet / week
◦◦ 2 weeks before to 4 weeks after (i.d. 6 weeks in
total)
-- Malarone (atovaquon + proguanil)
-- Riamet (artemether + lumefantrine)
-- doxycycline
• Chemoprophylaxis reduces the risk of a malaria by
83%, unfortunately it is carried out (correctly) only in
25%.
• is only carried out in 15% of trips to endemic areas
• only recommended for Africa, otherwise stand-by-the-
rapy (carrying the drugs) is sufficient
• A vaccination was unfortunately not (yet) possible for a
long time. Now a vaccine (RTS, S/AS01; trade name:
Mosquirix [GlaxoSmithKline]) is about to be appro-
ved. This is not intended for travel medicine, but for
small children (5-17 months) in endemic areas. The
protective effect lasts over 4 years and is only 39%.

Infectiology 1001
 intrinsic system extrinsic system
PTT Quick

XII, XI, IX tissue factor

VIIa VII
VIII
X

prothrombin (II) thrombin (IIa) XIII

fibrinogen (I) fibrin (Ia) fibrin

polymer
plasminogen plasmin
plasminogen fibrin degradation
activators products
Fig. 1234  Schematic representation of the coagulation cas-
cade: the intrinsic system is activated through the contact
of blood with foreign surfaces, the extrinsic system through
the contact of blood with the tissue factor (= factor III).

DIC: "Death is coming"

Definition
• DIC: disseminated intravasal coagulation
• syn.: consumption (consumptive) coagulopathy
• first description 1961 by Hanns Gotthard Lasch (Ger-
man internist; 1925-2009)
• a syndrome (no disease)
• The DIC is a coagulation disorder due to a lack of co-
agulation factors and thrombocytes. The cause of the
deficiency is increased consumption. The consumpti-
on is greater than the new synthesis.
Pathophysiology
• generalized intravascular activation of the coagu-
lation system → hypercoagulability → formation of
microthromboembolism → disturbance of microcir-
culation (early thrombosis) of the organs → ischemic
multiorgan failure (kidney, lung, liver)
• reactively and compensatory increased fibrinolysis
(partly excessive) to the dissolute the microthrombo-
embolism
• consumption of coagulation factors → bleeding in late
stage

Causes
• shock
• sepsis (35% of all patients with severe sepsis)
• polytrauma
• burns
• acute pancreatitis
• surgery or disease (mainly of the 4P organs [rich in
t-PA and thrombokinase = Factor X: activators of fibri-
nolysis]: pancreas, prostate, pulmo, placenta)
• intoxications
• trauma (TIC: trauma-induced coagulopathy) ; syn.:
ATC [acute traumatic coagulopathy])
• obstetric complications:
-- birth
-- septic / missed abortion
-- amniotic fluid embolism
-- premature placental separation
• infections, especially:
-- meningococcal sepsis (Waterhouse-Friderichsen
syndrome; Purpura fulminans)
-- malaria

1004 Hematology
 -- rickettsiosis
-- SARS-CoV-2 (COVID; here often excessive acti-
vation of coagulation [hypercoagulability; CIC: CO-
VID-19 associated coagulopathy])
• hemolysis, i.a.:
-- massive transfusion, mistransfusion (hemolytic
transfusion reaction [HTR])
-- HUS (hemolytic uremic syndrome)
-- severe relapse of AIHA (autoimmune hemolytic an-
emia)
• acute liver failure, decompensated liver cirrhosis
• extracorporeal circulation (ECMO)
• vascular anomalies (e.g. Kasabach-Merritt syndrome
[giant hemangiomas], Klippel-Trenaunay syndrome)
• advanced malignancies (e.g. pancreas, colon, sto-
mach, prostate)
• leukemia; especially acute promyelocytic leukemia
(APL; see infobox)
• heat emergencies (especially heat stroke)
• malignant hyperthermia (classic anesthetic emergen-
cy)
• diving accident (The gas bubbles activate the coagu-
lation.)

most frequent causes of DIC:

- sepsis
- shock
- polytrauma

Hematology 1005
Fig. 1235  Acute leukemia as a cause of DIC: The blasts Fig. 1236  acute promyelocytic leukemia (APL)
are recognizable. Especially acute promyelocytic leukemia
leads to DIC (courtesy of PD Dr. Drobnik, Medical Director
of the MVZ Synlab Regensburg).

Fig. 1237  sonography of the abdomen: pronounced sple-

nomegaly in acute myeloid leukemia (here APL)

Types
• according to duration:
-- acute
-- chronic (e.g. liver cirrhosis)
• according to course:
-- compensated (non-overt)
-- decompensated (overt)

Epidemiology
• 35% of all patients with severe sepsis
• one of the most frequently overlooked diagnoses in
intensive care
• mortality dependent on the underlying disease

DIC: often overlooked!

Almost everyone thinks of HIT,
almost nobody of DIC!

Laboratory
• platelets ↓ (most sensitive parameter)
• fibrinogen ↓ (cave acute phase protein → in inflamma-
tion ↑; also increased after HES administration)
• AT III ↓
• Quick ↓ or INR ↑
• PTT ↑ ­

1006 Hematology
Stages
• stage I: initial phase, activation phase (activation of
clotting), hypercoagulability
• stage II: early consumption phase; compensated DIC;
microthrombosis
• stage III: late consumption phase; reactive hyperfibri-
nolysis, collapse of clotting, bleeding

stage I stage II stage III

Quick n ↓ ↓↓
PTT n/↓ ↑ ↑↑
fibrinogen n/↑ n ↓
platelets ↓ ↓ ↓↓
AT III ↓ ↓ ↓↓
Fig. 1239  CCT: intracerebral hemaorrhage
D-dimer n ↑ ↑↑

DIC scores
Symptoms • DIC score according to JAAM (Japanese Association
• stage I: mostly only laboratory changes for Acute Medicine; see infobox)
• stage II: microthrombi → multiorgan failure • DIC score according to ISTH (International Society on
-- renal → kidney failure Thrombosis and Haemostasis; see infobox)
-- pulmonary → pulmonary failure (ARDS)
-- hepatic → liver failure
-- cerebral → encephalopathy (e.g. coma, seizures)
• Phase III: Blutungen

Bleedings
• petechia
• suggillations
• hematoma (e.g. bleeding into rectus sheath)
• bleeding from wounds and puncture canals
• hematuria
• gastrointestinal bleeding
• pulmonary hemorrhages, hemoptysis
• adrenocortical insufficiency due to bleeding
• intracerebral hemorrhage

Fig. 1238  CT abdomen: hematoma of the rectus sheath

Hematology 1007
 Heparin
• according to DIC stages:
-- stage I: only low dose to activate AT III: 400 IU/h, in
thrombocytopenia < 50000/μl → 200 IU/h (prophy-
laxis)
-- stage II: 200 IU/h
-- stage III: strictly contraindicated (in stage III p.d.
bleeding!)
• PTT should not increase (without PTT control)
• no s.c. administration (only i.v.) in shock:
-- shock → reduced absorption
-- better control (faster discontinuation) in bleeding and
possible antagonization with protamine with i.v. ad-
ministration
• DIC with bleeding: no heparin any more

HETRASE study

Unfractioned heparin for treatment of sepsis - a rand-

omized clinical trial
Jaimes et al, Crit Care Med 2009

Therapy • single-center, randomized-controlled study

• 319 patients with sepsis
• causal therapy (most important: DIC is a syndrome,
-- unfractionated heparin 500 IU/h (fixed dose without
not a disease. Therefore, the treatment of the underly-
PTT control) over 7 days
ing disease is crucial!)
-- placebo
• symptomatic therapy • result: no mortality benefit

no laboratory cosmetics in hemosta-

seology!

Therapie of DIC: almost no studies!

Etiology
• diseases or surgery on organs (4P organs) which are
rich in fibrinolysis activators
Causal therapy -- pankreas (e.g. acute pancreatitis)
• therapy of shock, sepsis, etc. -- prostate
• therapy of leukemia (especially acute promyelocytic -- plazenta, uterus
leukemia) -- pulmo
• uterine evacuation in "dead-fetus-syndrome" or septic • stage III of any DIC
abortion • obstetric complications:
-- birth
Symptomatic therapy -- septic / missed abortion
• heparin -- amniotic fluid embolism
• FFP: indicated in DIC stage III (Here bleeding occurs -- premature placental separation
due to the consumption of coagulation factors, so that • liver diseases
the coagulation factors have to be replaced again in • metastatic carcinomas (mainly pancreas, prostate,
the form of FFP.) ovary)
• if necessary AT III, fibrinogen • acute promyelocytic leukemia (AML M3)
• desmopressin (leads to increased fibrinolysis via an
increase in tPA
• ECMO (e.g. as a result of thrombosis of the oxygena-
tor)

1008 Hematology
Symptoms (diffuse bleeding!)
• petechiae Fibrinogen ↓↓ + D-dimer ↑↑:
• suggillations hyperfibrinolysis → tranexamic
acid + fibrinogen!
• hematomas
• bleeding from wounds and puncture canals
• hematuria
• gastrointestinal bleeding
Therapy
• pulmonary hemorrhages, hemoptysis • antifibrinolytics
• adrenocortical insufficiency due to bleeding -- aprotinin
• intracerebral hemorrhage -- tranexamic acid
• postpartal hemorrhage • fibrinogen (Haemocomplettan HS): administration indi-
cated with fibrinogen < 1 g/dl (and bleeding)

Aprotinin (Trasylol)
• 1 amp. = 500000 KIU (Kallikrein Inactivator Unit)
• initial 500000 KIU as slow infusion (max. 5ml/min),
then 200000 KIU/h every 4h
• due to danger of allergic reaction (isolated from bovine
lung) 10min before 1ml (10000 KIU) as test dose (cave
with previous aprotinin administration)
• Due to an increased risk of postoperative (after cardiac
thoracic surgery) kidney failure (Mangano et al, N Engl
J 2006; Karkouti et al, Transfusion 2006) and increa-
sed mortality in the BART study (Fergusson et al, N
Engl J 2008), the suspension of the marketing authori-
Fig. 1240  CT abdomen: hematoma in the left rectus abdo- zation was ordered in 2007. Due to proven deficiencies
minis muscle in these studies, this was reversed in 2013. Aprotinin
now has limited approval specifically for cardiothora-
cic surgery (prophylactic to reduce blood loss during
CABG surgery in patients at high risk of bleeding).

Tranexamic acid (Cyklokapron)

• ε-aminocaproic acid
• lysine analogue
• a plasminogen inactivator (binding to plasminogen,
thereby inhibiting the conversion of plasminogen to
plasmin and thus inhibiting the fibrin cleavage)
• 2 ampoule sizes (each 1ml = 100mg):
-- 5ml = 500mg
-- 10ml = 1000mg
• 1 capsule = 250mg
• dosage: Bolus 10-20 mg/kg BW (0.5-1.0g) i.v., then
0.125-0.5 g/h i.v. or 1 amp. i.v./i.m. 1-1-1 or 1g i.v. or 1
capsule p.o. 1-1-1
• side effects: i.a.
-- nausea, vomiting
-- colour sense disorder (if taken for a longer period
of time)
Fig. 1241  CCT: intracerebral hemorrhage -- seizures (tranexamic acid is a GABA antagonist;
therefore, be careful in epilepsy)
Diagnosis • As a result of the CRASH-2 study (see box), tranexa-
• fibrinogen ↓↓ mic acid is generously administered in the emergency
• D-dimer ↑­­↑ trauma room during a polytrauma with bleeding. In the
ERC guidelines 2015, 1g is recommended for 10min
• DD DIC:
as loading-dose and then 1g for 8h. The best way is
-- no thrombocytopenia to already administer it preclinically (out-of-hospital)..
-- no decrease of AT III • Tranexamic acid can be used generously for various
types of bleeding:

Hematology 1009
 -- i.a. very effective and life-saving also in postpartum • red cell concentrate (RCC)
hemorrhage / uterine atony (WOMAN study Lancet • platelet concentrates (PC)
2017) • fresh frozen plasma (FFP)
-- i.a. in traumatic brain injury with GCS < 12 or int- • PPSB
racranial hemorrhage in CCT (CRASH-3 study Lan- • antithrombin (Kybernin)
cet 2019: reduction of SHT-associated mortality
• fibrinogen (Haemocomplettan HS)
when administered within 3 hours)
• factor XIII (Fibrogammin)
-- no effect, however, in gastrointestinal bleeding
(HALT-IT study 2020) • factor VIIa (Novoseven)
• TFPI (tissue factor pathway inhibitor)
• human albumin (see page 251)

The aim is a rational handling of blood products. In the

sense of so-called patient blood management (PBM;
project initiated by the University Hospital Frankfurt am
Fig. 1242  Tranexamic acid (Cyklokapron): 1 amp. = 5ml = Main in Germany; i.a. Zacharowski, Meybohm, Spahn,
500mg Patient Blood Management, Thieme publishing company
[Stuttgart, Germany] 2. edition, 2018), anemia should be
avoided as far as possible and blood products should
only be used restrictively. The PBM concept consists of 3
CRASH-2 study pillars (see infobox).

Effects of tranexamic acid on death, vascular occlusive

events and blood transfusion in trauma patients with signi-
ficant haemorrhage
The CRASH-2 trial collaborators, Lancet 2010

• multicenter randomized controlled study

• 20211 trauma patients with significant bleeding (hemo-
dynamically unstable)
-- tranexamic acid 1g over 10min, then 1g within 8h
-- placebo
• result (tranexamic acid): significant reduction in mor-
tality

pronounced bleeding → generous

administration of tranexamic acid!

rational use of blood products!

Red cell concentrates (RCC)

1010 Hematology
Basics
• 95% of all ICU patients with a length of stay > 3 days
have anemia (Zarychanski et al, CMAJ 2007). This is
mostly multifactorial:
-- blood loss: i.a.
◦◦ surgery
◦◦ upper gastrointestinal bleeding in stress ulcer
◦◦ bleeding from wounds
◦◦ frequent blood sampling
▪▪ 200-300ml/week (incl. BGA, blood cultures)
▪▪ Therefore, one should reduce both the frequen-
cy and the amount of sampling. There are now
also monovettes that you only have to fill up to
half (and not completely).
-- anemia of inflammation (The acute phase protein
hepcidin is upregulated during an infection: This in-
hibits the absorption of iron in the intestine and the
release of iron from macrophages by inhibiting the
transporter protein ferroportin. This is physiological
as it inhibits the growth of the bacteria that would
need iron for this.)
-- hemodilution
-- nutritional deficiencies
-- renal insufficiency (renal anemia)
-- myelosuppression
• Red cell concentrates are administered not only to en-
sure adequate oxygen transport, but also to maintain
hemostasis: The release of ADP (adenosine diphos-
phate) stabilizes the primary hemostasis. The fewer
erythrocytes there are in the blood (anemia), the higher
the risk of bleeding. Anemia as part of the "lethal triad",
i.e. the three factors that increase the risk of bleeding
(especially in polytrauma): hypothermia, acidosis, ane-
mia. Also hypocalcemia increases the risk of bleeding.
• Red cell concentrates are leukocyte-depleted.
• costas for one red cell concentrate: approx. 80€
• Heating of RCC before transfusion is definitely not
necessary but even harmful! Indications for heating
are only the presence of cold agglutinins, massive
transfusion or transfusion in newborns. However, if the
massive transfusion is performed with a quick infusion
system (e.g. Level One), the heating takes place in the
system itself anyway.
• prerequisite: compatibility in the ABO and Rhesus sys-
tem
-- Therefore immediately before RCC transfusion ABO
identity test (bedside test) by the transfusing physi-
cian on the patient including written documentation
is obligatory (Half of all serious transfusion incidents
are based on a mix-up!). Th test (and also the trans-
fusion) may only be carried out by a licensed physi-
cian and not by a medicine student (famulus) or a
nurse (not delegable; assumption of fault). If the test
is omitted and a transfusion incident occurs, there is
gross negligence and, as a rule, one can even lose
the license to practice medicine. In addition, the in-
surance cover (liability) is also lost. Furthermore, the
test must also be carried out immediately before the
transfusion: If, for example, one has to care for an
emergency elsewhere in the house after the bedside
test has been carried out, so that the subsequent
transfusion was not possible possible, the bedside
test must then be repeated. Declare someone who
is still alive dead and attach the wrong RCC to some-
one without testing.
-- In an emergency, blood group 0 Rhesus negative is
considered a universal donor ("zero negative").
-- Rhesus-positive patients (D+) may always receive
rhesus-negative red cell concentrates. Rh-negative
patients (D-), however, are only allowed to receive
rhesus-positive red cell concentrates once. This is
because antibodies (anti-D) can then develop, which
can then lead to a hemolytic transfusion reaction.
These antibodies would then have to be excluded
before the RCC can be administered again.
• storage:
-- temperature: at 4°C (The cooling chain must not be
interrupted.)
-- duration: Within the permitted storage period, it is
not necessary to be requested generally only the red
cell concentrates that have been stored for a short
time. Red cell concentrates that have been stored
for a longer are also possible (e.g. INFORM study
2016 [see box]). Even in critically ill patients, red cell
concentrates that have been stored only for a short
time ("fresh" RCC) show no mortality advantage
compared to longer stored red cell concentrates
(TRANSFUSE study 2017 [see box]).
• erythropoietin in anemia of critically ill patients:
-- no reduction in mortality (i.a. meta-analysis Mesgar-
pour et al, Intensive Care Med 2013); therefore no
general recommendation (also expensive!)
-- only recommended for renal anemia, chronic renal
insufficiency or haemato-oncological patients under-
going chemotherapy
• The administration of iron is only indicated in the pre-
sence of a definite iron deficiency anemia (IDA), which
is rather rare with 20% in intensive care units. Iron is
contraindicated in anemia of inflammation or tumor.
The general administration of iron in anemia in inten-
sive care patients has no benefit (i.a. IRONMAN study
[Intensive Care Med 2016])
Hematology 1011
 Fig. 1243  ABO identity test (bedside test; here using a
Medtro card): Here blood is drawn from the patient's bed
side and his blood group is determined again immediately
before transfusion and compared with the blood group in-
dicated on the blood product.

INFORM study

Effect of Short-Term versus Long-Term Blood Storage on

Mortality after Transfusion
Heddle et al, N Engl J 2016

• multicenter randomized controlled study

Anti-A Anti-B blood • 20858 patients with transfusions of red cell concentrates
group (median 2); storage period
-- short (average 13 days)
-- long (average 23.6 days)
• result: no difference in mortality

A
TRANSFUSE study

B Age of Red Cells for Transfusion and Outcomes in Criti-

cally Ill Adults
Cooper et al, N Engl J 2017

AB
• multicenter randomized controlled study
• 4,994 critically ill patients (intensive care unit) with trans-
fusions of red cell concentrates; storage period:
-- short (average 12 days)
-- long (average 22 days)
• result: no difference in mortality

0 Transfusion regime
• In principle, the transfusion of red cell concentrates
should be restrictive and not liberal!
-- only from hemoglobin < 7 g/dl ([SI unit: 4.3 mmol/;
SSC guidelines 2012 + 2016)
-- exceptions: acute bleeding, severe hypoxemia, acu-
te cardiac ischemia, CAD
• Transfusion should also be restrictive during weaning.
Regarding the transfusion regime during weaning,
however, no consensus was found in the guidelines
conference within the framework of the preparation of
the S2k guideline "Prolonged weaning of the respira-

1012 Hematology
 tor" in 2014. In the revision of the S2k guideline 2019,
an agreement was finally reached: An "individualized
strategy" is recommended.
• further indication for RCC administration (the former
"Rivers-RCC indication"; no longer valid today, howe-
ver): sepsis patients in the first 6 hours if ScvO2 < 70%
+ hematocrit < 30% despite sufficient volume adminis-
tration and use of dobutamine
• Also in a cochrane analysis (Transfusion thresholds
and other strategies for guiding allogeneic red blood
cell transfusion; Carlon et al, 2012) a restrictive trans-
fusion regime showed a reduction in hospital mortality.
A restrictive transfusion regime also reduces the rate
of nosocomial infections (especially pneumonia, sep-
sis and wound infections [meta-analysis Rohde et al,
JAMA 2014]), since RCC also have an immunosup-
pressive effect and can thus increase the infection rate.
• Also in the case of an upper gastrointestinal bleeding
(whether varicose or non-varicose) red cell concentra-
tes should only be administered from hemoglobin < 7
g/dl (not already from < 9 g/dl). Furthermore, the tar-
get hemoglobin here is 7-9 g/dl and not 9-11 g/dl. The
transfusion of red cell concentrates should be restric-
tive in case of an upper gastrointestinal bleeding (e.g.
study of Villanueva, N Engl J 2013 [see page 778])
with the following exceptions:
-- massive bleeding ("exsanguination")
-- acute coronary syndrome
-- symptomatic PAD
-- TIA, stroke
• In principle, only one (and not automatically two)
red cell concentrate should be transfused, provided
there is no bleeding! In 70% (unnecessarily) two red
blood cell concentrates are always transfused! The-
re should be no transfusion with hemoglobin levels >
10 g/dl (SI unit: 8.2 mmol/l). The stupid saying "one is
none" is completely out of place here! An exception is
certainly hemorrhagic shock.
• Red cell concentrates (especially older preparations)
only fulfill their function as oxygen suppliers to a limi-
ted extent: They contain almost no 2,3-DPG (2,3-DPG
depletion), so that there is a left shift in the oxygen-
hemoglobin binding curve (see page 83). The ery-
throcytes contained in the erythrocyte red cell concen-
trates can still transport oxygen, but unfortunately only
release little oxygen to the tissue.
• 88% of all RCC transfusions in the intensive care unit
are not indicated and are unnecessary (Shander et al,
Ann Intern Med 2011).
• transfusion trigger in cardiovascular patients (espe-
cially coronary heart disease [CHD]):
-- overall little evidence
-- almost only studies on patients after surgery (only
one study in patients with acute myocardial infarc-
tion: REALITY [see box]; currently ongoing study:
MINT)
◦◦ after CABG surgery:
▪▪ studies: Bracey et al, Transfusion 1999; Haijar
et al, JAMA 2010 (TRACS-Studie); Murphy et
al, N Engl J 2015; Mazer et al, N Engl J 2018
(TRICS-Studie) → no benefit liberal versus re-
strictive
▪▪ meta-analysis (Curley et al, Crit Care Med
2014): no benefit liberal versus restrictive
◦◦ after hip surgery: FOCUS study (Carson et al,
Lancet 2015): patients with CHD or cardiovascular
risk factors after hip surgery → no benefit liberal
versus restrictive
◦◦ meta-analysis (Docherty et al, BMJ 2016): no be-
nefit liberal versus restrictive in cardiovascular pa-
tients after non-cardiac surgery
-- ESC guidelines 2015: both in acute coronary syn-
drome and in cardiogenic shock only from hemoglo-
bin < 7 g/dl (i.e. also restrictive)
• Not only the hemoglobin value (laborchemical transfu-
sion trigger) alone plays a role in the decision to trans-
fuse. According to the cross-sectional guidelines of
the German Medical Association, transfusions should
be performed from an hemoglobin value of < 8 g/dl, if
there are indications of anemic hypoxia (physiological
transfusion trigger):
-- clinical: tachycardia, hypotension, dyspnea
-- apparative:
◦◦ ECG: signs of ischemia
◦◦ echocardiography: wall motion abnormalities
(new)
-- laborchemical: lactate ↑, decrease of central venous
oxygen saturation (each without any other explana-
tion)
TRICC study
Multicenter, Randomized, Controlled Clinical Trial of Trans-
fusion Requirements in Critical Care
Hebert et al, N Engl J 1999
• TRICC: Transfusion requirements in critical care
• multicenter randomized controlled study
• 838 critically ill patients
• transfusion regime
-- restrictive: only from hemoglobin < 7 g/dl (SI unit: 4.3
mmol/l)
-- liberal: already from hemoglobin < 10 g/dl (SI unit: 6.2
mmol/l)
• result: liberal regime → increased mortality
• causes
-- negative effects on microcirculation (especially older
RCC)
-- blood → immunosuppressive effect
• note: did not apply to CHD patients
Often one hears the saying on the intensive care unit:
"Let's just give the patient two RCCs, that won't harm
him". But it definitely harms him (TRICC study)!
Hematology 1013
 TRISS study

Lower versus higher hemoglobin treshold for transfusion

in septic shock
Holst et al, N Engl J 2014

• TRISS: transfusion requirements in septic shock

• multicenter randomized controlled study Red cell concetra-
• 998 patients with septic shock tes can be fatal!
• transfusion regime
-- restrictive: only from hemoglobin < 7 g/dl
-- liberal: already from hemoglobin < 9 g/dl
• results:
-- primary endpoint (mortality after 90 days): no diffe-
rence
Fig. 1244  No liberal transfusion policy!
-- secondary endpoints: i.a.
◦◦ ischemic events: no difference
◦◦ duration of mechanical ventilation: no difference
◦◦ necessity of organ support procedures: no diffe-
rence
◦◦ frequency of transfusion reactions: no difference

REALITY study

Randomized Trial of Transfusion Strategies in Patients

With Myocardial Infarction and Anemia
Steg et al, ACC 2020

• multicenter randomized controlled study

• 630 patients with acute myocardial infarction and ane-
mia (hemoglobin < 10 g/dl)
• transfusion regime
-- restrictive: only from hemoglobin < 8 g/dl
-- liberal: already from hemoglobin < 10 g/dl
• results: liberal regime
-- primary endpoint (death, reinfarction, stroke, or emer-
gency revascularization): no difference
-- secondary endpoints: i.a.
◦◦ infections: significantly more frequent
◦◦ acute lung failure (ARDS): significantly more
frequent
◦◦ acute kidney failure: no difference
• annotations:
-- The study was primarily designed to demonstrate the
non-inferiority of the restrictive regime.
-- The transfusion trigger in the restrictive regime was 8
and not as usual 7 g/dl.
-- exclusion criteria: i.a.
◦◦ infarction-related cardiogenic shock
◦◦ massive bleeding RCC administration: restrictive (only
from hemoglobin < 7 g/dl; "permissi-
ve anemia")!

1014 Hematology
 • types:
RCC administration: no routinely
heating RCC (only necessary in the
case of a massive transfusion or the
presence of cold agglutinins!)
Immunological transfusion reactions (ITR)
RCC administration: always give only
one and not two RCCs (outside of a
bleeding)! RCCs don't just come in a
double pack! "Stay single! Prescribe
less!"
• allergic transfusion reaction (ATR)
Fig. 1245  No more standard heating of red cell concentra-
tes!
Complications (transfusion)
• hemolytic transfusion reaction (HTR)
• frequency: 0.1% of all transfusions
• compulsory reporting of serious transfusion incidents
according to §16, part 1 of the Transfusion Act (TFG)
in Germany to:
-- transfusion appointee (of the department)
-- transfusion person in charge (of the hospital)
-- transfusion laboratory (blood donation service, blood
bank)
-- federal authority (Paul Ehrlich Institute; carried out
by transfusion appointee and transfusion laboratory)
-- immunological transfusion reactions (ITR)
-- non-immunological transfusion reactions Immunolo-
gical transfusion reactions (NITR)
-- definition: allergic reaction by antibodies against so-
luble plasma components (mainly proteins, drugs,
IgA [frequent in patients with IgA deficiency!])
-- most frequent relevant transfusion reaction (fre-
quency: 28 cases per 1 million transfused units)
-- symptoms:
◦◦ as for allergy or anaphylaxis
◦◦ but no fever!
-- therapy:
◦◦ stop the transfusion (note: If only cutaneous sym-
ptoms appear, the transfusion can be continued
under monitoring).
◦◦ prednisolone 500mg i.v.
◦◦ antihistamines
▪▪ H1 blocker, e.g. dimetindene (Fenistil) 4mg i.v.
▪▪ H2 blocker, e.g. ranitidine (Zantic) 100mg or fa-
motidine (Pepcid, Pepdul) 20mg i.v.
▪▪ possibly adrenaline i.v.
◦◦ in case of proven IgA deficiency only transfusion of
washed blood components
-- definition:
◦◦ destruction of the erythrocytes by antibodies
(mostly IgM; complement activation) due to an
ABO-incompatible transfusion (false transfusion)
◦◦ most frequent lethal transfusion reaction (the
most important complication with regard to emer-
gency medicine; frequency: 11 cases per 1 million
transfused units; incidence: 1:25000 transfusions)
◦◦ Cell damage is mainly caused by the free hemo-
globin released during hemolysis: This leads to
oxidative stress in the cells of the kidney tubules
with consecutive necrosis and obstruction of the
tubules (hence also flank pain and renal failure).
Hematology 1015
 -- causes:
◦◦ mix-up of blood sample and patient (80%, more
frequent; therefore ABO identity test ([bedside
test] obligatory!)
◦◦ incorrect determination of blood group by the labo-
ratory (20%; less frequent)
-- types:
◦◦ early reaction: < 24h (usually begins immediately
and often after just a few millilitres; usually intrava-
scular; less frequent; more dangerous)
◦◦ late reaction: > 24h (mostly extravascular; more
frequent; less dangerous [mostly harmles]; boos-
ting of primary allo-antibodies, not safely avoida-
ble; in the course of transfusion unclear drop of
hemoglobin, hemolysis, jaundice)
-- symptoms:
◦◦ fever, chills
◦◦ pain (especially at injection site, flank, abdo-
men, back [especially in the lumbar spine region;
pathognomonic!])
◦◦ dyspnea, tachypnoea
◦◦ cave: oligosymptomatic in analgosedated patients
(e.g. mechanically ventilated patients in ICU!)
◦◦ jaundice
◦◦ dark urine
◦◦ arterial hypotension (blood pressure decline), ta-
chycardia
◦◦ diffuse bleeding
◦◦ oliguria, anuria
-- complications:
◦◦ shock
◦◦ DIC
◦◦ acute kidney failure
-- diagnosis:
◦◦ hemolysis parameters (hemoglobin ↓, LDH ↑, in-
direct bilirubin ↑, haptoglobin ↓, hemoglobinuria)
◦◦ direct Coombs test (positive)
◦◦ DIC: platelets ↓, AT III ↓, fibrinogen ↓, D-dimer ↑
◦◦ determination of blood group (ABO, rhesus) from
recipient and erythrocyte concentrate
-- therapy:
◦◦ stop the transfusion (but leave the i.v.-access in
situ and keep it free; reserve the rest of the RCC
and transfusion set)
◦◦ immediate reporting to the blood bank (If confused
by the laboratory, another patient may be at risk!);
send to the blood bank: 20ml native blood, 10ml
EDTA blood, rest of the RCC and transfusion set,
transfusion feedback and transfusion report
◦◦ prednisolone 500mg i.v.
◦◦ antihistamines
▪▪ H1 blocker, e.g. dimetindene (Fenistil) 4mg i.v.
▪▪ H2 blocker, e.g. ranitidine (Zantic) 100mg or fa-
motidine (Pepcid, Pepdul) 20mg i.v.
◦◦ therapy of shock
◦◦ therapy of acute kidney failure (if necessary renal
replacement therapy)
◦◦ therapy of DIC
1016 Hematology
◦◦ in particularly severe cases: exchange transfusion
• febrile non-hemolytic transfusion reaction (FNHTR)
-- definition: antibody-mediated activation of leukocy-
tes with consecutive release of cytokines
-- incidence: 1:200 transfusions (most often after trans-
fusion of platelet concentrates)
-- symptoms: fever, chills, sensation of cold (within 24h
after transfusion)
-- therapy:
◦◦ stop the transfusion
◦◦ antipyretics
-- prognosis: harmless (But always exclude HTR [no
hemolysis!] and bacterial contamination!)
• posttransfusion purpura (PTP; syn.: transfusion throm-
bopenia)
-- triggered by antibodies against thrombocytes (HPA-
1a [HPA: human platelet antigen])
-- approx. 5-10 days after blood transfusion (especially
of platelet concentrates)
-- almost exclusively (older) women (e.g. after several
pregnancies, e.g. after earlier transfusions)
-- massive decrease of platelets and severe bleeding
-- isolated thrombocytopenia
-- mortality: 15%
-- therapy:
◦◦ immunoglobulins (means of choice; IgG 1-2
mg/kg BW per day)
◦◦ steroids
◦◦ plasma exchange (very rarely indicated)
◦◦ Platelet concentrates are contraindicated here!
• TRALI (transfusion-related ALI [acute lung injury];
transfusion-associated acute respiratory insufficiency)
-- triggered by allo-antibodies against leukocytes from
the donor, which activate the leukocytes, which then
migrate into the lung (transmigration) and damage it
-- in case of massive transfusion (p.d.> 15 RCC in 24h)
-- but more frequent after FFP than after RCC ad-
ministration
-- symptoms within 6h after transfusion
-- Permeabilitätslungenödem (wie bei ARDS; p.d.
keine Volumenüberladung im Gegensatz zu TACO
[transfusion associated circulatory overload])
-- second most frequent lethal transfusion reaction
-- Gajic et al, Am J Respir Crit Care Med 2007:
◦◦ frequency: 8%
◦◦ risk factors: sepsis, alcohol abuse
-- mortality: 10%
-- mainly due to FFP donated by women after pregnan-
cy or childbirth
◦◦ formation of antibodies against HLA (human leu-
kocyte antigen) and HNA (human neutrophil an-
tigen)
◦◦ Since 2009, women with a positive pregnancy his-
tory have been excluded as FFP donors. Since
then the number of TRALI reports decreased si-
gnificantly!
• transfusion-associated graft-versus-host reaction (TA-
GvHD)
 -- definition:
◦◦ definition: response of transferred donor lympho-
cytes to recipient cells (especially in immunosup-
pressed patients)
-- symptoms: exanthema (maculopapular [typical]),
fever, diarrhea, hepatitis, lymphadenopathy, myelo-
suppression (pancytopenia)
-- prognosis: high mortality
-- prophylaxis: transfusion of irradiated concentrates
(especially with platelet concentrates)
• alloimmunization (detection of clinically relevant allo-
antibodies to blood cell antigens after transfusion that
were not present before transfusion)
• transfusion-associated autoimmune hemolytic anemia
(TA-AIHA)
suddenly severe back pain during
/ shortly after an RCC transfusion:
pathognomonic for a hemolytic
transfusion reaction (emergency)!
Non-immunological transfusion reactions
(NITR)
• TTI (transfusion-transmitted infections): transmission
of infectious diseases
-- bacteria (up to the so-called transfusion sepsis)
◦◦ cause: mainly due to contamination in non-sterile
conditions during manufacture or transfusion
◦◦ germs: mainly staphylococcus aureus, yersinia
enterocolitica, escherichia coli, pseudomonas
aeruginosa, citrobacter, serratia, llebsiella pneu-
moniae, campylobacter jejuni; rarely treponema
pallidum)
◦◦ frequency:
▪▪ erythrocyte concentrates: 1:65000
▪▪ platelet concentrates: 1:12000 (here more fre-
quent than with RCC!)
◦◦ diagnosis: blood cultures from patient and rest of
the concentrate
-- viruses
◦◦ HIV (risk of transmission 1:25 Mio)
◦◦ hepatitis: v.a.
▪▪ hepatitis B (risk of transmission 1:1 Mio)
▪▪ hepatitis C (risk of transmission 1:20 Mio)
▪▪ hepatitis E (is meanwhile also tested as stan-
dard)
◦◦ parvovirus B19
◦◦ CMV
◦◦ HHV-8, HTLV-1/2
-- parasites (e.g. malaria, toxoplasmosis, trypanoso-
mes [therefore routine screening for trypanosoma
cruzi in Central and South America])
-- prions (e.g. Creutzfeldt-Jakob disease)
• TACO (transfusion associated circulatory overload):
volume overload (especially in pre-existing chronic
heart failure; therapy: diuretics)
• TAD (transfusion-associated dyspnea): dyspnea within
12 hours after transfusion without evidence of an all-
ergic transfusion reaction, TRALI or volume overload
(TACO)
• hemosiderosis
• electrolyte disorders:
-- hyperkalemia (especially with massive transfusion,
irradiated or older erythrocyte concentrates and im-
paired renal function)
-- hypocalcemia
◦◦ Citrate binds calcium.
◦◦ cave: bleeding (hypocalcemia as a co-factor for
bleeding!)
• citrate intoxication (citrate accumulation; erythrocyte
concentrates contain citrate)
-- The ionized calcium decreases and thus hypocalce-
mia occurs clinically with the corresponding symp-
toms.
-- occurrence: especially
◦◦ massive transfusion and patients with impaired
liver function (e.g. esophageal variceal bleeding
◦◦ plasma exchange against FFP (On average 18-22
FFP are administered per session!)
-- symptoms: especially cardiac (arrhythmias [espe-
cially QT ↑], heart failure, blood pressure decline)
-- diagnosis:
◦◦ increased total calcium with normal ionized calci-
um (increased ratio total calcium / ionized calcium
[Ca ratio] > 2.5)
◦◦ metabolic acidosis with an increased anion gap (>
16 mmol/l; citrate is not measured)
-- therapy: administration of calcium
• hypothermia (especially with massive transfusion of
cold concentrates)
• arterial hypotension
• embolism (e.g. by clots, air; therefore use transfusion
filters)
Rapid infusion systems
• definition:
-- systems with which a high number of erythrocy-
te concentrates can be applied within a short time
(massive transfusion; up to 1000ml blood per minu-
te)
-- The erythrocyte concentrates are heated in the sy-
stem.
-- Prerequisite is a Shaldon catheter or at least a peri-
pheral cannula of size 17G (white needle).
• indication: hemorrhagic shock
• representatives:
-- Level 1 (Smiths Medical)
-- RIS (Hämonetics)
Hematology 1017

Fig. 1246  Level 1
Platelet concentrates (PC)
Definition
• Leukocyte filters are used in production. All platelet
concentrates are therefore usually leukocyte-depleted,
i.e. the number of remaining leukocytes is < 1 x 106
per concentrate.
• prerequisite: compatibility in ABO system
• The administration of one platelet concentrate increa-
ses the number of platelets by approx. 30,000/μl.
• shelf life: 5 days
-- at 22-24°C (i.e. room temperature; not in the refri-
gerator!)
-- always with constant movement, otherwise the
platelets will aggregate!
-- note: On principle, however, platelet concentra-
tes should always be transfused immediately and
should not be stored!
• costs per platelet concentrate: approx. 300€
1018 Hematology
Fig. 1247  Swiveling system: If platelet concentrates cannot
be transfused immediately as an exception, but have to be
stored, they should always be kept in motion, otherwise
platelet aggregation will occur.
Platelet concentrates: always
administer them immediately; if this is
exceptionally not possible, then store
them at room temperature (never in
refrigerator) and always with constant
movement!
Types
• pooled platelet concentrates (from multiple donors [4-
6])
-- The platelets from multiple whole blood donations
are isolated and pooled into a concentrate.
• apheresis platelet concentrates (from a single donor)
-- By means of platelet apheresis, only the platelets are
taken from the donor's blood, the remaining blood is
returned to the donor via an infusion.
-- no difference in quality or shelf life compared to
pooled platelet concentrates (Salge-Bartels et al,
Transfusion Medicine and Hemotherapy 2020)
• special form: irradiated platelet concentrates
-- method: The irradiation is performed with a dose of
30Gy.
-- reason: avoidance of transfusion-associated graft-
versus-host reaction (TA-GvHD)
-- Indikation: v.a. bei Immunsuppression, nach alloge-
ner Stammzelltransplantation
Indications
see infobox

Contraindications
• TTP (Moschcowitz syndrome)
• PTP (posttransfusion purpura)
• HIT II
Refractory state
• definition: inadequate increase in platelets after admi-
nistration of platelet concentrates
• causes:
-- non-immunological (most common): DIC, ITP, HIT,
splenomegaly, accessory spleen, drugs
-- immunological: HLA class I antibodies, HPA antibo-
dies (HPA: human platelet antigens), ABO incompa-
tibility
FFP
Definition
• fresh frozen plasma (cryoprecipitate)
• contains all coagulation factors and their inhibitors
(With FFP, the donor's coagulation balance is trans-
ferred.)
• 1 sachet = 250 ml
-- Quick ↑ by 6%
-- factors ↑­by 5%
-- fibrinogen ­↑ by 0.1 mg/dl
• 1 ml/kg FFP raises factor content by 1%; in case of
liver failure: 10-20 ml/kg (initial 4 units; daily require-
ment approx. 8 units)
• no single factor replacement with FFP (exception: fac-
tor V and XI [no single factors available])
• compatibility only in ABO system (Rhesus system
does not have to be considered.), in case of emergen-
cy for all AB
• transfuse within 30min after thawing (after 4h only
50% of activity left)
• The citrate contained in FFP can bind calcium so that
10ml CaGluconat 10% or 5ml CaChlorid i.v. recom-
mended to avoid hypocalcemia (not uniformly). Alter-
natively, calcium can only be substituted if a low calci-
um has been detected in the measurement indeed in
the close control.
• risik for TRALI (transfusion related acute lung inju-
ry): 8% (for FFP higher than for RCC!)
Fig. 1248  FFP: 1 sachet contains 250ml
Indications
• massive bleeding (the most frequent indication; a
pronounced bleeding leads classically to so-called loss
coagulopathy: Not only erythrocytes but also coagula-
tion factors are lost, which then intensifies the bleeding
[vicious circle], so that these have to be replaced again
in the form of FFP.)
• massive transfusion
-- from 5th RCC in the ratio RCC: FFP 2:1
-- cross-sectional guidelines of the German Medical
Association: FFP only if PTT > 45s or Quick < 50%
-- We administer FFP in case of bleeding (e.g. upper
gastrointestinal bleeding) but mostly more generous-
ly: per RCC also one FFP
-- The higher the FFP / RCC quotient, the better the
outcome of bleeding (i.a. study Taxera et al, Trauma
2009; meta-analysis Murad et al, Transfusion 2010).
• bleeding under VKA (coumarins) / NOAC in patients
with known HIT (PPSB preparations [such as Beriplex,
Baxalta] contain heparin. As an alternative to FFP you
can also give a heparin-free PCC [Cofact].)
• DIC stage III (here bleeding due to DIC), planned sur-
gery (no prophylactic FFP administration for DIC!)
• replacement of the single factors V or XI
• emergency therapy of C1-esterase inhibitor deficiency
(FFP also contains C1-esterase inhibitor; means of 1st
choice: icatibant [see page 252])
• plasma replacement in the context of plasma exchange
(e.g. TTP, HUS, Goodpasture syndrome)
Hematology 1019

classic indication for FFP: bleeding
(loss coagulopathy); one FFP per
RCC!
Side effects
• TRALI (transfusions-related acute lung injury; more
frequent by FFP than by RCC; see page 1016)
• volume load: Theoretically, one could also increase
the Quick value with FFP when bleeding under VKA
(coumarins): However, with approx. 2000-3000ml this
would represent a relatively high volume load. A sachet
of FFP (250ml) only increases the Quick value by 6%.
Therefore, with bleeding under VKA (coumarins), you
administer PPSB in addition to vitamin K and not FFP.
PPSB are superior to FFP for antagonizing coumarins
(i.a. Sarode et al, Circulation 2013; Goldstein et al,
Lancet 2015).
• increased rate of nosocomial pneumonia
• hypocalcemia
• citrate intoxication (citrate accumulation)
-- FFP contain citrate.
-- occurrence: especially with massive transfusion or
plasma exchange against FFP (18-22 FFP are ad-
ministered per session on average.)
-- for citrate intoxication see also page 1019
FFP only for bleeding or planned
surgery! FFP only therapeutic, not
prophylactic!
no laboratory cosmetics with FFP!
PPSB
Definition
• syn.:
-- prothrombin complex concentrate (PCC)
-- prothrombin complex preparation
• content: all vitamin K dependent factors (mnemonic:
"1972")
-- prothrombin complex
◦◦ factor II (Prothrombin)
◦◦ factor VII (Proconvertin)
◦◦ factor X (Stuart-Prower-Faktor; thrombokinase)
◦◦ factor IX (anti-hemophilic globulin B; standar-
dized in this respect)
-- protein C/S
• relatively short half life compared with VKA (couma-
rins) → once again decrease in Quick value after 8h
(therefore administration only approx. 30min preope-
ratively)
• preparations: ampoule a 20ml
-- Beriplex: 1 amp. = 500 IU
1020 Hematology
-- Baxalta: 1 amp. = 600 II
• 1 IU/kg PPSB raises
-- factor VII and IX: by 0.5-1
-- factor II and X: by 1-2%
-- Quick: by 1%; e.g. 70kg (actual Quick 40%, target-
Quick 70%: 70 x 30 IE = 2100 IE PPSB i.v.)
• slow application (max. 2ml per minute; total 20ml → at
least over 10min)
• In PPSB there are still residual amounts of active co-
agulation proteins. To block these, heparin is added:
However, heparin requires AT III for its effect; therefore
PPSB administration only after normalization of the AT
III level; Note: This only applies, however, if PPSB is
administered in the context of a DIC, where AT III is
usually also reduced. There would then be the dan-
ger of a therapy aggravated DIC. With a DIC, however,
PPSB are almost never given anyway! However, this is
not necessary in the context of bleeding, which is the
most frequent indication for PPSB administration. In
the case of a bleeding one would never give antithrom-
bin anyway, which would only increase the bleeding
due to its anticoagulant effect.
• There is also a heparin-free PCC (Cofact; 1 ampoule:
500 IU factor IX; bluish powder), which can be admi-
nistered e.g. in case of bleeding under VKA (couma-
rins) or NOAC with known HIT.
• In patients with liver insufficiency (Here also the syn-
thesis of coagulation inhibitors is reduced.) before
PPSB administration AT III level should be raised the >
80%. Otherwise there is danger of a therapy-induced
DIC.
Fig. 1249  Beriplex: 1 ampoule contains 500IU PPSB (exact-
ly: faktor IX).
PPSB administration (for DIC)
only after normalization of the AT
III level
Indications
• bleeding under anticoagulants:
-- bleeding under VKA (coumarins; rapid elimina-
tion of the coumarin effect [Theoretically this would
also be possible with FFP, but the volume load would
be too high here with 2000-3000ml!]) or requiring
surgery
-- bleeding under the new anticoagulants (NOAC:
rivaroxaban, dabigatran, apixaban, edoxaban); ge-
nerous administration here!
• bleeding in cirrhosis of the liver (in which usually FFP
instead of PPSB in addition to RCC is administered)
• note: but no "hemostasis cosmetics" with PPSB (e.g.
increase of the Quick value in patients with cirrhosis of
the liver without bleeding)
classic indication for PPSB: bleeding
or emergency surgery under oral
anticoagulants (VKA [coumarins],
NOAC)!
Contraindication
• DIC (as PPSB are procoagulatory; here only with nor-
mal AT III levels)
• HIT II: PPPSB preparations (e.g. Beriplex, Baxalta)
contain heparin. In the case of known HIT (e.g. blee-
ding under coumarins or NOAC with known HIT) one
can either give the heparin-free PPSC (Cofact) or al-
ternatively FFP (disadvantage: higher volume load).
Dosage
• bleeding under VKA (coumarins):
-- with bleeding :
◦◦ INR < 5: 30 IU/kg + 5mg vitamin K i.v./p.o.
◦◦ INR > 5: 50 IU/kg + 10mg vitamin K i.v.
-- with bleeding and INR > 9: 30 IU/kg
-- emergency surgery in patients taking coumarins: 60
IU/kg + 10mg vitamin K i.v.
• bleeding under new oral anticoagulants (NOAC): 50
IU/kg (note: 25 IU/kg almost always sufficient!)
dosage mostly in everyday clinical
practice: 1000 IU (2 amp. Beriplex) or
1200 IU (2 amp. Baxalta) i.v.
Side effects
• thromboembolic complications (e.g. myocardial infarc-
tion, pulmonary embolism) with former preparations
(no longer with modern preparations)
• formation of inhibitors (→ PPSB-DIC!)
Special form: FEIBA
• FEIBA: Factor Eight Inhibitor-Bypass-Activity
• special form of a PPSB preparation in which some fac-
tors (especially factor VII) are already pre-activated
• an activated PPSB (activated prothrombin complex
concentrate [APCC])
• indication: acquired hemophilia A (Here, factor VIII
does not work because of the inhibiting antibody
and cannot activate factor X and thus the formation
of thrombin. Factor VII [extrinsic system] already ac-
tivated in FEIBA activates factor X and not factor VIII
[intrinsic system], which in any case does not work
in aquired hemophilia A. Factor VIII is practically by-
passed).
• dosage: 50-100 U/kg i.v. 2-3x daily (max. 200 U/kg
daily)
Antithrombin (Kybernin)
• also called antithrombin III (AT III)
• effects:
-- anticoagulant (inhibition factor VII, IX, X); i.a. heparin
is only effective if sufficient AT III (AT III level > 80%)
is present!
-- antiinflammatory
• 1 bottle = 10ml = 500 IU; max. 1ml in 5min; dissolve in
water; e.g. 2 ml (= 1000 IU; mostly sufficient) a 10ml +
30ml NaCl 0.9% in 50ml perfusor syringe in 1h (infusi-
on rate 50 ml/h)
• If liver function is impaired, the antithrombin concentra-
tion [in %] should be higher than the Quick value.
• calculation of the units to be substituted according to
the formula: antithrombin (E) = (70 - measured anti-
thrombin level in %) x kgBW
• 1 IU/kg increases activity by 1.5 %.
• target level: > 80% or antithrombin > Quick
• injection solution: 500 IU, 1000 IU, 1500 IU
• if possible without heparin
• contraindicated in HIT II (Kybernin contains heparin →
heparin-free AT III [Atenativ])
• Antithrombin is only given very rarely, e.g. in the case
of frequent clotting of the hemofilter during CVVH (if
anticoagulation with heparin occurs [in our hospital
now citrate anticoagulation]) despite running heparin
perfusor or of the ECMO system if the antithrombin le-
vel (< 80%) is too low.
Hematology 1021
 meta-analysis

Antithrombin III in critically ill patients: systematic review

with meta-analysis and trial sequential analysis
Afshari et al, BMJ 2007

• meta-analysis (20 RCT)

• 3458 critically ill patients
-- AT III
-- placebo
• results: AT III
-- no reduction in mortality (not even in the subgroup
without heparin)
-- increased rate of bleeding

AT III: no general recommendation

Fig. 1250  Kybernin: 1 vial contains 500 IU of AT III. (not even in sepsis [SSC-Guidelines
2016])

KyberSept study

High-Dose Antithrombin III in Severe Sepsis

Warren et al, JAMA 2001

• multicenter randomized controlled phase III study

• 2314 patients with severe sepsis / septic shock
-- high-dose AT III administration (total 30000 IU over 4
days)
-- placebo
• results: AT III
-- no difference in mortality (28/90 days)
-- significantly lower 90-day mortality in the subgroup
(698 patients) who did not receive heparin simultane-
ously
-- significantly more bleeding
study

A randomized, controlled, multicenter trial of the effects of

antithrombin on disseminated intravascular coagulation in
patients with sepsis
Gando et al, Crit Care 2013

• multicenter randomized controlled study

• 60 patients with DIC in sepsis and decreased AT III level
(50-80% of norm)
-- AT III (30 IU/kg daily over 3 days)
-- placebo
• results: AT III
-- significant shortening of DIC duration
-- no increased bleeding rate

1022 Hematology
 Factor XIII (Fibrogammin)
• Factor XIII leads to fibrin polymer formation via cross-
linking (therefore syn.: fibrin stabilizing factor).
study
• factor XIII deficiency of → frequent perioperative blee-
ding (diffuse; usually only hours after surgery) and
wound healing disorders
• Factor XIII deficiency is (as well as the von Willebrand
Antithrombin and mortality in severe pneumonia patients
with sepsis-associated disseminated intravascular coagu- factor) not detected by the usual tests (Quick, PTT; not
lation: an observational nationwide study even by thrombelastometry).
Tagami et al, J Thromb Haemost 2014 • causes for factor XIII deficiency:
-- congenital (very rare)
• large Japanese retrospective observational study
-- acquired (e.g. consumption in DIC, dilution coagu-
• 9075 patients with DIC in sepsis caused by severe
lopathy, massive blood loss, after major surgery,
pneumonia
ECMO [in 88%], liver failure, formation of inhibitors
-- AT III
to factor XIII)
-- placebo
• result: AT III → significant reduction in mortality • only relevant if activity < 30%
• dosage:
-- 1 IU/kg increases activity by 1-2% (target value >
Fibrinogen (Haemocomplettan HS) 50%).
-- desired increase of factor XIII (IU/dl) x kg BW, e.g.
• syn.: factor I
10-30 IU/kg BW in 24h
• cave: The fibrinogen preparation is called Haemocom-
-- for severe bleeding 15-20 IU/kg daily until factor XIII
plettan and not Fibrogammin (= Factor XIII).
activity > 50% or hemostasis
• indication:
• cave: Fibrogammin is the drug name for factor XIII and
-- with bleeding: at fibrinogen-level < 1 g/l not for fibrinogen (drug name: Haemocomplettan)!
-- without bleeding: at fibrinogen level < 0,5 g/l • 1 vial of Fibrogammin: 250 IU
• false measurements of fibrinogen: • very long half-life (100-120h; therefore usually no re-
-- falsely high: peated administration necessary)
◦◦ in acute inflammation: Fibrinogen is an acute pha- • relatively rarely indicated
se protein and can therefore be normal in inflam-
mations (especially sepsis).
◦◦ after administration of hydroxyethyl starch
-- falsely low: after administration of argatroban
• hyperfibrinolysis → additional antifibrinolytics (tranex-
amic acid)
• dosage:
-- initial 1-2g (4-8g in case of severe bleeding)
-- formula: dose in mg = desired increase (g/l) x plas-
ma volume (40 ml/kg); e.g. 2g in 30min

Fig. 1252  Fibrogammin: 1 vial contains 250 IU of factor XIII.

Factor VIIa

Definition
• syn.: NovoSeven, Eptacog alpha
• recombinant activated factor VII
• As part of the extrinsic system, factor VII activates fac-
tor X and thus coagulation.
• dosage: 100 μg/kg i.v. over 5min
• preparations (solution: 1mg per 1mg, so that concent-
Fig. 1251  Haemocomplettan: 1 vial contains 1g of fibrino- ration then 1 mg/ml)
gen.

Hematology 1023
 -- 1mg (50 kIU)
-- 2mg (100 kIU)
-- 5mg (250 kIU)
• The effect takes place locally at the site of the tissue
injury, i.e. where tissue factor has been released, so
that excessive coagulation activation with the risk of
thromboembolic complications is almost impossible.
• Novoseven is available since 2009 in a new formulati-
on, which is also stable at room temperature. Storage
in the refrigerator is possible, but not necessary.
• very expensive (approx. 1800 € per bottle [2mg])
• very short half-life → substitution 3-4 x daily necessary
Fig. 1253  NovoSeven: 1 vial contains 2mg (100kIU) factor
VII.
Indications
• acquired hemophilia A (approved; alternative: FEIBA
thrombasthenia Glanzmann (approved)
• factor VII deficiency (factor VII: proconvertin)
-- causes:
◦◦ congenital (autosomal recessive [mutations in the
F7 gene]; frequency 1: 300,000; bleeding only in
the homo-, not in the heterozygous form)
◦◦ acquired (especially vitamin K deficiency [part of
the prothrombin complex; note: Here one does not
have to substitute factor VII, but only vitamin K.])
-- syn .: hypoproconvertinemia, parahemophilia
-- symptoms: hemorrhagic diathesis
-- routine laboratory: Quick ↓ resp. INR ↑ with normal
PTT ( The most common cause of an unclear de-
crease in Quick or an increase in INR without clinical
signs of bleeding is a heterozygous factor VII defi-
ciency!)
• intracerebral hemorrhage (off label): The Novo7 stu-
dy in 2005 showed benefits (significant reduction in
mortality and improvement in neurological outcome in
intracerebral bleeding). In the large FAST study 2007,
however, there was no advantage, so that it is not (any
longer) recommended!
• massive diffuse bleeding in DIC (off label)
• severe life-threatening bleeding under the new antico-
agulants (dabigatran, rivaroxaban, apixaban, edoxa-
ban) as ultima ratio
1024 Hematology
Prerequisites
• pH > 7.2
• fibrinogen > 1.0 g/l
• platelets > 50000/μl
• exclusion of hyperfibrinolysis
Excursus: Acquired Hemophilia A (AHA)
Definition
• inhibitors (inhibitory [neutralizing] polyclonal autoanti-
bodies of IgG type) against coagulation factors (most
frequently against factor VIII [hence hemophilia])
• This hemophilia acquired in contrast to the congeni-
tal hemophilia with a congenital factor VIII deficiency
(note: Also in the congenital hemophilia inhibitors can
develop: These are antibodies against the applied fac-
tor VIII as part of substitution therapy in hemophilia.)
• The antibodies against substituted factor VIII in conge-
nital hemophilia are allo-antibodies, whereas the anti-
bodies against factor VIII in acquired haemophilia are
auto-antibodies.
• is very often overlooked!
• a life-threatening disease (a hematological emer-
gency!)
Guidelines
International recommendations on the diagnosis and
treatment of acquired hemophilia A; Tiede et al, Haema-
tologica 2020
Epidemiology
• Inzidenz: 1.5:1,000,000
• two age peaks
-- especially older patients (60-85 years)
-- postpartum (here better prognosis)
• m = w (in contrast to congenital haemophilia A, in which
only men are clinically affected due to the X-linked re-
cessive inheritance)
Types
• primary (50%; idiopathic)
• secondary (50%)
-- malignancies (therefore generous tumor search!)
-- autoimmune diseases (e.g. SLE, rheumatoid arthri-
tis, Sjogren syndrome, AIHA, Goodpasture syndro-
me, multiple sclerosis, myasthenia gravis)
-- pregnancy / puerperium (most frequently postpar-
tum; relatively long latency period with an average of
77 days [Tengborn et al, BJOG 2012]!)
-- infections
-- drugs (e.g. penicillin, sulfonamides, phenytoin, clopi-
dogrel, L-DOPA)
-- inflammatory bowel diseases
-- skin diseases (psoriasis, pemphigus vulgaris)
Symptoms
sudden spontaneous bleeding in patients without previ-
ous bleeding history (previously always if known incons-
picuous coagulation), especially:
• mucocutaneous (most frequent; typical large-area skin
 bleeding [sugillations, ecchymoses], massive hemato- -- specification in Bethesda units: 1 Bethesda units
mas ["as if beaten"]) B.U. = amount of inhibitor necessary to halve factor
• musculoskeletal (bleeding into the musculature, pos- VIII activity in healthy plasma
sibly compartment syndrome, bleeding into joints [but -- classification:
in contrast to congenital hemophilia in acquired hemo- ◦◦ high antibody titre (high titre): > 5 B.U./ml
philia almost never]) ◦◦ low antibody titre (low titre): < 5 B.U./ml
• urogenital (hematuria) )
• gastrointestinal
• pulmonary unclear bleeding + PTT ↑ → acquired
• intraabdominal, retroperitoneal hemophilia A (AHA)!
• intrakranial
PTT ↑:
bleeding → acquired hemophilia A
(AHA)
thrombosis → antiphospholipid
syndrome (APS)

Never ignore unclear PTT increase

(always clarify!)

Fig. 1254  Distinct hematoma in the left flank (Large-scale

bleeding is a typical consequence of a plasmatic coagulati-
on disorder [disorder of secondary hemostasis].)

In older patients with sudden

spontaneous bleeding (especially
skin), always remember acquired
hemophilia A (AHA)!

Diagnosis
• (often no longer measurable)
• normal values for platelets, Quick / INR, fibrinogen,
thrombin time (syn.: plasma thrombin time [PTZ]; ex-
clusion of effect of unfractionated heparin), anti-factor-
Xa (exclusion of effect of low molecular weight hepa-
rins)
• exclusion of lupus anticoagulant as a cause of PTT
prolongation (An antiphospholipid syndrome does not
cause bleeding but thrombosis.)
• plasma exchange test (mixed test, in vitro tube test:
In the laboratory, normal plasma, i.e. plasma from a
very common and completely
healthy person, is mixed with the patient's plasma in a
harmless cause of a PTT prolongati-
tube at a ratio of 1:1: In contrast to a real factor defici-
on: factor XII deficiency!
ency, PTT does not normalize here. The PTT remains
extended.)
• reduced factor VIII level and activity (Factor VIII is an Therapy
acute phase protein, so the level can be false normal
• for the therapy of bleeding or prophylactically before
especially with inflammation)
emergency surgery: bypass preparation
• Bethesda sest:
-- recombinant activated factor VII (NovoSeven)
-- determination of antibody concentration to factor VIII
◦◦ officially also approved for this purpose
(inhibitor titre)
◦◦ means of first choice (especially for severe blee-

Hematology 1025
 ding; significantly better than FEIBA [but also more
expensive]) intrinsic system extrinsic system
◦◦ Factor VII alone is sufficient for thrombin formation PTT Quick
and is not dependent on factor VIII, which does not
work here anyway due to the inhibiting antibody. XII, XI, IX tissue factor
Factor VIII is practically bypassed. Only relatively VIIa VII
high doses of factor VII are necessary. VIII
◦◦ dosage: 100 μg/kg i.v. every 2-3h, until the blee- X
ding is stopped (A single dose is usually sufficient.)
◦◦ additionally tranexamic acid 25 μg/kg prothrombin (II) thrombin (IIa) XIII
-- activated prothrombin complex concentrate (APCC), fibrin
fibrinogen (I) fibrin (Ia)
e.g. FEIBA (Factor Eight Inhibitor-Bypass-Activity): polymer
◦◦ special form of a PPSB preparation in which some Fig. 1255  Both the recombinant activated factor VII (Novo-
factors (especially factor VII) are already pre-acti- Seven) and FEIBA (here, among other things, factor VII is
vated (an activated PPSB preparation) already pre-activated) bypass the non-functioning factor
◦◦ This is sufficient for thrombin formation. Factor VIII. Thrombin and finally fibrin formation then takes place
via factor X.
VIII, which in any case does not work due to the
inhibiting antibody, is therefore not necessary and Prognosis
is practically bypassed
• spontaneous remission: in 38%
◦◦ dosage: 50-100 U/kg i.v. 2-3x daily (max. 200 U/
kg daily) • bleeding requiring transfusion: in 87%
-- human factor VIII preparations (3 x 100-200 IU/kg • mortality: 20%
i.v. daily; only with low antibody titre, i.e. < 5 B.U./ml); • especially during procedures (surgery, interventions
new approach: porcine factor VIII preparation (Obi- [e.g. cardiac catheterization]) massively increased risk
zur; is not attacked by the human antibodies due to of bleeding (Patients can even bleed to death intra-
the different structure; dosage: 200 U/kg) operatively!)
• for elimination of the antibody ("eradication"): immuno- • relapse: in 20%
suppression (mostly combination therapy with steroids
and cyclophosphamide) TFPI (tissue factor pathway inhibitor)
-- steroids (standard: immediate start with predni- • tifacogin: rekombinanter tissue factor pathway-Inhibi-
solone 1 mg/kg p.o. over 4 weeks) tor
-- cyclophosphamide 1.5-2 mg/kg p.o. • tissue factor: a main trigger of increased coagulation
-- rituximab (Mabthera) in sepsis
◦◦ an anti-CD20 antibody • no recommendation
◦◦ in case of failure of combination therapy of stero-
ids and cyclophosphamide
◦◦ dosage: infusion with 375 mg/m2 BSA once a
week for 4 weeks
OPTIMIST study
-- immunoglobulins: not recommended
-- possibly emicizumab (Hemlibra)
◦◦ a factor VIII mimetic (monoclonal antibody) Efficacy and Safety of Tifacogin (Recombinant Tissue Fac-
◦◦ approved, however, only for congenital haemophi- tor Pathway Inhibitor) in Severe Sepsis
lia Abraham et al, JAMA 2003
◦◦ no combination with activated prothrombin com-
plex concentrate (FEIBA; otherwise DIC) • multicenter randomized controlled study
• 1,754 patients with severe sepsis and INR > 1.2
-- possibly apheresis with immune adsorption
-- tifacogin 0.025 mg/kg/h over 96h
-- possibly immunotolerance therapy
-- placebo
• result: tifacogin → no difference in 28-day mortality
(but significantly lower mortality in the subgroup that did
not receive heparin)

Desmopressin (Minirin)

Definition
• syn.: DDAVP (Deamino-D-Arginine-Vasopressin)
• effect: Release of vWF (von Willebrand factor; exactly:
multimer; 3-fold increase) and of factor VIII from the
Weibel-Palade bodies of the endothelial cells

1026 Hematology
• dosage: 1 amp. (= 1ml = 4μg) per 10kg, i.e. 0.4 μg/kg
as short infusion in 50ml NaCl 0.9% over 30min or in
10ml NaCl 0.9% over 10min; repetition after 6h theore-
tically possible, but mostly pointless, since the stores
are empty
• only singe dose possible (Desmopressin leads to
emptying the stores. It takes weeks to refill the sto-
rage!); repetition makes sense after 24 hours at the
earliest
• effective in thrombocytopenia (threefold increase in
thrombocytes, washout from the bone marrow) and
thrombocytopathies (promotes thrombocyte aggrega-
tion)
• Desmopressin not only causes an increased release
of vWF and factor VIII, but also of t-PA (tissue plami-
nogen activator), so that increased fibrinolysis can oc-
cur. A combination with an antifibrinolytic agent (e.g.
tranexamic acid 5 mg/kg over 1 hour) is therefore
recommended if the bleeding time does not decrea-
se after the first dose (The bleeding time is nowadays
only measured in vitro [PFA-100 test]. The whole blood
measurement in vitro has been abandoned).
Fig. 1256  Minirin (1 amp. = 1ml = 4μg)
Indications
• antidiuretic (Desmopressin [= synthetic derivative of
vasopressin] binds to the V2 receptors of the collecting
ducts of the kidneys and causes an increased incor-
poration of aquaporins into the cell membrane, so that
water retention occurs.): central diabetes insipidus (as
nasal spray or i.v.)
• antihemorrhagic:
-- thrombocytopathies
◦◦ hemophilia
◦◦ von Willebrand disease
-- bleeding under platelet aggregation inhibitors (ASA,
clopidogrel, prasugrel; not effective in ticagrelor [i.a.
Teng et al, J Clin Pharm Ther 2014]) or perioperative
antagonization
-- unclear bleeding perioperative or posttraumatic
-- bleeding in uremia
-- bleeding in liver cirrhosis
Side effects
• water retention, diuresis ↓ (due to the antidiuretic ef-
fect)
-- possibly oliguria to anuria (cave especially in case of
pre-existing renal failure)
-- therefore pay particular attention to the balance
• hyponatremia (due to dilution)
• BP ↓ (especially if the infusion is too rapid)
• flush
• Kopfschmerzen
• nausea, vomiting, crampy abdominal pain
Excursus: von Willebrand disease (vWD)
Definition
• syn.: von Willebrand-Jürgens syndroms (vWS)
• named after the Finnish physician Erik Adolf von Wille-
brand (1870-1949; discovered in the Sandblom family
on the Åland Islands off Finland) and German physici-
anRudolf Jürgens (1898-1961)
• deficiency of von Willebrand factor (vWF): This is a
macromolecule (multimer; the largest protein in the
human body), which is formed in endothelial cells
(Weibel-Palade bodies) and megakaryocytes and has
a double function:
-- On the one hand, it is important for platelet aggre-
gation. Deficiency leads to thrombocytopathy with
petechial bleeding.
-- On the other hand, it is important for factor VIII ("pa-
tron saint"): Factor VIII is a very unstable molecule
which is stabilized by vWF. A deficiency therefore
also leads to a disturbance of the plasmatic coagula-
tion with bleeding as in hemophilia (i.e. large areas).
• hemorrhagic diathesis (mixed)
-- disturbance of the primary hemostasis (cellular [pla-
telets]; platelet defect) → petechial bleeding (i.e.
only weakly pronounced and only superficial tissue
[skin, mucous membrane] affected)
-- disturbance of the secondary hemostasis (plasmatic;
clotting defect) → hemophilic bleeding (i.e. strongly
pronounced [ecchymoses] and also deeper tissue
[muscles, joints] affected)
Epidemiology
• prevalence: 1% (1: 100; mostly asymptomatic [symp-
tomatic: 0.1%])
• the most common congenital bleeding disorder
• m = w (in contrast to hemophilia, which clinically only
affects men)
Types
• congenital (often)
-- quantitative deficiency:
◦◦ partial: type I (80%; autosomal dominant; mild
form)
◦◦ complete: type III (5%; autosomal recessive; se-
vere form)
-- qualitative deficiency: type II (15%; autosomal do-
minant)
◦◦ A: defective polymerization (most common sub-
form; lack of large multimers)
◦◦ B: spontaneous platelet binding (structural defect
of the vWF with an increased affinity for the Gp-Ib
receptor)
◦◦ M: defective ligand binding (reduced interaction
between vFW and platelets)
◦◦ N: defective factor VIII binding (like haemophilia A)
• acquired (rarely)
Hematology 1027
 -- neoplastic ( most common cause of an acquired
vWD): lymphoproliferative diseases (especially lym-
phoma, plasmacytoma, MGUS [monoclonal gammo-
pathy of undetermined significance], Waldenström´s
disease), myeloproliferative syndrome
-- autoimmune (e.g. SLE, IgA vasculitis)
-- circulatory:
◦◦ aortic valve stenosis: Heyde´s syndrome (named
after the American internist Edward C. Heyde, who
described the syndrome in 1958)
▪▪ gastrointestinal bleeding from angiodysplasia
(especially large intestine, small intestine)
▪▪ The aortic valve stenosis leads to high shear
stress, which destroys the vWF. A lack of vWF
causes uncontrolled angiogenesis. After aortic
valve replacement, the angiodysplasias disap-
pear again.
◦◦ LVAD (left ventricular assist device), ECMO (de-
struction of the vWF due to excessive shear
stress; in 80%)
-- pharmacological (e.g. colloids ["coating" of the
platelets], valproin acid)
-- endocrinological: hypothyroidism
Symptome (Blutungen)
• mucosal bleeding (e.g. epistaxis)
• bruising, hematomas (especially after minor trauma)
• menorrhagia (often the first clinical sign of a vWD in
women!)
• post-bleeding (e.g. after tooth extraction, surgery)
• gastrointestinal bleeding
• joint bleeding (hemarthrosis; mostly only in type III)
Laboratory
• general:
-- Quick value (INR): normal
-- mostly PTT ↑ (due to the reduced factor VIII activity;
however, a normal PTT does not exclude vWD at all!
The von Willebrand factor is not recorded by Quick
and PTT [note: This also applies to factor XIII.]!)
-- platelets: mostly normal (reduced only with vWD
type IIB)
-- bleeding time ↑ (previously measured in vivo, today
in vitro [PFA-100 test]; normal in hemophilia)
-- Determination of the blood group: Physiologically,
patients with blood group 0 have lower levels of von
Willebrand factor and factor VIII. Therefore, these
patients also have a two-fold lower risk of thrombos-
embolism than patients with a different blood group
(non-0, i.e. A, B or AB).
• special:
-- von Willebrand antigen (immunological measure-
ment of the concentration of vWF by means of anti-
sera; reduced in vWD types I and III)
-- factor VIII activity (reduced especially in vWD type
III and IIN)
-- ristocetin cofactor (syn .: vWF activity)
◦◦ measurement of the ability of the vWF to aggluti-
nate washed platelets in vitro via the Gp-Ib recep-
1028 Hematology
tor in the presence of the antibiotic ristocetin
◦◦ ratio ristocetin cofactor / von Willebrand antigen
▪▪ > 0.7: type I and type III
▪▪ < 0.7: type II and aquired vWS
-- vWF multimer analysis (for exact typing)
Therapy
• usually no long-term therapy necessary
• issuing a bleeding card
• desmopressin (DDAVP; Minirin)
-- means of first choice
-- either i.v. (e.g. prophylactically before surgery) or
inhaled (e.g. in menorrhagia; 1 puff Octeostim per
nostril 1-2 x daily)
-- ineffective, however, for vWD type II (even contra-
indicated for IIB), here factor concentrates are ne-
cessary
• preoperative prophylactic administration:
-- Desmopressin (DDAVP; Minirin) i.v.
◦◦ 0.4 μg/kg as short infusion in 50ml NaCl 0.9% over
30min
◦◦ 3-fold increase in vWF
◦◦ testing recommended beforehand whether the
vWF actually increases (measurement of the level
after 1h, 2h and 4h)
-- tranexamic acid (1g i.v. before surgey, then three
times a day)
-- iron administration (e.g. Ferlecit 100mg; to prevent
anemia and thus to improve hemostasis)
-- in the case of very large interventions (major surge-
ry) additional factor concentrates:
◦◦ vWF + factor VIII (Haemate; standard): 40-80 IU/
kg vWF i.v. + 20-40 IU/kg factor VIII i.v. (if neces-
sary, repeat after 24 hours until the wound heals);
control by ristocetin cofactor, which should be nor-
mal
◦◦ factor VIII (Immunate): 30-80 IU/kg i.v.
◦◦ vWF (Vonvendi): 50 IU/kg i.v.
• tranexamic acid
• careful local hemostasis
• avoidance of platelet aggregation inhibitors (e.g. ASA)
• acquired vWS:
-- causal (therapy of the underlying disease)
-- symptomatic (e.g. immunoglobulins in lymphoproli-
ferative disease, plasmapheresis in plasmacytoma,
immunosuppressive therapy in autoimmune disea-
ses)
Excursus: New methods in coagulation
diagnostics
ROTEM
Definition
• ROTEM: rotational thrombelastometry
• Thrombelastometry (TEM) is a method that measures
the strength of the blood clot (a viscoelastic method).
The graphical representation is called thrombelasto-
 graphy (TEG). The procedure has been known since
1948 by Hartert. Several TEM methods have already
been introduced. Rotational thrombelastometry is now
a newer method in which the measurement is perfor-
med by means of a plunger ("spindle") rotating in a
stationary vessel. The reduction in the deflection of the
spindle due to clot formation is detected optically. Both
the formation and the breakdown (fibrinolysis) of the
clot are analyzed.
• can be performed on the bed side (e.g. in the emer-
gency room, intensive care unit or operation room) as
POCT (point of care testing)
• The purpose of the ROTEM system is to carry out a dif-
ferentiated individualized coagulation diagnosis quickly
and on the bed side in the case of bleeding, in order
to then specifically (theragnostically) use hemothera-
peutics. Among other things, the unnecessary admi-
nistration of hemotherapeutics and thus also costs are
to be reduced. Experience has shown that as a result
of ROTEM diagnostics, less FFP and more fibrinogen
are administered, so that in some places the ROTEM
is also disrespectfully referred to as a "fibrinogen de-
struction machine". A possible therapy algorithm (e.g.
procedure for acute bleeding in the emergency room)
is shown in the infobox.
• sample: citrate blood (recalcified with calcium chlori-
de); then adding an activator, if necessary also an in-
Fig. 1257  ROTEM system
hibitor
• activators: Indications
-- extrinsic route (EXTEM): recombinant tissue factor • unclear massive bleeding (especially polytrauma, pe-
-- intrinsic route (INTEM): ellagic acid rioperative)
• inhibitors: • monitoring fibrinogen substitution
-- tranexamic acid (inhibition of fibrinolysis; APTEM = • suspected hyperfibrinolysis
EXTEM + inhibitor tranexamic acid); abbreviation AP
comes from AProtinin (an older antifibrinolytic that
was previously used for this test)
-- cytochalasin D (inhibition of platelets; FIBTEM = Parameters
EXTEM + inhibitor cytochalasin D); abbreviation FIB • CT (clotting time):
comes from the fact that with this test only the pro- -- time from addition of the activator to the start of clot
portion of the FIBrinogen, i.e. without platelets, of the -- normal value:
clot formation ist measured
◦◦ EXTEM: 38-80s (corresponds to the prothrombin
-- Heparinase (inhibition of heparin; HEPTEM = IN- time [Quick value])
TEM + inhibitor heparinase)
◦◦ INTEM: 100-240s (corresponds to the PTT [partial
• measurement at a temperature of 37°C thromboplastin time])
• 4 blood samples can be analyzed in 4 channels at the -- pathological (i.e. prolonged): insufficient thrombin
same time generation (especially synthesis deficits in prothrom-
• costs: approx. € 5 per test series bin formation, thrombin inhibitors)
• devices: ◦◦ EXTEM-CT: deficiency of vitamin K-dependent co-
-- ROTEM gamma agulation factors
-- ROTEM delta ◦◦ INTEM-CT:
-- ROTEM sigma: This is the latest generation. Where- ▪▪ heparin (HEPTEM-CT: not prolonged)
as in the previous versions you always had to pipette ▪▪ deficiency of non-vitamin K-dependent coagu-
the activators and inhibitors in a laborious manner, lation factors or inhibitors (HEPTEM-CT: also
this is now done fully automatically in a single ready- prolonged)
made cuvette (e.g. ROTEM sigma complete = EX- • CFT (clot formation time):
TEM + INTEM + FIBTEM + APTEM + poddiblx [with
-- time from the start of clot formation to clot strength of
ROTEM sigma complete + hep] HEPTEM).
an amplitude of 20 mm in the curve
-- normal value: 35-160s
-- pathological (> 160s):
◦◦ thrombocytopathy, thrombocytopenia

Hematology 1029
 ◦◦ fibrinogen deficiency (or fibrinogen polymerization deflection in mm
disorder [i.e. factor XIII deficiency]) (firmness)

• A10 (amplitude 10min after CT; normal value: 40-

66mm [FIBTEM: 7-23mm]); analogous A15 (normal
100
value: 48-69mm), A20 (normal value: 50-71mm) and 80
A25 (normal value: 50-72mm) 60
40
• MCF (maximal clot firmness; highest amplitude of the 20
curve):
-- normal value: 50-72mm (FIBTEM: 9-25mm)
-- pathological (< 53mm):
◦◦ fibrinogen deficiency (here also FIBTEM-MCF re-
CT CFT time (minutes)
duced)
◦◦ thrombocytopathy, thrombocytopenia (here FIB- 10 20 30 40 50
TEM-MCF normal)
• alpha angle (rise of the measurement curve as an ang- Fig. 1260  massively elongated CT (clotting time) and CFT
le between measurement curve and time axis; tangen- (clot formation time); e.g. in case of overdose of anticoagu-
tial through the curve with a deflection of 2mm): mea- lants
surement of the kinetics of clot formation
-- The steeper, the faster the clot formation rate. deflection in mm
(firmness)
-- The shallower, the slower the clot formation rate.
• lysis indices: stability of the clot against fibrinolytic acti-
vity (CLI < 85% or ML > 15%: hyperfibrinolysis) 100
80
-- CLI (clot lysis index; usually CLI30 [30min after CT]) 60
40
-- ML (maximum lysis [maximum lysis during the mea- MCF
20
surement period in relation to the MCF])

deflection in mm
(firmness)
time (minutes)

100 10 20 30 40 50
80
ML CFT
60
40 A10 MCF Fig. 1261  curve in case of a disturbance of the platelet
20 CLI30 function (thrombocytopathy [e.g. platelet inhibitor] or
α
thrombocytopenia): prolonged CFT (clot formation time)
and reduced MCF (maximum clot firmness), which leads to
a flat curve

CT time (minutes) Tests

10 20
• without inhibitors
30 40 50
CFT -- EXTEM:
Fig. 1258  ROTEM parameters (normal curve) ◦◦ measurement of the extrinsic system
◦◦ activator: recombinant tissue factor
deflection in mm ◦◦ The EXTEM also contains hexadimethrine bromi-
(firmness)
de (Polybrene) to neutralize the heparin.
◦◦ The clotting time (CT) measured in the EXTEM
100
corresponds to the prothrombin time (Quick va-
80 lue): EXTEM-CT = prothrombin time (Quick).
60
40 -- INTEM:
20
◦◦ measurement of the intrinsic system
◦◦ activator: ellagic acid
◦◦ The clotting time (CT) measured in the INTEM cor-
responds to the PTT (partial thromboplastin time):
time (minutes) INTEM-CT = PTT.
• with inhibitors
10 20 30 40 50
-- APTEM:
Fig. 1259  curve for hyperfibrinolysis: clot formation is nor-
◦◦ for the detection of hyperfibrinolysis
mal, but clot dissolution is much too strong and too fast, so
that after 25 minutes there is no longer any clot. ◦◦ activation: like EXTEM + blockade of fibrinolysis
(previously with aprotinin, today with tranexamic
acid)
◦◦ Whereas EXTEM already shows dissolution of

1030 Hematology
 the clot early (including pathological lysis indices Fig. 1262  Interpretation of ROTEM (procedure for acute
[CLI, ML]), this is not the case with APTEM (here diffuse bleeding); as an alternative to the fibrinogen defi-
normal finding). The EXTEM-ML is pathological (> ciency, it can also be a fibrinogen polymerisation disorder
15%), the APTEM-ML is normal (<15%). Tranexa- (i.e. factor XIII deficiency); note: In the case of active blee-
ding despite normal CT and MCF in EXTEM and INTEM, the
mic acid should now administered therapeutically.
following should be considered or checked: cofactors (ge-
If, in addition to the EXTEM-ML, the APTEM-ML is neral conditions such as hypothermia, metabolic acidosis,
also pathological, the instability is not due to hy- hypocalcaemia), presence of bleeding that can be surgi-
perfibrinolysis, but (most often) due to a factor XIII cally stopped, von Willebrand disease, thrombocytopathy
deficiency in the sense of the term of a fibrinogen due to platelet inhibitors (e.g. ASA)
polymerization disorder. Then factor XIII should be
administered.
-- FIBTEM:
◦◦ to differentiate the plasmatic from the thrombocyte
part of the clot formation (only the part of the fibri-
nogen, i.e. without platelets, of the coagulation. is
measured)
◦◦ activation: like EXTEM + blockade of platelets (cy-
tochalasin D)
◦◦ FIBTEM-A10 < 7mm: fibrinogen deficiency → ad-
ministration of fibrinogen (target FIBTEM-A10: 10-
12mm)
-- HEPTEM:
◦◦ for the detection of a heparin effect: Here it is ex-
amined whether a heparin effect (i.e. too much
heparin; e.g. after intraoperative retransfusion of
blood from an autotransfusion system [CellSaver])
is the cause of a bleeding. If this is the case, pro-
tamine is administered to antagonize the heparin.
◦◦ for ROTEM analysis in fully heparinized patients
◦◦ activation: like INTEM + blockade of heparin (he-
parinase)
◦◦ Heparin effect is present if the CT and CFT are
prolonged in the INTEM, but normal in the HEP-
TEM.
-- note: NATEM (without activator and inhibitor; NA:
not activated; only addition of calcium chloride for
recalcification)

INTEM normal → oK EXTEM

CT MCF / CFT CLI,MI CT

Limitations
prolonged pathological pathological prolonged
(i.e. MCF ↓ / CFT ↑) (i.e. CLI ↓ / MI ↑)
• thrombocytopathies (e.g. thrombasthenia Glanzmann
[absence of GIIb/IIIa receptors])
HEPTEM FIBTEM APTEM
• platelet inhibitors (ASA, clopidogrel, prasugrel, ticag-
CT MCF CLI,MI relor)
normal prolonged reduced normal normal pathological • von Willebrand disease
heparin deficiency of fibrinogen thrombocyto- hyper- factor XIII deficiency of
• factor XIII deficiency
effect non-vitamin
K-dependent
deficiency penia or
thrombocyto-
fibrinolysis deficiency vitamin K-
dependent
• GpIIb-IIIa receptor antagonists (especially abciximab)
factors or
inhibitors
pathy factors • only relatively low sensitivity for oral anticoagulants
(e.g. coumarins; NOAC, however, have no influence
protamin FFP fibrinogen platelet concentrates or tranexamic factor XIII PPSB on the measured values), LMWH, danaparoid (Orga-
DDAVP (desmopressin) acid ran) and fondaparinux (Arixtra)
• no standard validation (yet) using round robin tests

Multiplate
Definition
• multiple platelet function analyzer (Roche company)
• measurement of platelet function (overview of possible

Hematology 1031
 methods: see infobox)
• method: impedance aggregometry
-- Platelets are activated and aggregated at the sur-
face of a sensor wire, leading to an increase in
electrical resistance (impedance). This resistance is
measured.
-- measurement of the increase of the impedance as
area under the curve after activation of the platelets
• can be performed on the bed side (e.g. in the emer-
gency room, intensive care unit or operation room) as
POCT (point of care testing; results within 10min)
• material: whole blood
• 4 channels for different activators:
-- TRAP (thrombin receptor activating peptide; princip-
le stimulability of platelets)
-- collagen (physiological stimulability of platelets)
-- arachidonic acid (measured value < 250 AUC: good Fig. 1264  Multiplate-System of the company Roche [41]
ASA effect)
-- ADP (adenosine diphosphate; measured value < Indications
200 AUC: good clopidogrel effect [responder]) • assessment of the effect of ASA, clopidogrel, GpIIb-IIIa
• only valide with a normal account of platelets and ery- receptor antagonists, especially to exclude resistance
throcytes is normal (applies to all methods of measu- (especially clopidogrel non-responders [especially af-
ring thrombocyte function) ter a coronary in-stent thombosis; note: in this case,
however, it is better to switch to prasugrel or ticagre-
lor.]); note: The standard for acute coronary syndrome
with PCI + stent implantation for DAPT (dual antipla-
telet therapy) in addition to ASA is prasugrel or ticag-
relor today. However, if there are contraindications to
it, clopidogrel must be given. Here, however, the non-
responder rate is 30%. Therefore the measurement of
the platelet function is mandatory here!
• preoperative exclusion of pharmacological platelet ag-
Fig. 1263  In the Multiplate system, the impedance increase gregation inhibition
is measured as an area under the curve (AUC) of aggregati-
on time after activation of the platelets [41].

Excursus: NOAC

Definition
• NOAC:
-- novel oral anticoagulants
-- non-vitamin K dependent oral anticoagulants
• direct inhibition of coagulation factors (hence also re-
ferred to as DOAC [direct oral anticoagulants]); for an
overview of the anticoagulants see infobox
• fixed dose (regardless of body weight)

1032 Hematology
• no more coagulation monitoring (e.g. INR measure- ciation Practical Guide on the use of non-vitamin K
ment) necessary antagonist oral anticoagulants in patients with atrial
• The novel anticoagulants (especially dabigatran and ri- fibrillation
varoxaban; Apixaban almost not) all lead to increased
INR and prolonged PTT (no misinterpretation).
• The main indication for NOAC is atrial fibrillation. They
are only officially approved for non-valvular atrial fib-
rillation. By definition, in valvular atrial fibrillation a he-
GALILEO study
modynamically relevant vitium must be present. Accor-
ding to the ESC / EACTS guidelines 2017 (Guidelines
for the management of valvular heart disease), NOACs
are now also possible for atrial fibrillation in aortic valve A Controlled Trial of Rivaroxaban after Transcatheter Aor-
stenosis, aortic valve insufficiency and mitral valve in- tic-Valve Replacement
Dangas et al, N Engl J 2019
sufficiency (only not for mitral valve stenosis [from mo-
derate]). They are also possible with biological artificial • multicenter, randomized, open-label phase III study
valves (incl. after TAVI; note: In the GALILEO study • 1644 patients after successful TAVI (exclusion criterion:
[see box], rivaroxaban led to more thromboembolism, especially atrial fibrillation)
more bleeding and ultimately to an increased all-cause -- or 90d ASA 75-100mg + rivaroxaban 10mg, then only
mortality in patients with TAVI. The study was termina- rivaroxaban
ted prematurely and a corresponding Red-Hand-Letter -- for 90d ASA 75-100mg + clopidogrel 75mg, then only
10/2018 for warning was published. In this study, how- ASA
ever, rivaroxaban was administered for thrombosis • Result: premature discontinuation because in the ri-
prophylaxis after TAVI and not for atrial fibrillation. Pati- varoxaban group
ents with atrial fibrillation were even excluded from this -- increased all-cause mortality
study). With mechanical artificial heart valves, howe- -- more thromboembolism
ver, only coumarins are still possible. The RE-ALIGN -- more bleeding
study (Eikelboom et al, N Engl J 2013) even showed
significantly more thromboembolism and bleeding in
mechanical artificial heart valves when using dabiga-
tran versus warfarin. In the case of renal insufficiency
with a GFR < 15 ml/min or dialysis requirement, only
coumarins are possible for oral anticoagulation. NOAC
should also not be used in the case of the antiphos-
pholipid syndrome, as the TRAPS study (Pengo et al,
Blood 2018]) showed significantly more thromboembo-
lism under NOAC (rivaroxaban) than under VKA (Red-
Hand-Letter 5/2019).
• Perioperative bridging therapy is no longer necessary.
This is bad and dangerous anyway (e.g. with atrial fi-
brillation)!
• Risk of gastrointestinal bleeding with apixaban or edo-
xaban lower than with dabigatran or rivaroxaban [me-
ta-analysis Guo et al, Clin Epidemiol 2019])
• A meta-analysis (Chatterjee et al, JAMA Neurol 2013)
showed that the use of the novel anticoagulants for
stroke prophylaxis in atrial fibrillation reduced the risk
of brain hemorrhage by 51% compared to warfarin.
However, there was (slightly) more gastrointestinal
bleeding. There was no advantage for a special novel
anticoagulant.
• contraindicated in pregnancy and lactation
• The kidney function should be checked regularly (rule
of thumb for the control interval: months = GFR / 10)
• expensive (approx. 10 times more expensive than cou-
marin)
• beware of interactions with other drugs: increase in
NOAC levels with a consequent increased risk of blee-
ding, especially at
-- macrolide antibiotics (especially clarithromycin)
-- azole antifungals (fluconazole, voriconazole)
• guideline: The 2018 European Heart Rhythm Asso-

Hematology 1033
 Nevertheless, the administration of PPSB is explicitly
No NOAC in valvular atrial recommended by the manufacturer in case of bleeding
fibrillation with mitral valve under dabigatran.
stenosis (from moderate), with • dialyzable (since with 35% only relatively low protein
mechanical artificial (prostethic) binding; 2h after dialysis only 60% are left, 4h after dia-
heart valves, during pregnancy lysis surgery is possible)
and lactation, with GFR < 15 ml/ • idarucizumab (Praxbind) approved as antidote (see
min and with antiphospholipid page 1040)
syndrome!
Approvals
• since 2008 approved for thrombosis prophylaxis after
Representatives hip/knee TEP (RE-NOVATE study); dosage: 1 x dai-
ly 220mg (creatinine clearance < 50 ml/min: 150mg;
• factor II inhibitor (factor II: thrombin): dabigatran
creatinine clearance < 30 ml/min: contraindicated) p.o.
(Pradaxa)
• since 2011 approved for the prevention of stroke and
• factor X inhibitor (factor X: thrombokinase, Stuart-
systemic embolism in non-valvular atrial fibrillation (do-
Prower factor; the name comes from the fact that they
sage: 2 x 150mg; dose reduction to 2 x 110mg in the
inhibit factor Xa ["Xa-bane"]):
following cases: age > 80 years, creatinine clearance
-- rivaroxaban (Xarelto) 30-50 ml/min, simultaneously verapamil [verapamil in-
-- apixaban (Eliquis) creases plasma level of dabigatran by 160%] or ASA,
-- edoxaban (Lixiana) clopidogrel, NSAID; contraindicated already from crea-
tinine clearance < 30 ml/min [for all other NOAC only
Dabigatran (Pradaxa) from < 15 ml/min])
• since 2014 approved for therapy and secondary pro-
Definition phylaxis in deep vein thrombosis or pulmonary embo-
• selective factor II (thrombin) inhibitor lism (dosage: first 10 days of parenteral anticoagulati-
• a prodrug (cave proton pump inhibitors: reduce on, then 2 x 150mg [if age > 80 years or verapamil: 2
bioavailability!) x 110mg])
• bioavailability: 6%
• no coagulation monitoring required (PTT possible, if
necessary measurement of thrombin time [only pos-
sible in special laboratories; e.g. HemoclotThrombin- RECOVER study
Inhibitor-Test])
• cave interactions with:
-- P-glycoprotein inhibitors (increased bleeding risk)
◦◦ azol antifungals (ketoconazole, itraconazole, vori- Dabigatran versus Warfarin in treatment of acute venous
conazole, posaconazole) thrombembolism
◦◦ ciclosporin, tacrolimus Schulmann et al, N Engl J 2009
-- amiodarone, dronedarone, verapamil, quinidine,
• multicenter randomized non-inferiority study
spironolactone, clarithromycin (enhanced effect of
• 2539 patients with deep vein thrombosis/ pulmonary
dabigatran with increased bleeding risk) embolism: over 6 months
-- St. John's wort (lowers plasma levels of dabigatran; -- warfarin
contraindicated) -- dabigatran
-- proton pump inhibitors • results: dabigatran
• monitoring (not obligatory; optional): -- primary endpoint (recurrent thromboembolic event,
-- Hemoclot-DTI (diluted thrombin time) death): equally effective (not inferior)
-- ECT (ecarin clotting time) -- secondary endpoint (bleeding): significantly reduced
-- ECA (ecarin chromogenic assay)
• patients who are under long-term medication with da-
bigatran and now have to undergo surgery on fibrinoly-
sis as an emergency: If the PTT (thrombin time) is not
increased (> 3 hours after ingestion), there is certainly
no therapeutic level left.
• It is not possible to administer it via nasogastric tube
or PEG, as the capsule must remain intact with the
pellet filling.
• PPSB for bleeding: This is not undisputed, because
in the study by Eerenberg (Circulation 2011) the admi-
nistration of PPSB was not effective in bleeding under
dabigatran in contrast to bleeding under rivaroxaban.

1034 Hematology

RELY study
Dabigatran versus Warfarin in Patients with Atrial Fibrilla-
tion
Conolly et al, N Engl J 2009
• multicenter randomized non-inferiority study
• 18,114 Patients with non-valvular atrial fibrillation
-- warfarin
-- dabigatran
• results: dabigatran
-- significantly fewer cardioembolic events
-- no increased bleeding rate
Rivaroxaban (Xarelto)
Definition
• selective factor X inhibitor
• bioavailability: 80%
• no coagulation monitoring required (but possible via
anti-factor Xa activity, but not via PTT)
• always leads to changes in coagulation parameters
(Quick ↓, INR ↑, PTT ↑)
• short half-life (7-13h); surgery possible if no rivaroxa-
ban is taken for 24h
• no anti-factor X activity or normal Quick (> 3h after in-
gestion) → certainly no longer a therapeutic level that
leads to an increased risk of bleeding (e.g. surgery and
possibly also fibrinolysis in case of stroke [however un-
reliable] possible)
• not dialyzable (because of 93% relatively high protein
binding)
Approvals
• thrombosis
-- prophylaxis (since 2008 approved for thrombosis
prophylaxis after hip TEP; dosage: 1 x daily 10mg
p.o.)
-- therapy (since 2011 approved for thrombosis thera-
py without pulmonary embolism; dosage: 2 x daily
15mg p.o. for 3 weeks, then 1 x 20mg; GFR 50-15
ml/min: also for 3 weeks 2 x 15mg, then only 1 x
15mg, GFR < 15 ml/min: not recommended)
• atrial fibrillation (non-valvular): for the prevention of
strokes and systemic embolisms (approved since
2011; dosage: 1 x 20mg p.o.; GFR 50-15 ml/min: 1 x
15mg, GFR < 15 ml/min: not recommended)
• pulmonary embolism (approved since 2012; dosage:
2 x daily 15mg p.o. for 3 weeks, then 1 x 20mg; GFR
50-15 ml/min: also for 3 weeks 2 x 15mg, then only 1 x
15mg, GFR < 15 ml/min: not recommended)
• acute coronary syndrome - secondary prevention (in
combination with standard antiplatelet drugs approved
since 2013; dosage 2 x 2.5mg)
Studies
• RECORD studies 1-3: compared to enoxaparin
-- significantly less thromboses
-- no increased bleeding rate
• ROCKET-AF (atrial fibrillation: rivaroxaban versus
warfarin): significant reduction of strokes and systemic
embolisms, bleeding rate not increased (see box)
• ATLAS ACS-TIMI 46 (ACS): stopped prematurely (no
effect)
• ATLAS ACS-TIMI 51 (Mega et al, N Engl J 2012): Ri-
varoxaban (in addition to ASS + thienopyridine) after
acute coronary syndrome → significant reduction of
primary endpoint (cardiovascular death, myocardial in-
farction, stroke) in significantly more bleeding
• ATLAS-ACS 2 TIMI 51 (see box)
• COMPASS (see box)
• PIONEER AF-PCI (see page 367)
• EINSTEIN-DVT (DVT: deep vein thrombosis; Bauer-
sachs et al, N Engl J 2010): rivaroxaban versus enoxa-
parin/ warfarin for deep vein thrombosis → not inferior
• EINSTEIN-PE (PE: pulmonary embolism; Büller et al,
N Engl J 2012): rivaroxaban versus enoxaparin/ warfa-
rin for pulmonary embolism → not inferior, less major
bleeding
• X-VeRT (Cappato et al, Eur Heart J 2014): Rivaroxa-
ban was not inferior to warfarin in patients undergoing
cardioversion for atrial fibrillation
ROCKET-AF study
Rivaroxaban once daily oral factor Xa inhibition compared
with vitamin k antagonism for prevention of stroke and em-
bolism trial in atrial fibrillation
Becker et al, Am Heart J 2010
• multicenter randomized controlled study
• 14262 patients with non-valvular atrial fibrillation
-- warfarin
-- rivaroxaban
• results: rivaroxaban
-- primary endpoint: stroke and systemic embolism →
significant reduction (relative risk reduction of
21%)
-- secondary endpoints
◦◦ hemorrhagic stroke: significant reduction
◦◦ bleeding (extracranial): no difference
Hematology 1035

ATLAS ACS 2-TIMI 51
Anti-Xa Therapy to Lower cardiovascular events in Addi-
tion to standard therapy in Subjects with Acute Coronary
Syndrome –Thrombolysis in Myocardial Infarction 51: A
randomized, double-blind, placebo-controlled study to
evaluate the efficacy and safety of rivaroxaban in subjects
with acute coronary syndrome
Gibson et al, Am Heart J 2011
• multicenter randomized controlled study
• 15526 patients with acute coronary syndrome; in additi-
on to standard
-- rivaroxaban (low dose: 2 x 2.5 or 2 x 5mg)
-- placebo
• results: rivaroxaban
-- significantly reduced combined primary endpoint
(cardiovascular mortality, myocardial infarction, stroke
-- significantly fewer stent thromboses (by 35%)
-- significantly reduced all-cause mortality
-- significantly more frequent major bleedings
tivity
• no anti-factor X activity (> 4h after ingestion) → cer-
tainly no longer a therapeutic level that leads to an
increased risk of bleeding (e.g. surgery and possibly
also fibrinolysis in case of stroke [however unreliable]
possible)
• additional benefit confirmed by the Joint Federal Com-
mittee according to §35a SGB
• in contrast to dabigatran and rivaroxaban no influence
on INR or PTT
Approvals
• thrombosis prophylaxis after hip/knee TEP (ADVANCE
studies)
• atrial fibrillation (non- valvular): on the prevention of
stroke and systemic embolism (studies: AVERROES,
ARISTOTLE [see box])
• since 2014 for the treatment and secondary preventi-
on of deep vein thrombosis and pulmonary embolism
(studies: AMPLIFY, AMPLIFY-EXT)
• note: APPRAISE-2 study (Alexander et al, N Engl
J 2011): Apixaban after acute coronary syndrome in
addition to platelet inhibitor → no reduction in primary
endpoint (cardiovascular death, myocardial infarction,
stroke) with significantly more bleeding

Dosage
• thrombosis prophylaxis after hip/knee TEP (2 x 2.5mg
COMPASS study daily p.o)
• atrial fibrillation
-- 2 x 5mg daily
-- dose reduction to 2 x 2,5mg if GFR 15-30 ml/min or
Rivaroxaban with or without Aspirin in Stable Cardiovas- two of the following criteria are met::
cular Disease ◦◦ creatinine > 1,5 mg/dl
Eikelboom et al, N Engl J 2017 ◦◦ age > 80 years
• multicenter randomized controlled study
◦◦ body weight < 60kg
• 27,395 patients with stable atherosclerotic vascular di- • for therapy and secondary prophylaxis in deep vein
sease (CHD [90%], PAD [29%]); secondary prevention: thrombosis or pulmonary embolism: for 7 days 2 x
-- ASA 10mg, then 2 x 5mg (from 6 months then [if still indica-
-- ASA + rivaroxaban 2 x 2.5mg ted] 2 x 2.5mg)
-- rivaroxaban 2 x 5mg • for GFR < 15 ml/min contraindicated (note: In a retros-
• results: ASA + rivaroxaban 2 x 2.5mg pective cohort analysis [Siontis et al, Circulation 2018],
-- significant reduction in the composite primary fewer thromboembolisms, less bleeding and a reduced
endpoint (cardiovascular death, myocardial infarction, mortality were found with apixaban in a dose of 2 x 5
stroke; by 24%) mg compared to warfarin in patients with renal insuffici-
-- significant reduction in all-cause mortality (by 18%) ency requiring dialysis and atrial fibrillation.)
-- increased bleeding rate

Apixaban (Eliquis)
Definition
• selective factor X inhibitor
• bioavailability 50%
• short half-life (T1/2 12h)
• metabolism
-- 50% renal (contraindicated at GFR < 15 ml/min)
-- 50% hepatic (contraindicated at > 2-fold increase of
transaminases)
• monitoring (not obligatory; optional): anti-factor Xa ac-

1036 Hematology
 ARISTOTLE study HOKUSAI study

Apixaban versus Warfarin in Patients with Atrial Fibrillation Edoxaban versus Warfarin for the Treatment of Sympto-
Granger et al, N Engl J 2011 matic Venous Thrombembolism
The Hokusai-VTE Investigators, N Engl J 2013
• multicenter randomized controlled study
• 18201 patients with non-valvular atrial fibrillation • multicenter randomized controlled non-inferiority study
-- warfarin • 8240 patients with acute venous thromboembolism
-- apixaban (2 x 5mg p.o.) (deep vein thrombosis, pulmonary embolism)
• results (apixaban) -- warfarin
-- Edoxaban 1 x 60mg (if GFR 30-50 ml/min or BW <
-- significantly fewer strokes and systemic embo-
60kg: 1 x 30mg)
lisms (relative risk reduction of 21%)
• results: ddoxaban
-- significantly less major bleeding
-- non-inferiority
-- significantly lower mortality
-- significantly less bleeding

AMPLIFY study

Oral Apixaban for Treatment of Acute Venous Thrombem-

bolism
Agnelli et al, N Engl J 2013

• multicenter randomized controlled study

• 5395 patients with thromboembolic events (deep vein
thrombosis / pulmonary embolism)
-- enoxaparin s.c., then warfarin
-- apixaban: 2 x 10mg frr 7d, then 2 x 5mg für 6 months
• results: apixaban
-- primary endpoint (recurrence rate, death): no diffe-
rence (not inferior)
-- secondary endpoint (bleeding): significantly reduced

ENGAGE-AF study
Edoxaban (Lixiana)
• selective factor X-inhibitor
• dosage: 1 x 60mg p.o. (for all indications); dose reduc-
tion to 1 x 30mg at: Edoxaban versus Warfarin in Patients with Atrial Fibrillation
-- GFR 15-50 ml/min Giugliano et al, N Engl J 2013
-- body weight ≤ 60kg • multicenter randomized controlled non-inferiority study
-- P-plycoprotein inhibitors: ketoconazole, dronedaro- • largest and longest (mean 2.8 years) stroke prevention
ne, ciclosporin, erythromycin study in atrial fibrillation
• studies: • 21105 patients with non-valvular atrial fibrillation with
-- atrial fibrillation: HOKUSAI study (see box) moderate to high cardioembolic risk
-- venous thromboembolism (VTE): HOKUSAI VTE -- warfarin
study (8240 patients with VTE, parenteral antico- -- edoxaban (1 x 30mg resp. 1 x 60mg)
agulation for 5 days, then warfarin or edoxaban: not • results: edoxaban
inferior) -- non-inferiority
-- significantly less bleeding (including halving the cere-
• approvals (since 2015):
bral hemorrhage rate)
-- atrial fibrillation (non-valvular): for the prevention of -- significantly lower cardiovascular mortality
stroke and systemic embolism
-- therapy and secondary prophylaxis for deep vein
thrombosis and pulmonary embolism

Hematology 1037

GFR < 15 ml/min: NOAC contrain-
dicated (here only VKA possible)
Management in case of bleeding (NOAC)
• wait and see (mostly sufficient, since only short half-life
anyway)
• activated charcoal (if ingested < 3h)
• PPSB (generous; 50 IU/kg recommended, but 25 IU/
kg usually sufficient [exception: intracranial hemorrha-
ge]), possibly FFP
• tranexamic acid
• if necessary recombinant factor VIIa (Novoseven; 100
μg/kg) in case of severe life-threatening bleeding (e.g.
intracranial bleeding)
• if necessary activated prothrombin complex prepara-
tion (FEIBA: Factor Eight Inhibitor Bypassing Activity)
50 IU/kg i.v. (instead of recombinant factor VIIa)
• antidotes (very rarely necessary due to the short half-
life of NOAC; very expensive)
• extracorporeal removal (theoretically possible, but only
rarely practicable):
-- dialysis: factor II inhibitor (only possible with dabiga-
tran; the factor X inhibitors have too high a protein
binding)
-- plasma exchange: Factor X inhibitors (rivaroxaban,
apixaban, edoxaban)
Bleeding under NOAC: generous
PPSB!
1038 Hematology
rule of thumb: no more therapeutic
level present (i.e. surgery [or maybe
even fibrinolysis] possible), if > 3h after
ingestion:
for factor II inhibitor (dabigatran): PTT
normal
for factor X inhibitor (rivaroxaban,
spixaban, rdoxaban):
Quick (+ anti-factor Xa) normal
Antidots
• selective (specific)
-- against factor II inhibitor: idarucizumab (Praxbind)
◦◦ antidote for dabigatran
◦◦ a monoclonal antibody
◦◦ a humanized antibody fragment (Fab; aDabi-FAB)
◦◦ Boehringer Ingelheim company
◦◦ REVERSE-AD study (Phase III study; Pollack et
al, N Engl J 2015): rapid (within minutes) termina-
tion of effect by idarucizumab 5mg i.v. (2 boli at a
distance of 15min)
◦◦ approved since 2015
◦◦ 1 amp. = 50ml = 2.5g
◦◦ dosage: 5g (2 amp.) as short infusion over 5min
◦◦ storage in refrigerator (but do not freeze)
◦◦ price for 1 amp: 1400€ (will be charged by the
company upon expiration of the expiration date
free of charge)
-- against factor X inhibitors: andexanet alfa (On-
dexxya)
◦◦ antidote aganist factor X inhibitors
◦◦ Portola Pharmaceuticals company
◦◦ ANNEXA studies
◦◦ approved in the USA and now also in Europe (but
only as an antidote against rivaroxaban and apixa-
ban, not against edoxaban), also sold in Germany
since 9/2019
◦◦ dosagse: 1 amp. = 200mg
▪▪ low: initially bolus of 400 mg (infusion rate 30
mg/min), then 4 mg/min over 120 min
▪▪ high: initially a bolus of 800 mg (infusion rate 30
mg/min), then 8 mg/min over 120 min
◦◦ costs: very expensive (price for 1 amp .: 3200 €;
only available in a 4-pack)
▪▪ for low dosage (5 amp. necessary): 16,000 €
▪▪ for high dosage (9 amp. necessary): 28,800 €
• unselective (general; "global"): aripazine (Ciparantag,
Perosphere; in testing [not yet approved]): a global
antagonist (against factor X inhibitors [rivaroxaban,
apixaban, edoxaban], factor II inhibitors (including da-
bigatran), heparin [UFH, LMWH], but not against cou-
marins)
Fig. 1265  Idarucizumab (Praxbind): the antidote against
dabigatran; 1 amp. = 50ml = 2.5g

parenteral administration of vitamin K

(Konakion): never as a short infusion
(since it is fat-soluble and thus
precipitates and becomes ineffecti-
ve), but always only i.v. (alternatively:
p.o.)!

Fig. 1266  Protamin: 1 amp. = 5ml = 5000 IU (1ml = 1000 IU

= 10mg)

Hematology 1039
 -- in 20% before platelet drop
-- venous (mostly), arterial
• HIT-TS: heparin induced thrombocytopenia and throm-
bosis syndrom (= HIT + thrombosis)
• HIT II is one of the strongest thrombophilia!
• dangerous (mortality: 20%)
HIT type I HIT type II
• clinical warning signs:
dangerous no yes -- hemorrhagic skin necrosis at s.c. injection sites
frequency 5% 0.5% -- acral gangrene (finger / toe ischemia)
immediate • guideline: American Society of Hematology 2018 gui-
occurrence (early) late (from d5) delines for management of venous thromboembolism:
platelets > 100000/μl < 100000/μl heparin-induced thrombocytopenia (Cuker et al, Blood
thromboses no yes
Advances 2018)
dose-dependent yes no
no necessity to dis-
continue heparin no yes

Fig. 1267  Acral gangrene as here (ischemia of the toes) are

occasionally an early sign of HIT.

Epidemiology
HIT type I • occurrence
• dose-dependent -- with UFH (unfractionated heparin): 0.5%
• early onset (immediate) -- with LMWH: almost never
• in 5% • w > m
• direct interaction of heparin with platelets (proaggrega- • approx. 60000 cases in Germany/year
tory effect of heparin by inhibition of adenylate cyclase) • frequently postoperative in orthopedics or cardiothora-
• mild course (platelets usually > 100000/μl) cic surgery
• no discontinuation of heparin necessary • incidence ↓ (as heparins are increasingly used as
LMWH instead of UFH)

HIT type II Types

• rapid-onset (< 5d)
Definition • typical onset (5-10d)
• dose-independent (immunological) • late onset (> 10d)
• late onset
-- usually after 5d at the earliest (typical: day 5-10) from d5 regular control of the
-- if heparin is already administered earlier (in the last platelets under therapy with
100 days): also possible before unfractionated heparin (not only
• severe course (platelets < 100000/μl or decrease > PTT controls)!
50% of initial value)
• complication: thromboses (despite thrombocytopenia
[hence the expression "paradoxical coagulation syn-
drome"])

1040 Hematology
 -- strikingly frequent clotting of the filter in CVVH (often
If possible use LMWH instead of UFH! first sign!)
UFH: 10 times more HIT than LMWH! • arterial (20%)
-- acute myocardial infarction
-- stroke
Pathophysiology -- acute vascular occlusion (especially lower extremity)
• auto-antibodies against complex of heparin (strongly -- skin necrosis (microthrombosis)
negatively charged) and platelet factor IV (strongly po- • acute systemic reaction after heparin i.v. (anaphylac-
sitively charged) toid; shock)
-- antibody-mediated destruction and degradation of
thrombocytes → thrombocytopenia
-- antibody-mediated activation (via the Fc part) of thrombosis / pulmonary embolism
thrombocytes → release of procoagulatory media- despite adequate heparinization → do
tors → thrombocyte aggregation → thromboses not increase heparin, but think of HIT
II!
• HIT-antibodies destroy and activate the platelets.
• white clot syndrome

Heparin forms a complex

Diagnosis
with platelet factor 4 (PF4).
• thrombocytopenia
Antibody reacts to the complex
of heparin and PF4.
-- platelets < 100000/μl or decrease > 50% of the initial
value
-- but mostly only moderate: platelets almost never <
20000/μl (atypical for HIT → possibly additional DIC
[In the combination of HIT and DIC e.g. in the context
of severe sepsis, however, severe thrombocytope-
nia may occur!] or other cause [e.g. ITP, leukemia])
-- in 10-15% HIT without thrombocytopenia
• PTT ↓ (despite actually relatively high dose heparin
perfusor)
A complex of the
antibody (IgG),
heparinand platelet
• tests
factor 4
(PF4) is formed.
-- immunological (ELISA)
-- functional (HIPA)
• scores

thrombosis & thrombocytopenia

Think of:
This complex destroys the platelets. This complex activates the platelets.
HIT II (PTT ↓)
platelet aggregation
release of Antiphospholipid syndrome (PTT ­↑)
procoagulatory
mediators

Tests
Thrombocytopenia • antibody test (ELISA)
• HIPA test
Thrombosis • serotonin release test (radioactive; clinically insignifi-
cant)
Fig. 1268  Pathophysiology of HIT II [18]
ELISA
Complications • detection of heparin-induced platelet factor IV / heparin
during ongoing (adequate) heparin therapy! antibody (standard)
• venous (80%) • duration: 1-2 hours
-- deep vein thrombosis (possibly with phlegmasia co- • high sensitivity (99.5%): negative test (almost) ex-
erulea dolens [most frequent cause of amputation in cludes HIT II!
HIT!]), acute pulmonary embolism (50%!) • low specificity (only 50%; 40% of all patients who
-- sinus vein thrombosis received heparin develop antibodies)
-- adrenal vein thrombosis (frequent on both sides) → • often false positive results!
acute adrenocortical insufficiency (Addison crisis)
-- mesenteric vein thrombosis
HIPA test
-- CVC thrombosis • heparin-induced platelet activation
• not suitable for emergency diagnosis (duration: 1-2

Hematology 1041
 days)
• indication: only in the case of a positive antibody
test ro exclude false positive results (confirmation test)
• false negative under ticagrelor (congress presenta-
tion Greinacher DIVI [German Interdisciplinary Asso-
ciation for Intensive Care and Emergency Medicine]
06.12.2018)

occasional error: with normal platelet

count HIT test → positive: no HIT II
(40% of all patients treated with
heparin have antibodies!)

HIT-antibody test (ELISA) negative →

discontinue alternative anticoagulant
(no HIPA test necessary anymore!)

Scores
• 4T score (Lo et al, J Thromb Haemost 2006; see in-
fobox)
• HEP score (Guker et al, J Thromb Haemost 2010; see
infobox)

Therapy
• discontinue heparin (but not enough alone! 50%
otherwise suffer a thromboembolic event without alter-
native anticoagulant!)
• no heparin-containing drugs / infusions
-- flushing of Shaldon-catheter, accesses, dialysis
-- heparin-containing blood substitute products, e.g.:
◦◦ PPSB (In the case of bleeding e.g. under oral an-
ticoagulants [coumarin, NOAC] with known HIT II
one should not administer PPSB, since these con-
tain heparin, but FFP! Alternatively, you can also
give a heparin-free PPSB [Cofact].)
◦◦ AT III (Kybernin): Here you can use Atenativ (he-
parin-free AT III).

1042 Hematology
 -- Icy catheter of the Coolgard system (Thermoguard):
The catheter was coated with heparin for a long
time. However, the catheters have been heparin-free
since 2013.
-- Heparin clotting prophylaxis of the CeVOX probe
-- ECMO:
◦◦ in 30% positive HIT antibodies, but only in 3% then
also positive HIPA test (i.e. confirmed HIT)
◦◦ If a HIT occurs during ECMO, the anticoagulation
is changed from heparin to argatroban. The sys-
tem, which is also coated, is usually left as it is.
Due to the biofilm that has formed, there is usually
no longer any contact. Alternatively (if available),
you can switch to a heparin-free system (EOS
ECMO system from Sorin: not coated with hepa-
rin, but with phosphorylcholine).
• no administration of platelet concentrates (only for
bleeding [rare in HIT; mostly thromboses!])
• alternative anticoagulant
-- immediate start of therapy, no waiting for the test re-
sult!
-- duration: until normalization of platelets
• no heparin for at least 100 days
-- then no more HIT antibodies present
-- prerequisite for re-exposure: negative HIT anti-
bodies
-- acute myocardial infarction + HIT II
◦◦ > 100 days: single dose administration of heparin
(e.g. out-of-hospital UFH 5000E) absolutely possi-
ble even without determination of the HIT antibo-
dies (HIT antibody formation takes at least 5 days
again!)
◦◦ < 100 days: Heparin administration is contraindi-
cated here. This can lead to acute HIT via boos-
ting. Here you should not administer any antico-
agulant at all out-of-hospital, where you usually
do not have an alternative anticoagulant with you.
In-hospital then an alternative anticoagulant (e.g.
argatroban; in the ESC guidelines bivalirudin [An-
giox; see page 360] is recommended as part of
acute PCI, if HIT is known) is administered.
• If the administration of heparin is unavoidable in the
acute phase and HIT antibodies are still positive (e.g.
urgently indicated [e.g. cardiogenic shock] CABG sur-
gery with the use of the heart-lung machine), then the
HIT antibodies can be removed preoperatively using
plasmapheresis.
Alternative anticoagulants
Lepirudin (Refludan)
• a recombinant hirudin (a polypeptide isolated from the
medicinal leech [Hirudo medicinalis])
• direct thrombin inhibitor (factor II; irreversible inhibiti-
on)
• 1 amp. = 50mg; only i.v. available (not s.c.)
• more expensive than danaparoid (500 € vs. 150 € per
day)
• dosage
-- prophylaxis: perfusor (2 amp. in 50ml NaCl 0,9%):
0,1 mg/kg/h
-- therapy (e.g. for thrombosis / pulmonary embolism
with HIT II) or for CVVH: initially 0.4 mg/kg (50mg
dissolved in 10ml NaCl 0.9%), then 0.10-0.15 mg/
kg/h (perfusor 100mg dissolved in 50ml NaCl 0.9%);
for patients > 110kg dose applies as for 110kg
• control
-- via PTT (target: 1.5-2.5-fold)
-- better however via ECT (ecarin clotting time)
• maximum therapy duration: 10 days
• elimination: renal (100%; with impaired renal function
the half-life extends up to 300h!)
• dose reduction in renal insufficiency
-- creatinine 1.6 - 2.0 mg/dl: to 50%
-- creatinine 2.0 - 3.0 mg/dl: to 30%
-- creatinine 3.0 - 6.0 mg/dl: to 15%
• extracted from mucosa of pigs → risk of anaphylaxia
• frequently from day 5 antibody formation
• also possible during pregnancy
• withdrawn from the market since 2020
Danaparoid (Orgaran)
• a heparinoid (derivative of heparin)
• a partially degraded GAG mixture (GAG: glycosami-
noglycans)
• factor X inhibitor (thrombokinase)
• 1 amp. = 0.6ml = 750 IU (1ml = 1250 IU)
• application
-- s.c.
-- i.v.
• 150 €/d (cheaper than lepirudin: 500 €/d)
• in 10% cross-reaction with heparin at HIT II
• maximum therapy duration: 10 days
Hematology 1043
• dosage
-- prophylaxis: 2x daily 1 amp. (750 IU) s.c. (if > 95kg:
3x)
-- therapy (or for CVVH): initial 2600 IU i.v. (< 55kg:
1250 IU, > 95kg: 3750 IU), then for 4h 400 IU/h, then
for 4h 300 IU/h, then ED 150-200 IU/h
• monitoring with antifactor Xa activity (target for thera-
py: 0.5-0.8 IU/ml)
• antagonization partly by protamin
• also possible during pregnancy ( means of choice
for the therapy of HIT II during pregnancy)
Fondaparinux (Arixtra)
• a synthetic selective factor Xa inhibitor (thrombokina-
se)
• a pentasaccharide ("miniaturized" heparin)
• 1 amp. = 0.5ml = 2.5mg
• dosage
-- prophylaxis: 2.5mg (= 1 amp.) s.c.
-- therapy: 7.5mg s.c. (< 50kg: 5mg, > 100mg: 10mg);
single dose sufficient
• no effect on platelets (therefore no HIT)
• also individual cases with HIT II described under
fondaparinux (also immunization possible)!
• costs: 16 €/d (LMWH: 10 €/d)
• contraindication: i.a. creatinine clearance < 20 ml/min
• monitoring with anti-factor Xa activity possible
• side effect: i.a. transaminases ­↑
• also possible during pregnancy
• not (yet) approved for the therapy of HIT II (only for
prophylaxis)
◦◦ CVVH: 100 µg/kg for flushing the system, then
0.5-1 µg/kg/min
◦◦ hemodialysis: 250 µg/kg as bolus, then 2 µg/kg/
min
• dose reduction
-- renal insufficiency: not necessary
-- hepatic insufficiency
◦◦ light to moderate → 0.5 µg/kg/min
◦◦ severe → contraindicated
• no cross-reactions to other heparins
• The infusion solution contains ethanol (400 mg ethanol
per ml solution). At the maximum daily dose (10 µg/kg/
min), a 70 kg patient receives 4 g of ethanol per day,
which corresponds to 100 ml of beer.
• pregnancy: insufficient data on safety (furthermore al-
cohol content; therefore better danaparoid)
• INR increase (mostly INR 4-5; laboratory artifact;
pseudo-Quick [completely normal coagulation factors;
no dose reduction necessary!])
• also false determinations of fibrinogen (measured fal-
sely too low) and AT III (measured falsely too high) un-
der argatroban

Argatroban (Argatra) Fig. 1269  Argatroban (Argatra): Means of choice today for
the therapy of HIT II!
• synthetic direct thrombin inhibitor (factor II; reversible
inhibition)
• L-arginine derivative
• approved since 2005 as alternative anticoagulant for study
HIT II
• bottle 2.5ml (250mg) → dissolve in 250 ml infusion so-
lution (NaCl 0.9%, G5%); meanwhile also ready-to-use
infusion solution (50ml vial; 1ml = 1mg) Argatroban Anticoagulation in Patients With Heparin-In-
• hepatic elimination duced Thrombocytopenia
Lewis et al, Arch Int Med 2003
• almost no protein binding → few interactions
• very short T1/2 (50min) → good controllability • multicenter, prospective, non-randomized observational
• means of choice study
• dosage • 418 patients with HIT II
-- start with 2 µg/kg/min (according to the manufactu- -- argatroban 2 μg/kg/min i.v. (target PTT: 1.5-3-fold in-
crease)
rer; mostly overdosed; better start with 0.5-1 µg/kg/
-- comparison with historical control cohort (hirudin, he-
min; in the updated information of the manufacturer,
parinoid)
a start with 0.5 µg/kg/min is recommended for criti-
• results: argatroban
cally ill patients ) i.v., then according to PTT
-- faster increase in platelets
-- maximum daily dose: 10 µg/kg/min
-- significantly reduced combined primary endpoint
-- control via PTT (target: 1.5-3-fold of the normal ran- (death, thrombocytopenia, amputation)
ge)
-- myocardial infarction: 250 μg/kg as bolus, then 15
μg/kg/min
-- renal replacement therapy (use of argatroban
instead of unfractionated heparin in HIT II; alternati-
ve: citrate anticoagulation):

1044 Hematology
 Danapa- Fondapa- Argatro- Definition
Lepirudin roid rinux ban • syn.: Hughes syndrome (named after the English rheu-
Refludan Orgaran Arixtra Argatra matologist Graham Hughes, who first described the
syndrome in 1982)
factor II factor II
(throm- (throm- • autoimmune disease with antibodies against phospho-
bin), irre- bin), lipids (syn .: antiphospholipid antibodies; especially co-
inhibition versible factor X factor X reversible agulation factors, platelet receptors) and consecutive
T1/2 90min 24h 17h 45min pronounced thrombophilia (acquired)
• diagnostic criteria (Sydney criteria): see infobox
anti-factor anti-factor
control PTT Xa Xa PTT
Epidemiology
applica-
• incidence: 5/100,000
tion i.v. i.v., s.c. s.c. i.v.
• prevalence: 50/100,000
renal renal renal hepatic
dose insuffici- insuffici- insuffici- insuffici-
• w:m = 4:1
reduction ency ency ency ency
Types
• primary APS (less often [20%])
Oral anticoagulant • secondary APS (more often [80%]):
• then indicated afterwards if a thromboembolic event -- other autoimmune diseases (especially [ most
occurred as part of the HIT (HIT-TS [thrombosis syn- common cause of APS: every 3rd patient with SLE
drome]) has APS!], rheumatoid arthritis, polymyalgia rheu-
• contraindicated during thrombocytopenia; only start matica, Sjögren's syndrome, scleroderma [systemic
when platelets > 100000/μl sclerosis], vasculitis)
• at the earliest after 1 week -- malignancies
• for at least 3 months -- infections (e.g. HIV, hepatitis C, syphilis, malaria)
• types: -- drugs (e.g. phenothiazine, procainamide, quinine,
-- VKA (e.g. warfarin or phenprocoumon): gold, TNFα blockers)
◦◦ overlapping for at least 5 days (increased risk of Laboratory
coumarin-induced skin necrosis: A too early start
• thrombocytopenia (mostly only mild to moderate, i.e.
with insufficient overlap time with VKA is the most
50,000-100,000/μl; prognostically unfavorable; but
common reason for an amputation in a HIT!)
only present in 20%)
◦◦ problem pseudo-Quick in argatroban → over-
• PTT ↑ (spontaneous, i.e. without heparin; due to
lap phase with fondaparinux (7,5mg) instead of
interaction with phospholipids)
argatroban or discontinue argatroban if INR > 4
(according to manufacturer) • possibly hemolytic anemia
-- NOAC: no overlap necessary here; relatively ele- • serology ( repeated measurement of the parame-
gant, because on the one hand you have no problem ters necessary after 12 weeks, i.e. the respective para-
with the pseudo-Quick and on the other hand you meter must be positive twice within 3 months):
save yourself the five-day overlap phase (no risk of -- positive lupus anticoagulant (LA; from citrate blood;
coumarin-induced necrosis with NOAC) under anticoagulation [heparin, oral anticoagulation
such as VKA or NOAC] it cannot be reliably deter-
Excursus: Antiphospholipid syndrome mined; the strongest thrombogenic parameter [risk
of cerebral infarction x 48↑, for myocardial infarction
(APS)
x 11↑])
-- antibodies (antiphospholipid antibodies; from serum;
IgG or IgM; at least medium to high titers, i.e.> 40
PL-U/ml [PL-U: phospholipid units; GLP: for IgG,
MLP: for IgM] or > 99th percentile; can also be reli-
ably determined under anticoagulation [heparin, oral
anticoagulation such as VKA or NOAV])
◦◦ anti-cardiolipin antibodies
◦◦ anti-β2 glycoprotein antibodies
◦◦ note: Anti-phosphatidylserine antibodies are no
longer necessary (too unspecific; positive in 2-5%
of the population with no disease value)

Complications
• thromboembolism (especially recurrent)
-- venous (50%; e.g. deep leg vein thrombosis, pulmo-
nary embolism, portal vein thrombosis, sinus vein

Hematology 1045
 thrombosis, adrenal vein thrombosis [possibly Addi- Therapy
son crisis]) • primary prophylaxis (i.e. no thromboembolic event has
-- arterial (50%; infarctions), especially: occurred yet): ASA 100mg
◦◦ cerebral infarction (stroke; most common; 20% -- elimination or optimization of cardiovascular risk fac-
of all patients < 45 years) tors (including smoking, oral contraceptives, hyper-
◦◦ myocardial infarction (10% of all patients < 45 lipidemia [if necessary, initiation of statin therapy],
years) arterial hypertension)
◦◦ renal infarction -- i.a. even after obstetric complications (e.g. abortion;
◦◦ mesenteric infarction in the event of renewed pregnancy then additional
• visual disturbances, possibly blindness (due to infarc- LMWH in prophylactic dosage up to 6 weeks post-
tion of the retinal arteries) partum)
• skin: -- ASA for primary prophylaxis is always controversial.
It is clearly indicated in high-risk patients, i.e.:
-- livedo racemosa
◦◦ persistent positive lupus anticoagulant
◦◦ through thrombosis of small skin vessels
◦◦ highly positive anti-cardiolipin antibody (> 40 PL
◦◦ "interrupted circles" (in contrast to the livedo reti-
U/ml)
cularis: Here the circles are not interrupted.)
◦◦ triple-positive APS (i.e. all 3 serological markers
◦◦ if additional cerebral infarction: Sneddon syndro-
are positive; very high risk of thromboembolism!)
me
◦◦ SLE (here in addition to ASA also hydroxychloro-
-- Raynaud's syndrome
quine)
-- leg ulcers
◦◦ presence of other thromboembolic risk factors
-- acral gangrene
-- generous thrombosis prophylaxis (e.g. during opera-
• endocarditis Libman-Sacks (especially mitral valve, tions, bed rest, puerperium)
less often aortic valve)
• secondary prophylaxis (after a thromboembolic event
• obstetric (pregnancy-associated) [venous or arterial]; note: The acute phase of a throm-
-- abortions (mainly recurrent, habitual; due to pla- boembolism is treated in the same way as in patients
centa infarcts) without APS, i.e. full anticoagulation with LMWH or
-- premature birth, placental insufficiency UFH. Secondary prophylaxis is then initiated.): oral
-- preeclampsia / eclampsia anticoagulation
• catastrophic APS (CAPS) -- high risk of recurrence: 30% per year (without
-- p.d. involvement of at least 3 organs prophylaxis)
-- often multiple organ failure (due to microthrombosis) -- duration: lifelong
-- especially in active SLE (with complement consump- -- preparation:VKA (e.g. warfarin, phenprocoumon);
tion, i.e. C4 ↓) note: insufficient evidence still for NOAC (RAPS stu-
-- mortality: 44% dy [Cohen et al, Lancet Haematol 2016]: rivaroxaban
is not inferior to warfarin in secondary prophylaxis
[but only a small phase III study]; in the TRAPS stu-
dy [Pengo et al, Blood 2018], however, significantly
more thromboembolism under rivaroxaban than un-
der warfarin [therefore i.a. Red-Hand-Letter 5/2019
for all NOACs at APS!]; however, APS does not have
to be ruled out immediately for every venous throm-
bosis or pulmonary embolism before starting NOAC
therapy, but only if one has an urgent suspicion of
APS [especially arterial thrombosis, thrombocytope-
nia, PTT prolongation, known SLE].)
-- target INR:
◦◦ venous thromboembolism: 2-3
◦◦ arterial thromboembolism or recurrence of venous
thromboembolism: 3-4 (alternatively: target INR
2-3 and additionally ASA); note: after a cerebral
infarction (stroke; pure "CNS-APS") ASA may also
be sufficient (oral anticoagulation with VKA not
unclear thrombosis / infarction superior [APASS study 2004]; if recurrence with
(especially in younger patients), ASA: oral anticoagulation with VKA)
thrombopenia and PTT ↑ → think -- in the case of thrombocytopenia < 50,000/μl LMWH
of APS! in half-therapeutic dosage
• with severe thrombopenia (but rarely with APS): pro-
ceed as with ITP (see page 1049; i.a. steroids, cyclo-
phosphamide, azathioprine)

1046 Hematology
• catastrophic APS (CAPS): -- most frequent cause of death: intracranial hemorrha-
-- full heparinization ge
-- immunosuppression (steroid pulse therapy, cyclo-
phosphamide, immunoglobulins, rituximab, eculi- Symptoms
zumab) • symptoms - skin bleeding: especially petechiae, pur-
-- if necessary plasmapheresis pura, ecchymoses, hematomas (bruising)
• therapy of the underlying disease in secondary APS • gum bleeding
(especially in SLE: hydroxychloroquine [intrinsic anti- • epistaxis
thrombotic effect; basic therapy for almost every SLE, • gastrointestinal bleeding (melena, hematemesis, he-
i.e. even without APS]) matochezia)
• pulmonary bleeding (hemoptysis)
• urogenital bleeding
• vaginal bleeding:
-- menorrhagia (increased menstruation)
-- metrorrhagia (bleeding outside the cycle)
Definition • prolonged bleeding after surgery / trauma
• idiopathic thrombocytopenic purpura (now outdated • retinal bleeding (possibly blindness)
term) • possibly intracranial hemorrhage (most common
• syn.: primary immune thrombocytopenia cause of death)
• an autoimmune disease
-- auto-antibodies (mainly IgG) against adhesion mo-
lecules (mainly glycoproteins) of the thrombocyte
membrane (especially GpIIb/IIIa [receptor for fibrino-
gen]; more rarely GpIb/IX [receptor for von Willeb-
rand factor], GpIa/IIa [receptor for collagen])
-- The platelets loaded with antibodies are degraded in
the spleen (phagocytosis by macrophages), so that
the survival time of the platelets (normally 10 days)
is significantly reduced.
-- The main production site of autoantibodies and the
main degradation site of platelets is the spleen,
which is usually not enlarged or only slightly enlar-
ged.
• always an exclusion diagnosis Fig. 1270  Petechiae (flea-like bleeding) are a typical con-
sequence of a corpuscular (thrombocytopenia or throm-
• If autoimmune hemolytic anemia is also present, this is bocytopenia) coagulation disorder (disturbed primary
referred to as Evans syndrome. hemostasis; mostly only superficial tissue [skin, mucous
• leading symptom: bleeding (usually only in platelets < membrane] affected]). Large-scale bleeding (ecchymosis),
30000/μl) on the other hand, suggests a plasmastic coagulation dis-
order (disturbed secondary hemostasis; mostly deeper ly-
ing tissue [muscles, joints] also affected).
Types
• acute (< 3 months): especially children
-- mostly associated with infection (often 1-3 weeks af- disturbance of the primary
ter a respiratory or gastrointestinal infection [mostly hemostasis (cellular; platelet defect
viral]; caused by cross antigens ["molecular mimic- [thrombocytopenia or -pathia]) →
ry"]) petechial bleeding (i.e. only weakly
-- w:m = 1:1 pronounced and only superficial
-- incidence: 4/100,000 tissue [skin, mucous membrane]
affected)
-- mostly self-limiting (spontaneous remission in 90%
disturbance of the secondary
after 2-3 months; usually no therapy necessary; very
hemostasis (plasmatic; clotting
good prognosis)
defect) → hemophilic bleeding (i.e.
• chronic (> 3 months; syn. Werlhof´s disease [named
strongly pronounced [ecchymoses]
after the German physician Paul Gottlieb Werlhof,
and also deeper tissue [muscles,
1699-1767]): especially adults (average age: 56 years)
joints] affected)
-- w:m = 3:1
-- incidence: 2/100,000
-- most frequent cause of thrombocytopenia in
adulthood
-- mortality: 2%

Hematology 1047
 ters are increased: Evans syndrome (here additio-
nally positive direct Coombs test)
-- blood group (in case of necessary transfusion [red
cell / platelet concentrates])
-- exclusion of pseudo-thrombopenia
-- detection of antibodies against thrombocytes (only
detectable in 70%; but not necessary for diagnosis)
-- exclusion of other causes:
◦◦ differential blood count (inconspicuous; i.a. no
fragmentocytes in blood smear [DD TTP])
◦◦ ANA, double-strand antibody, c-/p-ANCA, rheu-
matoid factor, antiphospholipid syndrome (lupus
anticoagulant, anti-cardiolipin antibodies, anti-β2
glycoprotein antibodies)
◦◦ hepatitis serology (B, C), possibly HIV test (for
high-risk patients
◦◦ HIT test
-- normal values for Quick (INR), PTT, fibrinogen, D-
dimer, antithrombin III (to exclude DIC)
-- TSH (since in 10% also Hashimoto thyroiditis)
• bone marrow puncture
-- indication: previously always recommended to ex-
clude another underlying hematological disease; to-
day only recommended if one of the following criteria
is met:
◦◦ atypical findings (e.g. additional leukopenia, sple-
nomegaly, enlarged lymph nodes)
◦◦ age > 60 years
◦◦ before planned splenectomy
-- findings: increased megakaryocyte count (reactively
increased megakaryopoiesis); the megakaryocyte
count can also be normal (Bone marrow puncture
is mainly performed to exclude other hematological
diseases.)

Werlhof´s disease (chronic primary

ITP) is always an exclusion diagnosis!

Diagnostics Differential diagnoses

• anamnesis (especially infections, bleeding, underlying
• pseudo-thrombocytopenia (clumping of platelets in
diseases, drugs), clinical examination (note: Spleno-
EDTA blood) → renewed measurement in citrate blood
megaly and palpable lymph nodes speak against the
(citrate tubes, Thrombo-Exact tubes)
diagnosis!)
• especially secondary immune thrombocytopenia (es-
• sonography
pecially SLE [ most frequent cause of secondary
-- abdomen: i.a. immune thrombocytopenia], malignant lymphomas,
◦◦ no splenomegaly (Splenomegaly does not fit to infections [especially hepatitis B / C], drugs)
Werlhof´s idsease. It is alwasy indicative for a • for DD of thrombocytopenia in general and in special
secondary immune thrombocytopenia [especially (in intensive care medicine) see infobox
lymphoma].)
◦◦ no hepatomegaly
-- lymph nodes: The typical stations should be so- Thrombocytopenia: always exclude
nographically examined. At Werlhof´s disease the pseudo-thrombocytopenia first!
lymph nodes are not enlarged.
• laboratory
-- thrombocytopenia (< 100000/μl; isolated, i.e. no leu-
kopenia, no anemia)
-- possibly anemia (due to bleeding), possibly iron defi-
ciency (ferritin ↓, transferrin ↑); if hemolysis parame-

1048 Hematology
 DD Thrombocatopenia
special (intensive care)

Therapy
• indication: Therapy is only indicated for platelet count
< 30000/μl or bleeding. As long as the platelets are >
30000/μl and there is no bleeding, you wait. In addition
to the platelet count, the severity of the bleeding is also
of considerable importance for the therapy decision.
This can be indicated by means of the WHO bleeding
score (see infobox; according to Miller et al, Cancer
1981). According to the current recommendations, no
therapy is indicated for platelets < 30000/μl, if there is
no bleeding or only bleeding of WHO severity I/II, i.e.
a therapy for platelets < 30000/ μl is only indicated for
bleeding of WHO severity III/IV.
• steroids (therapy of the first choice; response in 80%,
sustained full remission but only in 30%):
-- prednisolone 1.5mg/kg for 2-3 weeks, then reduction
every 5 days by 25mg to 50mg, then by 10mg to
30mg, then by 5mg (maximum therapy duration: 3
months)
-- in an emergency (e.g. acute bleeding) pulse therapy:
prednisolone 250mg i.v. or methylprednisolone (Ur-
bason) 5-10mg/kg i.v. daily (e.g. 250mg) for 3 days
• immunoglobulins
-- indication:

Hematology 1049
 ◦◦ acute bleeding (as an emergency measure in ad- -- Vinca alkaloids (e.g. vincristine 1-2mg/week i.v., e.g.
dition to steroids) vinblastine 5-10mg/week i.v.)
◦◦ increase in platelet count before surgery (espe- • new substances (optional)
cially with planned splenectomy -- rituximab (Mabthera)
-- e.g. endoglobin S/D 5g/100ml (cost for one bottle: ◦◦ anti-CD20-antibody
340€) ◦◦ reserve agent in case of insufficient response to
-- always exclude IgA deficiency beforehand (cave al- steroids (however officially not approved for the-
lergic reaction) rapy of ITP)
-- 0.4mg/kg i.v. daily over 5 days or 0.5mg/kg i.v. daily ◦◦ 375 mg/m2 i.v. once a week for 4 weeks
over 4 days ◦◦ response rate: 50%
-- therapy costs: approx. 10000€ -- thrombopoietin analogues (stimulation of platelet
-- usual scheme (for emergency therapy): methylpred- formation)
nisolone (Urbason) 250mg i.v. + 20g immunoglobu- ◦◦ eltrombopag (Revolade): 50-75 mg p.o. daily
lins i.v. daily for 3 days ◦◦ romiplostim (Nplate): 1-10 mg/kg s.c. weekly
• splenectomy -- other: danazol (an androgen), dapsone
-- indication: steroid-refractory (prerequisite: at least
6 months therapy) or recurrent in case of dose re-
duction and still platelets < 10000/μl and especially
repeated (severe, i.e. grade III/IV) bleeding; should Acute therapy (emergency; severe
only be performed in exceptional cases bleeding) for ITP: steroid pulse +
immunoglobulins i.v. + platelet
-- permanent full remission: in 2/3 of the cases (in 1/3
concentrates (in the case of
of the patients however persistent despite steroids
massive bleeding usually also red
and splenectomy!)
cell concentrates and FFP
-- mortality:
necessary)
◦◦ laparoscopy: 0.2%
◦◦ laparotomy: 1%
-- The size of the spleen does not play a role, i.e. a
splenomegaly does not necessarily have to be pre-
sent (is usually not present anyway).
-- Preoperatively the platelet count must be increased
to > 50000/μl (by immunoglobulins and administrati-
on of platelet concentrates if necessary).
-- 14 days before vaccination (OPSI prophylaxis
[pneumococcus, haemophilus influenzae type B,
meningococcus])
-- accessory spleens: If thrombocytopenia continues
to occur after splenectomy, one should also think of
accessory spleens. The blood smear shows Howell
Jolly bodies (cell nucleus fragments in erythrocytes,
which normally have no nucleus). Secondary spleen
can best be detected in scintigraphy (with 51Cr-la-
belled thrombocytes).
• platelet concentrates (PC): The administration of pla-
telet concentrates is usually not indicated (only in an
emergency with severe bleeding). Despite the admi-
nistration of platelet concentrates, the platelets fall
off again rapidly in the course of the disease, as the
autoantibodies also shorten the survival time of the
transfused platelets. Furthermore, repeated transfusi-
ons may lead to the formation of iso-antibodies against
platelets with a further worsening of thrombocytopenia
during the course.
• immunosuppression (only in case of relapse after or
contraindications against splenectomy; as ultima ra-
tio):
-- cyclophosphamide (Endoxan): either i.v. (pulse the-
rapy 15 mg/kg every 2-3 weeks; lower cumulative
total dose) or p.o. (1.5-2 mg/kg)
-- azathioprine (Imurek): 2 mg/kg p.o. daily (before de-
termination of the TPMT level)

1050 Hematology
 TTP (thrombotic thrombocytopenic
purpura)

Definition
• syn.: Moschcowitz syndrome (named after the Ameri-
can physician Eli Moschcowitz [1879-1964], who first
described the syndrome in 1924)
• a thrombotic microangiopathy (microangiopathic
haemolytic anaemia [MAHA; see infobox for an over-
view])
• triad:
-- thrombocytopenia
-- MAHA (microangiopathic haemolytic anaemia)
-- microthrombosis (mainly brain, kidney, heart, eye)
• pathophysiology: deficiency of metalloproteinase
ADAMTS-13 (vWF cleaving protease; ADAMTS: a
disintegrin and metalloproteinase with a thrombos-
pondin-like domains) → von Willebrand factor (the
largest protein in the human body; is formed as an
ultra-long multimer) cannot be cleaved → formation of
microthrombi
• incidence: 5/1,000,000
• age: 30-40 years
• w:m = 2:1
• mortality:
-- untreated: 90%
-- treated: 20%
• recurrence: 36% in 10 years

Causes
• congenital (cTTP; 1%; congenital deficiency of
ADAMTS-13; syn .: Shulman-Upshaw syndrome])
• acquired (aTTP; 99%; autoimmune: inhibiting auto-an-
tibodies against ADAMTS-13 [ADAMTS-13 inhibitors];
more common)
DD DIC TMA
fibrinogen ↓ normal Classification
AT III ↓ normal The previous division into a primary (85%; without cau-
ses ["idiopathic"]) and secondary (15%; with causes)
haptoglobin normal ↓
form has been abandoned today. The entities previously
PTT ↑ normal listed under the secondary forms are now understood
INR ↑ normal as triggers (see infobox) which can then trigger throm-
BP ↓ ↑ botic microangiopathy (TMA), if there is a corresponding
disposition (in case of TTP congenital deficiency of or

Hematology 1051
auto-antibodies against ADAMTS-13 or in csae of aHUS
congenital deficiency of or auto-antibodies against com-
plement inhibitors).
• cardiac: acute myocardial ischemia
• gastrointestinal: nausea, vomiting, diarrhea, abdomi-
nal pain
• pulmonary: dyspnea, bleeding, pulmonary edema
• ophthalmologic: blindness
• fever

Fig. 1271  Purpura

Diagnosis
• thrombocytopenia (mostly pronounced; < 30000/μl)
• microangiopathic hemolytic anemia (MAHA):
-- hemoglobin ↓
-- Hämolyse-Parameter: LDH­ ↑, indirect bilirubin­↑,
haptoglobin ↓ (note: Haptoglobin is an acute phase
protein and can therefore be false normal in inflam-
mation.), reticulocytes ↑, hemoglobinuria
-- Coombs test negative
-- fragmentocytes (syn. schistocytes) in blood smear
> 2%
• ADAMTS-13 activity (reduced [almost always < 5%]),
auto-antibodies against ADAMTS-13
-- EDTA tube (not serum tube)
-- always draw the sample before the first plasmaphe-
resis
-- result usually only after 3-4 days (not suitable for
emergency diagnosis, do not wait for the result with
plasmapheresis in any case!); meanwhile also quick
test available (e.g. Haemochrom Diagnostica com-
pany)
-- possibly use of the PLASMIC score to detect a se-
Symptoms vere ADAMTS-13 deficiency (see infobox; based on
Bendapudi et al, Lancet Hematology 2017)
• hematological: bleeding (petechiae, purpura)
-- decreased ADAMTS-13 activity also in sepsis (down
• neurological (main manifestation):
regulation of ADAMTS13 transcription) and liver in-
-- headache
sufficiency, but (almost) never < 5%
-- focal-neurological deficits
-- Platelets > 30000/μl almost rule out severe
-- loss of consciousness ADAMTS-13 deficiency.
-- visual disturbance • in contrast to DIC normal values for Quick / INR, PTT,
-- speech disturbance AI III and fibrinogen
-- seizures
• renal: renal failure (in 50%; creatinine ↑, urea ↑, pro-
teinuria, hematuria)

1052 Hematology
 • ASS 100mg once daily if platelets > 50000/μl (espe-
cially in case of cerebral or coronary circulation disor-
ders; alternatively also clopidogrel 75mg)
• causal therapy (therapy of the underlying disease) with
present triggers
• possibly immunosuppressive therapy
-- steroids (methylprednisolone 1g i.v. for 3 days; stan-
dard)
-- vincristine (1 mg/d i.v. for 3 days)
-- cyclophosphamide
-- rituximab (Mabthera: 375-500 mg/m2/week i.v. for 4
weeks; especially for relapses)
• caplacizumab (Cablivi):
-- a highly selective humanized bivalent nanobody (ori-
ginally derived from lamas)
Fig. 1272  Detection of fragmentocytes (schistocytes) in -- inhibition of the interaction between the ultra-long
microscopic blood smear (courtesy of PD Dr. Drobnik, Me- von Willebrand factor multimer (binding to the A1 do-
dical Director of the MVZ Synlab Regensburg [Germany])
main) and the platelets → reduction in the formation
of microthrombi
-- dosage:
◦◦ 1 amp. = 1ml = 10mg
◦◦ initial 10mg i.v. before the first plasmapheresis,
then 10mg s.c. after each plasmapheresis, then
after completing the plasmapheresis 10 mg s.c.
daily for 30 days
◦◦ no dose reduction necessary in case of renal or
hepatic insufficiency
-- approved since 2018 (for the acquired TTP [aTTP]
in combination with plasmapheresis or immunosup-
pressants; studies: TITAN [phase II], HERCULES
[phase III; see box])
-- cost for 1 ampoule: 4600€
-- main side effect: bleeding (especially mucocutane-
ous [especially epistaxis, bleeding of gums])
-- duration: until ADAMTS 13 activity > 20%
• new: recombinant ADAMTS-13 (Baxter company; still
in clinical testing)
• possibly eculizumab (because here also uncontrolled
complement activation; however, off-label use; see
page 1056)
Therapy
• even before receiving the test results
• immediate administration of FFP
• hematological emergency (if necessary, transfer pati-
ent to a corresponding center)
• plasmapheresis (plasma exchange)
-- against FFP
-- means of choice (reduces mortality from 90% to
10%!)
-- dose: 3-5 l/d complete replacement by FFP; plasma
volume = (0.065 x kgBW) x (1-Hkt), e.g. in a patient
with 70kg 15 FFP per plasmapheresis session ne-
cessary
-- duration: until platelets > 150000/µl
• The administration of platelet concentrates is
contraindicated! This should also not be done before
surgery, the patients almost never bleed despite pro-
nounced thrombocytopenia! The administration of red
cell concentrates is possible (if necessary).

Hematology 1053
 Definition
• enterohaemorrhagic escherichia coli
HERCULES-Studie • gram-negative rod
• carrier of a plasmid for extended spectrum beta-
lactamase (EHEC germs are ESBL germs!)
• diseases (food infection):
Caplacizumab in Patients with Acquired Thrombotic -- enterohaemorrhagic colitis
Thrombocytopenic Purpura -- HUS (hemolytic uremic syndrome)
Scully et al, Blood 2017 • pathomechanisms:
• a phase III study -- production of toxins:
• 145 patients with aTTP and already receiving plasma- ◦◦ Shiga toxin (named after the Japanese bacterio-
pheresis once (then continued with plasmapheresis and logist Kiyoshi Shiga [1871-1957]; STEC: Shiga
immunosuppression) toxin-producing Escherichia coli]; former name:
-- caplacizumab verotoxin [VTEC: verotoxin-producing escherichia
-- placebo coli]; has a cell destroying effect on the endothelial
• results: caplacizumab cells of the capillaries; causes uncontrolled com-
-- primary endpoint: platelet increase (> 150,000/µl) → plement activation)
significantly more frequently and faster ◦◦ hemolysin (toxin that triggers hemolysis of eryth-
-- secondary (combined) endpoint (TTP-associated rocytes)
mortality, TTP relapse, major thromboembolic event):
-- a special envelope protein (adhesin) by which the
significantly reduced
bacteria adhere to the epithelial cells of the intestinal
wall

ADAMTS-13 (active) ADAMTS-13 (inactive)

Epidemiology
platelets
auto-antibody against
• host: cattle (Human is a false host.)
ADAMTS-13

blood flow
• transmission
-- direct (food: contaminated sprouts, raw meat, raw
von Willebrand factor milk, contaminated drinking water)
(vWF; multimer) caplacizumab
thrombus
-- indirect (fecal oral)
• epidemics: i.a.
Fig. 1273  Normally the ultra-long von Willebrand factor -- 1996 Japan (7966 cases, of which 106 patients with
multimer is split by the ADAMTS-13 "cutting machine". In HUS)
the case of acquired TTP (aTTP), ADAMTS-13 is defective
due to inhibiting antibodies, so that the multimer can no -- 2011 in Northern Germany (approx. 3300 cases; new
longer be cleaved. Platelets accumulate and microthrom- serotype: O104, up to now always serotype O157)
bosis occurs. Caplacizimab prevents the accumulation of • incubation period: 3-4 days
platelets on the uncut von Willebrand factor multimer and • notification already necessary on suspicion
thus prevents the formation of microthromboses [45].

Symptoms
TTP: a hematological emergency!
• bloody diarrhea
Standard therapy: plasmaphere-
sis + steroids • severe cramp-like abdominal pain
• typically no fever
• neurological (mostly present!)
-- - headaches
EHEC (HUS) -- disturbance of consciousness
◦◦ quantitative (somnolence, coma)
◦◦ qualitative (delirium)
-- myoclonus, tremor
-- seizures (often up to status epilepticus)
-- hemisymptomatic (e.g. hemiparesis)

HUS (hemolytic uremic syndrome)

• syn .: Gasser syndrome (first description 1955 by the
Swiss pediatrician Conrad Gasser [1912-1982])
• a thrombotic microangiopathy (TMA; microangiopa-
thic-hemolytic anemia [MAHA; for overview see page
1051])
• frequency of occurrence of HUS in an EHEC infection:

1054 Hematology
 10% (in pediatrics; HUS epidemic 2011: 30%)
• main age: children (mean age: 3 years; HUS epidemic
2011: 30-40 years, w > m)
• HUS is the most common cause of acute kidney
failure in children!
• occurring on average 4 days after onset of diarrhea
• triad:
-- microangiopathic hemolytic anemia (MAHA):
◦◦ hemoglobin ↓
◦◦ hemolysis parameters: LDH ↑, bilirubin ↑ (indi-
rect), haptoglobin ↓, reticulocytes ↑
◦◦ Coombs test: negative
◦◦ fragmentocytes (syn.: schistocytes; in the blood
smear; microscopic blood count)
-- thrombocytopenia (however in contrast to the DIC
normal values for Quick / INR, PTT, AT III and fibri-
nogen)
-- acute kidney failure (in 30% hemodialysis obligato-
ry, in 10% a dialysis dependent renal insufficiency is
remaining)
• types:
-- according to germs:
◦◦ enteropathic HUS: EHEC, VTEC
◦◦ non-enteropathic HUS: neuraminidase-producing
pneumococci
-- according to questioning whether diarrhea is pre-
sent:
◦◦ typical HUS (95%; D+): with diarrhea (classically
as a result of an EHEC infection; also called
STEC-HUS [STEC: Shiga toxin-producing E. coli])
◦◦ atypical HUS (aHUS; syn.: idiopathic HUS; 5%;
D-; aHUS): without diarrhea
• diagnosis (typical HUS [STEC-HUS]):
-- Shiga toxin (serum): positive
-- EHEC (stool): positive
• mortality: 3%
Fig. 1274  Detection of fragmentocytes (syn.: schistocytes)
in microscopic blood smear (courtesy of PD Dr. Drobnik,
Medical Director of the MVZ Synlab Regensburg [Germa-
ny])
Therapy
• causal: antibiotics
-- EHEC infection without HUS: antibiotics contra-
indicated, as they lead to increased toxin production
-- EHEC-Infektion mit HUS: In many hospitals an an-
tibiotic is administered to eradicate the germs from
the intestine and thus eliminate the source of toxin
production. Antibiosis is recommended especially for
serotype O104: H4.
-- EHEC infection with sepsis: antibiosis recommen-
ded (means of choice: carbapenem, as EHEC is an
ESBL germ!)
• symptomatic:
-- volume and electrolyte balance
-- loperamide (Imodium): contraindicated
-- isolation (strict hygiene measures)
-- anticonvulsive therapy (in the event of a seizure; of-
ten even induction of anesthesia necessary to break
the status epilepticus)
-- plasmapheresis
-- eculizumab (Soliris; see page 1056)
Plasmapheresis
• plasmapheresis with replacement of plasma volume
by FFP (not human albumin): plasma volume = (0.065
x kg BW) x (1-hematocrit), e.g. in a patient weighing 15
FFP per plasmapheresis session necessary
• indication (During the HUS epidemic in Northern Ger-
many in 2011 plasmapheresis was necessary in 95%.):
-- severe hemolysis (i.a. LDH > 400 U/l)
-- thrombocytopenia < 100000/μl
-- renal involvement
-- neurological symptoms
• Plasmapheresis can be stopped if:
-- hemoglobin stable > 48h
-- platelets > 100000/μl
-- LDH < 400 U/l
-- neurological improvement
Excursus: aHUS
Definition
• atypical hemolytic uremic syndrome
• a chronic systemic (mostly genetic) life-threatening di-
sease
• defect of complement inhibitors (especially CFH [com-
plement factor H], CFI [complement factor I], MCP
[membrane cofactor protein], thrombomodulin), so that
there is permanent (chronic) overactivation of the com-
plement factor C3, which activates the complement
system via the complement factor C5 (C3-dependent
cascade of the alternative complement pathway [this is
always active]; hyperactive complement system)
• The complement factor C5 activates i.a. the endothe-
lium and platelets. This leads to damage to the endo-
thelium and thus to a permanent platelet aggregation.
The result is microvascular thrombosis (thrombotic
microangiopathy) with consecutive organic ischemia.
The endothelial injury in turn activates the complement
system, creating a vicious circle.
Hematology 1055
 normal chronic activation aggregation complement mediated TMA
genetic deficiency
of complement
inhibitors
chronic
uncontrolled
complement
activation
Fig. 1275  Pathophysiology of aHUS [43]
Etiologyy
• congenital (mostly): mutation in genes for complement
inhibitors (often positive family history)
• acquired (rarely; auto-antibodies against complement
inhibitors [especially against the complement factor H])
Epidemiology
• incidence: 2/1,000,000 (rarer than TTP)
• prevalence: 10/1,000,000
• especially children and young adults
• w>m
Classification
• The previous division into a primary (85%; without cau-
ses ["idiopathic"]) and secondary (15%; with causes)
form has been abandoned today. The entities previ-
ously listed under the secondary forms are now un-
derstood as triggers (see page 1052) which can then
trigger thrombotic microangiopathy (TMA), if there is a
corresponding disposition (in case of TTP congenital
deficiency of or auto-antibodies against ADAMTS-13
or in csae of aHUS congenital deficiency of or auto-
antibodies against complement inhibitors).
• triggers: These further intensify the activity of the al-
ready chronically over-activated complement system
(sote: The triggers of aHUS are the same as the trig-
gers of a TTP.)
Symptoms and complications
• similar to TTP
• mainly affects the kidneys (as is typical for a HUS; fre-
quently acute kidney failure, possibly permanent he-
modialysis); note: 2/3 of all patients will develop end
stage renal disease (requiring permanent hemodialy-
sis) or die (Noris et al, Clin J Am Soc Nephrol 2010).
Diagnosis
• microangiopathic hemolytic anemia (MAHA):
1056 Hematology
-- hemoglobin ↓
-- hemolysis parameters: LDH ↑, bilirubin ↑ (indirect),
haptoglobin ↓ (note: Haptoglobin is an acute phase
protein and can therefore be false normal in inflam-
mation.), reticulocytes ↑, hemoglobinuria
-- Coombs test: negative
-- fragmentocytes (syn.: schistocytes; in the blood
smear; microscopic blood count)
• thrombocytopenia < 150000/μl and/or decrease > 25%
of the initial value
• exclusion:
-- TTP
◦◦ ADAMTS-13 activity > 5%
◦◦ auto-AB against ADAMTS-13: negative
-- typical HUS (STEC-HUS)
◦◦ Shiga toxin (serum): negative
◦◦ EHEC (stool): negative
• not recommended:
-- genetic tests: not useful (since numerous mutations;
gene mutation also only detectable in 50% of pati-
ents; very expensive), but also not necessary
-- complement diagnostics (mostly normal comple-
ment values)
Therapy
• causal therapy (therapy of the underlying disease) in
the presence of triggers
• plasmapheresis
-- initially mostly urgently required as an emergency
measure in thrombotic microangiopathy in general,
where as a rule there is no time to wait for the labo-
ratory results for further differentiation into a special
thrombotic microangiopathy
-- in the longer term, however, not efficient in the case
of confirmed atypical HUS (in contrast to TTP)
• eculizumab (Soliris)
Eculizumab (Soliris)
• complement antibody (monoclonal humanized antibo-
dy against C5 [thus blocks the alternative complement
cascade that is classically activated in atypical HUS];
terminal [distal] complement inhibitor; note: The im-
mune response of the proximal complement remains
intact.)
• previously only approved for paroxysmal nocturnal
hemoglobinuria (PNH; also here uncontrolled comple-
ment activation), since 2011 now also officially appro-
ved for the therapy of HUS in childhood and adulthood
(note: but only for atypical HUS)
• also possible optionally (but off-label-use) for TTP or
HELLP syndrome (permitted in pregnancy), since here
too, pathophysiologically an uncontrolled complement
activation takes place
• indication for typical HUS (STEC-HUS; off-lable; du-
ring the HUS epidemic in Northern Germany in 2011
eculizumab was necessary in 50%; the Shiga toxin
also causes an uncontrolled complement activation):
despite 3 plasmaphereses still (no improvement under
plasmapheresis):
-- platelets < 50000/μl
 -- thromboembolic events HELLP syndrome
-- neurological symptoms
-- acute kidney failure
• studies (i.a. Legendre et al, N Engl J 2013; Licht et al,
Kidney Int 2015): significant reduction of terminal com-
plement activity, rapid and permanent improvement of
platelet count, improvement of renal function
• dosage:
-- 1 amp. = 30ml = 300mg
-- in the first 4 weeks 1 x per week, in maintenance the- Definition
rapy then every 2 weeks; 900 mg i.v. on day 0, 7, 14 • HELLP: hemolysis, elevated liver enzymes, low plate-
and 21, then 1200 mg i.v. on day 28 (then in the case lets
of aHUS possibly maintenance phase in the sense
• first description in 1982 by the American gynecologist
of a long-term therapy [approved for lifelong therapy;
Louis Weinstein
mean duration of therapy in the case of aHUS: 29
weeks]: every 2 weeks 1200 mg) • a microangiopathic hemolytic anemia (MAHA)
-- If both plasmapheresis and therapy with eculizumab • a hypertensive pregnancy disorder (p.d. RR > 140/90
are used, eculizumab should always be administe- mmHg after the 20th WOP [week of pregnancy])
red after plasmapheresis. • severe course of pre-eclampsia (former designation:
• costs for 1 amp .: € 6,000 (very expensive; costs for EPH-gestosis [Edema, Proteinuria > 300mg/24h, Hy-
the first 28 days: € 96,000 (16 amp.), annual therapy pertension with RR > 140/90 mmHg])
costs [at aHUS]: approx. € 500,000)
• The inhibition of the terminal complement system by Epidemiology
eculizumab increases the risk of infection (especially • incidence: 1-2/300 pregnancies
for encapsulated bacteria); especially increased risk • typically occurring in late pregnancy (on average in the
of meningitis → meningitis prophylaxis recommended: 34th WOP); after the delivery (> 72h) there is no more
Vaccination (tetravalent meningococcal conjugate vac- HELLP, here you have to think of other differential dia-
cine i.m.) should be carried out. However, there have gnoses (especially aHUS)!
been repeated reports of meningicoccal meningitis • occurring in 12% of all pregnant women with existing
despite vaccination. Patients < 18 years must also pre-eclampsia
be vaccinated against haemophilus influenzae and
pneumococci. The vaccination protection does not oc-
cur before 14 days. If you do not have this time, ecu-
Symptoms
lizumab should be given under antibiotic prophylaxis • pain in the right upper abdomen (due to the tension
with the following antibiotics: of the liver capsule; the leading symptom!)
-- azithromycin p.o. day 1-3 500 mg, day 4-10 250 mg • nausea, vomiting
or • arterial hypertension
-- rifampicin p.o. 2 x 600 mg for 14 days • headaches
• will be delivered by the company Alexion if required • visual disturbances (e.g. blurred vision, visual field
immediately and only if the prerequisites mentioned defects [scotoma], flickering, flashing lights or sparks,
above are fulfilled (regulatory requirement for the com- double vision)
pany; a stocking is therefore not possible) • bleeding (e.g. mucosal bleeding, petechiae)
• most common side effects: headache, leukopenia • hyperreflexia
• further development: ravulizumab (Ultomiris) • edema (ascites, pleural effusion, pericardial effusion)
-- chemical change of eculizumab (4 amino acids
changed) with a significantly longer T1/2 (51 days Complications
instead of 13-17 days)
• hepatic:
-- Infusion interval: only every 8 weeks (instead of eve-
-- hematoma (subcapsular)
ry 2 weeks)
-- liver rupture (in 1.5%)
-- annual therapy costs: 33% less than eculizumab
-- acute liver failure
-- dosageÖ
• hematological:
◦◦ 40-60kg: initially 2400mg, then after 2 weeks
3000mg as maintenance dose (then every 8 -- bleeding (dangerous, especially intracerebral)
weeks) -- DIC
◦◦ 60-100kg: initially 2700mg, then after 2 weeks • cardiovascular:
3300mg as maintenance dose (then every 8 -- hypertensive crisis
weeks) -- pulmonary edema
◦◦ > 100kg: initially 3000mg, then after 2 weeks -- pericardial effusion, pleural effusion
3600mg as maintenance dose (then every 8 • neurological (central nervous):
weeks) -- hypertensive encephalopathy, PRES (posterior re-

Hematology 1057
 versible encephalopathy syndrome) • Strictly speaking, "plasmapheresis" refers to the remo-
-- stroke val of plasma for diagnostic purposes without being re-
-- seizure placed and given back into the body. The correct term
• ophthalmological: blindness is "plasma exchange".
• renal: acute kidney failure (due to acute tubular necro- • necessary vascular access: Shaldon catheter (e.g. in
sis) V. jugularis int.), but also possible via two larger peri-
pheral cannulas (green; 18G)
• placental: premature placental separation
• For plasmapheresis the same machine is used as for
CVVH, only a special filter is needed (e.g. Prismaflex
Laboratory TPE 2000 [Gambro]).
• hemolysis (hemoglobin ↓, LDH­ ↑, indirect bilirubin­↑,
haptoglobin ↓, reticulocytes ↑, hemoglobinuria)
• fragmentocytes (schistocytes) in blood smear backflow pressure
air detector
+ hose detector
• platelets < 100000/μl + air separator + blood detector

• elevated liver function parameters (GOT, GPT, biliru- syringe pump backflow clamp
bin) + hose separator
hemofilter
• proteinuria filter blood inlet
outlet pressure pump pressure
pressure

Therapy
BLD (blood not
upper swit-
leck detector) bilanced
ching valve

• procedure: plasma
substitute PBP (pre blood pump)
-- before 34th WOP (no lung maturity yet): steroids (e.g. solution outflow infusion

dexamethasone 10mg i.v. 2 x daily, e.g. betametha- heparin (UHF)

sone 12mg i.v. 2 x daily; plasmapheresis if steroids for anticoagu-
lation
are ineffective); effects of steroids:
◦◦ lung maturity ↑ Fig. 1276  TPE (therapeutic plasma exchange; syn.: plas-
mapheresis): flow circulation [18]
◦◦ platelets ↑
◦◦ immunosuppressive (HELLP syndrome is partly Indications
also understood as an immunological reaction to
the "transplant" fetus.)
-- after 34th WOP (lung maturity present): sectio (be-
fore mostly administration of platelet concentrates
necessary)
• possibly eculizumab (because here also uncontrolled
complement activation; allowed in pregnancy; howe-
ver off-label-use; see page 1056)
• antihypertensive therapy: dihydralazine, α-methyldopa,
urapidil, metoprolol
• anticonvulsive therapy (in case of eclampsia): magne-
sium sulfate 4g i.v. over 20min + diazepam 10-15mg i.v
• pulmonary edema: loop diuretics (e.g. furosemide
40mg i.v.)

Prognosis
• mortality:
-- mother: 5%
-- child: 15%
• risk of recurrence: 10%

Excursus: Plasmapheresis
Definition
• syn.: TPE (therapeutic plasma exchange)
• removal of large-lumen plasma proteins and replace-
ment with (depending on indication)
-- FFP (standard; usually 18-22 FFP per session; cave
citrate accumulation [see page 1019; therefore 10 ml
calcium gluconate 10% is usually administered] and
metabolic alkalosis) or
-- albumin (e.g. 500 ml human albumin 20%)

1058 Hematology
Procedure
• premedication: dimetindene (Fenistil) 4mg, ranitidine
50mg (or famodipine 20mg), prednisolone 100mg i.v.
• total exchange 3000ml, duration 3h
• a total of mostly 7 sessions in 14 days (of which daily
in the first three days, then alternating)
• 5 liter bag: remove 2.5l, then 500ml human albumin
20% (5 bottles a 100ml) or FFP settings

Settings (example)
• blood flow rate: 120 ml/min
• total substitution volume: 3000 ml
• substituate flow rate: 1000 ml/h
• patient plasma loss: 0 ml/h Fig. 1277  Plasmapheresis (TPE: therapeutic plasma ex-
• pre-blood flow: 0 ml/h change): conventional renal replacement machine (here
• effluent rate: 1000 ml/h Prismaflex, Gambro) with a special filter (here Prismaflex
• anticoagulation: TPE 2000
-- heparin (UFH)
◦◦ continuous 1000 E/h
◦◦ control after ACT (decrease 1 x 30 min after start,
target 200-220s) or PTT (target 60-80s)
-- alternative anticoagulation (e.g. citrate anticoagula-
tion)

Hematology 1059
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Heft 3, 11. Jahrgang, August 2015
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- Intensivmedizin und Notfallmedizin, Band 109, Heft 5, Juni 2014
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• Akute Pankreatitis; Bittinger, Meßmann; Medizinische Klinik – Inten-
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1064 Appendix
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• Akuter Intestinalarterienverschluß - Leitlinien der Deutschen Gesell-
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Appendix 1065
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• Beatmungsmodi in der Intensivmedizin; Deden, Dräger (www.drae-
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• Beatmungsstrategien bei chronisch obstruktiver Lungenerkrankung;
1066 Appendix
Stein, Joannidis; Medizinische Klinik - Intensivmedizin und Notfall-
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• Bedeutung und Einsatz der Beatmung bei akut dekompensierter
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• Best of ECCMID 2014: Bakterielle Infektionen und Antibiotika - Leitli-
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• Best of ECCMID 2015: Bakterielle Infektionen und Antibiotika Heft
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• Best of ICAAC (Interscience Conference on Antimicrobial Agents an
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• Blutgase - www.springer.com/cda/content/document/cda_downloa-
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• Cardiovascular life support; American Heart Association Guidelines
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• Catheter-directed embolectomy, fragmentation, and thrombolysis for
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• Catheterization of the heart in man with use of a flow-directed bal-
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• Central venous access in the home parenteral nutrition population-
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• Cerebral herniation in patients with acute liver failure is correlated
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• Chronisch thrombembolische pulmonale Hypertonie - Diagnostik
und individuelles therapeutisches Vorgehen; Wilkens et al, Klinikarzt
- Medizin im Krankenhaus, August 2017, 46. Jahrgang
• Citrate anticoagulation for continuous venovenous hemofiltration;
Dudemans-van Straaten et al, Crit Care Med 2009
• Classification of acute pancreatitis 2012: revision of the Atlanta clas-
sification and definitions by international consensus; Banks et al, Gut
2013
• Clinical and microbiological features of necrotizing fasciitis; Brook et
al, J Clin Microbiol 1995
• Clinical and therapeutic profile of patients presenting with acute co-
ronary syndromes who do not have significant coronary artery disea-
se.The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor
Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators;
Roe et al, Circulation 2000
• Clinical aspects of DIC - disseminated intravascular coagulation;
Matsuda, Pol J Pharmacol 1996
• Clinical characteristics of patients with acute pulmonary embolism;
Stein et al, Am J Cardiol 1991
• Clinical classification of pulmonary hypertension; Simonneau et al, J
Am Coll Cardiol 2004
• Clinical decision rules for excluding pulmonary embolism: a meta-
analysis; Lucassen et al, Ann Intern Med 2011
• Clinical features of adrenal insufficiency in patients with acquired
immunodeficiency syndrome; Piédrola et al, Clin Endocrinol 1996
• Clinical features and management of lithium poisoning; Amdisen,
Med Toxicol Adverse Drug Exp 1988
• Clinical features and prognostic factors in adults with bacterial me-
ningitis; van de Beek et al, N Engl J Med 2004
• Clinical features, site of involvement, bacteriologic findings, and out-
come of infective endocarditis in intravenous drug users; Mathew et
al, Arch Intern Med 1995
• Clinical information determines the impact of transesophageal echo-
cardiography on the diagnosis of infective endocarditis by the duke
criteria; Roe et al, Am Heart J 2000
• Clinical, laboratory, roentgenographic, and electrocardiographic fin-
dings in patients with acute pulmonary embolism and no pre-existing
cardiac or pulmonary disease, Stein et al, Chest 1991
• Clinically suspected pulmonary embolism: utility of spiral CT; Kim et
al, Radiology 1999
• Clinical manifestations and prognostic features of acute metham-
phetamine intoxication; Lan et al, J Formos Med Assoc 1998
• Clinical practice guidelines by the Infectious Diseases Society of
America for the treatment of methicillin-resistant Staphylococcus
aureus infections in adults and children; Liu et al, Clin Infect Dis 2011
• Clinical practice guideline for the use of antimicrobial agents in
neutropenic patients with cancer: 2010 update by the Infectious Di-
seases Society of America; Freifeld et al, Clin Infect Dis 2011
• Clinical practice guidelines for the management of candidiasis: 2009
update by the Infectious Diseases Society of America; Pappas et al,
Clin Infect Dis 2009
Appendix 1067
• Clinical practice guidelines for the sustained use of sedatives and
analgesics in the critically ill adult; Jacobi et al, Crit Care Med 2002
• Clinical practice guidelines on diagnosis and treatment of hypona-
traemia; Spasovski et al, European Journal of Endocrinology 2014
• Clinical practice - Superior vena cava syndrome with malignant cau-
ses; Wilson et al, N Engl J 2007
• Clinical presentation, etiology, and outcome of infective endocarditis
in the 21st century: the International Collaboration on Endocarditis-
Prospective Cohort Study; Murdoch et al, Arch Intern Med 2009
• Clinical presentation, treatment and complications of malignant hy-
perthermia in North America from 1987 to 2006; Larach et al, Anesth
Analg 2010
• Clinical Review - Management of hypercalcemia; Bilezikian et al, J
Clin Endocrinol Metab 1993
• Clinical Review - The diagnosis and management of central hypoad-
renalism; Grossman et al, J Clin Endocrinol Metab 2010
• Clinical risk factors for pulmonary barotrauma: a multivariate analy-
sis; Gammon et al, Am J Respir Crit Care Med 1995
• Clinical significance of pulmonary artery occlusion pressure; Pinsky,
Intensive Care Med 2003
• Clopidogrel with or without Omeprazole in Coronary Artery Disease;
Bhatt et al, N Engl J 2010
• Clostridium difficile – Infektionen oft mit schweren Komplikationen;
Pharma Report, Medizinische Klinik – Intensivmedizin und Notfall-
medizin, Band 108. Heft 6, September 2013
• Clostridium difficile - state of the art; Martin et al, Intensivmedizin
up2date, Heft 2, 8. Jahrgang, Mai 2012
• Clostridium-difficile-Infektionen: Wie gefährlich sind die neuen Stäm-
me? Kola, Internist, Band 51, Heft 2, Februar 2010
• Clostridium-difficile-Kolitis - ein unterschätztes Problem; Salzberger,
Intensivmedizin und Notfallmedizin, Band 47, Heft 4, Mai 2010
• Cocaine-associated dissection of the thoracic aorta; Fisher et al, J
Emerg Med 1992
• Community-acquired pneumonia; Bartlett, N Engl J Med 1995
• Community-acquired pneumonia; File, Lancet 2003
• Comparative analysis of therapeutic options used for myasthenia
gravis; Mandawat et al, Ann Neurol 2010
• Comparative bactericidal activities of daptomycin and vancomycin
against glycopeptide-intermediate Staphylococcus aureus (GISA)
and heterogeneous GISA isolates; Wootton et al, Antimicrob Agents
Chemother 2006
• Comparison between intrathoracic blood volume and cardiac filling
pressures in the early phase of hemodynamic instability of patients
with sepsis or septic shock; Sakka et al, J Crit Care 1999
• Comparison between single-step and balloon dilatational tracheo-
stomy in intensive care unit: a single-centre, randomized controlled
study; Cianchi et al, Br J Anaesth 2010
• Comparison of alteplase versus heparin for resolution of major pul-
monary embolism, Konstantinides et al, Am J Cardiol 1998
• Comparison of Angioplasty with Stenting, with or with-out Abciximab,
in Acute Myocardial Infarction; Stone et al, N Engl J Med 2002
• Comparison of Dopamine and Norepinephrine in the Treatment of
Shock (SOAP-II); de Backer et al, N Engl J 2010
• Comparison of early invasive and conservative strategies in patients
with unstable coronary syndromes treated with the glycoprotein IIb/
IIIa inhibitor tirofiban; Cannon et al, N Engl J Med 2001
• Comparison of fondaparinux and enoxaparin in acute coronary syn-
dromes¸ Fifth Organization to Assess Strategies in Acute Ischemic
Syndromes Investigators, Yusuf et al, N Engl J Med 2006
• Comparison of percutaneous and surgical tracheostomies; Fried-
man et al, Chest 1996
• Comparison of percutaneous coronary intervention and coronary
artery bypass grafting after acute myocardial infarction complicated
by cardiogenic shock: results from the Should We Emergently Re-
vascularize Occluded Coronaries for Cardiogenic Shock (SHOCK)
trial; White et al, Circulation 2005
• Comparison of pulmonary artery and aortic transpulmonary thermo-
dilution for monitoring of cardiac output in patients with severe heart
failure: validation of a novel method; Friesecke et al, Crit Care Med
2009
• Comparison of Rate Control and Rhythm Control in Patients with
Atrial Fibrillation. The Atrial Fibrillation Follow-up Investigation of
Rhythm Management (AFFIRM) Investigators, N Engl J 2002
• Comparison of two fluid-management trials in acute lung injury; Wie-
1068 Appendix
demann et al, ARDS Clinical Trials Network; FACTT (fluid and cathe-
ters treatment trials), N Engl J 2006
• Complications of anaesthesia in neuromuscular disorders; Klingler
et al, Neuromuscul Disord 2005
• Complications of central venous catheters: internal jugular versus
subclavian access - a systematic review; Ruesch et al, Crit Care
Med 2002
• Complications of femoral and subclavian venous catheterization in
critically ill patients: a randomized controlled trial; Merrer et al, JAMA
2001
• Complications during and following radial artery cannulation: a pro-
spective study; Weiss et al, Intensive Care Med 1986
• Complications of noninvasive positive pressure ventilation; Hill et al,
Respir Care 1997
• Consensus guidelines on the management of community-acquired
pneumonia in adults - Infectious Diseases Society of America/Ame-
rican Thoracic Society; Mandell et al, Clin Infect Dis 2007
• Contemporary management of paroxysmal supraventricular tachy-
cardia; Ferguson et al, Circulation 2003
• Continuous lateral rotation therapy to prevent ventilator-associated
pneumonia: The neglected effects of gravity on pathogenesis of ven-
tilator-associated pneumonia; Staudinger et al, Crit Care Med 2010
• Continuous thermodilution cardiac output measurement in intensive
care unit patients; Yelderman et al, J Cardiothorac Vasc Anesth 1992
• Continuous venovenous haemodiafiltration versus intermittent
haemodialysis for acute kidney failure in patients with multiple-organ
dysfunction syndrome: a multicenter randomized trial; Vinsonneau
et al, Lancet 2006
• Continuous versus intermittent renal replacement therapy for critical-
ly ill patients with acute kidney injury: a meta-analysis; Bagshaw et
al, Crit Care Med 2008
• Control of serum phosphate in patients with renal failure--new ap-
proaches; Mucsi et al, Nephrol Dial Transplant 1998
• Controversial issues in the treatment of hyperkalaemia; Kamel et al,
Nephrol Dial Transplant 2003
• „Cooling“ nach kardiopulmonaler Reanimation im Jahr 2011 - Indika-
tionen und Durchführung; von Lewinski, Pieske; Intensivmedizin und
Notfallmedizin, Band 48. Heft 3, April 2011
• COPD-Exazerbation und Intensivtherapie; Koczulla et al, Intensiv-
medizin und Notfallmedizin, Band 46, Heft 4, Mai 2009
• Cor pulmonale: an overview; Budev et al, Semin Respir Crit Care
Med 2003
• Cor pulmonale und pulmonale Hypertonie; Rosenkranz; Herz, Band
39, Heft 1, Februar 2014
• Coronary artery bypass graft surgery provides better survival in pa-
tients with acute coronary syndrome or ST-segment elevation myo-
cardial infarction experiencing cardiogenic shock after percutaneous
coronary intervention: A propensity score analysis; Chiu et al, J Tho-
rac Cardiovasc Surg 2009
• Coronary stenting versus balloon angioplasty for acute myocardial
infarction: a meta-regression analysis of randomized trials; De Luca
et al, Int J Cardiol 2008
• Corticoide in der Therapie von Sepsis und ARDS; Keh et al, Intensiv-
medizin up2date, Heft 4, 4. Jahrgang, November 2008
• Corticosteroid treatment and intensive insulin therapy for septic
shock in adults: a randomized controlled trial - COIITSS Study Inve-
stigators; Annane et al, JAMA 2010
• Corticosteroids to prevent extubation failure: a sytemic review and
meta-analysis; McCaffrey et al, Journal of Intensive Care Medicine
2009
• Costs containment and mechanical ventilation in the United States;
Cohen et al, New Horiz 1994
• COVID-update DGIM (Deutsche Gesellschaft für Innere Medizin;
www.streamed-up.com/kategorie/gesellschaften/dgim/covid-19-up-
date; abgerufen am 31.07.2020)
• COVID-19-Pneumonie; Pfeifer, Hamer, Der Internist 8/2020
• Critical-Illnes-Polyneuropathie und Critical-Illness-Myopathie;
Grimm et al, Medizinische Klinik - Intensivmedizin und Notfallmedi-
zin, Band 107, Heft 8. November 2012
• Critical-Illness-Myopathie und -Polyneuropathie; Senger, Erbguth,
Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band 112,
Heft 7, Oktober 2017
• Critical illness polyneuropathy and myopathy: a major cause of mu-
scle weakness and paralysis; Latronico et al, Lancet Neurol 2011
• Critical illness polyneuropathy and myopathy in patients with acute
respiratory distress syndrome; Bercker et al, Crit Care Med 2005
• Critical pathways for management of patients with acute coronary
syndromes: an assessment by the National Heart Attack Alert Pro-
gram; Cannon et al, Am Heart J 2002
• Current outcome of portal vein thrombosis in adults: risk and benefit
of anticoagulant therapy; Condat et al, Gastroenterology 2001
• Current understanding of disseminated intravascular coagulation;
Levi, Br J Haematol 2004
• Cyanid-Intoxikationen; Rump, Notfall + Rettungsmedizin, Band 16,
Heft 5, August 2013
• Cyanide poisoning by fire smoke inhalation: an European expert
consensus; Anseeuw et al, Eur J Emerg Med 2013
• Dabigatran versus Warfarin in Patients with Atrial Fibrillation (RELY);
Conolly et al, N Engl J 2009
• Dabigatran versus Warfarin in treatment of acute venous thrombo-
embolism (RECORD); Schulmann et al, N Engl J 2009
• Daily Hemodialysis and the Outcome of Acute kidney failure; Schiffl
et al, N Engl 2002
• Daily Interruption of Sedative Infusions in Critically Ill Patients Under-
going Mechanical Ventilation; Kress et al, N Engl J 2000
• Daily sedation interruption in mechanically ventilated critically ill pati-
ents cared for with a sedation protocol: a randomized controlled trial;
Mehta et al, JAMA 2012
• Daptomycin versus Standard Therapy for Bacteremia and Endocar-
ditis Caused by Staphylococcus aureus; Fowler et al N Engl J 2006
• Darmmotilitätsstörungen beim Intensivpatienten; Madl et al, Gastro-
enterologe 1/2019
• Darmpassagestörungen in der Intensivtherapie; Kirchberg et al, In-
tensivmedizin up2date, Heft 3, 8. Jahrgang, August 2012
• Das abdominelle Kompartmentsyndrom; Reibetanz, Germer, Medi-
zinische Klinik - Intensivmedizin und Notfallmedizin; Band 108. Heft
8. November 2013
• Das abdominelle Kompartment; Schaaf et al, Intensivmedizin up-
2date, Mai 2018. 14. Jahrgang
• Das akute Aortensyndrom; Semsroth et al, Medizinische Klinik - In-
tensivmedizin und Notfallmedizin, Band 109, Heft 5, Juni 2014
• Das akute Aortensyndrom - Aktueller Stand der Ätiologie, Diagnostik
und Therapie; Akin, Nienaber, Klinikarzt Juni 2017, 46. Jahrgang
• Das akute Guillain-Barré-Syndrom; Sindern et al, Deutsches Ärz-
teblatt 1996
• Das akute Koronarsyndrom; Staudacher et al, Intensivmedizin up-
2date, Heft 2, 10. Jahrgang, Mai 2014
• Das Delir auf Intensivstation; Luetz et al, Medizinische Klinik - Inten-
sivmedizin und Notfallmedizin, Band 107, Heft 4, Mai 2012
• Das 1 x 1 der Beatmung; Bremer, 2. Auflage, Lehmanns media
• Das hämolytisch-urämische Syndrom; Wiesmann, Intensivmedizin
up2date, Heft 2, 8. Jahrgang, Mai 2012
• Das HELLP-Syndrom - eine interdisziplinäre Herausforderung;
Rath, Deutsches Ärzteblatt, Heft 47, 1998
• Das hepatorenale Syndrom; Kurschat et al, Intensivmedizin up-
2date, Heft 1, 6. Jahrgang, Februar 2010
• Das ICU-Delir – die sekundäre Psychose auf der Intensivstation; Bi-
niek et al, Intensivmedizin up2date, Heft 4, 4. Jahrgang, November
2008
• Das Konzept der „5A“ für die Intensiv- und Notfallmedizin; Trappe,
Intensivmedizin und Notfallmedizin, Band 45, Heft 5, Juni 2008
• Das medikamentös induzierte Long-QT-Syndrom - Bedeutung in der
Intensivmedizin; Laszlo et al, Medizinische Klinik – Intensivmedizin
und Notfallmedizin, Band 107, Heft 4, Mai 2012
• Das posteriore reversible Enzephalopathie-Syndrom (PRES); Diet-
rich et al, Intensivmedizin und Notfallmedizin, Band 44, Heft 7, Ok-
tober 2007
• Das Recht auf ein menschenwürdiges Sterben: Überlegungen zu
Voraussetzungen und Grenzen der Sterbehilfe; Schröder, Logos
Berlin 2003
• Das toxische Megakolon; Leppkes et al, Medizinische Klinik – In-
tensivmedizin und Notfallmedizin, Band 110, Heft 7, Oktober 2015
• Das ZNA-Buch; Moecke, Medizinisch Wissenschaftliche Verlagsge-
sellschaft 2011
• D-dimer for the exclusion of acute venous thrombosis and pulmona-
ry embolism: a systematic review; Stein et al, Ann Intern Med 2004
• Decannulation following tracheostomy for prolonged mechanical
ventilation; O'Connor et al, J Intensive Care Med 2009
• Decontamination of the Digestive Tract and Oropharynx in ICU Pati-
ents; de Smet et al, N Engl J 2009
• Deep-vein thrombosis; Weinmann et al, N Engl J Med 1994
• Deep venous thrombosis caused by femoral venous catheters in cri-
tically ill adult patients; Joynt et al, Chest 2000
• Definition and evaluation of transient ischemic attack: a scientific
statement for healthcare professionals from the American Heart As-
sociation/American Stroke Association Stroke Council; Council on
Cardiovascular Surgery and Anesthesia; Council on Cardiovascular
Radiology and Intervention; Council on Cardiovascular Nursing; and
the Interdisciplinary Council on Peripheral Vascular Disease. The
American Academy of Neurology affirms the value of this statement
as an educational tool for neurologists; Easton et al, Stroke 2009
• Definition, Epidemiologie und ökonomische Aspekte der Sepsis bei
Erwachsenen; Moerer et al, Internist, Band 50, Heft 7, Juli 2009
• Dekompressive Hemikraniektomie beim mailgnen Mediainfarkt;
Neugebauer et al, Intensivmedizin up2date, Heft 2, 11. Jahrgang,
Mai 2015
• Delir auf der Intensivstation – Klinische Wertigkeit, Diagnostik und
Therapie; Medizinische Klinik – Intensivmedizin und Notfallmedizin,
Band 109, Heft 2, März 2014
• Der infektiologische Notfall auf Intensivstation - tägliches Üben für
den Ernstfall; Friedrich et al, Intensivmedizin up2date, Heft 4, 6.
Jahrgang, November 2010
• DGEM (Deutsche Gesellschaft für Ernährungsmedizin): Leitlinien
Parenterale Ernährung und Enterale Ernährung (www.dgem.de)
• Delirium as a predictor of mortality in mechanically ventilated pati-
ents in the intensive care unit; Ely et al, JAMA 2004
• Der adipöse Patien auf der Intensivstation; Bone et al, Intensivmedi-
zin up2date, Heft 1, 10. Jahrgang, Februar 2014
• Der chronisch kranke Patient aus der Perspektive des Kardiologen;
Janssens et al, Medizinische Klinik – Intensivmedizin und Notfallme-
dizin, Band 108. Heft 4, Mai 2013
• Der chronisch kritisch kranke Patient aus der Perspektive des Hä-
matoonkologen; Staudinger et al, Medizinische Klinik – Intensivme-
dizin und Notfallmedizin, Band 108. Heft 4, Mai 2013
• Der Dialysepatient auf der Intensivstation; Kierdorf, Medizinische
Klinik – Intensivmedizin und Notfallmedizin, Band 108. Heft 4, Mai
2013
• Der Einschluß von Intensivpatienten in klinische Studien – Ethische,
rechtliche und organisatorische Probleme aus interdisziplinärer
Sicht; Weimann et al, Medizinische Klinik – Intensivmedizin und Not-
fallmedizin, Band 108. Heft 4, Mai 2013
• Der hämatologische Patient im Intensivmanagement; Staudinger,
Medizinische Klinik – Intensivmedizin und Notfallmedizin, Band 108.
Heft 3, April 2013
• Der hämatologisch-onkologische Patient auf der Intensivstation:
Therapieziele, Ethik, Palliation; Schellongowski, Medizinische Klinik
– Intensivmedizin und Notfallmedizin, Band 108. Heft 3, April 2013
• Der immunosupprimierte Patient mit Sepsis: Eine besondere Her-
ausforderung für die Intensivmedizin; Nachtkamp, Kondakci; Klini-
karzt - Medizin im Krankenhaus, 43. Jahrgang, 2/2014
• Der kritisch chronisch kranke Patient aus pneumologischer Sicht;
Pfeifer, Medizinische Klinik – Intensivmedizin und Notfallmedizin,
Band 108. Heft 4, Mai 2013
• Der Leukämiepatient auf der Intensivstation; Zierhut, Reichle; Inten-
sivmedizin und Notfallmedizin, Band 44, Heft 5, Juni 2007
• Der palliativmedizinische Dienst auf der Intensivstation; Klein et al,
Medizinische Klinik – Intensivmedizin und Notfallmedizin, Band 107,
Heft 4, Mai 2012
• Der Patient mit implantiertem Device in der Intensivmedizin; Hein-
roth, Medizinische Klinik – Intensivmedizin und Notfallmedizin, Band
107, Heft 5, Juni 2012
• Der Pulmonaliskatheter in der Intensivmedizin; Janssens, Graf; In-
tensivmedizin und Notfallmedizin, Band 44, Heft 5, Juni 2007
• Der reanimierte Patient mit frischem Herzinfarkt - Thrombolyse oder
Herzkatheter? Eisenburger, Intensivmedizin und Notfallmedizin,
Band 46, Heft 2, März 2009
• Der rheumatologische Patient auf der Intensivstation; Lehmann et
al, Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band
107, Heft 5, Juni 2012
• Der schwer entwöhnbare Patient; Funk, Medizinische Klinik - Inten-
sivmedizin und Notfallmedizin, Band 107, Heft 8. November 2012
Appendix 1069
• Der schwierige Atemweg - Epidemiologie, Diagnose und Manage-
ment; Henschke et al, Intensivmedizin und Notfallmedizin, Band 43,
Heft 4, Mai 2006
• Der schwierige Atemweg auf der Intensivstation; Meißner, Intensiv-
medizin up2date, Heft 3, 5. Jahrgang, August 2009
• Der zentrale Venenkatheter; Beutlhauser, Intensivmedizin up2date,
Heft 2, 8. Jahrgang, Mai 2012
• Dermale und inhalative Intoxikationen – seltene Gäste auf unseren
Intensivstationen? Sagoschen, Medizinische Klinik - Intensivmedizin
und Notfallmedizin, Band 108. Heft 6, September 2013
• Determining prognosis in patients with fulminant hepatic failure:
when you absolutely, positively have to know the answer; Lake et
al, Hepatology 1995
• Deutscher Interdisziplinärer Kongreß für Intensiv- und Notfallmedi-
zin (Kongreß der Deutschen Interdisziplinären Vereinigung für In-
tensiv- und Notfallmedizin [DIVI]) 01.-04.12.2004, 08.-11.11.2006,
03.-06.12.2008. 01.-04.12.2010, 05.-07.12.2012, 03.-05.12.2014,
01.-04.12.2015, 30.11.-02.12.2016, 05.-08.12.2017, 05.-07.12.2018.
04.-06.12.2019 (Kongreßbeiträge, Workshops)
• Development and first validation of the COPD Assessment Test
(CAT); Jones et al, Eur Resp J 2009
• Dexamethasone in adults with bacterial meningitis - European Dexa-
methasone in Adulthood Bacterial Meningitis Study Investigators; de
Gans et al, N Engl J Med 2002
• Dexmedetomidin in der Intensivmedizin; Paris et al, Intensivmedizin
up2date, Heft 1, 8. Jahrgang, Februar 2012
• Dexmedetomidine vs Midazolam for Sedation of Critically Ill Pati-
ents; Riker et al, JAMA 2009
• Diabetesnotfälle; Scherbaum, Medizinische Klinik – Intensivmedizin
und Notfallmedizin, Band 109, Heft 4, Mai 2014
• Diabetisches Koma; Berndt, Lehnert, Intensivmedizin up2date, Heft
4, 12. Jahrgang, November 2016
• Diagnose und kausale Therapie der Sepsis; Brunkhorst, Welte; In-
tensivmedizin und Notfallmedizin, Band 46, Heft 8. November 2009
• Diagnose und kausale Therapie der Sespsis; Brunkhorst et al, Pa-
thophysiologie und Keimspektrum der Sepsis; Hauber et al, Inter-
nist, Band 50, Heft 7, Juli 2009
• Diagnose und Klassifikation des akuten Nierenversagens; Reindl-
Schwaighofer et al, Intensivmedizin und Notfallmedizin, Band 47,
Heft 6, September 2010
• Diagnose und Therapie der COPD-Exazerbation; Bauer et al, Medi-
zinische Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft
3, April 2012
• Diagnose, Prävention und Therapie des akuten Nierenversagens;
Kielstein et al, Intensivmedizin up2date, Heft 3, 3. Jahrgang, August
2007
• Diagnose und Therapie von parapneumonischen Pleuraergüssen
und Empyemen; Tasci, Selçuk; Ewig, Santiago; Lüderitz, Berndt;
Deutsches Ärzteblatt 2004
• Diagnose von Gerinnungsstörungen; Honickel, Grottke, Medizini-
sche Klinik - Intensivmedizin und Notfallmedizin, Band 113, Heft 7,
Oktober 2018
• Diagnosis and assessment of pulmonary arterial hypertension; Ba-
desch et al, J Am Coll Cardiol 2009
• Diagnosis and classification of the antiphospholipid syndrome; Gó-
mez-Puerta, Cervera, Journal of Autoimmunity 48-49 (2014) 20-25
• Diagnosis and localization of accessory pathways; Cain et al, Pacing
Clin Electrophysiol 1992
• Diagnosis and management of aortic dissection; Erbel et al, Eur
Heart J 2001
• Diagnosis and management of hypocalcaemia; Cooper et al, BMJ
2008
• Diagnosis and treatment of acute tubular necrosis; Esson et al, Ann
Intern Med 2002
• Diagnosis and treatment of digoxin toxicity; Lip et al, Postgrad Med
J 1993
• Diagnosis and treatment of gastrointestinal bleeding secondary to
portal hypertension. American College of Gastroenterology Practice
Parameters Committee; Grace et al, Am J Gastroenterol 1997
• Diagnosis and treatment of severe hematochezia. The role of urgent
colonoscopy after purge; Jensen et al, Gastroenterology 1988
• Diagnosis of acute aortic dissection by D-dimer: the International
Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-
Bio) experience; Suzuki et al, Circulation 2009
1070 Appendix
• Diagnosis of ascending aortic dissection by transesophageal echo-
cardiography: utility of M-mode in recognizing artifacts; Evangelista
et al, J Am Coll Cardiol 1996
• Diagnosis of pulmonary embolism in patients with proximal deep
vein thrombosis: specificity of symptoms and perfusion defects at
baseline and during anticoagulant therapy; Girard et al, Am J Respir
Crit Care Med 2001
• Diagnosis, prevention and treatment of hepatorenal syndrome in cir-
rhosis; Salerno et al, Gut 2007
• Diagnostic and classification criteria for the Guillain-Barré syndrome;
Van der Meché, Eur Neurol 2001
• Diagnostic value of arterial blood gas measurement in suspected
pulmonary embolism; Rodger et al, Am J Respir Crit Care Med 2000
• Diagnostic criteria, clinical features, and incidence of thyroid storm
based on nationwide surveys; Akamizu et al, Thyroid 2012
• Diagnostic value of echocardiography in suspected endocarditis. An
evaluation based on the pretest probability of disease; Lindner et al,
Circulation 1996
• Diagnostic value of transesophageal compared with transthoracic
echocardiography in infective endocarditis; Shively et al, J Am Coll
Cardiol 1991
• Diagnostik bei ambulant erworbener Pneumonie; Flückiger et al, In-
ternist, Band 48. Heft 5, Mai 2007
• Diagnostik der pulmonalen Hypertonie; Leschke et al, Internist,
Band 50, Heft 9, September 2009
• Diagnostik der rechtsventrikulären Funktionsstörung; Ewert et al, In-
tensivmedizin up2date, Heft 1, 2. Jahrgang, Februar 2006
• Diagnostik der venösen Thrombose und Lungenembolie; Schellong,
Internist, Band 51, Heft 3, März 2010
• Diagnostik und Behandlung des akuten Leberversagens - Wissen-
schaftliche Entwicklungen; Ott et al, Der Internist, Band 55, Heft 11,
November 2014
• Diagnostik und Therapie der Immunthrombozytopenie - Empfeh-
lungen einer gemeinsamen Expertengruppe der DGHO, DGTI und
GTH; Matzdorff et al, Onkologie 2010; 33(suppl 3): 2-20
• Diagnostik und Therapie der mikrobiell verursachten Endokarditis;
Horstkotte et al, Internist, Band 49, Heft 1, Januar 2008
• Diagnostik und Behandlungskonzept bei Hämoptoe; Franzen et al,
Mini-Review, Praxis 2013
• Diagnostik und Therapie der Malaria, Leitlinien der Deutschen Ge-
sellschaft für Tropenmedizin und Internationale Gesundheit (AWMF
online)
• Dialyse auf der Intensivstation; Kielsetin, Intensivmedizin und Not-
fallmedizin, Band 46, Heft 4, Mai 2009
• Dialysis modality and dosing strategy in acute kidney failure; Palev-
sky et al, Semin Dial 2006
• Diaphragmale Dysfunktion; Bruells, Marx, Medizinische Klinik - In-
tensivmedizin und Notfallmedizin, Band 113, Heft 7, Oktober 2018
• Die akute intermittierende Porphyrie; Petrides, Deutsches Ärzteblatt,
Heft 50, 1997
• Die akute Nierenschädigung; Schmid et al, Medizinische Klinik - In-
tensivmedizin und Notfallmedizin, Band 107, Heft 4, Mai 2012
• Die akuten Porphyrien; Petrides, Falk Gastro-Kolleg Leber und Gal-
lenwege; www.drfalkpharma.de/uploads (abgerufen am 11.09.2014)
• Die akzidentelle Hypothermie - Initiales Management am Unfallort
und in der Notaufnahme; Grape, Walker, Ravussin, Curriculum,
Schweiz Med Forum 2012, 12(9): 199-202
• Die Bedeutung des „second hit“ für den Sepsisverlauf; Engelmann et
al, Intensivmedizin und Notfallmedizin, Band 43, Heft 3, März 2006
• Die Behandlung des schweren akuten Lungenversagens (ARDS);
Busch et al, Intensivmedizin up2date, Heft 1, 3. Jahrgang, Februar
2007
• Die Berlin-Definition - Neue Kriterien und Klassifikation des ARDS;
Hecker, Seeger; Mayer; Medizinische Klinik - Intensivmedizin und
Notfallmedizin, Band 107, Heft 6, September 2012
• Die blaue Blume im Pilzsalat – Eine beinahe tödliche Intoxikation mit
Aconitum napellus (Blauer Eisenhut); Compagnoni et al, Notfall +
Rettungsmedizin, Band 16, Heft 4, Juni 2013
• Die chronisch-obstruktive Lungenerkrankung (COPD): Aktuelle
Konzepte und neue Therapieoptionen; Klemmer et al, Der Internist,
Band 55, Heft 4, April 2014
• Die Diagnose der Sepsis; Engelmann; Intensivmedizin und Notfall-
medizin, Band 43, Heft 8. November 2006
• Die Echokardiographie auf der Intensivstation; Hansen et al, Inten-
 sivmedizin up2date, Heft 4, 3. Jahrgang, November 2007
• Die extrakorporale Therapie septischer Patienten - Gibt es eine ext-
rarenale Indikation? Schefold et al, Intensivmedizin und Notfallmedi-
zin, Band 44, Heft 2, März 2007
• Die hämophagozytische Lymphohistiozytose (HLH) und das Makro-
phagenaktivierungssyndrom (MAS): Klinisches Erscheinungsbild
und Diagnostik; La Rosée et al, J Lab Med 2013; 37(5): 217-225
• Die häufigsten Elektrolytstörungen in der Notaufnahme - Was ist so-
fort zu tun? Schmidt, Der Internist, Band 56, Heft 7, Juli 2015
• Die infektiöse Endokarditis bei Intensivpatienten; Dietz et al, Medi-
zinische Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft
1, Februar 2012
• Die metabolische Alkalose - Diagnostik und Therapie; Koball et al,
Intensivmedizin und Notfallmedizin, Band 45, Heft 7, Oktober 2008
• Die neuen Leitlinien zur kardiopulmonalen Reanimation; Braunecker
et al, Intensivmedizin up2date, Heft 1, 7. Jahrgang, Februar 2010
• Die nosokomiale Pneumonie - state of the art; Welte, Intensivmedi-
zin und Notfallmedizin, Band 43, Heft 4, Mai 2006
• Die obere gastrointestinale Blutung: Differenzialdiagnose und The-
rapie; Pohl et al, Intensivmedizin up2date, Heft 3, 5. Jahrgang, Au-
gust 2009
• Die perioperative Therapie des von-Willebrands-Syndroms; Klein-
schmidt et al, Anästhesist 10/2002
• Die retrograde Intubation in Notfallsituationen - Indikation, techni-
sche Durchführung, Risiken und Fehlerquellen; Timmermann, Anäs-
thesiol Intensivmed Notfallmed Schmerzther 2012
• Die Rolle der Echokardiographie bei der Abklärung eines hämody-
namisch instabilen Patienten; Bolliger et al, Intensivmedizin und Not-
fallmedizin, Band 43, Heft 8. November 2006
• Die Schweigepflicht bei der Behandlung von Patienten; Lissel, Not-
fall + Rettungsmedizin, Band 9, Heft 2, März 2006
• Die schwierige Extubation; Windisch et al, Medizinische Klinik - In-
tensivmedizin und Notfallmedizin, Band 107, Heft 7, Oktober 2012
• Die septische Herdenzephalitis; Prange, Intensivmedizin und Not-
fallmedizin, Band 43, Heft 2, März 2006
• Die Tracheotomie auf der Intensivstation; Baumann et al, Intensiv-
und Beatmungsmedizin 2010
• Die Überwachung der Leberfunktion in der Intensivmedizin; Umgel-
ter et al, Intensivmedizin und Notfallmedizin, Band 45, Heft 7, Ok-
tober 2008
• Die Virologie von SARS-CoV-2; Höhl, Ciesek, Der Internist 8/2020
• Different modes of assisted ventilation in patients with acute respira-
tory failure; Chiumello et al, Eur Respir J 2002
• Differentialdiagnose und Management von Weaningproblemen;
Funk, Intensivmedizin und Notfallmedizin, Band 48. Heft 4, Mai 2011
• Differentialdiagnosen thrombotischer Mikroangipathien; Haller, Me-
dizinische Klinik - Intensivmedizin und Notfallmedizin, Band 109,
Heft 8. November 2014
• Differentialdiagnostik der pulmonalen Hypertonie - Ursachen, Sym-
ptome und klinische Einteilung; Halank et al, Klinikarzt - Medizin im
Krankenhaus, August 2017, 46. Jahrgang
• Differential diagnosis of hypercalcemia; Lafferty et al, J Bone Miner
Res 1991
• Differential diagnostic value of procalcitonin in surgical and medical
patients with septic shock; Clec'h et al, Crit Care Med 2006
• Differentiation between organophosphate and carbamate poisoning;
Rotenberg et al, Clin Chim Acta 1995
• Differentiation of paroxysmal narrow QRS complex tachycardias
using the 12-lead electrocardiogram; Kalbfleisch et al, J Am Coll
Cardiol 1993
• Differenzierter Einsatz kardiovaskulär aktiver Substanzen; Ellger et
al, Intensivmedizin up2date, Heft 4, 2. Jahrgang, November 2006
• Differenzierter Einsatz kardiovaskulär wirksamer Substanzen; Reh-
berg et al, Intensivmedizin up2date, Mai 2018. 14. Jahrgang
• Difficult airway management in the emergency department; Ore-
baugh et al, J Emerg Med 2002
• Difficult Airway Society Guidelines; Henderson et al, Anaesthesia
2004
• Digoxin use and digoxin toxicity in the post-DIG trial era; Hussain et
al, J Card Fail 2006
• DGINA (Deutsche Gesellschaft Interdisziplinäre Notfall- und Akut-
medizin): 7. Jahrestagung 20.-22.09.2012, Berlin
• Direct arterial pressure monitoring; Gardner et al, Curr Anaesth Crit
Care 1990
• Direct or modified Seldinger guide wire-directed technique for arteri-
al catheter insertion; Mangar et al, Anesth Analg 1993
• Discovery and validation of cell cycle arrest biomarkers in human
acute kidney injury; Kashani et al, Crit Care Med 2013
• Dissektion der Halsarterien; Lerch et al, Cardiovasc, Oktober 2014
• Disseminierte intravasale Gerinnung; Dempfle, Borggrefe; Intensiv-
medizin und Notfallmedizin, Band 43, Heft 2, März 2006
• Diuretics, mortality, and nonrecovery of renal function in acute kid-
ney failure; Mehta et al, JAMA 2002
• DIVI-Jahrbuch 2014/2015 - Fortbildung und Wissenschaft in der
interdisziplinären Intensivmedizin und Notfallmedizin; Jorch, Kluge,
Markewitz, Putensen, Quintel, Sybrecht (Hrsg.); Medizinische Wis-
senschaftliche Verlagsgeschellschaft
• Dobutamin bei schwerer Herzinsuffizienz; Janssens, Medizinische
Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft 1, Fe-
bruar 2012
• Does bicarbonate therapy improve the management of severe dia-
betic ketoacidosis? Viallon et al, Crit Care Med 1999
• Does dopamine administration in shock influence outcome? Results
of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study; Sakr
et al, Crit Care Med 2004
• Does enteral nutrition affect clinical outcome? A systematic review of
the randomized trials; Koretz et al, Am J Gastroenterol 2007
• Does a higher PEEP decrease mortality in acute respiratory distress
syndrome? Phoenix et al, Anesthesiology 2009
• Double-dose versus standard-dose clopidogrel and high-dose ver-
sus low-dose aspirin in individuals undergoing percutaneous coro-
nary intervention for acute coronary syndromes (CURRENT-OASIS
7): a randomized factorial trial; Mehta et al, Lancet 2010
• Drogen in der Kardiologie und Intensivmedizin; Böhm et al, Intensiv-
medizin und Notfallmedizin, Band 43, Heft 5, Juni 2006
• Drogenintoxikationen; Eyer, Zilker; Notfall + Rettungsmedizin, Band
15, Heft 7, November 2012
• Droge ist nicht gleich Droge; Weilemann, Medizinische Klinik – Inten-
sivmedizin und Notfallmedizin, Band 108. Heft 6, September 2013
• Drug-Eluting or Bare-Metal Stents for Acute Myocardial Infarction;
Mauri et al, N Engl J 2008
• Drug-induced hyperthermia and muscle rigidity: a practical ap-
proach; Hadad et al, Eur J Emerg Med 2003
• DSO (Deutsche Stiftung Organtransplantation) - Leitfaden für die
Organspende (www.dso.de)
• Duration of hypotension before initiation of effective antimicrobial
therapy is the critical determinant of survival in human septic shock;
Kumar et al, Crit Care Med 2006
• Dynamic changes in arterial waveform derived variables and fluid
responsiveness in mechanically ventilated patients: A systematic
review; Marik et al, Crit Care Med 2009
• Dysphagie-Management im Akut- und Langzeitverlauf bei kritisch
kranken intensivpflichtigen Patienten; Zielske et al, Medizinische Kli-
nik - Intensivmedizin und Notfallmedizin, Band 109, Heft 7, Oktober
2014
• Dysphagiemanagement in der internistischen Intensivmedizin; Mi-
chels et al, Medizinische Klinik – Intensivmeidzin und Notfallmedizin,
Band 110, Heft 3, Mai 2015
• Early administration of corticosteroids in emergency room treatment
of acute asthma; Stein et al, Ann Intern Med 1990
• Early administartion of terlipressin plus glyceryl trinitrate to control
active upper GI-bleeding in cirrhotic patients; Levacher et al, Lancet
1995
• Early and late effects of clopidogrel in patients with acute coronary
syndromes; Yusuf et al, Circulation 2003
• Early decompressive surgery in malignant infarction of the middle
cerebral artery: a pooled analysis of three randomized controlled tri-
als; Vahedi et al, Lancet 2007
• Early enteral nutrition in acutely ill patients: a systematic review; Ma-
rik et al, Crit Care Med 2001
• Early enteral nutrition, provided within 24h of injury or intensive care
unit admission, significantly reduces mortality in critically ill patients:
a meta-analysis of randomized controlled trials; Doig et al, Journal of
Intensive Care Medicine 2009
• Early goal-directed hemodynamic optimization combined with thera-
peutic hypothermia in comatose survivors of out-of-hospital cardiac
arrest; Gaieski et al, Resuscitation 2009
Appendix 1071
• Early goal-directed Therapy in the Treatment of Severe Sepsis and
Septic Shock; Rivers et al, N Engl J 2001
• Early indicators of prognosis in fulminant hepatic failure: an assess-
ment of the Model for End-Stage Liver Disease (MELD) and King's
College Hospital criteria; Dhiman et al, Liver Transpl 2007
• Early nasogastric feeding in predicted severe acute pancreatitis: A
clinical, randomized study; Eckerwall et al, Ann Surg 2006
• Early non-invasive ventilation averts extubation failure in patients at
risk: a randomized trial; Ferrer et al, Am J Respir Crit Care Med 2006
• Early predictors of severe lower gastrointestinal bleeding and adver-
se outcomes: a prospective study; Velayos et al, Clin Gastroenterol
Hepatol 2004
• Early revascularization and long-term survival in cardiogenic shock
complicating acute myocardial infarction; Hochman et al, JAMA 2006
• Early revascularization in acute myocardial infarction complicated
by cardiogenic shock. SHOCK Investigators. Should We Emergently
Revascularize Occluded Coronaries for Cardiogenic Shock; Hoch-
man et al, N Engl J Med 1999
• Early revascularization is associated with improved survival in elder-
ly patients with acute myocardial infarction complicated by cardio-
genic shock: a report from the SHOCK Trial Registry; Dzavik et al,
Eur Heart J 2003
• Early severe acute pancreatitis: characteristics of a new subgroup;
Isenmann et al, Pancreas 2001
• Early use of the pulmonary artery catheter and outcomes in patients
with shock and acute respiratory distress syndrome: a randomized
controlled trial; Richard et al, JAMA 2003
• Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding;
Garcia-Pagan et al, N Engl J 2010
• Early versus late parenteral nutrition in critically ill adults; Casaer et
al, N Engl J Med 2011
• EASL clinical practice guidelines on the management of ascites,
spontan bacterial peritonitis and hepatorenal syndrome in cirrhosis
2010 (J Hepatol)
• ECASS-III-Studie: Thrombolysis with Alteplase 3 to 4.5 Hours after
Acute Ischemic Stroke; Hacke et al, N Engl J 2008
• ECC Committee, Subcommittees and Task Forces of the American
Heart Association. 2005 American Heart Association Guidelines for
Cardiopulmonary Resuscitation and Emergency Cardiovascular
Care; Circulation 2005
• Echinocandin antifungal drugs; Denning, Lancet 2003
• Echinocandins for candidemia in adults without neutropenia; Ben-
nett, N Engl J Med 2006
• Echocardiographic findings in myocarditis; Pinamonti et al, Am J
Cardiol 1988
• Echocardiography in diagnosis of aortic dissection; Erbel et al, Lan-
cet 1989
• Echocardiography in the management of pulmonary embolism;
Goldhaber, Ann Intern Med 2002
• Echokardiografie in der Intensivmedizin; Schmidt et al, Intensivmedi-
zin up2date, Heft 3, 7. Jahrgang, August 2011
• Echokardiographie in der Notaufnahme; Schmidt et al, Medizinische
Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft 7, Ok-
tober 2012
• Echokardiographie - Lehrbuch und Atlas; Bartel, Urban & Fischer-
Verlag 2006
• Echokardiographische Abklärung des Patienten mit akutem Thorax-
schmerz auf der Notfallstation; Eggebrecht et al, Intensivmedizin
und Notfallmedizin, Band 43, Heft 1, Februar 2006
• Effect of failed extubation on the outcome of mechanical ventilation;
Epstein et al, Chest 1997
• Effect of Intravenous Albumin on Renal Impairment and Mortality in
Patients with Cirrhosis and Spontaneous Bacterial Peritonitis; Sort
et al, N Engl J 1999
• Effect of the dynamic response of transducer-tubing system on ac-
curacy of direct blood pressure measurement in patients; Boutros et
al, Crit Care Med 1983
• Effect of the implementation of NICE guidelines for ultrasound
guidance on the complication rates associated with central venous
catheter placement in patients presenting for routine surgery in a
tertiary referral centre; Wigmore et al, Br J Anaesth 2007
• Effect of systemic glucocorticoids on exacerbations of chronic ob-
structive pulmonary disease. Department of Veterans Affairs Coope-
rative Study Group; Niewoehner et al, N Engl J Med 1999
1072 Appendix
• Effect of tilarginine acetate in patients with acute myocardial infarc-
tion and cardiogenic shock: the TRIUMPH randomized controlled
trial; TRIUMPH-Investigators; JAMA 2007
• Effect of Treatment With Low Doses of Hydrocortisone and Fludro-
cortisone on Mortality in Patients With Septic Shock; Annane et al,
JAMA 2002
• Effectiveness of implantable defibrillators for preventing arrhythmic
events and death: a meta-analysis; Lee et al, J Am Coll Cardiol 2003
• Effects of branched-chain amino acids supplementation in patients
with cirrhosis and a previous episode of hepatic encephalopathy: a
randomized study; Les et al, Am J Gastroenterol 2011
• Effects of different doses in continuous veno-venous haemofiltration
on outcomes of acute kidney failure: a prospective randomized trial;
Ronco et al, Lancet 2000
• Effects of dopamine, norepinephrine, and epinephrine on the
splanchnic circulation in septic shock: which is best? De Backer et
al, Crit Care Med 2003
• Effects of early enteral feeding on the outcome of critically ill mecha-
nically ventilated medical patients; Artinian et al, Chest 2006
• Effects of histamine H1- and H2-receptor antagonists on cardiova-
scular function during systemic anaphylaxis in guinea pigs; Felix et
al; Agents Actions, 1991
• Effects of prior aspirin and anti-ischemic therapy on outcome of pa-
tients with unstable angina. TIMI 7 Investigators. Thrombin Inhibition
in Myocardial Ischemia; Borzak et al, Am J Cardiol 1998
• Effects of spontaneous breathing during airway pressure release
ventilation on renal perfusion and function in patients with acute lung
injury; Hering et al, Intensive Care Med 2002
• Effects of steroids on reintubation and post-extubation stridor in
adults: meta-analysis of randomized controlled trials; Jaber et al,
Crit Care 2009
• Effects of tracheotomy on respiratory mechanics in spontaneously
breathing patients; Moscovici da Cruz et al, Eur Respir J 2002
• Efficacy and economic assessment of conventional ventilatory sup-
port versus extracorporeal membrane oxygenation for severe adult
respiratory failure (CESAR): a multicenter randomized controlled tri-
al; Peek et al, Lancet 2009
• Efficacy and safety of a paired sedation and ventilator weaning pro-
tocol for mechanically ventilated patients in intensive care (Awake-
ning and Breathing Controlled trial): a randomized controlled trial;
Girard et al, Lancet 2008
• Efficacy and Safety of Corticosteroids for Persistent Acute Respi-
ratory Distress Syndrome; ARDS Clinical Trials Network, N Engl J
2006
• Efficacy and safety of intravenous infusion of doripenem versus imi-
penem in ventilator-associated pneumonia: a multicenter, randomi-
zed study; Chastre et al, Crit Care Med 2009
• Efficacy and Safety of Recombinant Human Activated Protein C for
Severe Sepsis; Bernard et al, N Engl J 2001
• Efficacy and Safety of Tifacogin (Recombinant Tissue Factor Pa-
thway Inhibitor) in Severe Sepsis; Abraham et al, JAMA 2003
• Ein europäisches Register für sepsisassoziierte Purpura fulminans
(SAPFIRE); Brunkhorst, Patchev, Medizinische Klinik – Intensivme-
dizin und Notfallmedizin, Band 109, Heft 8. November 2014
• Electrocardiographic criteria for ventricular tachycardia in wide com-
plex left bundle branch block morphology tachycardias; Kindwall et
al, Am J Cardiol 1988
• ELSO guidelines for ECMO centers (updated February 2005) http://
www.elso.med.umich.edu/guide.htm
• Empfehlungen der Deutschen Gesellschaft für Klinische Neurophy-
siologie und funktionelle Bildgebung zur Bestimmung des Hirntodes,
Walter et al 2014; www.dgkn.de/fileadmin/user_upload/pdfs/eeg/
EEG33.pdf (abgerufen am 27.05.2015)
• End-of-life discussions, goal attainment, and distress at the end of
life: predictors and outcomes of receipt of care consistent with prefe-
rences; Mack et al, J Clin Oncol 2010
• Endoskopische Therapie bei schwerer COPD – Eine neue Option
zur Reduzierung der Lungenüberblähung; Gompelmann et al, Kli-
nikarzt – Medizin im Krankenhaus, Demeter-Verlag, 42. Jahrgang,
Heft 4/2013
• Einfache Maßnahmen zur Prävention von Krankenhausinfektionen;
Schaber et al, Intensivmedizin up2date, Heft 1, 9. Jahrgang, Februar
2013
• Einmaleins der Beatmung; Frank Brehmer, 2. Auflage 2009; Leh-
manns Media
• Einsatz externer Ventrikeldrainagen auf der Intensivstation; Prange
et al, Intensivmedizin up2date, Heft 4, 6. Jahrgang, November 2010
• Einsatz von Diuretika bei der akut dekompensierten Herzinsuffizi-
enz; Akin et al, Intensivmedizin und Notfallmedizin, Band 46, Heft
6, September 2009
• Einsatz von inotropen und vasopressorischen Substanzen bei der
akut dekompensierten Herzinsuffizienz; Geppert, Intensivmedizin
und Notfallmedizin, Band 46, Heft 6, September 2009
• Einsatz von Nierenersatzverfahren bei akut dekompensierter Herz-
insuffizienz; Kierdorf, Intensivmedizin und Notfallmedizin, Band 46,
Heft 6, September 2009
• Einsatz externer Ventrikeldrainagen auf der Intensivstation; Prange
et al, Intensivmedizin up2date, Heft 4, 6. Jahrgang, November 2010
• Einsatz von Diuretika bei der akut dekompensierten Herzinsuffizi-
enz; Akin et al, Intensivmedizin und Notfallmedizin, Band 46, Heft
6, September 2009
• Einsatz von inotropen und vasopressorischen Substanzen bei der
akut dekompensierten Herzinsuffizienz; Geppert, Intensivmedizin
und Notfallmedizin, Band 46, Heft 6, September 2009
• Einsatz von Nierenersatzverfahren bei akut dekompensierter Herz-
insuffizienz; Kierdorf, Intensivmedizin und Notfallmedizin, Band 46,
Heft 6, September 2009
• Electrocardiographic manifestations: digitalis toxicity; Ma et al, J
Emerg Med 2001
• Elektrotherapie bei bradykarden oder tachykarden Herzrhythmus-
störungen und akutem Koronarsyndrom; Trappe, Intensivmedizin
und Notfallmedizin, Band 46, Heft 3, April 2009
• ELT-Studie: Early versus Late Tracheotomy for Prevention of Pneu-
monia in Mechanically Ventilated Adult ICU Patients; Terragni et al,
2010 (JAMA)
• Emboli in infective endocarditis: the prognostic value of echocardio-
graphy, Steckelberg et al, Ann Intern Med 1991
• Embolic Protection in Patients with Atrial Fibrillation (PROTECT-AF);
Holmes et al, Lancet 2009
• Emergency treatment of anaphylaxis; Simons et al, BMJ 2008
• Empfehlungen der Bundesärztekammer und der Zentralen Ethik-
kommission bei der Bundesärztekammer zum Umgang mit Vorsor-
gevollmacht und Patientenverfügung in der ärztlichen Praxis. Dtsch
Ärztebl 2010
• Empfehlungen zur Diagnostik und Therapie der Schockformen der
IAG Schock der DIVI; Adams et al, Deutscher Ärzte-Verlag, Köln
2005
• Empfehlungen zur intensivmedizinischen Therapie von Patienten
mit COVID-19; Kluge et al, Medizinische Klinik - Intensivemdizin und
Notfallmedizin, März 2020
• Empfehlungen zur Prognosebeurteilung bei zerebraler Hypoxie
nach kardiopulmonaler Reanimation - Österreichische interdiszipli-
näre Konsensuskonferenz; Madl et al, Wien Klin Wochenschr 2002
• Empfehlungen zur Prophylaxe und Therapie der Malaria der DTG
2013; www.dtg.org
• Empfehlungen zur Therapie der malignen Hyperthermie (DGAI info);
Anästhesiologie & Intensivmedizin, 49. Jahrgang, September 2008
• Endokrinologie in der Intensivmedizin; Ellger et al, Intensivmedizin
up2date, Heft 3, 9. Jahrgang, August 2013
• End-of-life practices in European intensive care units: the Ethicus
Study; Sprung et al, JAMA 2003
• End-tidal carbon dioxide and outcome of out-of-hospital cardiac ar-
rest; Levine et al, N Engl J Med 1997
• Endokrinologische Notfälle im Kindes- und Jugendalter; Göpel, In-
tensivmedizin up2date, Heft 3, 3. Jahrgang, August 2007
• Endoscopic treatment of esophagogastric variceal bleeding in pa-
tients with noncirrhotic extrahepatic portal vein thrombosis: a long-
term follow-up study; Spaander et al, Gastrointest Endosc 2008
• Endoscopic treatment versus endoscopic plus pharmacologic treat-
ment for acute variceal bleeding: a meta-analysis; Bañares et al,
Hepatology 2002
• Endoskopie in der Intensivmedizin; Schaible et al, Intensivmedizin
up2date, Heft 1, 3. Jahrgang, Februar 2007
• Endoskopische Blutstillungstechniken - Puder, Spray und Bären-
kralle; Rey, Hoffman, Kiesslich, Klinikarzt - Medizin im Krankenhaus,
5/2014
• Endovascular stent-graft placement for the treatment of acute aortic
dissection; Dake et al, N Engl J Med 1999
• Enemy of the (immunosuppressed) state: an update on the pathoge-
nesis of Aspergillus fumigatus infection; Ben-Ami et al, Br J Haema-
tol 2010
• Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial In-
farction Treatment (ExTRACT-TIMI 25); Gruberg et al, N Engl J 2007
• Enteral nutrition is superior to parenteral nutrition in severe acute
pancreatitis: Results of a randomized prospective trial; Kalferenzos
et al, BJS 1997
• Enterale Ernährung beim Intensivpatienten; Schneider, Intensivme-
dizin und Notfallmedizin, Band 48. Heft 2, März 2011
• Entwöhnung von der Beatmung (Weaning) - aktuelle Aspekte; Pfei-
fer, Dtsch med Wochenschr 2012
• Entwöhnung von der Beatmung; Dembinski, Intensivmedizin up-
2date, Heft 1, 8. Jahrgang, Februar 2012
• Entwöhnung von der Beatmungstherapie; Schönhofer, Dtsch Med
Wochenschr 2008
• Entzündliche Erkrankungen des kindlichen Nervensystems; Häusler
et al, Intensivmedizin up2date, Heft 2, 7. Jahrgang, Mai 2011
• Entzündliche Erkrankungen der Aorta; Czihal et al, Der Internist,
Band 54, Heft 5, Mai 2013
• Epidemiologie und Prävention bakterieller Infektionen; Gastmeier,
Intensivmedizin up2date, Heft 3, 7. Jahrgang, August 2011
• Epidemiologie von SARS-CoV-2-Infektion und COVID-19; Salzber-
ger et al, Der Internist, Juni 2020
• Epidemiology and clinicopathology of aortic dissection; Mészáros et
al, Chest 2000
• Epidemiology, antibiotic therapy, and clinical outcomes in health
care-associated pneumonia: a UK cohort study; Chalmers et al, Clin
Infect Dis 2011
• Epidemiology of acute lung injury and acute respiratory distress syn-
drome; Frutos-Vivar et al, Curr Opin Crit Care 2004
• Epidemiology of anaphylaxis: findings of the American College of
Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Wor-
king Group; Lieberman et al, Ann Allergy Asthma Immunol 2006
• Epidemiology of Sepsis in Germany – a national prospective multi-
center study; Engel et al, J Int Care Med 2007
• ERC-Leitlinien (European Resuscitation Council) 2005, 2010 (htt-
ps://www.erc.edu)
• Erkennen und behandeln des Status epilepticus; Hoppner, Klinger,
Notfall + Rettungsmedizin, Band 17, Heft 1, Februar 2014
• Ernährung – Bedeutung von Spurenelementen und Vitaminen; Goe-
ters, Intensivmedizin uo2date, Mai 2017
• Ernährung des Intensivpatienten - early goal directed nutrition;
Druml, Madl; Intensivmedizin und Notfallmedizin, Band 47, Heft 4,
Mai 2010
• Ernährung kritisch kranker Patienten auf Intensivstation; Kreymann
et al, Internist, Band 48. Heft 10, Oktober 2007
• Ernährung und Leberversagen; Plauth, Medizinische Klinik – Inten-
sivmedizin und Notfallmedizin, Band 108. Heft 5, Juni 2013
• Ernährung und Lungenversagen; Weimann et al, Medizinische Klinik
– Intensivmedizin und Notfallmedizin, Band 108. Heft 5, Juni 2013
• Ernährung und metabolische Kontrolle bei Sepsis; Mayer et al, In-
tensivmedizin und Notfallmedizin, Band 46, Heft 8. November 2009
• Ernährung und Niereninsuffizienz; Druml, Medizinische Klinik – In-
tensivmedizin und Notfallmedizin, Band 108. Heft 5, Juni 2013
• Ernährungstherapie bei akuter Pankreatitis; Ockenga, Medizinische
Klinik – Intensivmedizin und Notfallmedizin, Band 108. Heft 5, Juni
2013
• Ernährungstherapie bei kritisch Kranken - Update 2010; Goeters,
Intensivmedizin up2date, Heft 1, 7. Jahrgang, Februar 2010
• Erreger nosokomialer Infekionen auf Intensivstation; Breier et al, In-
tensivmedizin und Notfallmedizin, Band 46, Heft 4, Mai 2009
• Erstdiagnose und Erstbehandlungen von Vergiftungen; Pemmerl,
Medizinische Klinik – Intensivmedizin und Notfallmedizin, Band 108.
Heft 6, September 2013
• Erste Maßnahmen und Verhalten bei Störungen eines Kunstherzsy-
stems; Vierecke et al, Notfall Rettungsmed 2011
• Ertrinkungsunfälle bei Kindern; Rellensmann, Rieger-Fackeldey,
Omran, Intensivmedizin up2date, Heft 4, 7. Jahrgang, November
2011
• Ertrinkungsunfälle im Kindesalter; Thüner, Sefrin, Intensivmedizin
und Notfallmedizin, Band 43, Heft 2, März 2006
• Erworbene Atemstörungen beim reifen Neugeborenen: Diagnostik
und Therapie einschließlich extrakorporaler Membranoxygenierung;
Appendix 1073
 Schaible, Intensivmedizin und Notfallmedizin, Band 45, Heft 3, April
2008
• Erworbene Hemmkörper-Hämophilie - Bedeutung für die operative
Praxis; Rott, Journal für Anästhesie und Intensivbehandlung 2005
• Erythromycin improves the quality of EGD in patients with acute up-
per GI bleeding: a randomized controlled study; Coffin et al, Gastro-
intest Endosc 2002
• Erythromycin intravenous bolus infusion in acute upper gastrointesti-
nal bleeding: a randomized, controlled, double-blind trial; Frossard
et al, Gastroenterology 2002
• ESA-Guidelines Management of severe perioperative bleeding;
Kozek-Langenecker et al, Eur J Anaesthesiol 2013
• ESC-Guidelines for prevention, diagnosis and treatment of infective
endocarditis 2009
• ESC-Guidelines for the diagnosis and management of acute pul-
monary embolism 2008
• ESC Guidelines on the diagnosis and management of acute pul-
monary embolism 2014; The Task Force for the Diagnosis and Ma-
nagement of Acute Pulmonary Embolism of the European Society of
Cardiology (ESC); Endorsed by the European Respiratory Society
(ERS); Eur Heart J 2014
• ESC-Guidelines for the diagnosis and treatment of acute and chro-
nic heart failure 2012: The Task Force for the Diagnosis and Treat-
ment of Acute and Chronic Heart Failure 2012 of the European So-
ciety of Cardiology. Developed in collaboration with the Heart Failure
Association (HFA) of the ESC; McMurray et al, Eur Heart J 2012
• ESC-Guidelines for the diagnosis and treatment of pulmonary hy-
pertension 2009
• ESC-Guidelines for the management of acute myocardial infarction
in patients presenting with ST-segment elevation - The Task Force
on the management of ST-segment elevation acute myocardial in-
farction of the European Society of Cardiology (ESC) 2012
• ESC-Guidelines for the management of acute coronary syndromes
in patients presenting without persistent ST-segment elevation: The
Task Force for the management of acute coronary syndromes (ACS)
in patients presenting without persistent ST-segment elevation of the
European Society of Cardiology (ESC); Eur Heart J 2011
• ESC-Guidelines on diagnosis and management of acute pulmonary
embolism. Task Force on Pulmonary Embolism; Eur Heart J 2008
• ESC-Guidelines on the diagnosis and treatment of aortic diseases;
Eur Heart J 2014
• ESC-Leitlinien 2008 - Leitlinien zur akuten Herzinsuffizienz; Link,
Böhm; Intensivmedizin und Notfallmedizin, Band 46, Heft 6, Sep-
tember 2009
• ESPEN (European Society for Nutrition and Metabolism): Guidelines
for Enteral Nutrition and Parenteral Nutrition (www.espen.org)
• ESO-Guidelines 2014; Steiner et al, Int J Stroke 2014
• Estimation of mean left atrial pressure from transesophageal pulsed
Doppler echocardiography of pulmonary venous flow; Kuecherer et
al, Circulation 1990
• Ethik auf der Intensivstation; Prien, Intensivmedizin up2date, Heft 4,
5. Jahrgang, November 2009
• Ethik in der Intensivmedizin - wo stehen wir? Schmucker, Intensiv-
medizin und Notfallmedizin, Band 47, Heft 1, Februar 2010
• Ethikvisite auf der Intensivstation; Scheffold et al, Medizinische Kli-
nik - Intensivmedizin und Notfallmedizin, Band 107, Heft 7, Oktober
2012
• Ethische Aspekte in der Therapie am Lebensende; Nauck, Medizi-
nische Klinik - Intensivmedizin und Notfallmedizin, Band 106, Heft
2, Oktober 2011
• Ethische Aspekte in der Therapie kritisch kranker Tumorpatienten;
Hahn et al, Intensivmedizin und Notfallmedizin, Band 44, Heft 7, Ok-
tober 2007
• Ethische Bewertung von Entscheidungen am Lebensende von In-
tensivpatienten; Druml, Intensivmedizin und Notfallmedizin, Band
47, Heft 1, Februar 2010
• Ethylenglycolintoxikation - ein Case Report; Guralnik et al, Intensiv-
medizin und Notfallmedizin, Band 46, Heft 2, März 2009
• Ethylene glycol intoxication: evaluation of kinetics and crystalluria;
Jacobsen et al, Am J Med 1988
• Etiology and outcome for 295 patients with acute liver failure in the
United States; Schiodt et al, Liver Transpl Surg 1999
• Etiology of community-acquired pneumonia treated in an ambulatory
setting; Marrie et al, Respir Med 2005
1074 Appendix
• Etomidate versus Ketamine for rapid sequence intubation in acutely
ill patients; Jabre et al, Lancet 2009
• European Guidelines on cardiovascular disease prevention in cli-
nical practice. The Fifth Joint Task Force of the European Society
of Cardiology and Other Societies on Cardiovascular Disease Pre-
vention in Clinical Practice (constituted by representatives of nine
societies and by invited experts). Developed with the special contri-
bution of the European Association for Cardiovascular Prevention &
Rehabilitation (EACPR); Perk et al, Eur Heart J 2012
• European Heart Rhythm Association, Heart Rhythm Society, ACC/
AHA/ESC 2006 guidelines for management of patients with ventricu-
lar arrhythmias and the prevention of sudden cardiac death: a report
of the American College of Cardiology/American Heart Association
Task Force and the European Society of Cardiology Committee for
Practice Guidelines (Writing Committee to Develop Guidelines for
Management of Patients With Ventricular Arrhythmias and the Pre-
vention of Sudden Cardiac Death). J Am Coll Cardiol 2006
• European Resuscitation Council Guidelines for Resuscitation Sec-
tion 8. Cardiac arrest in special circumstances: electrolyte abnorma-
lities, poisoning, drowning, accidental hypothermia, hyperthermia,
asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electro-
cution; Soar et al, Resuscitation 2010
• European Resuscitation Council Guidelines for Resuscitation 2015;
Monsieurs et al, Resuscitation 2015
• European Society of Cardiology Guidelines (www.escardio.org/gui-
delines)
• European Society of Hypertension Scientific Newsletter: treatment
of hypertensive urgencies and emergencies; Rosei et al, J Hyper-
tens 2006
• European Resuscitation Council (ERC): Leitlinie zur kardiopulmo-
nalen Reanimation (CPR) des Erwachsenen und Notfallversorgung
von Patienten mit akutem Koronarsyndrom 2010; Kardiologe 2010
• Evaluating and optimizing outcomes of surgery for endocarditis; Du-
rack, JAMA 2003
• Evaluation of delirium in critically ill patients: validation of the Confu-
sion Assessment Method for the Intensive Care Unit (CAM-ICU); Ely
et al, Crit Care Med 2001
• Evolution of mechanical ventilation in response to clinical research;
Esteban et al, Am J Respir Crit Care Med 2008
• Evolving global epidemiology, syndromic classification, general ma-
nagement, and prevention of unknown mushroom poisonings; Diaz,
Crit Care Med 2005
• Evaluation of pretest clinical score (4 T's) for the diagnosis of he-
parin-induced thrombocytopenia in two clinical settings; Lo et al, J
Thromb Haemost 2006
• Evaluation of the specificity of morphological electrocardiographic
criteria for the differential diagnosis of wide QRS complex tachycar-
dia in patients with intraventricular conduction defects; Alberca et al,
Circulation 1997
• Evaluation study of congestive heart failure and pulmonary artery
catheterization effectiveness: the ESCAPE trial; Binanay et al, JAMA
2005
• Evidence-based use of enteral nutrition in acute pancreatitis; Olah et
al, Archive of Surgery 2010
• Evita Trainer (CD) - EvitaXL, Evita 4 edition, Evita 2 dura, Dräger
Medical AG & Co. KG, www.draeger-medical.com
• Evolution of aortic dissection after surgical repair; Fattori et al, Am
J Cardiol 2000
• Evolution of mechanical ventilation in response to clinical research;
Esteban et al, Am J Respir Crit Care Med 2008
• Exocrine pancreatic function in critically ill patients: septic shock ver-
sus non-septic patients; Tribl et al, Crit Care Med 2000
• Extended-spectrum beta-lactamases in the 21st century: charac-
terization, epidemiology, and detection of this important resistance
threat; Bradford, Clin Microbiol Rev 2001
• Extracorporeal membrane oxygenation in adults with severe respi-
ratory failure: a multi-center database; Brogan et al, Intensive Care
Med 2009
• Extracorporeal pumpless interventional lung assist in clinical prac-
tice: determinants of efficacy; Müller et al, ERJ 2009
• Extrakorporale Gasaustauschverfahren; Staudinger, Medizinische
Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft 8. No-
vember 2012
• Extrakorporale Nierenersatztherapie bei akuter Nierenschädigung
- Empfehlungen der Sektion „Niere“ der DGIIN, ÖGIAIN und DIVI;
 Schwenger et al, Medizinische Klinik - Intensivmedizin und Notfall-
medizin, Band 113, Heft 5, Juni 2018
• Extrakorporale Lungenunterstützungsverfahren beim ARDS des
Erwachsenen: eine Standortbestimmung; Müller, Lubnow, Bein,
Philipp, Pfeifer; Intensivmedizin und Notfallmedizin, Band 46, Heft
2, März 2009
• Extrakorporale Lungenunterstützung bei schwerem Lungenversa-
gen des Erwachsenen - Wiederentdeckung eines Therapieverfah-
rens; Müller, Bein, Philipp, Graf, Schmid, Riegger; Deutsches Ärzte-
blatt, Heft 10, März 2013
• Extrakorporale Lungenunterstützungsverfahren; Hecker et al, Medi-
zinische Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft
6, September 2012
• Extrakorporale Membranoxygenierung: Systemauswahl, (Kontra-)
Indikationen und Management; Staudinger, Medizinische Klinik - In-
tensivmedizin und Notfallmedizin, Band 112, Heft 4, Mai 2017
• Extrakorporale Therapien bei Lebererkrankungen; Jarczak et al,
Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band 112,
Heft 5, Juni 2017
• Extrakorporale Therapien bei Patienten mit Lebererkrankungen auf
der Intensivstation; Fuhrmann et al, Medizinische Klinik - Intensiv-
medizin und Notfallmedizin, Band 109, Heft 4, Mai 2014
• Femoral vs jugular venous catheterization and risk of nosocomial
events in adults requiring acute renal replacement therapy: a rando-
mized controlled trial; Parienti et al, JAMA 2008
• Fettembolie-Syndrom: Forster et al, Schweiz Med Forum, Nr.28.
Juli/2002
• First-line therapy for adult patients with acute asthma receiving a
multiple-dose protocol of ipratropium bromide plus albuterol in the
emergency department; Rodrigo et al, Am J Respir Crit Care Med
2000
• Fischvergiftung; Schaper et al, Deutsches Ärzteblatt 2002
• Flow triggering, pressure triggering, and autotriggering during me-
chanical ventilation; Hill et al, Crit Care Med 2000
• Flüssigkeits- und Volumentherapie in der Intensivmedizin; Ertmer et
al, Intensivmedizin up2date, Heft 3, 7. Jahrgang, August 2011
• Focused update incorporated into the ACC/AHA 2005 Guidelines for
the Diagnosis and Management of Heart Failure in Adults: a report
of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines: developed in colla-
boration with the International Society for Heart and Lung Transplan-
tation; Circulation 2005
• Focused update of the 2010 ESC Guidelines for the management of
atrial fibrillation; Eur Heart J 2012
• Formate kinetics in methanol poisoning; Kerns et al, J Toxicol Clin
Toxicol 2002
• Fresh frozen plasma transfusion in critically ill patients; Lauzier et al,
Crit Care Med 2007
• Friends and foes in the plant world: a profile of plant ingestions and
fatalities; Krenzelok et al, Clin Toxicol 2011
• Fruchtwasserembolie - eine interdisziplinäre Herausforderung; Rath
et al, Deutsches Ärzteblatt, Jahrgang 111, Heft 8. Februar 2012
• Frühmobilisierung des chirurgischen Intensivpatienten; Weiterer et
al, Intensivmedizin up2date, Heft 3, 8. Jahrgang, August 2012
• Fulminante Pneumokokkensepsis nach Splenektomie; Fuchs et al,
Anaestesist 2014
• Functional disability 5 years after acute respiratory distress syndro-
me; Herridge et al, N Engl J Med 2011
• Gastric residual volume during enteral nutrition in ICU patients: the
REGANE study; Montejo et al, Intensive Care Med 2010
• Gastrointestinal Failure score in critically ill patients: a prospective
observational study; Reintam et al, Crit Care 2008
• Gastrointestinale Auswirkungen des (septischen) Schocks; Knaebel
et al, Intensivmedizin up2date, Heft 4, 3. Jahrgang, November 2007
• Gastrointestinale Blutungen; Kienle et al, Intensivmedizin up2date,
Heft 1, 2. Jahrgang, Februar 2006
• Gastrointestinale Blutungen bei Intensivpatienten - von der Präven-
tion zur Therapie; Klebl, Intensivmedizin und Notfallmedizin, Band
47, Heft 4, Mai 2010
• Gastrointestinale Blutungen beim kardiologischen Patienten; Braun,
Messmann, Medizinische Klinik - Intensivmedizin und Notfallmedi-
zin; Band 108. Heft 8. November 2013
• Gastrointestinale Motilitätsstörungen in der Intensivmedizin; Al-
lescher, Intensivmedizin und Notfallmedizin, Band 47, Heft 4, Mai
2010
• Gefäßkomplikationen nach perkutanen Interventionen; Hartveg, Im-
hof, Intensivmedizin up2date März 2017
• Gemeinsame Jahrestagungen der Deutschen Gesellschaft für In-
ternistische Intensivmedizin und Notfallmedizin (DGIIN) und Öster-
reichischen Gesellschaft für Internistische und Allgemeine Inten-
sivmedizin (ÖGIAIM) 10.-13.06.2009 (Hamburg), 09.-12.06.2010
(Berlin), 15.-18.06.2011 (Wien), 06.-09.06.2012 (Köln), 19.-
22.06.2013 (Berlin), 17.-19.06.2015 (Köln), 08.-10.06.2016 (Berlin),
07.-10.06.2017 (Innsbruck), 13.-15.06.2018 (Köln), 12.-14.06.2019
(Berlin): Kongreßbeiträge, Workshops
• Genetisch bedingte thorakale Aortensyndrome (GAS) - Eine strate-
gische Analyse zur Versorgung durch den Klinikarzt; von Kodolitsch,
Gehle, Schüler, Klinikarzt Juni 2017, 46. Jahrgang
• Gerinnung im klinischen Alltag; IGS (Interdisziplinäre Gerinnungs-
gruppe Steiermark), 7. überarbeitete und erweiterte Auflage, Her-
ausgeber und Projektleitung: Tschulik
• Gerinnungsprobleme in der Intensivmedizin; Ney, Spannagl, Inten-
sivmedizin up2date, Februar 2017, 13. Jahrgang
• Giftpflanzen, Pflanzengifte; Roth, Daunderer, Kormann; 4. überar-
beitete Auflage, Nikol-Verlag
• Giftpflanzen: www.botanikus.de, www.giftpflanzen.com
• Global strategy for the diagnosis, management, and prevention of
COPD: Revised 2011. Global initiative for Chronic obstructive lung
disease (GOLD); www.goldcopd.org
• Glucosekontrolle bei kritisch Kranken – Innovationen und kontempo-
räre Strategien; Holzinger, Medizinische Klinik – Intensivmedizin und
Notfallmedizin, Band 108. Heft 5, Juni 2013
• Grundlagen der Atmung und Beatmung - Dräger Academy (www.
draeger.com)
• Grundlagen der maschinellen Beatmung; Rathgeber, Georg Thieme
Verlag 2010
• Grundlagen und Fallstricke der arteriellen Blutdruckmessung - Mei-
dert, Briegel, Saugel; Anästhesist 9/2019
• Grundsätze der Bundesärztekammer zur ärztlichen Sterbebeglei-
tung; Deutsches Ärzteblatt, Heft 19, Mai 2004
• Guidelines for empiric antimicrobial prescribing in community-ac-
quired pneumonia; File et al, Chest 2004
• Guidelines for percutaneous coronary interventions. The Task Force
for Percutaneous Coronary Interventions of the European Society of
Cardiology; Silber et al, Eur Heart J 2005
• Guideline for Reversal of Antithrombotics in Intracranial Hemorrha-
ge: A Statement for Healthcare Professionals from the Neurocritical
Care Society and Society of Critical Care Medicine; Frontera et al,
Neurocritical Care 2016
• Guidelines for the diagnosis and antibiotic treatment of endocarditis
in adults: a report of the Working Party of the British Society for Anti-
microbial Chemotherapy; Gould et al, J Antimicrob Chemother 2012
• Guidelines for the diagnosis and management of disseminated intra-
vascular coagulation. British Committee for Standards in Haemato-
logy; Levi et al, Br J Haematol 2009
• Guidelines for the diagnosis and treatment of pulmonary hyperten-
sion: the Task Force for the Diagnosis and Treatment of Pulmonary
Hypertension of the European Society of Cardiology (ESC) and the
European Respiratory Society (ERS), endorsed by the International
Society of Heart and Lung Transplantation (ISHLT); Galiè et al, Eur
Heart J 2009
• Guidelines for the early management of adults with ischemic stroke:
a guideline from the American Heart Association/American Stroke
Association Stroke Council, Clinical Cardiology Council, Cardiova-
scular Radiology and Intervention Council, and the Atherosclerotic
Peripheral Vascular Disease and Quality of Care Outcomes in Re-
search Interdisciplinary Working Groups: the American Academy of
Neurology affirms the value of this guideline as an educational tool
for neurologists; Adams et al, Stroke 2007
• Guidelines for the management of acute pancreatitis; Toouli et al, J
Gastroenterol Hepatol 2002
• Guidelines for the management of aneurysmal subarachnoid he-
morrhage: a statement for healthcare professionals from a special
writing group of the Stroke Council, American Heart Association; Be-
derson et al, Stroke 2009
• Guidelines for the management of pediatric and adult tumor lysis
syndrome: an evidence-based review; Coiffier et al, J Clin Oncol
2008
• Guidelines for the management of spontaneous intracerebral he-
Appendix 1075
 morrhage in adults: 2007 update: a guideline from the American
Heart Association/American Stroke Association Stroke Council, High
Blood Pressure Research Council, and the Quality of Care and Out-
comes in Research Interdisciplinary Working Group; Broderick et al,
Stroke 2007
• Guidelines for the prevention of intravascular catheter-related infec-
tions. Centers for Disease Control and Prevention; O'Grady et al,
MMWR Recomm Rep 2002
• Guidelines for the Provision and Assessment of Nutrition Support
Therapy in the Adult Critically Ill Patient: Society of Critical Care
Medicine (SCCM) and American Society for Parenteral and Enteral
Nutrition (A.S.P.E.N.); McClave et al, J Parenter Enteral Nutr 2009
• Guidelines for the use of fresh-frozen plasma, cryoprecipitate and
cryosupernatant; O'Shaughnessy et al, Br J Haematol 2004
• Guidelines on prevention, diagnosis and treatment of infective endo-
carditis executive summary; the task force on infective endocarditis
of the European society of cardiology; Horstkotte et al, Eur Heart J
2004
• Guidelines on the Diagnosis and Management of Pericardial Di-
seases Executive Summary: The Task Force on the Diagnosis and
Management of Pericardial Diseases of the European Society of
Cardiology; Maisch et al, Eur Heart J 2004
• Guidelines on myocardial revascularization - Task Force on Myo-
cardial Revascularization of the European Society of Cardiology
(ESC) and the European Association for Cardio-Thoracic Surgery
(EACTS), European Association for Percutaneous Cardiovascular
Interventions (EAPCI); Wijns et al, Eur Heart J 2010
• Guidelines on the prevention, diagnosis, and treatment of infective
endocarditis (new version 2009): the Task Force on the Prevention,
Diagnosis, and Treatment of Infective Endocarditis of the European
Society of Cardiology (ESC). Endorsed by the European Society of
Clinical Microbiology and Infectious Diseases (ESCMID) and the In-
ternational Society of Chemotherapy (ISC) for Infection and Cancer;
Habib et al, Eur Heart J 2009
• Guillain-Barré-Syndrom - was der erstversorgende Arzt wissen soll-
te; Bardutzky, Notfall + Rettungsmedizin, Band 16, Heft 6, Oktober
2013
• Hämatologische Störungen bei Intensivpatienten; Siebig, Langgart-
ner et al; Intensivmedizin und Notfallmedizin, Band 44, Heft 8. No-
vember 2007
• Hämatologische und onkologische Notfälle; von Bergwelt-Baildon et
al, Medizinische Klinik – Intensivmedizin und Notfallmedizin, Band
108. Heft 3, April 2013
• Hämodynamisches Monitoring in der Intensiv- und Notfallmedizin -
Intergration klinischer und sonographischer Befunde; Hempel et al,
Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band 111,
Heft 7, Oktober 2016
• Hämodynamisches Monitoring kritisch Kranker - bettseitige Interpre-
tation von Messdaten; Janssens, Medizinische Klinik - Intensivmedi-
zin und Notfallmedizin, Band 111, Heft 7, Oktober 2016
• Hämodynamisches Monitoring und Herz-Kreislauf-Therapie: S3-
Leitlinie der Deutschen Gesellschaft für Thorax-, Herz- und Gefäß-
chirurgie (DGTHG) und der Deutschen Gesellschaft für Anästhe-
siologie und Intensivmedizin (DGAI); Carl et al, Thorac Cardiovasc
Surg 2007
• Hämoptysen; Eberhardt et al, Intensivmedizin up2date, Heft 3, 4.
Jahrgang, August 2008
• Hämostaseologische Diagnostik und Therapie in der Intensivmedi-
zin; Mayer, Langgartner; Intensivmedizin und Notfallmedizin, Band
44, Heft 6, September 2007
• Haemostasis and Thrombosis Task Force of the British Committee
for Standards in Haematology - The management of heparin-indu-
ced thrombocytopenia; Keeling et al, Br J Haematol 2006
• Handlungsempfehlung für das präklinische Atemwegsmanagement.
Für Notärzte und Rettungsdienstpersonal; Timmermann et al, An-
ästh Intensivmed 2012
• Handlungsempfehlung zur prähospitalen Notfallnarkose beim Er-
wachsenen (S1-Leitlinie 2015) der Deutschen Gesellschaft für
Anästhesiologie und Intensivmedizin (DGAI; AWMF-Register Nr.
001/030)
• Häufigkeit, Diagnostik und Therapie von Herzrhythmusstörungen in
der Schwangerschaft; Trappe, Intensivmedizin und Notfallmedizin,
Band 46, Heft 5, Juli 2009
• Hantaviren als zoonotische Krankheitserreger in Deutschland; Krü-
ger et ak, Deutsches Ärzteblatt Juli 2013
1076 Appendix
• Haut- und Weichgewebsinfektionen auf der Intensivstation; Kujath
et al, Intensivmedizin up2date, Heft 1, 6. Jahrgang, Februar 2010
• Healthcare-associated pneumonia in adults: management principles
to improve outcomes; Craven et al, Infect Dis Clin North Am 2004
• Heart disease and stroke statistics - 2011 update: a report from the
American Heart Association; Roger et al, Circulation 2011
• Heart failure etiology and response to milrinone in decompensated
heart failure: Results from the OPTIME-CHF study; Felker et al, J
Am Coll Cardiol 2003
• Hemodynamic monitoring; Bigatello et al, Minerva Anestesiol 2002
• HBO (hyperbare Oxygenierung) - www.vdd-hbo.de (abgerufen am
10-04.2016)
• HBO-Therapie bei CO-Intoxikation; Welslau et al, Traum und Be-
rufskrankheit 2004
• Hematologic management of gastrointestinal bleeding; Maltz et al,
Gastroenterol Clin North Am 2000
• Hemodynamic effects of propofol: data from over 25,000 patients;
Hug et al, Anesth Analg 1993
• Heparin-induced thrombocytopenia in the critical care setting: dia-
gnosis and management; Napolitano et al, Crit Care Med 2006
• Heparin plus Alteplase Compared with Heparin Alone in Patients
with Submassive Pulmonary Embolism; Konstantinides et al, N Engl
J 2002
• Hepatic hydrothorax; Kinasewitz et al, Curr Opin Pulm Med 2003
• Hepatische Enzephalopathie; Tryc et al, Intensivmedizin und Notfall-
medizin, Band 47, Heft 8. November 2010
• Hepatopulmonary syndrome - a liver induced lung vascular disorder;
Rodríguez-Roisin et al, N Engl J Med 2008
• Hepatopulmonary syndrome. Current concepts in diagnostic and
therapeutic considerations; Krowka et al, Chest 1994
• Hepatorenal syndrome; Ginès et al, Lancet 2003
• Hepatorenales Syndrom; Canbay et al, Intensivmedizin und Notfall-
medizin, Band 47, Heft 8. November 2010
• Hepatorenales Syndrom; Einmann-Menke et al, Der Nephrologe
4/2018
• Hereditary angioedema; Zuraw, N Engl J Med 2008
• Hereditäres Angioödem; Mygören-Pürün, Bork; Internist 9/2019
• Herdsanierung in der operativen Intensivmedizin; Klar et al, Intensiv-
medizin und Notfallmedizin, Band 43, Heft 5, Juni 2006
• Herzkatheterbuch, Lapp / Krakau, 3. Auflage, Thieme-Verlag
• High-Dose Antithrombin III in Severe Sepsis (KyberSept); Warren
et al, JAMA 2001
• Higher vs Lower Positive End-Expiratory Pressure in Patients With
Acute Lung Injury and Acute Respiratory Distress Syndrome; Briel
et al, JAMA 2010
• High-Flow-Sauerstofftherapie in der Intensivmedizin; Simon et al,
Intensivmedizin up2date März 2017
• High-Frequency Oscillatory Ventilation for Acute Respiratory
Distress Syndrome in Adults; Derdak et al, Resp Crit Care Med 2002
• High-intensity versus low-intensity non-invasive ventilation in pati-
ents with stable hypercapnic COPD: a randomized crossover trial;
Dreher et al, Thorax 2010
• Hinweise und Empfehlungen zum Umgang mit Vorsorgevollmachten
und Patientenverfügungen im ärztlichen Alltag; Bundesärztekammer
/ Zentrale Ethikkommission bei der Bundesärztekammer, Deutsches
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• Infarktbedingter kardiogener Schock; Buerke, Ruß, Werdan; Notfall
Appendix 1077
 + Rettungsmedizin, Band 9, Heft 6, Oktober 2006
• Infarktbedingter kardiogener Schock; Ruß, Buerke, Werdan; Inten-
sivmedizin up2date, Heft 2, 3. Jahrgang, Mai 2007
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• Initiation of inappropriate antimicrobial therapy results in a fivefold
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• Inhalative Anästhetika in der Intensivmedizin; Bellgardt et al, Inten-
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• Innere Medizin, Gerd Herold 2010 (Selbstverlag)
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• Intensity of Renal Support in Critically Ill Patients with Acute Kidney
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• Intensive versus moderate lipid lowering with statins after acute co-
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1078 Appendix
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halts; Schmitz et al, Intensivmedizin und Notfallmedizin, Band 47,
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• Intensivmedizinische Aspekte bei hämatologischen und onkolo-
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2date, Heft 3, 12. Jahrgang, August 2016
• Intensivmedizinische Behandlung der thyereotoxischen Krise; Zen-
der et al, Intensivmedizin up2date, Heft 3, 12. Jahrgang, August
2016
• Intensivmedizinische Behandlung neuromuskulärer Erkrankungen;
Müllges, Stoll; Intensivmedizin up2date, Heft 3, 5. Jahrgang, August
2009
• Intensivmedizinische Komplikationen autoimmuner Enzephalitiden;
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• Intensivmedizinische Probleme des hämatoonkologischen Patien-
ten; Schellongowski, Staudinger; Medizinische Klinik – Intensivme-
dizin und Notfallmedizin, Band 107, Heft 5, Juni 2012
• Intensivmedizinische Therapie der aneurysmatischen Subarachnoi-
dalblutung; Schmutzhard et al, Intensivmedizin und Notfallmedizin,
Band 47, Heft 3, April 2010
• Intensivmedizinische Therapie intrazerebraler Blutungen; Rutter et
al, Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band
113, Heft 3, April 2018
• Intensivpflege von Patienten mit Guillain-Barré-Syndrom; Bertram et
al, Intensivmedizin und Notfallmedizin 2000
• Intensivpflichtige Virusinektionen der unteren Atemwege; Drick,
Welte, Intensivmedizin up2date, Heft 2, 12. Jahrgang, Mai 2016
• Intensivtherapie des Organspenders; Gruß et al, Intensivmedizin
up2date, Heft 2, 6. Jahrgang, Mai 2010
• Intensivtherapie in der Postreanimationsphase; van Tulder, Holzer;
Intensivmedizin und Notfallmedizin, Band 48. Heft 4, Mai 2011
• Interdisziplinäre S2-Leitlinie - Diagnostik und Therapie der Bein- und
Beckenvenenthrombose und der Lungenembolie; Intensivmedizin
und Notfallmedizin, Band 43, Heft 1, Februar 2006
• International consensus recommendations on the management of
patients with nonvariceal upper gastrointestinal bleeding; Barkun et
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• International Liaison Committee on Resuscitation. 2005 Internatio-
nal Consensus on Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care Science with Treatment Recommendations;
Resuscitation 2005
• International multicenter trial protocol to assess the efficacy and sa-
fety of tenecteplase during cardiopulmonary resuscitation in patients
with out-of-hospital cardiac arrest: the Thrombolysis in Cardiac Ar-
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• Internet-Homepage www.dosing.de/niere/arzneimittel (abgerufen
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• Internet-Homepage www.gifte.de (abgerufen am 26.10.2013)
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für Jedermann; Funk et al, IntensivNews 4/2008
• Interpretation von Säure-Basen-Störungen; Hochrainer, Funk, Medi-
zinische Klinik - Intensivmedizin und Notfallmedizin, Band 114, Heft
8. November 2019
• Interruptions of chest compressions during emergency medical sy-
stems resuscitation; Valenzuela et al, Circulation 2005
• Interstitielle Lungenerkrankungen und pulmonale Hypertonie; Hau-
ber, Internist, Band 50, Heft 9, September 2009
• Interventional and surgical modalities of treatment in pulmonary hy-
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• Interventionelle Theapieverfahren bei akuter nekrotisierender Pan-
kreatitis; Brünnler et al, Intensivmedizin und Notfallmedizin, Band
46, Heft 5, Juli 2009
• Interventions for paracetamol (acetaminophen) overdose; Brok et al,
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• Intoxikationen als Ursachen von Bewusstseinsstörungen; Zilker, In-
tensivmedizin und Notfallmedizin, Band 47, Heft 2, März 2010
• Intoxikationen mit Herzmedikamenten; Trappe, Notfall + Rettungs-
medizin, Band 15, Heft 7, November 2012
• Intraaortale Ballonpumpe beim infarktbedingten kardiogenen
Schock; Janssens, Medizinische Klinik - Intensivmedizin und Not-
fallmedizin, Band 107, Heft 7, Oktober 2012
• Intraaortic balloon counterpulsation in patients with acute myocardial
infarction complicated by cardiogenic shock: The prospective, ran-
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• Intramural hemorrhage of the thoracic aorta - Diagnostic and thera-
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• Intranasale Medikamentenapplikation im Notfall; Fandler, Gotthardt,
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• Intranasale Medikamentenapplikation im Rettungsdienst bei Kin-
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• Intravenous immunoglobulin for Guillain-Barré syndrome; Hughes et
al, The Cochrane Library 2002
• Intravenous N-acetylcysteine improves transplant-free survival in
early stage non-acetaminophen acute liver failure; Lee et al, Gastro-
enterology 2009
• Intrazerebrale Blutung: "hot topics"; Sprügel, Huttner; Nervenarzt
November 2019
• Intrazerebrale Blutung: Update zur Intensivtherapie; Kollmar et al,
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• Introduction to the Revised American Association for the Study of
Liver Diseases Position Paper on Acute Liver Failure; Lee et al, He-
patology 2012
• Invasive aspergillosis following hematopoietic cell transplantation:
outcomes and prognostic factors associated with mortality; Upton et
al, Clin Infect Dis 2007
• Invasive aspergillosis in the intensive care unit; Meersseman et al,
Clin Infect Dis 2007
• Invasive Pilzinfektionen; Uekötter et al, Intensivmedizin up2date,
Heft 3, 9. Jahrgang, August 2013
• Invasive Techniken in der Notfallmedizin; Mutzbauer et al, Anaes-
thesist 2005
• Invasive compared with non-invasive treatment in unstable coro-
nary-artery disease: FRISC II prospective randomized multicenter
study. FRagmin and Fast Revascularisation during InStability in Co-
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• Invasive und nichtinvasive Möglichkeiten des hämodynamischen
Monitorings; Huber, Rockmann; Intensivmedizin und Notfallmedizin,
Band 45, Heft 6, September 2008
• Inzidenz, Ursachen und Prognose von Organversagen bei Patienten
mit malignen Erkrankungen; Brünnler, Krause; Intensivmedizin und
Notfallmedizin, Band 44, Heft 1, Februar 2007
• Is early invasive treatment of unstable coronary artery disease
equally effective for both women and men? FRISC II Study Group
Investigators; Lagerqvist et al, J Am Coll Cardiol 2001
• Isolierungsmaßnahmen in der Intensivmedizin; Meyer et al, Intensiv-
medizin up2date, Heft 2, 5. Jahrgang, Mai 2009
• Is traditional reading of the bedside chest radiograph appropriate
to detect intraatrial central venous catheter position? Wirsing et al,
Chest 2008
• Jahrestagung der Deutschen Gesellschaft für Kardiologie 08.-
10.04.2010 (Kongreßbeiträge)
• Kammerflattern, Kammerflimmern und ventrikuläre Tachykadien -
Strategien für die Notfall- und Intensivmedizin; Trappe, Intensivme-
dizin und Notfallmedizin, Band 46, Heft 2, März 2009
• Kardiale Biomarker beim kritisch Kranken; Reith et al, Medizinische
Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft 1, Fe-
bruar 2012
• Kardiale Unterstützungs- und Ersatzsysteme; Graf, Thiele, Medizi-
nische Klinik - Intensivmedizin und Notfallmedizin, Band 112, Heft
5, Juni 2017
• Kardiologie compact - Alles für Station und Facharztprüfung; Mewis,
Riessen, Spyridopoulos; 2. Auflage, Thieme Verlag
• Kardiopulmonale Notfälle in Schwangerschaft und Postpartalperi-
ode; Rosenberg et al, Medizinische Klinik - Intensivmedizin und Not-
fallmedizin, Band 107, Heft 4, Mai 2012
• Katecholamine im kardiogenen Schock: hilfreich, nutzlos oder ge-
fahrlich? Chwertz et al, Dtsch Med Wochenschr 2004
• KDIGO Clinical Practice Guidelines for Acute Kidney Injury; Khwaja
et al, Nephron Clin Pract 2012
• Klinische Anwendung von Antimykotika; Cornely, Ullmann; Uni-Med-
Verlag AG 2005
• Klinische Kardiologie; Erdmann, 7. Auflage, Springer-Verlag
• Klinische Toxikologie für die Notfall- und Intensivmedizin; Zilker,
UNI-MED-Verlag 2008
• Klinisch relevante pharmakokinetische Arzneimittelinteraktionen in
der Intensivmedizin; Kämmerer, Medizinische Klinik - Intensivmedi-
zin und Notfallmedizin, Band 107, Heft 4, Mai 2012
• Kohlenmonoxidintoxikation in suizidaler Absicht durch ein Gemisch
aus Schwefelsäure und Ameisensäure; Santamaria et al, Notfall +
Rettungsmedizin, Band 16, Heft 6, Oktober 2013
• Kombinierte enterale und parenterale Ernährung; Felbinger, Inten-
sivmedizin und Notfallmedizin, Band 48. Heft 2, März 2011
• Kommentar zu den Leitlinien der Europäischen Gesellschaft für
Kardiologie (ESC) zur Therapie des akuten Herzinfarkts bei Patien-
ten mit ST-Streckenhebung (STEMI); Zeymer et al, Der Kardiologe,
Band 7, Heft 6, Dezember 2013
• Kompaktkurs Endokrinologie & Stoffwechsel, München-Großha-
dern, 19.-24.9.2005 (Kursskript)
• Kompaktkurs Internistische Intensivmedizin, Regensburg, 04.-
06.02.2011 (Kursbuch)
• Kompaktkurs Internistische Sonographie, Regensburg, 12.-
15.05.2011 (Kursbuch)
• Kompaktkurs Notfallmedizin der Bayerischen Landesärztekammer,
07.-14.02.2004 in Berchtesgaden
• Komplikationen bei immuninkompetenten Patienten; Heußel et al,
Intensivmedizin und Notfallmedizin, Band 48. Heft 5, Juni 2011
• Komplikationen bei intensivmedizinischen Standardinterventionen;
Lunz, Zausig; Intensivmedizin up2date, Heft 4, 6. Jahrgang, Novem-
ber 2010
• Komplikationen des zentralen Venenkatheters bei Erwachsenen
und Kindern; Lewandowski et al, Anaesthesiologie und Intensivmed
2003
• Kongreß der Deutschen Gesellschaft für Innere Medizin 22.-
26.04.2006, 14.-18.04.2007, 29.03.-02.04.2008 (Kongreßbeiträge,
Workshops)
• Kontinuierliche Nierenersatztherapie in der Behandlung des akuten
Nierenversagens: Geschichte und Entwicklung; Kierdorf, Intensiv-
medizin und Notfallmedizin, Band 45, Heft 4, Mai 2008
• Kontinuierliches biochemisches Gewebsmonitoring zur Therapie-
überwachung nach hämorrhagischem Schock; Keck et al, Intensiv-
medizin und Notfallmedizin, Band 43, Heft 3, März 2006
• Konzept zur Therapiebegrenzung in der Intensivmedizin; Scheffold
et al, Intensivmedizin und Notfallmedizin, Band 47, Heft 2, März
2010
• Kortikosteroide bei schwerer Sepsis und septischem Schock; Keh,
Briegel et al; Intensivmedizin und Notfallmedizin, Band 46, Heft 8.
November 2009
• Krankheitsbilder und Differentialdiagnose des Guillain-Barré-Syn-
droms, der chronisch-inflammatorischen demyelinisierenden Polyn-
europathie und der multifokalen motorischen Neuropathie; Neundör-
fer et al, Nervenheilkunde 2001
• Kreislaufunterstützungssysteme in der Internistischen Intensivmedi-
zin; Ferrari, Intensivmedizin up2date, November 2017, 13. Jahrgang
• Kursbuch Echokardiographie; Flachskampf; Springer-Verlag 2006
• Laboratory diagnostic tests in acute pancreatitis; Smotkin et al, J
Clin Gastroenterol 2002
• Lactate homeostasis and lactic acidosis; Kreisberg, Ann Intern Med
1980
• Lagerungstherapie beim akuten Lungenversagen; Bein, Medizini-
sche Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft 8.
November 2012
• Lampenöle und flüssige Grillanzünder: Eine Gefahr für Kleinkinder;
Schiller, Barben, Gallen; Paediatrica Vol.16, Nr.5, 2005
• Langzeitbeatmung und Entwöhnung vom Beatmungsgerät; Schön-
hofer, Intensivmedizin up2date, Heft 4, 2. Jahrgang, November 2006
• Langzeitfolgen der Sepsis; Graf et al, Intensivmedizin und Notfall-
medizin, Band 46, Heft 8. November 2009
• Late mortality in patients with severe acute pancreatitis; Gloor et al,
Br J Surg 2001
• Lebensmittelvergiftungen; Egli, Federspiel, Meier-Abt, Kupfer-
schmidt, Schweiz Med Forum 2005
Appendix 1079
• Lebensqualität nach Intensivmedizin; Bone, Intensivmedizin up-
2date, Heft 2, 8. Jahrgang, Mai 2012
• Leberunterstützungstherapien 2010 - mehr Fragen als Antworten;
Al-Chalabi et al, Intensivmedizin und Notfallmedizin, Band 47, Heft
8. November 2010
• Leberversagen bei Sepsis und Multiorganversagen; Lenz, Intensiv-
medizin und Notfallmedizin, Band 43, Heft 1, Februar 2006
• Leitfaden extrakorporale Zirkulation, Alois Philipp, Christof Schmid;
Springer-Verlag 2011
• Leitlinie: Akuttherapie anaphylaktischer Reaktionen (www.awmf.org)
• Leitlinien der DGN (Deutschen Gesellschaft für Neurologie) 2008
• Leitlinie: Diagnostik und Therapie der Malaria; Version November
2013 (S1-Leitlinie) der Deutschen Gesellschaft für Tropenmedizin
und Internationale Gesundheit (DTG); AWMF online
• Leitlinien für die Diagnostik und Therapie in der Neurologie: Akut-
therapie des ischämischen Schlaganfalls; Diener et al, Thieme 2008
• Leitlinien DGEM (Deutsche Gesellschaft für Ernährungsmedizin)
2007
• Leitlinien ESPEN (European Society for clinical nutrition and me-
tabolism): Guidelines for parenteral nutrition (Intensive Care 2009)
• Leitlinien & Empfehlungen der Paul-Ehrlich-Gesellschaft (www.p-e-
g.org)
• Leitlinie Hirnabszeß der Deutschen Gesellschaft für Neurologie;
www. awmf.org (abgerufen am 22.05.2014)
• Leitlinie zur Akuttherapie und Management der Anaphylaxie; Ring et
al, Allergo J Int 2014
• Leitlinie zur Therapie der malignen Hyperthermie - Deutsche Gesell-
schaft für Anästhesiologie und Intensivmedizin; Anästh Intensivmed
2002
• Leitliniengerechte Therapie des Asthma bronchiale; Sieren et al, In-
ternist, Band 49, Heft 11, November 2008
• Letale Intoxikation mit Zinkhexafluorosilikat (Flußsäure); Marx et al,
Intensivmedizin und Notfallmedizin, Band 43, Heft 3, März 2006
• Letale Vergiftung nach Verwechslung von Krokus (Crocus species)
mit Herbstzeitloser (Colchicum autumnale); Hermanns-Clausen et
al, Intensivmedizin und Notfallmedizin, Band 44, Heft 2, März 2007
• Leukostase und Tumorlyse - wichtige Komplikationen der Hyper-
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• Levosimendan bei der Therapie der akuten hämodynamisch bedeut-
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• Levosimendan for the treatment of acute severe heart failure: A
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• Levosimendan vs dobutamine for patients with acute decompensa-
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• Liste chemischer Kampfstoffe - www.deacademic.com/dic.nsf/dewi-
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• Lithium intoxication; Timmer et al, J Am Soc Nephrol 1999
• Long-term cognitive and psychological outcomes in the awakening
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Med 2010
• Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa
blockade vs heparin and planned glycoprotein IIb/IIIa blockade du-
ring percutaneous coronary revascularization (REPLACE-2); Linkoff
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• Long-term follow-up of patients with portal vein thrombosis and mye-
loproliferative neoplasms; Hoekstra et al, J Thromb Haemost 2011
• Long-term mortality and quality of life in sepsis: a systematic review;
Winters et al, Crit Care Med 2010
• Long-term mortality benefit with the combination of stents and abci-
ximab for cardiogenic shock complicating acute myocardial infarc-
tion; Chan et al, Am J Cardiol 2002
• Long-term Results of Carotid Stenting versus Endarterectomy in
High-Risk Patients (SAPHIRE-Studie); Gurm et al, N Engl J 2008
• Long-term survival of post-infarction free wall rupture without opera-
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• Low-efficiency acute renal replacement therapy: role in acute kidney
injury; Marshall et al, Semin Dial 2011
• Lower GI bleeding: epidemiology and diagnosis; Strate, Gastroente-
rol Clin North Am 2005
1080 Appendix
• Low-molecular-weight heparin compared with intravenous unfractio-
nated heparin for treatment of pulmonary embolism: a meta-analysis
of randomized, controlled trials; Quinlan et al, Ann Intern Med 2004
• Lungenembolie; Janssens, Intensivmedizin und Notfallmedizin,
Band 48. Heft 4, Mai 2011
• Lungenembolie auf der Intensivstation; Dürschmied, Heinz, Siepe,
Bode, Intensivmedizin up2date, Heft 1, 11. Jahrgang, Februar 2015
• Lungenembolie; Hecker et al, Medizinische Klinik - Intensivmedizin
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• Lungenerkrankungen - pulmonale Hypertonie; Strauer et al, Inter-
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• Lungenersatzverfahren; Bein, Intensivmedizin up2date, Heft 2, 5.
Jahrgang, Mai 2009
• Lungenersatzverfahren; Bickenbach et al, Intensivmedizin up2date,
Mai 2018. 14. Jahrgang
• Magnesium therapy for torsades de pointes; Tzivoni et al, Am J Car-
diol 1984
• Tropical malaria und Dengue-Fieber - eine Herausforderung der In-
tensivmedizin; Eder et al, Intensivmedizin up2date, August 2018. 14.
Jahrgang
• Malignant hyperthermia; Rosenberg et al, Orphanet J Rare Di-
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• Malignant hyperthermia; Wappler et al, Eur J Anaesthesiol 2001
• Maligne hypertherme Syndrome auf der Intensivstation - Differen-
tialdiagnostik und Akutmaßnahmen; Grander, Medizinische Klinik
- Intensivmedizin und Notfallmedizin, Band 111, Heft 5, Juni 2016
• Maligne Hyperthermie, Rüffert et al; www.kai-uniklinikleipzig.de/ima-
ges/downloads/anaesthesie/MH_Information_fuer_Aerzte.pdf
• Management der dekompensierten Leberzirrhose auf der Intensiv-
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dizin und Notfallmedizin; Band 108. Heft 8. November 2013
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• Management der kritischen Atemwegsobstruktion; Jerrentrup et al,
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• Management des refraktären und superrefraktären Status epilepti-
cus; Erbguth, Medizinische Klinik - Intensivmedizin und Notfallmedi-
zin, Band 114, Heft 7, Oktober 2019
• Management of acute coronary syndromes: acute coronary syndro-
mes without persistent ST segment elevation; recommendations of
the Task Force of the European Society of Cardiology; Bertrand et
al, Eur Heart J 2000
• Management of acute exacerbations of chronic obstructive pul-
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• Management of acute hypercalcemia; Bilezikian, N Engl J Med 1992
• Management of blood pressure for acute and recurrent stroke; Aiya-
gari et al, Stroke 2009
• Management of cocaine-associated chest pain and myocardial in-
farction: a scientific statement from the American Heart Association
Acute Cardiac Care Committee of the Council on Clinical Cardiolo-
gy; McCord et al, Circulation 2008
• Management of drug and alcohol withdrawal; Kosten et al, N Engl
J 2003
• Management of hyperglycemic crises in patients with diabetes; Ki-
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• Management of life-threatening acid-base disorders. First of two
parts; Adrogué et al, N Engl J Med 1998
• Management of massive pulmonary embolism; Kucher et al, Circu-
lation 2005
• Management of patients with ulcer bleeding; Laine et al, Am J Ga-
stroenterol 2012
• Management of severe sepsis and septic shock; Sessler et al, Curr
Opin Crit Care 2004
• Management of the adult patient with acute lower gastrointestinal
bleeding. American College of Gastroenterology. Practice Parame-
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• Management und Diagnostik von Staphylococcus-aureus-Blutstro-
minfektionen (Weis, Hagel, Letzt; Klinikarzt, November 2019, 48.
Jahrgang)
• Management von Blutungsdiathesen in der Intensivmedizin; Petros,
Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band 106,
Heft 3, November 2011
• Managing out-of-hospital cardiac arrest survivors: Neurological per-
 spective; Grubb, Heart 2001
• Mannitol - the treatment of choice in the acute phase of ciguatera;
Lewis et al, SPC Ciguatera Information Bulletin 1992
• Mechanical reperfusion and long-term mortality in patients with acu-
te myocardial infarction presenting 12 to 48 hours from onset of sym-
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• Mechanical Reperfusion in Patients With Acute Myocardial Infarc-
tion Presenting More Than 12 Hours From Symptom Onset (BRAVE
2-Studie); Schoemig et al, JAMA 2005
• Mechanical ventilation; Tobin et al, N Engl J Med 1994
• Mechanische Assist-Systeme zur Herzunterstützung; Klotz et al, In-
tensivmedizin up2date, Heft 2, 4. Jahrgang, Mai 2008
• Medical therapy for pulmonary arterial hypertension: ACCP evi-
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• Medikolegale Probleme auf einer Intensivstation; Biermann, Inten-
sivmedizin up2date, Heft 3, 5. Jahrgang, August 2009
• Medizin & Recht. Rechtliche Sicherheit für den Arzt; Dettmeyer, 2.
Auflage 2006, Springer-Verlag
• Methämoglobinämie nach Inhalation von Poppers; Janssens et al,
Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band 114,
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• Mesenteric venous thrombosis; Kumar et al, N Engl J Med 2001
• Messung des intraabdominellen Drucks; von Delius et al, Intensiv-
medizin und Notfallmedizin, Band 47, Heft 5, Juni 2010
• Meta-analysis: Noninvasive ventilation in acute cardiogenic pul-
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• Meta-analysis of frusemide to prevent or treat acute kidney failure.;
Ho et al, BMJ 2006
• Meta-analysis of parenteral nutrition versus enteral nutrition in pati-
ents with acute pancreatitis, Marik et al, BMJ 2004
• Meta-analysis of usefulness of d-dimer to diagnose acute aortic dis-
section; Shimony et al, Am J Cardiol 2011
• Meta-analysis: the significance of screening for JAK2V617F mutati-
on in Budd-Chiari syndrome and portal venous system thrombosis;
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• Metabolic alkalosis; Galla et al, J Am Soc Nephrol 2000
• Metabolic alkalosis; Khanna et al, J Nephrol 2006
• Metabolische Ursachen von Bewusstseinsstörungen; Sayk et al, In-
tensivmedizin und Notfallmedizin, Band 47, Heft 2, März 2010
• Mikrobielle Endokarditis: leitliniengerechte Diagnostik und Therapie;
Horstkotte et al, Intensivmedizin up2date, Heft 3, 3. Jahrgang, Au-
gust 2007
• Mikrobiell verursachte Endokarditis; Horstkotte et al, Herz März
2015
• Minimal-invasives hämodynamisches Monitoring - toy or tool? Met-
zelder et al, Intensivmedizin und Notfallmedizin, Band 47, Heft 5,
Juni 2010
• Möglichkeiten und Zukunftsperspektiven der Leberersatztherapie;
Al-Chalabi et al, Intensivmedizin und Notfallmedizin, Band 46, Heft
5, Juli 2009
• Modern treatment of pulmonary embolism; Goldhaber, Eur Respir
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• Molecular mechanisms of fibrinolysis; Cesarman-Maus et al, Br J
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• Monitoring der künstlichen Ernährung bei kritisch kranken Patienten;
Hartl, Kuppinger; Intensivmedizin und Notfallmedizin, Band 48. Heft
2, März 2011
• Monitoring sedation status over time in ICU patients: reliability and
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• Monitoring von Organfunktionen; Lehner et al, Medizinische Klinik -
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• Morbus Addison; Quinkler, Medizinische Klinik – Intensivmedizin
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• Morbus Addison - primäre Nebenniereninsuffizienz; Pulzer, Burger-
Stritt, Hahner, Internist 5 / 2016
• Mild Therapeutic Hypothermia to Improve the Neurologic Outcome
after Cardiac Arrest; The Hypothermia after Cardiac Arrest Study
Group (HACA) N Engl J 2002
• Mikrobiologische Infektionsdiagnostik auf der Intensivstation;
Kochanek et al, Intensivmedizin up2date, Heft 3, 10. Jahrgang, Au-
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• Mütterliche Notfälle während der Schwangerschaft; Strauß, Gynä-
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• Multicenter, randomized, controlled trial of 150-J biphasic shocks
compared with 200- to 360-J monophasic shocks in the resuscitation
of out-of-hospital cardiac arrest victims. Optimized Response to Car-
diac Arrest (ORCA) Investigators; Schneider et al, Circulation 2000
• Multicenter, Randomized, Controlled Clinical Trial of Transfusion
Requirements in Critical Care (TRICC); Hebert et al, N Engl J 1999
• Multidetector computed tomography for acute pulmonary embolism;
Stein et al, N Engl J Med 2006
• Multidisciplinary practical guidelines for gastrointestinal access for
enteral nutrition and decompression from the Society of Interventio-
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Association (CIRA) and Cardiovascular and Interventional Radiolo-
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• Multiorganversagen nach Suizidversuch mit Aluminiumphosphid;
Müssigbrodt et al, Intensivmedizin und Notfallmedizin, Band 44, Heft
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• Multiresistente Erreger - Infektionsmanagement 2015; Pletz et al,
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• Multiresistente gramnegative Bakterien – Problemkeime des 21.
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• Muskelrelaxantien in der Anästhesie und Intensivmedizin; Wars-
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• Muskelerkrankungen auf der Intensivstation; Schneider-Gold, Müll-
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• Myasthenia gravis: management of myasthenic crisis and periopera-
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• Myasthenic crisis: guidelines for prevention and treatment; Jani-
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• Myokarditis - frühzeitige Biopsie ermöglicht differenzierte regenera-
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• NAP4-Report: National Audit Project, The royal College of Anaesthe-
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• Narkose in der Notfallmedizin: Ein Leitfaden für den Rettungsdienst;
Kuhnigk, Georg Thieme Verlag, 2006
• National Asthma Education and Prevention Program: Expert Panel
Report III: Guidelines for the diagnosis and management of asthma.
Bethesda, MD. National Heart, Lung, and Blood Institute, 2007
• National Comprehensive Cancer Network (NCCN) Clinical Practice
Guidelines in Oncology - Prevention and treatment of cancer-related
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• Natriuretic peptides in acute pulmonary embolism: a systematic re-
Appendix 1081
 view; Cavallazzi et al, Intensive Care Med 2008
• Necrotizing fasciitis: clinical presentation, microbiology, and determi-
nants of mortality; Wong et al, J Bone Joint Surg Am 2003
• Necrotizing soft-tissue infection: diagnosis and management; Anaya
et al, Clin Infect Dis 2007
• Neonatologische Notfälle beim reifen Neugeborenen; Tutdibi et al,
Intensivmedizin und Notfallmedizin, Band 48. Heft 1, Februar 2011
• Neue Antibiotika - Stillstand oder Fortschritt; Rademacher, Welte,
Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band 112,
Heft 3, April 2017
• Neue Definition des Herzinfarkts – Was ist wichtig für den Notfall-
mediziner? Vafaie et al, Notfall + Rettungsmedizin, Band 16, Heft
1, Februar 2013
• Neue europäische Leitlinien zur kardiopulmonalen Reanimation;
Arntz, Baubin, Böttiger et al; Intensivmedizin up2date, Heft 2, 2.
Jahrgang, Mai 2006
• Neue Leitlinien des European Resuscitation Council zur Reanima-
tion; Raaz et al, Intensivmedizin und Notfallmedizin, Band 48. Heft
3, April 2011
• Neue Leitlinien und Daten zu Clostridium difficile - Was hat sich ge-
ändert? Lübbert et al, DMW 2018 143. Jahrgang
• Neue orale Antikoagulantien (NOAK) in der Intensivmedizin; Lutz et
al, Intensivmedizin up2date, Heft 2, 9. Jahrgang, Mai 2013
• Neue Therapiekonzepte bei akut dekompensierter Herzinsuffizienz;
Lehinant et al, Intensivmedizin und Notfallmedizin, Band 46, Heft 6,
September 2009
• Neue Therapiestrategien bei zerebraler intraventrikulärer Blutung;
Staykov et al, Medizinische Klinik - Intensivmedizin und Notfallmedi-
zin, Band 107, Heft 4, Mai 2012
• Neue US-Leitlinien zur Behandlung der aneurysmalen Subarach-
noidalblutung - Übersicht, Kommentar und Vergleich mit deutschen
Leitlinien; Bösel, Intensivmedizin und Notfallmedizin, Band 46, Heft
7, Oktober 2009
• Neue Wege in der Beatmungstherapie. Einsatz der nichtinvasiven
Ventilation (NIV) im intensivtherapeutischen Arbeitsbereich; Rot-
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• Neues zu Diagnostik und Monitoring bei akutem Koronarsyndrom
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• Neugeborenen-Notfälle, ein praktischer Leitfaden für Erstversor-
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Georg Hansmann, Thieme-Verlag
• Neurally adjusted ventilatory assist (NAVA). Ein neuartiges assistier-
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• Neurologie; Lehrbuch Poeck / Hacke 10. Auflage, Springer-Verlag
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• Neurologische Frührehabilitation bei beatmeten Patienten mit ZNS-
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• Neurologische Intensivmedizin; Schwab, Springer-Verlag 1999
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• Neuromuscular manifestations of critical illness; Bolton, Muscle Ner-
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• Neurothrombektomie – eine neue Ära der Schlaganfallbehandlung;
Ringleb et al, Intensivmedizin up2date, Heft 4, 11. Jahrgang, No-
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• Neuro-Thrombektomie – Mechanische Rekanalisierung akuter zere-
braler Gefäßverschlüsse; Rohde et al, Intensivmedizin up2date, Heft
1, 10. Jahrgang, Februar 2014
• New Comprehensive Amatoxin Mushroom Poisoning (AMP) Treat-
ment Protocol; Mitchell et al, Clin Tox 2010
• New criteria for diagnosis of infective endocarditis: utilization of spe-
cific echocardiographic findings. Duke Endocarditis Service; Durack
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• New guidelines for potassium replacement in clinical practice: a con-
temporary review by the National Council on Potassium in Clinical
1082 Appendix
Practice; Cohn et al, Arch Intern Med 2000
• New Oral Anticoagulants and the Risk of Intracranial Hemorrhage-
Traditional and Bayesian Meta-analysis and Mixed Treatment Com-
parison of Randomized Trials of New Oral Anticoagulants in Atrial
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• New prognostic scoring model for liver transplantation in patients
with non-acetaminophen-related fulminant hepatic failure; Miyake et
al, Transplantation 2005
• New treatment of acute hypoxemic respiratory failure: noninvasive
pressure support ventilation delivered by helmet - a pilot controlled
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• Nicht-invasive Beatmung auf der Intensivstation: Vorteile, Anwen-
dungsmöglichkeiten und praktische Aspekte; Keymel, Dinjus; Klini-
karzt – Medizin im Krankenhaus, 43. Jahrgang, 2/2014
• Nichtinvasive Beatmung bei COPD; Funk, Medizinische Klinik - In-
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• Nichtinvasive Beatmung bei der Entwöhnung vom Respirator; Leg-
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2006
• Nichtinvasive Beatmung bei Patienten mit Lungenödem und akuter
respiratorischer Ateminsuffizienz; Köhnlein et al, Pneumonologe
2005
• Nichtinvasive Beatmung - gestern, heute und morgen; Schönhofer;
Intensivmedizin und Notfallmedizin, Band 45, Heft 4, Mai 2008
• Nichtinvasive Beatmung in der präklinischen Notfallmedizin; Dopp-
ler, Medizinische Klinik – Intensivmedizin und Notfallmedizin, Band
109, Heft 2, März 2014
• Nichtinvasive Beatmung - Physiologische Grundlagen, Technik, Indi-
kationen; Köhnlein et al, Pneumonologe 2005
• Nichtinvasive Beatmung: was gibt es Neues? Heinemann, Intensiv-
medizin und Notfallmedizin, Band 46, Heft 1, Februar 2008
• Nichtinvasive Beatmung – update; Geiseler et al, Intensivmedizin
up2date, Heft 2, 9. Jahrgang, Mai 2013
• Nichtinvasive Beatmung zur Behandlung akuter respiratorischer In-
suffizienz; Cornelissen, Dreher, Medizinische Klinik - Intensivmedi-
zin und Notfallmedizin, Band 113, Heft 1, Februar 2018
• Nicht-invasives hämodynamisches Monitoring bei Intensivpatienten;
Stemmler et al, Intensivmedizin und Notfallmedizin, Band 44, Heft
6, September 2007
• Nicht-medikamentöse Therapie der COPD; Watz et al, Klinikarzt
– Medizin im Krankenhaus, Demeter-Verlag, 42. Jahrgang, Heft
4/2013
• Nicht-Vitamin-K orale Antikoagulation in der Klinik; Epple et al, Inten-
sivmedizin up2date, Februar 2017, 13. Jahrgang
• Nierenersatztherapie als mögliches Trauma im akuten Nierenversa-
gen; John, Medizinische Klinik – Intensivmedizin und Notfallmedizin,
Band 109, Heft 5, Juni 2014
• Nierenersatztherapie - unterschiedliche Verfahren und Differenzia-
lindikationen; Jörres, Intensivmedizin und Notfallmedizin, Band 47,
Heft 6, September 2010
• Nierenersatztherapie mittels SLEDD; Zierhut, Kammerl; Intensivme-
dizin und Notfallmedizin, Band 46, Heft 7, Oktober 2009
• Nierenersatztherapie: Wann? Wie? Wie lange? Joannidis, Intensiv-
medizin und Notfallmedizin, Band 48. Heft 4, Mai 2011
• Nierenersatzverfahren auf der Intensivstation: Indikation, Einsatz-
möglichkeiten und Therapie-Empfehlungen; Woznowski, Schieren;
Klinikarzt – Medizin im Krankenhaus, 43. Jahrgang, 2/2014
• Nierenersatzverfahren bei akutem Nierenversagen auf der Intensiv-
station; Schwenger et al, Intensivmedizin up2date, Heft 4, 5. Jahr-
gang, November 2009
• Nierenersatztherapie bei kritisch kranken Patienten mit akuter Nie-
renschädigung; Zarbock, Kümpers, Intensivmedizin up2date, Heft 2,
10. Jahrgang, Mai 2014
• Niereninsuffizienz bei Patienten mit Leberinsuffizienz; Lenz et al,
Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band 109,
Heft 4, Mai 2014
• Nomenklatur, Definition und Differenzierung der Schockformen;
Standl et al, Deutsches Ärzteblatt, Heft 45, November 2018
• Non-dialytic treatment of acute hyperkalemia in the dialysis patient;
Emmett, Semin Dial 2000
• Non-invasive positive pressure ventilation (CPAP or bilevel NPPV)
for cardiogenic pulmonary edema; Vital et al, Cochrane Database
Syst Rew 2008
• Noninvasive Positive-Pressure Ventilation for Postextubation Respi-
ratory Distress; Keenan et al, JAMA 2002
• Noninvasive positive pressure ventilation in status asthmaticus; Me-
duri et al, Chest 1996
• Noninvasive positive pressure ventilation: Predictors of success and
failure for adult acute care applications; Hess et al, Respir Care 1997
• Noninvasive positive-pressure ventilation to treat hypercapnic coma
secondary to respiratory failure; Díaz et al, Chest 2005
• Noninvasive positive pressure ventilation to treat respiratory failure
resulting from exacerbations of chronic obstructive pulmonary disea-
se: Cochrane systematic review and meta-analysis; Lightowler et al,
Br Med J 2003
• Non-invasive pressure support ventilation and CPAP in cardiogenic
pulmonary edema: a multicenter randomized study in the emergen-
cy department; Nouira et al, Intensive Care Med 2011
• Noninvasive proportional assist ventilation compared with noninva-
sive pressure support ventilation in hypercapnic acute respiratory
failure; Wysocki et al, Crit Care Med 2002
• Noninvasive ventilation as a weaning tool; Ferrer et al, Minerva
Anesthesiol 2005
• Noninvasive ventilation for acute exacerbations of chronic obstructi-
ve pulmonary disease; Brochard et al, N Engl J Med 1995
• Noninvasive ventilation in acute respiratory failure - a meta-analysis
update; Peter et al, Crit Care Med 2002
• Noninvasive ventilation in immunosuppressed patients with pul-
monary infiltrates, fever, and acute respiratory failure; Hilbert et al,
N Engl J 2001
• Noninvasive ventilation in severe hypoxemic respiratory failure: a
randomized clinical tria; Ferrer et al, Respiratory and Critical Care
Medicine 2003
• Nonvariceal Upper GI Bleeding Consensus Conference Group. Con-
sensus recommendations for managing patients with nonvariceal
upper gastrointestinal bleeding; Barkun et al, Ann Intern Med 2003
• Norepinephrine plus dobutamine versus epinephrine alone for ma-
nagement of septic shock: a randomized trial; Annane et al, Lancet
2007
• Nosokomial erworbene Pneumonie; Tello et al, Medizinische Klinik
- Intensivmedizin und Notfallmedizin, Band 113, Heft 8. November
2018
• Nosokomiale Infektionen - evidenzbasierte Maßnahmen; Gastmeier,
Internist, Band 51, Heft 2, Februar 2010
• Nosokomiale Infektionen - Herausforderung MRSA und CDAD; Kern
et al, Internist, Band 50, Heft 6, Juni 2009
• Notarzt-Leitfaden, Ulrich von Hintzenstern, 5. Auflage, Urban &
Fischer-Verlag
• Notfallkoniotomie - chirurgisch oder doch Punktion? Mohr, Göring,
Knapp, Notfall Rettungsmed 2/2019
• Notfall-Manual, Sefrin / Schua, 4. Auflage, Urban & Fischer-Verlag
• Notfall Hitzschlag; Ziegenfuß, www.thieme.de/viamedici/klinik-
faecher-notfallmedizin-1539/a/hitzschlag-4187.htm (abgerufen am
15.05.2014)
• Notfallmedizin, Handbuch für den Bereitschaftsdienst, Peter Rupp,
consilium cedip
• Notfallmedizin, Hans-Peter Schuster, 5. überarbeitete Auflage, En-
ke-Reihe
• Notfälle bei Herzschrittmacherpatienten; Trappe, Intensivmedizin
und Notfallmedizin, Band 45, Heft 7, Oktober 2008
• Notfallmedikamente bei Schwangeren; Fink et al, Medizinische Kli-
nik - Intensivmedizin und Notfallmedizin, Band 107, Heft 4, Mai 2012
• Notfallmedizinisches Management von Patienten mit akutem Hirnin-
farkt oder TIA; Schwarting et al, Intensivmedizin und Notfallmedizin,
Band 47, Heft 2, März 2010
• Notfallmedizinische Versorgung von Patienten mit Kunstherz; Bec-
kendorf et al, Notfall Rettungsmed 6/2019
• Notfallnarkose, Atemwegsmanagement und Beatmung beim Poly-
trauma: Hintergrund und Kernaussagen der interdisziplinaren S3-
Leitlinie Polytrauma; Bernhard et al, Anaesthesist 2011
• Notfalltherapie der Bradykardien; Deubner et al, Medizinische Klinik
- Intensivmedizin und Notfallmedizin, Band 113, Heft 6, September
2018
• Notfalltherapie tachykarder Herzrhythmusstörungen; Deubner et al,
Medizinische Klinik - Intensivmedizin und Notfallmedizin, Band 112,
Heft 3, April 2017
• Nutrition Support in Acute Pancreatitis: A Systematic Review of the
Literature; McClave et al, Journal of Parenteral and Enteral Nutrition
2006
• Nutrition therapy in the critical care setting: What is "best achievable"
practice? An international multicenter observational study; Cahill et
al, Crit Care Med 2010
• Obstruktive Lungenerkrankungen und pulmonale Hypertonie; Neu-
mann et al, Internist, Band 50, Heft 9, September 2009
• Ogilvie-Syndrom - akute idiopathische Kolondilatation; Kirchberg et
al, Intensivmedizin up2date, Heft 1, 6. Jahrgang, Februar 2010
• Ogilvie's syndrome: colonoscopic decompression and analysis of
predisposing factors; Jetmore et al, Dis Colon Rectum 1992
• Olanzapine vs haloperidol: treating delirium in a critical care setting;
Skrobik et al, Intensive Care Med 2004
• Onkologische Notfälle in der Chemotherapie; von Amsberg, Der
Urologe 5/2018
• Open pulmonary embolectomy for treatment of major pulmonary
embolism; Yalamanchili et al, Ann Thorac Surg 2004
• Operative Intensivmedizin - Sicherheit in der klinischen Praxis; Hans
Walter Striebel, 2. Auflage, Schattauer-Verlag
• Opportunistische Infektionen des ZNS; Storch-Hagenlocher et al,
Intensivmedizin up2date, Heft 1, 7. Jahrgang, Februar 2010
• Optimal Medical Therapy with or without PCI for Stable Coronary
Disease (COURAGE); Boden et al, N Engl J 2007
• Optimierung des Sauerstofftransports; Meier et al, Intensivmedizin
up2date, Heft 2, 4. Jahrgang, Mai 2008
• Oral anticoagulant therapy: Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians Evi-
dence-Based Clinical Practice Guidelines; Ageno et al, Chest 2012
• Oral rivaroxaban for the treatment of symptomatic pulmonary embo-
lism; EINSTEIN–PE Investigators. N Engl J Med 2012
• Orale Thromboseprophylaxe; Schwarz et al, Intensivmedizin up-
2date, Heft 1, 5. Jahrgang, Februar 2009
• Organisation medizinischer Entscheidungen am Lebensende; Wall-
ner, Intensivmedizin und Notfallmedizin, Band 47, Heft 1, Februar
2010
• Organische Psychosyndrome: Eine Synopsis mit kritischer Würdi-
gung; Haupt et al, Intensivmedizin und Notfallmedizin, Band 45, Heft
7, Oktober 2008
• Organophosphorus intoxication; Khurana et al, Arch Neurol 2000
• Organspende in Deutschland - wann und wie? Ein Fall für Trans-
plantationsbeauftragte; Söffker et al, Medizinische Klinik - Intensiv-
medizin und Notfallmedizin, Band 109, Heft 6, September 2014
• Outcomes and long-term quality-of-life of patients supported by
extracorporeal membrane oxygenation for refractory cardiogenic
shock; Combes et al, Crit Care Med 2008
• Outcome at 1 year after an invasive compared with a non-invasive
strategy in unstable coronary-artery disease: the FRISC II invasi-
ve randomized trial. FRISC II Investigators. Fast Revascularisation
during Instability in Coronary artery disease; Wallentin et al, Lancet
2000
• Outcomes of medical management of acute type B aortic dissection;
Estrera et al, Circulation 2006
• Outcomes of patients hospitalized with community-acquired, health
care-associated, and hospital-acquired pneumonia; Venditti et al,
Ann Intern Med 2009
• Outcomes of patients with do-not-intubate orders treated with nonin-
vasive ventilation; Levy et al, Crit Care Med 2004
• Out-of-hospital administration of intravenous glucose-insulin-po-
tassium in patients with suspected acute coronary syndromes: the
IMMEDIATE randomized controlled trial; Selker et al, JAMA 2012
• Palliative cancer care: an epidemiologic study; Becker et al, J Clin
Oncol 2011
• Palliativmedizin; Valentin, Intensivmedizin und Notfallmedizin, Band
47, Heft 1, Februar 2010
• Paraquatintoxikation; Spangenberg et al, Medizinische Klinik - Inten-
sivmedizin und Notfallmedizin, Band 107, Heft 4, Mai 2012
• Parenteral anticoagulants: Antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians Evi-
dence-Based Clinical Practice Guidelines; Garcia et al, Chest 2012
Appendix 1083
• Paresis acquired in the intensive care unit: a prospective multicenter
study; De Jonghe et al, JAMA 2002
• Parkinson-Syndrome: Diagnostik und Therapie; Leitlinien der Deut-
schen Gesellschaft für Neurologie, S2-Leitlinie (AWMF online)
• Pathophysiologic basis of acute respiratory distress in patients who
fail a trial of weaning from mechanical ventilation; Jubran et al, Am J
Respir Crit Care Med 1997
• Pathophysiologie der Sepsis; Ertmer, Rehberg, Intensivmedizin up-
2date, Heft 3, 10. Jahrgang, August 2014
• Pathophysiologie des rechten Ventrikels bei Lungenerkrankungen;
Steiner et al, Internist, Band 50, Heft 9, September 2009
• Pathophysiologie des Schocks; Thiel et al, Notfall + Rettungsmedi-
zin, Band 9, Heft 6, Oktober 2006
• Pathophysiologie und Keimspektrum der Sepsis; Hauber et al, Inter-
nist, Band 50, Heft 7, Juli 2009
• Pathophysiologie und Therapie bei Ertrinkungsunfällen; Groneberg,
Mönig, Welte, Intensivmedizin up2date, Heft 3, 3.Jahrgang, August
2007
• Pathophysiologie und Therapie des akuten Leberversagens; Hadem
et al, Intensivmedizin up2date, Heft 1, 4. Jahrgang, Februar 2008
• Pathophysiology and management of right heart ischemia; Goldstein
et al, J Am Coll Cardiol 2002
• Pathophysiology and management of self-poisoning with beta-bloc-
kers; Taboulet et al, J Toxicol Clin Toxicol 1993
• Pathophysiology and treatment of carbon monoxide poisoning; Har-
dy et al, J Toxicol Clin Toxicol 1994
• Pathophysiology of bacterial meningitis: mechanism(s) of neuronal
injury; Scheld et al, J Infect Dis 2002
• Patient Blood Management; www.patientbloodmanagement.de (ab-
gerufen am 27.05.2015)
• Patient Blood Management in der Intensivmedizin; Meybohm,
Choorapoikayil, Zacharowski, Intensivmedizin up2date März 2017
• Patienten mit Klappenvitium auf der Intensivstation; Geppert, Medi-
zinische Klinik - Intensivmedizin und Notfallmedizin, Band 108. Heft
7, Oktober 2013
• Patienten mit Problemkeimen; Kampe et al, Intensivmedizin up-
2date, Heft 3, 6. Jahrgang, August 2010
• Patient outcomes after acute pulmonary embolism. A pooled survival
analysis of different adverse events; Klok et al, Am J Respir Crit Care
Med 2010
• Patient-ventilator asynchrony during assisted mechanical ventilati-
on; Thille et al, Intensive Care Med 2006
• Patient-ventilator asynchrony during non-invasive ventilation for
acute respiratory failure: a multicenter study; Vignaux et al, Intensive
Care Med 2009
• Patientenverfügung in der Intensiv- und Notfallmedizin; Simon, In-
tensivmedizin und Notfallmedizin, Band 47, Heft 1, Februar 2010
• Patientenverfügungen unter ärztlicher Deutungshoheit? Duttge, In-
tensivmedizin und Notfallmedizin, Band 48. Heft 1, Februar 2011
• PCR-Erregerdiagnostik bei Sepsis - technische Validität und klini-
sche Relevanz; Welte, Intensivmedizin und Notfallmedizin, Band 47,
Heft 6, September 2010
• Pediatric basic and advanced life support: 2010 International Con-
sensus on Cardiopulmonary Resuscitation and Emergency Cardio-
vascular Care Science with Treatment Recommendations; Kleinman
et al, Pediatrics 2010
• Pediatric basic life support: American Heart Association Guidelines
for Cardiopulmonary Resuscitation and Emergency Cardiovascular
Care; Berg et al, Circulation 2010
• Pediatric plant exposures in Germany, 1998-2004; Pietsch et al, Clin
Toxicol 2008
• PEEP-Beatmung und Nierenfunktion; Francis et al, Intensivmedizin
up2date, Heft 1, 3. Jahrgang, Februar 2007
• Percutaneous coronary intervention for cardiogenic shock in the
SHOCK trial; Webb et al, J Am Coll Cardiol 2003
• Percutaneous dilatational tracheostomy in the ICU: optimal organi-
zation, low complication rates, and description of a new complicati-
on; Polderman et al, Chest 2003
• Percutaneous dilatational tracheostomy versus surgical tracheosto-
my in critically ill patients: a systematic review and meta-analysis;
Delaney et al, CritCare 2006
• Percutaneous or surgical tracheostomy: a meta-analysis; Dulguerov
et al, Crit Care Med 1999
• Percutaneous transtracheal ventilation: effects of a new oxygen flow
1084 Appendix
modulator on oxygenation and ventilation in pigs compared with a
hand triggered emergency jet injector; Preussler et al, Resuscitation
2003
• Performance standards for therapeutic abdominal paracentesis;
Grabau et al, Hepatology 2004
• Perioperative Antikoagulation und Thrombolyse; Dellas et al, Inten-
sivmedizin up2date, Heft 1, 6. Jahrgang, Februar 2010
• Perioperatives akutes Koronarsyndrom; Schwab et al, Intensivmedi-
zin up2date, Heft 2, 6. Jahrgang, Mai 2010
• Perkutane mechanische Kreislaufunterstützung; Seidler, Der Inter-
nist, Band 55, Heft 11, November 2014
• Persistent hyperammonemia is associated with complications and
poor outcomes in patients with acute liver failure; Kumar et al, Clin
Gastroenterol Hepatol 2012
• Pflegerische Betreuung von Patienten mit intrakranieller Drucker-
höhung und liegender Hirndrucksonde; Dittrich, Helbok; Intensiv-
News, Jahrgang 17, Ausgabe 5/13
• Phäochromozytom: Klinik, Diagnostik und Therapie; Höppner et al,
Dtsch Arztebl 2001; 98(39): A-2502 / B-2154 / C-2000
• Pharmacokinetics of sulfobutylether-beta-cyclodextrin and vorico-
nazole in patients with end-stage renal failure during treatment with
two hemodialysis systems and hemodiafiltration; Hafner et al, Anti-
microb Agents Chemother 2010
• Pharmacokinetics, safety and tolerance of voriconazole in renally
impaired subjects: two prospective, multicenter, open-label, parallel-
group volunteer studies; Abel et al, Clin Drug Investig 2008
• Pharmakokinetische und pharmakodynamische Aspekte in der Anti-
biotikatherapie; Bellmann, Medizinische Klinik – Intensivmedizin und
Notfallmedizin, Band 109, Heft 3, April 2014
• Pharmakorefraktärer Status epilepticus; Kurthen et al, Intensivmedi-
zin up2date, Heft 2, 7. Jahrgang, Mai 2011
• Pharmakotherapie der akuten schweren Herzinsuffizienz; Boldt,
Lehmann; Intensivmedizin und Notfallmedizin, Band 44, Heft 1, Fe-
bruar 2007
• Phenytoin Toxicity; Miller et al, www.emedicine.medscape.com/artic-
le/816447 (abgerufen am 24.03.2015)
• Phosphorus ans an early predictive factor in patients with acute liver
failure; Baquerizo et al, Transplantation 2003
• Physiologische Grundlagen der perioperativen Flüssigkeitstherapie;
Ertmer et al, Intensivmedizin up2date, Heft 1, 5. Jahrgang, Februar
2009
• Pituitary insufficiency; Lamberts, Lancet 1998
• Plant poisoning; Froberg et al, Emerg Med Clin North Am 2007
• Plasminogen deficiency, Schuster et al, J Thromb Haemost 2007
• Plötzlicher Herztod - Trifft er das Opfer ohne Vorwarnung? Arntz et
al, Notfall + Rettungsmedizin, Band 16, Heft 1, Februar 2013
• Pneumonien bei Immunosuppression; Dalhoff et al, Internist, Band
48. Heft 5, Mai 2007
• Pneumocystis carinii infection - update and review; Wazir et al, Arch
Pathol Lab Med 2004
• Pneumocystis jirovecii-Pneumonie - eine opportinistische Infektion
im Wandel; Hitzenbichler, Mohr, Salzberger; Internist 7/2019
• PneuX P.Y.-System - klinischer Einsatz und Reduktion des Clinical
Pulmonary Infection Score (CPIS) bei langzeitbeatmeten Intensiv-
patienten; Hilbert et al, Intensivmedizin und Notfallmedizin, Band 48.
Heft 1, Februar 2011
• Poisoning by anti-malarial drugs; Tibbutt, SSMJ 2013 (http://www.
southsudanmedicaljournal.com/archive/august-2013/poisoning-by-
anti-malarial-drugs.html; abgerufen am 13.01.2017)
• Population Trends in the Incidence of Acute Myocardial Infarction;
Yeh et al, N Engl J 2010
• Portal hypertension-related complications after acute portal vein
thrombosis: impact of early anticoagulation; Turnes et al, Clin Ga-
stroenterol Hepatol 2008
• Portopulmonary hypertension and hepatopulmonary syndrome; Ho-
eper et al, Lancet 2004
• Portopulmonary hypertension: Results from a 10-year screening al-
gorithm; Krowka et al, Hepatology 2006
• Position paper update: gastric lavage for gastrointestinal decontami-
nation; Benson et al, Clin Toxicol 2013
• Positionspapier der Österreichischen Kardiologischen Gesellschaft
zum Einsatz der extrakorporalen Membranoxygenation (ECMO) bei
Erwachsenen kardiologischen Patienten; Medizinische Klinik - Inten-
sivmedizin und Notfallmedizin, Band 110, Heft 6, September 2015
• Positionspapier zur „Automatisierten Externen Defibrillation“; Trap-
pe, Intensivmedizin und Notfallmedizin, Band 43, Heft 1, Februar
2006
• Positionspapier zur praktischen Umsetzung der apparativen Dif-
ferenzialtherapie der akuten respiratorischen Insuffizienz bei CO-
VID-19 der Deutsche Gesellschaft für Pneumologie und Beatmungs-
medizin 2020
• Positive End-Expiratory Pressure Setting in Adults With Acute Lung
Injury and Acute Respiratory Distress Syndrome (EXPRESS study);
Mercat et al, JAMA 2008
• Posteriores reversibles Enzephalopathiesyndrom (PRES); Roth et
al, Intensivmedizin und Notfallmedizin, Band 47, Heft 7, Oktober
2010
• Posterior reversible encephalopathy syndrome: prognostic utility of
quantitative diffusion-weighted MR images; Covarrubias et al, AJNR
Am J Neuroradiol 2002
• Postreanimationserkrankung und Postreanimationstherapie; Busch
et al, Intensivmedizin up2date, Heft 3, 6. Jahrgang, August 2010
• Potenziell letale Methämoglobinämie nach Ingestion von Alkylnitri-
ten („Poppers“); Wellershoff, Notfall + Rettungsmedizin, Band 7, Heft
2, März 2014
• Practice guidelines for outpatient parenteral antimicrobial therapy.
IDSA guidelines; Tice et al, Clin Infect Dis 2004
• Practice guidelines for the management of bacterial meningitis; Tun-
kel et al, Clin Infect Dis 2004
• Practice Parameters Committee of the American College of Gastro-
enterology. Practice guidelines in acute pancreatitis; Banks et al, Am
J Gastroenterol 2006
• Präeklampsie und HELLP-Syndrom als geburtshilfliche Notfälle;
Tallarek et al, Medizinische Klinik - Intensivmedizin und Notfallme-
dizin, Band 107, Heft 2, März 2012
• Prähospitaler Herzkreislaufstillstand - Therapeutische Hypothermie
beim Erwachsenen; Arntz, Medizinische Klinik – Intensivmedizin und
Notfallmedizin, Band 107, Heft 5, Juni 2012
• Prähospitalversorgung und Akuttherapie des ischämischen Schlag-
anfalls; Köhrmann, Intensivmedizin und Notfallmedizin, Band 47,
Heft 3, April 2010
• Prasugrel versus clopidogrel in patients with acute coronary syndro-
mes; Wiviott et al, N Engl J Med 2007
• Predictors of noninvasive ventilation failure in patients with hemato-
logic malignancy and acute respiratory failure; Adda et al, Crit Care
Med 2008
• Prevalence and clinical implications of hypocalcemia in acutely ill pa-
tients in a medical intensive care setting; Desai et al, Am J Med 1988
• Prevalence of pulmonary embolism in acute exacerbations of COPD:
a systematic review and meta-analysis; Rizkallah et al, Chest 2009
• Prävalenz und Schweregrad von Begleitverletzungen alkoholintoxi-
kierter Patienten in der Notaufnahme; Grüttner et al, Notfall Ret-
tungsmed 2008
• Prävention der akuten Nierenschädigung beim kritisch kranken Pa-
tienten - Empfehlungen der Sektion „Niere“ der DGIIN, ÖGIAIN und
DIVI; Joannidis et al, Medizinische Klinik - Intensivmedizin und Not-
fallmedizin, Band 113, Heft 5, Juni 2018
• Prävention der beatmungsassoziierten Pneumonie; Lewalter et al,
Intensivmedizin up2date, Heft 2, 10. Jahrgang, Mai 2014
• Prävention in der klinischen Toxikologie Was ist gesichert – was ist
Mythos? Schrettl, Eyer; Bayerisches Ärzteblatt Dezember 2013
• Prävention nosokomialer Infektionen durch Bündel – Evidenz und
praktische Umsetzung; Gebhardt et al, Medizinische Klinik – Inten-
sivmedizin und Notfallmedizin, Band 108. Heft 2, März 2013
• Praktische Echokardiographie; Kuhnert, Deutscher Ärzte-Verlag
2010
• Prasugrel versus Clopidogrel in Patients with Acute Coronary Syn-
dromes (TRITON TIMI 38); Wiviott et al, N Engl J 2007
• Praxisbuch Beatmung, Ulrich von Hintzenstern und Thomas Bein, 3.
Auflage, Urban & Fischer-Verlag
• Praxisbuch Endokrinologie und Stoffwechsel; 1. Auflage, Auernham-
mer; Urban & Fischer-Verlag
• Praxisbuch Ethik in der Intensivmedizin - Ethische Herausforderun-
gen und konkrete Entscheidungshilfen in Grenzsituationen; Salo-
mon, Medizinisch Wissenschaftliche Verlagsgesellschaft 2009
• Precipitants of post-traumatic stress disorder following intensive
care: a hypothesis generating study of diversity in care; Jones et al,
Intensive Care Med 2007
• Predicting success in weaning from mechanical ventilation; Meade
et al, Chest 2001
• Predictors of extubation failure in myasthenic crisis; Seneviratne et
al, Arch Neurol 2008
• Prediction of extubation outcome: a randomized, controlled trial with
automatic tube compensation versus pressure support ventilation;
Cohen et al, Crit Care 2009
• Prediction of post-extubation work of breathing; Mehta et al, Crit
Care Med 2000
• Predictive power of serum NSE and OHCA score regarding 6-month
neurologic outcome after out-of-hospital ventricular fibrillation and
therapeutic hypothermia; Oksanen et al, Resuscitation 2009
• Predisposing factors for delirium in the surgical intensive care unit;
Aldemir et al, Crit Care 2001
• Prehospital epinephrine use and survival among patients with out-of-
hospital cardiac arrest; Hagihara et al, JAMA 2012
• Prehospital reperfusion therapy: a strategy to improve therapeutic
outcome in patients with ST-elevation myocardial infarction; Huber
et al, Eur Heart J 2005
• Preload index and fluid responsiveness: different aspects of the new
concept of functional hemodynamic monitoring; Della Rocca et al,
Minerva Anestesiol 2008
• Preoxygenation and prevention of desaturation during emergency
airway management; Weingart et al, Ann Emerg Med 2012
• Prevalence and economic burden of pulmonary embolism in Germa-
ny; Kröger et al, Vasc Med 2012
• Prevalence and risk of rupture of intracranial aneurysms: a systema-
tic review; Rinkel et al, Stroke 1998
• Preventing complications of central venous catheterization; McGee
et al, N Engl J Med 2003
• Prevention and management of gastroesophageal varices and va-
riceal hemorrhage in cirrhosis; Garcia-Tsao et al, Hepatology 2007
• Prevention of Hospital associated pneumonia and ventilator-asso-
ciated pneumonia; Kollef et al, Crit Care Med 2004
• Prevention of infective endocarditis: guidelines from the American
Heart Association: a guideline from the American Heart Association
Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee,
Council on Cardiovascular Disease in the Young, and the Council on
Clinical Cardiology, Council on Cardiovascular Surgery and Anes-
thesia, and the Quality of Care and Outcomes Research Interdisci-
plinary Working Group; Wilson et al, Circulation 2007
• Probiotic prophylaxis in predicted severe acute pancreatitis; Besse-
link et al, Lancet 2008
• Probleme der Behandlungsbegrenzung im Kontext einer internisti-
schen Intensivstation; Reiter-Theil, Zeitschrift für Medizinische Ethik
1999
• Problemfeld Clostridium-difficile-Infektionen; Ebigbo et al, Medizini-
sche Klinik - Intensivmedizin und Notfallmedizin; Band 108. Heft 8.
November 2013
• Prognose und Monitoring bei akuter Pankreatitis; Huber, Schmid;
Intensivmedizin und Notfallmedizin, Band 47, Heft 4, Mai 2010
• Prognoseabschätzung nach therapeutischer Hypothermie; Hasper
et al, Intensivmedizin und Notfallmedizin, Band 48. Heft 3, April 2011
• Prognose nach Herz-Kreislauf-Stillstand – ein Update; Kollmar,
Storm, Intensivmedizin up2date, Heft 1, 11. Jahrgang, Februar 2015
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• Prognosis of coma after therapeutic hypothermia: a prospective co-
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• Prognostic value of right ventricular dysfunction in patients with
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• Prognostic value of the ECG on admission in patients with acute
major pulmonary embolism; Geibel et al, Eur Respir J 2005
• Prognostic value of troponins in acute pulmonary embolism: a meta-
Appendix 1085
 analysis; Becattini et al, Circulation 2007
• Progress in Guillain-Barré syndrome; Hartung et al, Curr Opin 2001
• Prone Positioning in Patients With Acute Respiratory Distress Syn-
drome; Taccone et al, JAMA 2009
• Prone ventilation reduces mortality in patients with acute respiratory
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• Prophylactic antibiotic treatment in patients with predicted severe
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et al, Gastroenterology 2004
• Prophylactic antibiotics cannot reduce infected pancreatic necro-
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• Prophylactic use of an implantable cardioverter-defibrillator after
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• Prophylaxis of infective endocarditis: current tendencies, continuing
controversies; Duval et al, Lancet Infect Dis 2008
• Propofol-associated hypertriglyceridemia and pancreatitis in the in-
tensive care unit: an analysis of frequency and risk factors; Devlin et
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puted tomography, magnetic resonance angiography, and real-time
1086 Appendix
magnetic resonance imaging; Haage et al, Am J Respir Crit Care
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• Resistente Erreger auf der Intensivstation - wohin fährt der Zug?
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• Respiratorische Viren; Hauptmeier et al, Intensivmedizin up2date,
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• Revascularization, stenting, and outcomes of patients with acute
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Appendix 1087
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1088 Appendix
Goyal et al, JAMA 2012
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• Spektrum akuter Vergiftungen in einer Notaufnahme; Testori et al,
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• Spiral computed tomography for acute pulmonary embolism; Scho-
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• Spondylodiszitis; Jung et al, Der Internist, Band 54, Heft 8. August
2013
• Spontaneous bacterial peritonitis; Sheer et al, Dig Dis 2005
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2001
• Spontan bakterielle Peritonitis bei Leberzirrhose; Wasmuth et al, In-
tensivmedizin und Notfallmedizin, Band 47, Heft 8. November 2010
• Spontan bakterielle Peritonitis; Schmid, Wiest, Salzberger, Klebl;
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Heft 7, Oktober 2012
• Spontane intrakranielle Blutung; Sammler et al, Intensivmedizin up-
2date, Heft 2, 2. Jahrgang, Mai 2006
• SSC-Leitlinien 2002 - Surviving Sepsis Campaign: International Gui-
delines for Management of Severe Sepsis and Septic Shock (Dellin-
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• SSC-Leitlinien 2008 - Surviving Sepsis Campaign: International Gui-
delines for Management of Severe Sepsis and Septic Shock (Dellin-
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• SSC-Leitlinien 2012 - Surviving Sepsis Campaign: International Gui-
delines for Management of Severe Sepsis and Septic Shock (Dellin-
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• SSC-Leitlinien 2016 - Surviving Sepsis Campaign: International Gui-
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• Sterben mit / trotz Schrittmachers; Reith, Janssens, Medizinische
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• Stewart and beyond: new models of acid-base balance; Corey, Kid-
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• Störungen der gastrointestinalen Motilität - aktuelle Pharmakothe-
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• Störungen des Natriumhaushalts; Schneider, Intensivmedizin und
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• Störungen des Phosphathaushaltes; Waldegger, Intensivmedizin
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• Strategien in der Intensiv- und Notfallmedizin für Patienten mit
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• Strategien zur Vermeidung von Antibiotikaresistenzen; Kees, Medi-
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• Tachykardien mit breiten QRS-Komplexen; Reithmann, MMW Fort-
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Appendix 1089
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al, J Crit Illn 1989
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• Therapeutische Hypothermie - Aktuelle Einsatzmöglichkeiten und
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• Therapie akuter Intoxikationen; Hofer, Kielstein, Intensivmedizin up-
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• Therapie bradykarder Herzrhythmusstörungen mit passageren
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• Therapie des akuten und chronischen Rechtsherzversagens;
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• Therapie der akuten Herzinsuffizienz – Medikamentöse, interventio-
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• Therapie der akuten Pankreatitis; Mayerle et al, Intensivmedizin up-
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• Therapie der ambulant erworbenen Pneumonie; Welte, Internist,
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• Therapie des nichtinfarktbedingten kardiogenen Schocks; Geppert,
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• Therapie des Vorhofflimmerns; Meinertz, Intensivmedizin up2date,
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• Therapie mit Blutprodukten; Petros, Medizinische Klinik - Intensiv-
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• Therapie schwerer COVID-19-Verläufe in der Intensivmedizin; Wies-
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• Therapieentscheidung bei akuter Subarachnoidalblutung; Forsting,
 Intensivmedizin up2date, Heft 4, 2. Jahrgang, November 2006
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• Thoraxradiologie auf der Intensivstation; Schülke et al, Medizinische
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• Thirty-Year Trends (1975 to 2005) in the Magnitude, Management
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• Thirty years of personal experience in hyperglycemic crises: diabetic
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• Thrombembolien und pulmonale Hypertonie; Drömann, Internist,
Band 50, Heft 9, September 2009
• Thrombolysis compared with heparin for the initial treatment of pul-
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• Thrombolysis during Resuscitation for Out-of-Hospital Cardiac Ar-
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• Thrombolysis in Acute Myocardial Infarction Complicated by Cardio-
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• Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stro-
ke; Hacke et al, N Engl J Med 2008
• Thrombotic microangiopathy, hemolytic uremic syndrome and
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• Thrombolytic therapy for pulmonary embolism. Frequency of intrac-
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• Thrombolytic therapy for pulmonary embolism; Dong et al, Cochrane
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• Thrombolytic therapy in unstable patients with acute pulmonary em-
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• Thrombolytic therapy of pulmonary embolism: a meta-analysis; Tha-
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• Thrombophile Zustände in der Intensivmedizin; Engelmann, Medizi-
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• Thrombotische Mikroangiopathien; Beutel et al, Der Internist, Band
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• Thrombozytenfunktion: Impedanzaggregometrie mit dem Multiplate-
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• Thrombozytenhemmung auf der Intensivstation; Dürschmied, Bode,
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• TIMI, PURSUIT, and GRACE risk scores: sustained prognostic value
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• Toxisches Schock-Syndrom; Schrag, Kleger, www.medicalforum.ch/
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• Tracheotomie in der Intensivmedizin; Byhahn, Intensivmedizin up-
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• Tracheobronchial aspiration of gastric contents in critically ill tube-
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• Transfusion-related acute lung injury: definition and review; Toy et
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• Transfusionstrategien: leitliniengerechte Diagnostik und Therapie;
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Appendix 1091
 et al, Gut 2005
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• Unfractioned heparin for treatment of sepsis - a randomized clinical
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• Use of self-expanding vascular endoprostheses in superior vena
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• Use of surgery in patients with native valve infective endocarditis:
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• Use of Transesophageal Echocardiography to Guide Cardioversion
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1092 Appendix
2012
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Heft 1, 5. Jahrgang, Februar 2009
• Venous air embolism from central venous catheterization: a need for
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• Ventilation with lower tidal volumes as compared with traditional tidal
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• Ventilatory care in myasthenia gravis crisis: assessing the baseline
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• Verbrauchskoagulopathie - disseminierte intravasale Gerinnung;
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• Vergiftungen mit psychotropen Substanzen; Bellmann, Joannidis,
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112, Heft 6, September 2017
• Vermeidbare Fehler bei der Intubation; Sopka et al, Medizinische
Klinik - Intensivmedizin und Notfallmedizin, Band 107, Heft 7, Ok-
tober 2012
• Vermeidbare Todesfälle nach Trauma; Buschmann, Tsokos, Kleber,
Notfall + Rettungsmedizin, Band 18. Heft 4, Juni 2015
• Versagen der Atempumpe - Klinik, Diagnostik und Therapie; Pfeifer,
Internist, Band 53, Heft 5, Mai 2012
• Versorgung verletzter schwangerer Patientinnen; Martiny et al, Not-
fall + Rettungsmedizin, Band 17, Heft 4, Juni 2014
• Virale Enzephalitis/Meningitis; Menon et al, Intensivmedizin up-
2date, Heft 2, 4. Jahrgang, Mai 2008
• Vocal cord dysfunction - Eine wichtige Differenzialdiagnose zum
Asthma bronchiale; Kenn, Hess, Dtsch Arztebl 2008; 105 (41): 699;
DOI: 10.3238/arztebl.2008.0699
• Volatile agents for ICU sedation? Bracco et al, Intensive Care Med
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• Volumenersatztherapie - Pharmakotherapie; Eichhorn et al, Inten-
sivmedizin up2date, Heft 1, 2. Jahrgang, Februar 2006
• Volumenersatztherapie - Ziele; Reuter et al, Intensivmedizin up-
2date, Heft 1, 2. Jahrgang, Februar 2006
• Volumenubstitution mit NaCl 0,9%. Segel oder Fluch? Kümpers, Der
Internist, Band 56, Heft 7, Juli 2015
• Volumentherapeutische Möglichkeiten bei kritisch kranken Patien-
ten; Wiedermann, Medizinische Klinik - Intensivmedizin und Notfall-
medizin, Band 106, Heft 1, September 2011
• Vom Badezimmer in die Druckkammer – erfolgreiche HBO-Therapie
bei schwerer Kohlenmonoxidintoxikation eines Kleinkindes; Wagner
et al, Notfall + Rettungsmedizin, Band 16, Heft 5, August 2013
• Vorhofflimmern auf der Intensivstation; Heinz, Medizinische Klinik -
Intensivmedizin und Notfallmedizin, Band 108. Heft 7, Oktober 2013
• Vorhofflimmern - Strategien für die Intensiv- und Notfallmedizin;
Trappe, Intensivmedizin und Notfallmedizin, Band 46, Heft 2, März
2009
• Wann Sie die Schweigepflicht brechen dürfen; Penning, MMW Fort-
schritte der Medizin, 14/158. 2016
• Was muß der Intensivmediziner über den implantierbaren Kardiover-
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 dizin und Notfallmedizin, Band 108. Heft 7, Oktober 2013 15. ERBE Elektromedizin GmbH
• Weaning from mechanical ventilation; Alia et al, Crit Care 2000 16. FRC Medizintechnik
• Weaning from mechanical ventilation. In: Principles and Practice of 17. Fresenius Medical Care D-GmbH
Mechanical Ventilation, Jubran A, Tobin MJ (Eds), McGraw Hill, New 18. Gambro Hospal GmbH
York 2006 19. Glaxo Smith Kline
20. Karl Storz GmbH & CoKG
• Weaning from mechanical ventilation (TASK-FORCE); Boles et al,
21. KCI
ERJ 2007
22. LMA Deutschland GmbH
• Weaning from tracheotomy in long-term mechanically ventilated 23. Maquet GmbH & CoKG
patients: feasibility of a decisional flowchart and clinical outcome; 24. Medisize Deutschland GmbH
Ceriana et al, Intensive Care Med 2003 25. Novalung GmbH
• Welcher Patient profitiert im Operationssaal vom erweiterten hämo- 26. Olympus Deutschland GmbH
dynamischen Monitoring? Wiesenack, Intensivmedizin und Notfall- 27. Pentax Europe GmbH LIFE CARE
medizin, Band 47, Heft 5, Juni 2010 28. PfalzMed Notfallmedizinisches Equipment
• Wernicke's encephalopathy - prevalence and clinical spectrum; Tor- 29. Pfizer Pharma GmbH
vik, Alcohol Alcohol Suppl 1991 30. Pulsion Medical Systems AG
• WHO guidelines for the treatment of malaria - World Health Orga- 31. Sensor Medics
nization 2006 32. Smith Medical Deutschland GmbH
• Wide QRS complex tachycardias; Gupta et al, Med Clin North Am 33. VMB Medizintechnik GmbH
2001 34. Zoll Medical Deutschland GmbH
35. LiDCO Ltd
• Wide-complex tachycardia: continued evaluation of diagnostic crite-
36. LEA Medizintechnik
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37. BARD GmbH
• Wieviel Ernährung braucht der Intensivpatient? Weimann et al, In- 38. Sequana Medical
tensivmedizin und Notfallmedizin, Band 44, Heft 1, Februar 2007 39. Ovesco Endoscopy AG
• Wie viel Hb braucht der Intensivpatient? Neumann et al, Intensivme- 40. Pulmonx
dizin up2date, Heft 4, 11. Jahrgang, November 2015 41. Roche - Verum Diagnostica GmbH
• Work of breathing as a weaning parameter in mechanically ventila- 42. Alexion
ted patients; Levy et al, Chest 1995 43. Fisher & Paykel Healthcare GmbH & Co. KG
• Workshop und Skript Säure-Basen-Haushalt, 47. Gemeinsame Jah- 44. Abbott
restagung der Deutschen Gesellschaft für Internistische Intensivme- 45. Sanofi-Aventis
dizin und Notfallmedizin (DGIIN) Köln, 19. Juni, Dr. med. Carsten
Hafer, Helios Klinikum Erfurt, Medizinische Klinik II, Abteilung Ne-
phrologie
• Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task
Picture directory
Force for the Universal Definition of Myocardial Infarction; Thygesen
et al, Eur Heart J 2012
(source: Fotolia)
• Zeitschrift "Der Internist", Springer-Verlag, Jahrgänge 2003-2015
• Zeitschrift "Intensivmedizin und Notfallmedizin", Springer-Verlag,
Absinth mit brennendem Würfelzucker © Marian Schrader
Jahrgänge 2006-2015
A medical team performing an operation © Astoria
• Zeitschrift "Intensivmedizin up2date", Thieme-Verlag, Jahrgänge Achtung – Spannung © Dark Vectorangel
2006-2015 Achtung © Peter
• Zeitschrift "Intensiv-News", Medicom-Verlag, Jahrgänge 2006-2015 Achtung gelb / attention yellow © mercury
• Zentraler Venendruck: Validität, Aussagekraft und korrekte Mes- actual work of the equipment in the hospital © sudok1
sung; Schummer, Anästhesist 2009 Agaricus xanthoderma / Psalliota xanthoderma / Agaric jaunissant ©
• Zerebrale Sinusvenenthrombosen - klinische Symptomatik, Diagno- Pixaterra
stik und Therapie; Mashur, Cardiovasc Oktober 2014 Alcoholic liver harm disease. Fatty liver fibrosis hepatitis cirrhosis of al-
• Zielgerichtete Behandlung akuter Hämostasestörungen mit Hilfe der cohol harm vector illustration. Lifestyle problem unhealthy alcohol harm
ROTEM-Analyse; Calatzis, Spannagl, Vorweg; Leitfaden 2005 can cause liver damage social cartoon concept © stockvectorsstoker
Alveolus © 7activestudio
• Zitratantikoagulation in der akuten Nierenersatztherapie – Methode
Alveolus. gas exchange © designua
der Wahl; Frank et al, Medizinische Klinik – Intensivmedizin und Not-
Allium ursinum- Bärlauch © by-studio
fallmedizin, Band 109, Heft 5, Juni 2014
Amanita verna © cehermosilla
An asthma-inflamed bronchial tube © blueringmedia
Anatomie der Hirnhaut, Meningen © bilderzwerg

Picture directory
anfeuern © Yantra
Anthracene molecular structure on white background © ollaweila
Apoplectic And Epileptic Stroke © style-photography.de
(source: Companies) Arterien des Herzens © lom123
arterie mit fließendem blut © Sebastian Kaulitzki
Aspergilloma of the brain, 3D illustration. Also known as mycetoma,
or fungus ball, an intracranial lesion produced by fungi Aspergillus in
Courtesy of the following companies: immunocompromised patients © Kateryna_Kon
ASR © DeVIce
1. AAT Alber Antiebstechnik GmbH Asthma Treatment © Sherry Young
2. Abviser atherosclerosis plaque front and side view illustration © bilderzwerg
3. AGA Medical Deutschland GmbH A to Z Button © Marima
4. Ambu Aufpassen: Baby will mit Putzmittel spielen © Heiko Barth
5. Atritech bacteria © Irochka
6. Baxter Deutschland GmbH Bacteria © Mardre
7. Biotronik Bacteria © zentilia
8. B. Braun Melsungen AG Bad Smiley © Instantly
9. CareFusion Germany GmbH Berlin skyline in watercolor © paulrommer
10. Cook Medical blind justice © ioannis kounadeas
11. Covidien Deutschland GmbH blind worm © PRILL Mediendesign
12. Venner Medical Deutschland GmbH blood cells © V. Yakobchuk
13. Humedics GmbH Berlin Blood cells in the brain flowing through veins © freshidea
14. Edwards Lifesciences Germany GmbH Blood clot © Luk Cox

Appendix 1093
blood pressure cuff and gauge © Leah-Anne Thompson Glossy Pictogram "Anesthesia" © Ben Chams
Blue eye on White Background © Serj Siz`kov Glucose Metabolism © 7activestudio
Blue Oxygen symbol © Boris Roz Goldregen - Laburnum © M. Schuppich
Blutblättriger Hautkopf © Frank Waßerführer Grüner Knollenblätterpilz © Visions-AD
Blutkonserven von Spenderblut im Blutlabor © Gina Sanders Gyromitra esculenta © Maslov Dmitry
Bluttropfen EKG © Schlegelfotos Handicap sign © iofoto
Boîtes de conserve © Richard Villalon Hand lights a kerosene lamp on dark grey background © Africa Studio
Book - vector icon © lovemask hausapotheke © Pixel
Brain © V. Yakobchuk hazardous operation © Andrey Kiselev
Brausetabletten © PhotoSG head housing a globe © Christos Georghiou
British flag © daboost heart rate monitor in hospital © fivepointsix
Bronchiole mit Alveolen © psdesign1 hemoglobin molecule © designua
Bronchus © arsdigital.de hemorrhagic stroke. insult. rupture of the vessel © Artemida-psy
Breathing cycle, in and out © Alila Medical Media Herbstzeitlose (Colchicum autumnale) © Christian Pedant
Bunte, farbenfrohe Medikamente - Tabletten, Pillen, Kapseln - Textfrei- Herpes Virus - 3d Render © fotoliaxrender
raum - happy pills © marog-pixcells Herz Isoliert EKG © Schlegelfotos
Bunte Mischung aus vielen verschiedenen Sorten von Obst © unpict Herz © rdnzl
Button Info #1 © posterdeluxe Herzinfarkt © Sebastian Kaulitzki
button notruf © LaCatrina Herzschrittmacher Closeup © psdesign1
calculator © ioannis kounadeas high voltage © swa182
Calculator © Style Media & Design hilfe button © fotoflash
Cancer © kentoh hitze thermometer II © WoGi
Cell structure © Andrea Danti Hospital Supergug Signs © Devonsun
Chemical structure of propane © lculig Human biological digestive / digestion system flat color diagram for me-
chemielabor © Schlierner dical apps and websites © martialred
Chloroform © cuhle-fotos Human hair structure anatomy illustration. Vector © emaria
Clitocybe Nebularis – Clouded Clitocybe edible forest fungus © Spring- human heart, Heart model, Human heart model, Full clipping path in-
field Gallery cluded, Human heart for medical study, Human Heart Anatomy, heart
Close up 3d render of an influenza-like virus isolated on white © sitox side view © ugreen
CMYK Lettern © Tim Friedrich Human heart © hywards
coeur poumons © E Human Kidneys © London_England
Cooperation,partner,team © Jane Human Mind © Tonis Pan
CO2 © psdesign1 Human oxyhemoglobin on white © lculig
Cute Chameleon Vector Illustration © Christos Georghiou ICU cardiac monitor © beerkoff
Cyclohexane chemical solvent molecule © molekuul.be ICU with ECG monitor © beerkoff
Delirium in mind © alexskopje illustration - muscle man © eblue
Dengue disease - drop of blood with mosquito © Helder Sousa Info Box Blue © Tristan3D
Der Mars © Michael Rosskothen information button © fotoflash
Dipl. Ing. Simone Rößling © Sagittaria Intensive Care sign © nmcandre
dna 1 © Spectral-Design intensive care unit monitor © beerkoff
Docteur © julien tromeur Interdit de fumer © Nimbus
dont do it! © ioannis kounadeas In the middle of medical equipment. Blood oxygenator (ECMO) in t ©
Dried seeds of fragrant nutmeg and grated nutmeg isolated on white sudok1
background © arielle58 Intoxication alimentaire – Restauration © mimon
Drip © krishnacreations Intubation © Stephan Morrosch
drowned doll in the pool © Photo Tuller isolierter influenza virus © Sebastian Kaulitzki
Drowning Hand © Danomyte Jede Minute zählt © fotokalle
Eberesche © M. Schuppich Jüdischer Friedhof Heiliger Sand, Worms, Rheinland-Pfalz, D © STIMA
E.coli - Escherichia coli © decade3d Kirschlorbeer_5326 © Omika
EHEC / Enterohämorrhagische Escherichia coli in Petrischale © Atelier kokain © photographer2222
W. Kokain © zylox
Eisenhut Blauer © emer kopfschmerz / migräneanfall / schlaganfall © Sebastian Kaulitzki © kts-
EKG, Herz, Kardiogramm © sashpictures design
Electrocautery Device © Sherry Yates K.o.-Tropfen © Gerhard Seybert
Emperor penguins © kotomiti Kreuzotter © Hansderzweite
Engelstrompeten © VRD Kugelfisch © Li-Bro
erste hilfe © michanolimit Kundeninformation © Aamon
Erste Hilfe bei Stromschlag © Henrie kurz nach 12 © Falko Matte
erste hilfe bei verletzungen © yvart Lebensgefahr © Denis Junker
Fehltritt © Jan Schumann leber mit krebs © Sebastian Kaulitzki
Feuerwehrmänner an einer Unfallstelle © benjaminnolte Lecture © ioannis kounadeas
feuerwehrmänner mit atemschutz bei feuer © Gerhard Seybert Legionellen - 3D Render © fotoliaxrender
Fingerhut © Hans-Jürgen Lange Leopard portrait © byrdyak
flag of France © moZz Lifeboy and help concept © Sebastian Duda
fliegenpilz © Ideen Lily © Zbyszek Nowak
four emoticons © AlienCat Luftverschmutzung © Christian Pedant
fragezeichen frage button © Daniel Fleck Lucky Smiley © Instantly
Fünf vor Zwölf © Bernd_Leitner lunge mit bronchien © Sebastian Kaulitzki
Fungi Aspergillus, Aspergillus fumigatus, Aspergillus niger, black mold, Lungenflügel in der Vorderansicht © Sagittaria
which produce aflatoxins, cause pulmonary infection aspergillosis. 3D lungeninfektion © Sebastian Kaulitzki
illustration © Kateryna_Kon lungenkrebs © Sebastian Kaulitzki
Gas exchange in lungs illustration © extender_01 Mahonien © M. Schuppich
Gefahrstoffe © Andreas F. malaria © kotoyamagami
Gelber Knollenblätterpilz © style-photography.de Male Cheetah (Acinonyx jubatus), South Africa © stuporter
Gemeiner Stechapfel - Datura stramonium © Daorson Manometer © Hubert Körner
Gerechtigkeit © GaToR-GFX mechanical engineer © reji
Giftpflanzen © PhotoSG medical devices, drip infusion sets, and other equipment in oper © su-
Giftschirmling im Wald © vitala1985 dok1
Glasmurmeln © remar medically accurate illustration of the brain sections © Sebastian Kau-

1094 Appendix
litzki Schierlingsblueten © emer
Medikamente, Gesundheit und Geld © Sven Bähren schild schnecke © scusi
Medizinische Fußpflege - Foot care - Chiropody © thomasklee schild rutschgefahr © LaCatrina
mehrere Buschbohnen im Hochformat © josef grimschitz Schild 966 © ufotopixl10
menschliche leber © Sebastian Kaulitzki Schweinegrippe Symbol © openwater
menschliche lungen © Sebastian Kaulitzki Science // Rainbow Series © Palsur
menschlicher darm © Sebastian Kaulitzki Seringue © julien tromeur
menschlicher kehlkopf © Sebastian Kaulitzki sleep under sun © ioannis kounadeas
menschliches herz © Sebastian Kaulitzki smiley daumen runter © Andreas Meyer
Mercury pouring from a pipette © marcel smiley punk 1 © Jeffrey Collingwood
messband © Anne Katrin Figge Smilie © Sossi
metabolism of vitamin D © designua Sortiment von Gefahrenzeichen © Abe Mossop
Miesmuschelschalen vor weissem Hintergrund © cmnaumann spinal chord © Stephen Sweet
Model of the human kidney isolated on white © Andreas Odersky spurensucher © kaipity
Mouvement hippie © chandelle Stahlrohre © beermedia
Multicolored Chemistry vials - Focus on hazardous to the environment stairs in sky © Lilya
danger © antoine2k Stent angioplasty procedure with placing a balloon © hywards
Mundgeruch - 3D Render © fotoliaxrender Stockschwämmchen (Kuehneromyces mutabilis) © arolina66
muscle man clipping mask © Peter Galbraith Stockschwämmchen - Kuehneromyces mutabilis © Distrikt3
Mutterkornpilz; Claviceps purpurea © emer stomach © Artur Steinhagen
Myelin deterioration © blueringmedia Stomach internal lining and ulcer, colorful drawing © reineg
Nerve Cell. 3D. Neurons © BillionPhotos.com Stop mosquito cartoon © irwanjos
nerve cells concept for tumors,brain surgery © ralwel stop sign © Mograph
Neu rot © DeVIce Streptokokken - 3d Render © fotoliaxrender
Neurons © ktsdesign superbug bacteria or Staphylococcus aureus (MRSA) bacteria © royal-
Neu-Stern © Cmon tystockphoto
Niere © arsdigital.de Superheros © julien tromeur
No Salt Sign © BasheeraDesigns Sun and moon © olga_igorevna
Nutrition © JJAVA Swiss Flag Badge - Flag of Switzerland Button Isolated on White ©
Obésité et stress © julien tromeur Fredex
off balance © Felix Pergande symbol giftig © WoGi
Oleander typical mediterranean bush on Isle of Corfu Greece © Synapsenfunktion © xtaska
quasarphotos syringe © ioannis kounadeas
operation © Gina Sanders taste hilfe © Catrina
Organspendeausweis wird präsentiert © fovito Termin Uhr © JENS
Organspende in Kühlbox © Dan Race test-tubes © tom
Oxygen Cylinder © krishnacreations Thallium form Periodic Table of Elements © www.fzd.it
Pancreas © krishnacreations Thermometer glossy icon © castelberry
Pantherpilz (chinesische Schrift) © shima-risu Thermometer © ktsdesign
Paracelsus, Drawing Bocourt, after a painting of the Naney Museu © The circulatory system © elenabsl
Morphart The Satan's bolete (Rubroboletus satanas) one of the most danger ©
Paragraph - Justice © Daniel Fleck juancarlos196
Paragraph - Richterhammer © arahan Thinking man and question mark. 3d rendered illustration.© skvoor
Parasolpilz, Macrolepiota, procera © emer three medicated inhalers againsta white background © Gethin
Parkinson's disease symbol isolated on white © paradox Three train with powered locomotive, cisterns oil, coal freight © Mad-
Passed Out on Giant Pill © Scott Maxwell Dog
Patientenverfügung © Dan Race Thromboembol in blood vessel. Clot formation. Red blood cells and
patient with mask ventilation © beerkoff white blood cells © Kateryna_Kon
Persona sagoma depressione insnnia farmaci pilloe © Naeblys thumbs up © nightfly84
Pfaffenhütchen, Euonymus europaeus © hjschneider Tollkirsche; Atropa Bella-donna © emer
Pharmacy.Vector interface element © Vladyslav Makarov totenkopf © pdesign
Pillen © fotokalle totenkopf © WoGi
Pilules © julien tromeur Totenkopf-Schild © Dark Vectorangel
Pistol bullets © Scanrail Tracheostomy Labeled Diagram © joshya
Pflaumen ,frisch und getrocknet © Printemps Treffer © TM – Design
Pneumonia. Illustration shows normal and infected alveoli. © designua Tricholoma equestre mushroom isolated on white © aragami
Pneumothorax - Collapsed Lung © decade3d Tropfensammlung © Visions-AD
poison chimie © Danielle Bonardelle vascular system © Roman Dekan
Poisonous mushrooms grow in wood, Coprinus Atramentarius © Be- vasculäres system © Sebastian Kaulitzki
layaMedvedica Vector: Happy blue smiley face © JohanSwanepoel
pouring creamy milk in a transparent glass © dip Vector. Old scroll, manuscript © Vangelis76
Pregnancy © Scott Maxwell Verbraucht © djama
psilocybe semilanceata © yellowj versorgungsanschlüsse © Thomas Aumann
Pulmonary embolism, eps10 © Alila VeSilvio - Fotolia.com
Pump jack oil crane thin line icon © VIGE.co Viren in der Blutbahn © Spectral-Design
pumpkin on table © neirfy Virus © julien tromeur
read it © ioannis kounadeas Virusnahaufnahme © Sebastian Kaulitzki
reagenzgläser auf formel © Schlierner Vitamins © Tenica Florin
Realistic illustration of healthy and sick human livers © eranicle Warnschild: Alkoholmissbrauch © checker
red blood cells,activated platelet and white blood cells microscopic Warnschild Warnzeichen Stromschlaggefahr Stromunfall © T. Michel
photos © royaltystockphoto wecker © fotoman_65
red steam locomotive with tank wagon © mirrra Wegweiser © Phoenixpix
Respiration or Breathing © designua white columns in blue background of sky © Stasys Eidiejus
Riesenbärenklau und Maßstab © Heinz Waldukat Wiesenchampignon, Champignon, Wiesen, Agaricus © emer
Ringelnatter im Wasser © sommersprossen Wiesenkümmel © ernstboese
Risk © JJAVA Wirtschaftskrise © Julian Weber
Rhododendron ponticum © Richard Griffin wso206 WarnSchildOrange - Biogefährdung durch Cucurbitacine -
ruler © ioannis kounadeas g3896 © fotohansel
Salzstreuer mit Metalldeckel und Salz © rsester wso282 WarnSchildOrange - german - warnzeichen: Kohlenmonoxid /

Appendix 1095
Schädel - Totenkopf - english - warning sign / carbon monoxide / skull
and bones - xxl g4989 © fotohansel
Wunderbaum - castor oil plant 15 © LianeM
yes! © ioannis kounadeas
Yew tree berries © Bogdan Wankowicz
Young zucchini © Dionisvera
zdrowie medycyna badania zestaw ikon szary monochrom © demo-
nique
3d colorfull folders, on white background © DigitalGenetics
3d doctor © ioannis kounadeas
3d human at a stop pose © ioannis kounadeas
3d human read his news paper © ioannis kounadeas
3d human try to turn the page © ioannis kounadeas
3d illustration of fungi Candida albicans which cause candidiasis,
thrush, on colorful background. Pathological fungus or yeast. Health-
care background © Kateryna_Kon
3d Kugeln / Ball / Balls © Huna
3d little guy with red boxing gloves in hands © ioannis kounadeas
3d Man point at Book © Spencer
3d Man reading master © Spencer
3d Man with exclamation mark © Spencer
3d rendered depiction of Stem Cells and a human figure © Elena Pan-
kova
3d Rendering Angry Character Emoji saying OMG with Colorful Spee
© xtock
3d Smiley © Andreas Meyer
3d tablets on white background © microcosm
3d viren © Sebastian Kaulitzki
3d white peaople. Good morning. Wake up © Texelart
Picture directory
(source: ADOBE STOCK)
3D illustration of hantavirus virus (Bunyaviridae) © Ahmet Aglamaz (ID
332685765)
Acute promyelocytic leukemia cells or APL, analyze by microscope,
original magnification 1000x © jarun011 (ID 302027882)
Adrenal glands vector illustration. Labeled scheme with hormones
types © VectorMine (ID 231011346)
antibiotics © greenapple78 (ID 95776931)
Artery Dissection © 7activestudio (ID 121920816)
Aortic dissection © designua (ID 316866175)
Asian lady woman patient have abnormal enlargement of thyroid
gland Hyperthyroidism (overactive thyroid) at the throat © amazing
studio (ID 227495311)
strong medical
Atrial Fibrillation © freshidea (ID 199955974)
Bacteria Neisseria gonorrhoeae, gonoccoccus, diplococci which cau-
se sexually transmitted infection gonorrhoea. 3D illustration © Katery
na_Kon (160900079)
Calcium Ca chemical element. 3D rendering © alexlmx (ID
193195436)
checkpoint charlie - Thomas Röske (ID 982447)
Collection of colorful pills © Leigh Prather (ID 87693883)
container with helium and balloons 3d © Alexey Achepovsky (ID
196390250)
Coronavirus COVID-19 Microbiology And Virology Concept Panoramic
Image © Feydzhet Shabanov (ID 332552151)
Corona Virus banner illustration - Microbiology And Virology Concept ©
Mike Fouque (ID 329115246)
Danger Cyanide Symbol Sign, Vector Illustration, Isolate On White
Background Label (ID 266182664)
Diagram showing inside of human heart © GraphicsRF (ID 118589400)
Digital illustration of pancreas © nicolasprimola (ID 221941854)
EKG © Spectral-Design (ID 62566660)
Glasflasche mit Aufschrift: Strychnin © monropic (ID136352636)
Golden Gate bridge, San Francisco California © Mariusz Blach (ID
197649489)
Heart muscle proteins and philament structure. Myosin, actin and titin
illustration © alkov (ID 188129658)
Human anatomy xray view of respiratory system, showing lungs and
outline of body on plain white background © Anatomy Insider (ID
103102098)
human heart © abhijith3747 (ID 61017946)
1096 Appendix
Human thyroid anatomy. 3d illustration © Rasi (ID 303529781)
Image of a little boy’s body suffering severe urticaria, nettle rash ©
uwimages (ID 126521442)
Infographic Depicting the External and Internal Coronavirus Structure,
Vector Illustration © Penwin (ID 319329940)
Kissing bug chagas disease vector triatomine; human health emerging
zoonotic disease © David (ID 170661597)
Large Intestine © freshidea (ID 158235649)
Leonardo da Vinci - Proportionsschema der menschlichen Gestalt
nach Vitruv © euthymia (ID 89097295)
limone und halbe neben milchshake auf weissem hintergrund © Rob
Stark (ID 34946529)
Magensonde legen © Martha Kosthorst (ID 48870954)
Magnesium Mg chemical element. 3D rendering © alexlmx (ID
193196330)
Measles, vintage engraving © Morphart (ID 125655166)
menschlicher darm © Sebastian Kaulitzki (ID 3856116)
metal bulb and balloons for laughing gas, party drugs, on grass field
© Corinne (ID 257836546)
Minimally invasive cardiology transcatheter closure treatment for
patent foramen ovale PFO defects with occluder © Damian (ID
192016346)
Pheochromocytoma (PH or PCC). Adrenal Gland Tumor © sakurra (ID
352930148)
Phosphate, molecular model © molekuul.be (ID 50512831)
Pneumocystis jirovecii, opportunistic fungus which causes pneumonia
in patients with HIV, 3D illustration © Kateryna_Kon (ID 108361008)
Potassium Ion Channel - active © scienceDISPLAY (ID 42940585)
Potassium K chemical element. 3D rendering © alexlmx (ID
193196797)
Red and white pills capsule with antibiotic © gamjai (ID 175214268)
Sodium Na chemical element. 3D rendering © alexlmx (ID
193197100)
sternum icon vector sign symbol © Best Icons (ID 307813865)
stop © Rui Vale de Sousa (ID 3086935)
Tail of a rabbit © serikbaib (ID 166232925)
Tetanus word cloud © ibreastock (ID 144660140)
The life cycle of Malaria parasite © designua (ID)
Troponin - Doctor in smock holds stethoscope © MQ-Illustrations (ID
333267235)
Trypanosoma cruzi parasite 3D illustration © Kateryna_Kon (ID
253146711)
Tuberculosis (TB) © 7activestudio (ID 121921635)
Vaccination against Corona Virus SARS-CoV-2 / Covid-19: A glass
with 10 doses of vaccination and a syringe in front of it. The word
vaccination in English, Spanish, French and German on the label ©
Andreas Prott (ID 385384920)
Vector illustration about dysphagia and compered it in scheme. Close-
up human with nasal cavity, mouth, tongue, epiglottis, larynx, food,
trachea and esophagus © VectorMine (ID 211652869)
Vena arteria rottura taglio emorragia sangue © Naeblys (ID 62102180)
Verkehrsunfall - Rettungskräfte befreien eingeklemmte Person ©
benjaminnolte (ID 55900128)
Virus mit Antikörper - 3d Render © fotoliaxrender (ID 56010650)
3d render of abstract organic mold structure © Alexey Brin (ID
100151424)
Appendix 1097