Sepsis

Acute Respiratory Distress Syndrome

-ARDS

Prof. Dr. Lale Karabıyık - 2020

Gazi University Medicine Faculty

Department of Anesthesiology and Reanimation
Division of Critical Care
•  There is an infection

•  Infection causes immunosuppression

•  Results are life-threatening

•  Early diagnose increases survival chance

 Sepsis
Incidence
•  There is an increase over the past decade
–  Increase in elderly popullation
–  immunosupression
–  Multiple drug resistance

The disease causing N.İ. Taken into intensive care unit

Problem of 30 million patients annually
50 people die every hour...
Sources of Sepsis
•  Lungs
•  Blood stream (lack of another source)
•  Abdomen
•  Urinary system
•  Soft tissues
DEFINITIONS of SEPSIS

•  In 1991: Sepsis-1
•  In 2001: Sepsis-2
•  In 2016: Sepsis-3
SEPSIS-1
Classical Findings

•  Fever
•  Hypothermia
•  Leukocytosis
•  Leukopenia
•  Tachycardia
•  Hypotension
 SEPSIS - 2
Infection + 2≥ SIRS Criteria = Sepsis
Sepsis + Organ dysfunction = Severe sepsis
Severe sepsis + Persisting Hypotension Despite Adequate Fluid
Resuscitation= Septic shock

SIRS Criteria:
Body temperature> 38 C or < 36 °C
Heart rate > 90/dk
Respiratory rate>20/dk, PaCO2 < 32 mmHg
Wbc > 12 000 or < 4 000 or
%10>Immature forms in peripheral blood smear
SIRS criteria were removed from the definition
•  Infection or clinical findings of infection may exist
even though absence of SIRS criteria
•  SIRS criteria may be existed despite the absence
of sepsis
•  Fever and tachycardia doesn’t always mean to be
a response to infection.
 SEPSIS - 3 (2016)
•  Host response to infection has a key role
•  Various maladaptive responses
•  Sepsis ≠ Infection + 2≥ SIRS criteria
•  Sepsis is “BAD” infection

‘’Life-threatening organ dysfunction due to

disorganised host response to infection’’

Definition of “Severe sepsis” was excluded

 Clinical Criteria of Septic Shock

Sepsis + Despite Adequate Fluid Resuscitation

•  Persisting Hypotension

•  Mean arterial pressure<65 mmHg or/and need for inotropic

agents

•  Elevated Lactate Levels

Greater than or equal to 2 mmol/l

 Definition of Organ Dysfunction
6 systems are
evaluated
Neurological
SOFA score ≥ 2
Respiratory
Cardiovascular Sequential Organ Failure Assessment
Hepatic
Coagulation Sepsis-related Organ Failure Assessment
Renal
Bedside Quick SOFA (qSOFA)
Numerous laboratory parameters are necessary for
calculating SOFA score. Thus, qSOFA may be suggested.

3 clinical criteria to predict “Bad patient’’?

1. Mental state alteration
GKS less than or equal to13
2. Tachypnea
Respiratory rate greater than or equal to22/min.
3. Hypotension
Systolic blood pressure less than or equal to 100 mmHg
 2016
SUSPECTED /DOCUMANTED INFECTION
SEPSIS +
qSOFA 2 or 3:
Hypotension
Alteration in mental status
Tachypnea
or
Elevation in SOFA score more than or equal
to 2

SEPSIS
SEPTIC +
SHOCK Need for vasopressors to keep MAP>65
mmHg
LACTATE≥2 mmol/L
Risk factors for Sepsis
•  ICU patients
•  Bacteremia
•  Elderly popullation( ≥65 yrs)
•  Immunosupression
•  DM
•  Malignancies
•  Community - acquired pneumonia
•  Hospital inpatients
•  Genetic factors
Hemodynamic monitorization

•  Aim: Providing adequate tissue perfusion

and preventing MODS
•  Reduces mortality in septic shock
–  Hemodynamic instability results tissue hypoxia
resulting altered organ microcirculation and reduced
tissue perfusion

–  MODS is the most common cause of death

Evaluation of global and regional
perfusion

Start-up
1.  Clinical evaluation
2.  Basic monitorization of global perfusion
3.  Preload monitorization and fluid response

Advanced Monitorization
1.  Cardiac output
2.  Cardiac contractility
3.  Evaluation of tissue perfusion
 Clinical evaluation

Hypoperfusion Inadequate global Septic shock

•  Thirst perfusion early stage
•  Cold extremities •  Tachypnea •  Skin is red, warm
•  Weak peripheral •  Tachycardia and
pulses •  Confusion vasodilatated
•  Disregulation in •  Alteration in skin
capillary refill perfusion •  Next stage:
time •  Oliguria extremities are
cold and
hypoperfused
 Clinical evaluation

Inadequate Dysregulation in Inadequate renal

cerebral myocardial perfusion
perfusion oxygen demand •  Oliguria
•  Awake and supply
•  Talkative •  Patient
complaining about
ischemic chest
pain

Spotting
Predictive for mortality in septic shock
Basic monitorization of global perfusion

•  EKG

•  Arterial blood pressure

•  Pulse oximetre (SpO2)

•  Serum lactate level

•  Biochemical variables
 Response to fluid rescucitation

Static measurements Dynamic measurements

•  Central vein pressure •  Fluid challenge
•  Pulmonary capillary •  Arterial waveform
wedge pressure alteration
•  Left ventricule end
diastolic area
 Passive Leg Raising
•  Semi-recumbent patient is taken to recumbent
position and lag raised
•  If 300-400 mL of venous blood returns back to
heart end elevates cardiac output, this shows
patient is fluid responsive
 Monitorization of microcirculation
Indirect Methods Direct Methods

Measuring Tissue Evaluating tissue

oxygenization microcirculation
•  Gastric tonometry •  Clinical examination
•  Sublingual capnometry –  Capillary refill time
–  Mottling
•  Tissue oxygenization
–  Heat alteration from central
electrodes
to periphere
•  Near-infrared •  Videomicroscopy
spectroscopy
Sepsis-bacteremia

•  May not show-up simultaneously with microbiological

findings
•  Waiting for microbiological findings may cause a
serious time loss
•  There is no microbiological finding in many clinical
infections
•  Recently, “microbiological evidence is not necessary
for diagnosing sepsis ”
 C-Reactive Protein -CRP
•  Leading acute phase protein synthesised from the liver
by IL-6, IL-1 ve TNF-alfa stimulation.
•  Synthesised 4-6 hours after stimulation and peak level
is about 36-50 hours.
•  CRP elevations depending on single stimuli like
trauma and surgical interventions return to normal
levels following days.
•  Diagnostic sensitivity %68-98.5, specifity %40-78
•  Single measurement is not reliable for diagnosing
sepsis and predicting prognosis

Isn’t preferred as a sepsis diagnostic test

Procalsitonin -PCT
•  Calcitonin polypeptide secreted from Tiroid C cells
•  Normal plasma level is 5-50 pg/mL
•  Secreted from mononuclear cells with Bacterial
lipopolisaccharide stimuli and secreted from
liver with TNF-alfa and IL-6 stimuli
•  Elevated 3-4 hrs and peaks 6 hrs after stimulation
Half-life: 25-30 hrs
Prokalsitonin -PCT
•  Viral infections, fungal infections, inflammatory
conditions local bacterial infections→ mild elevation
•  Systemic bacterial infection → severe elevation
•  PCT sensitivity %65-97, specivity %48-94
•  PCT >11.6 ng/mL → septic shock
•  More successful than CRP measurements for
diagnosing bacterial infections.
Source Identification
• Systemic Evaluation
• Surgical and other wounds(decubitis)
• Catheter insertion sites
• Extremities
• Flebitis
• Selulitis
• Sinuzitis
• Candida infection, focal chorioretinitis, vitritis
• Diarrea and clostridium difficile
• Purulent urinary infection
• CT, MR, EKO…
Taking Cultures
•  At least two blood culture and one culture from each
possible sources of infection should be taken
–  Should be done before beginning antimicrobial therapy
–  femoral or problematic area shouldn’t be preferred
–  Iodine antiseptic solution should be dried 30-60 seconds
before the application
–  Sterile gloves should be used for palpating veins

•  Searching for the microbial agent from blood

sample using direct PCR methods is faster than
culture (4 hrs)
Sepsis treatment-
Multidiciplinary approach

•  Steps of early diagnose and resuscitation should be

initiated immediately.

•  Initiation should begin in primary health care services,

outside the hospital, inpatient clinics or emergency
departmens.

•  For patients with insufficient initiative treatment, even best

intensive care unit support may not be enough to improve
prognosis.
Threat: Host response:
•  Trauma
§  Molecular patern of the
•  Acute pancreatitis
•  İschemia-reperfusion Sepsis pathogen
§  Damage related molecular
• 
injury
Major surgery
triangle pattern
•  Burns §  Innate immunity
•  Infection §  Acquired immunity

Severity and Results

Adjuvant
treatments
Immunglobulins
Steroids
Ekstracorporeal
treatment etc.
Organ support
IPPV, hemodynamic, renal,
nutrition, etc
Source controle
Antibiyotics, surgery, invazive radiolojy

Rescucitation
Oxygene, fluid rescusitation, cathecolamines, transfusion etc.
Treatment at Hemodynamic
Instability
Fluid rescuscitation

Vazopressor agents

İnotropic treatment
 What Should Mean Arterial
Pressure(MAP) Be in Septik Shock?

•  MAP equal to or above 65 mmHg

•  In patients with chronic arterial hypertension, MAP to
be kept higher like 80-85 mmHg reduces the risk of
acute kidney injury
•  Microcirculatory response to MAP alters from patient
to patient
•  Optimal MAP should be personelized
Which Vasopressor Should be
Used in Septic Shock?
•  First choice: Norepinephrin
•  Epinephrin may cause early lactic acidosis
•  Dopamin may negatively effect neurohumoral and
immune function.
•  There is a lacking evidence about Dobutamine
restoring outcome in septic shock
•  Phenylephrine is less potent than norepinephrine
•  Arginine vasopressine combination is suggested in
septic shock which doesn’t respond to
cathecolamines
Ampirical antibiotic treatment
•  Initatiation of ampirical antimicrobial treatment is
vital.
•  In generel, broad spectrum antibiotics including
all possible microbiological agents should be
agressively initiated.
o  Source of infection?

o  Immune state of the patient?

o  Nasocomial infection?

o  Community acquired infecton?

o  Resistance rates of antimicrobial agents that will be

applied ?
 DE-ESCALATION
Purpose
ü  Preventing antimicrobial resistance

ü  Decreasing drug related toxicity risk

ü  Lowering costs

Ø  Initatiative broad spectrum ampirical antimicrobial treatment

should be replaced with narrow spectrum ones microbiological
results

Ø  If high dose antimicrobial treatment is ampirically initiated, dose

should also be revised.

Ø  If antimicrobial treatment vas initiated for suspected infection

and no infectious source is detected antimicrobial treatment
should be ceased
Surviving Sepsis Campaing
Sepsis-3 Recommendations

•  For diagnosing infections earlier, symptoms

and findings of infection should be followed
carefully in hospitals
•  Treatment of infection is crucial
•  Patients in which organ dysfunction is
detected with qSOFA, monitorization should be
done closely.
•  In patients with organ dysfunction, ‘’3 hours’’
model should be applied
Surviving Sepsis Campaing
Sepsis-3 Recommendations
First 3 hours
Ø Measure lactate level
Ø Take blood culture before antimicrobial
treatment
Ø Use broad spectrum antibiotics
Ø In patients with infection and hypotension if
lactate level is equal or more than 4 tissue
perfusion should be evaluated and infuse 30
mL/kg cristalloids
Surviving Sepsis Campaing
Sepsis-3 Recommendations

Septic shock-First 6 hours

Ø In patients without response despite

adequate fluid resuscitation use vasopressors
for keeping MAP≥ 65 mmHg

Ø Initiative lactate levels higher than 2 mmol/L,

measure again after fluid rescusitation
PREVENTING SEPSIS

•  Vaccine
•  Influenza
•  Pneumonia
•  Preventing infections
•  Wound disinfection
•  Following hygiene and asepsi rules
•  Recognizing symptoms early
•  Confusion, elevated respiratory effort,
hypotension…
Acute Respiratory Distress Syndrome
ARDS
Acute Respiratory Distress Syndrome
ARDS

Acute respiratory failure syndrome

•  Acute onset
•  Elevation in alveolar endothelium and epithelium
permeability
•  Diffuse radiographic findings
•  Alveolary edema including high protein component

Concomitant Physiological Changes

–  Severe Hypoxemia
•  Resistant to oxygene therapy
–  Decrease in alveolar compliance
 ARDS
Acute, Adult and Acquired
Respiratoty Distress Syndrome
• Acute respiratory failure related with pulmonary
edema related with increased capillary permeability
• Edema fluid in ARDS is related with cell damage more
than elevated capillary hydrostatic pressure

– “non cardiogenic”
pulmonary edema
 Pathogenesis and pathology
Cause of the clinical presentation; diffuse alveolar
damage related with intensive inflammation
•  At early stage;TNF, IL-1 and proinflammatory
cytokines, IL-6 and IL-8 are related with gathering
leukocytes
•  Leukocytes gathered in lungs get activated and
secretion of reactive oxygene products and
proteases harms capillary alveoli epithelium.
2011 Berlin ARDS Definition
ARDS classification
Primary-Pulmonary (direct)
•  Trigger causes epithelial damage directly

Secondary-Ekstrapulmonary (indirect)
•  Mediators in circulating blood firstly damages
capillary endothelium and causes lung damage
than.
 ARDS Risk Factors
Factors
Pulmonary Extrapulmonary increasing
mortality
Often Often
Aspiration pneumonia Sepsis
Diffuse lung infections Trauma Infection
Hypovolemic shock Age
Alcoholism
Massive transfusion
Comorbidities
Rare Rare Cancer
Pulmonary vasculitis Toxemia Immunsupression
Drowning Acute pancreatitis Organ failure
Toxic steam/gas inhalation Cardiopulmonary bypass Hypertension
Genetic factors
Lung contussion DIC
Fat emboli Burns
Reperfusion damage Amnion embolization
SARS Drugs
Other
Pulmonary ARDS

Pneumonia related ARDS

Patched and assymetric consolidations
PEEP related lung paranchyme barotrauma
Subplevral multipl cysts and pneumothorax
Ekstra-pulmoner ARDS’de
Gravitational movement

After Multitrauma
SYMETRIC
ARDS- Stages
1.  Exudative (acute) stage
•  Excessive fluid, protein and inflammation in alveoli,
•  Edema and hemoraghe
2.  Proliferative(fibroproliferative = intermediate) stage
•  Fibroproliferative phase of organization and repair
•  Proliferation in lung connective tissue and other constructive
elements
•  Dense cellular microscopic structure
•  Pneumonia, sepsis and risk of rupture
3.  Fibrotic (resolution-recovery) stage
•  Lung gets reorganised
4.  Symptoms may continue 6-12 months. Cough, excercise
intolerance, fatigue, anxiety, depression
 Hystopathological stages of ARDS
Exudative Proliferative Fibrotic
First week 2. week After10.th day
Macroscopic Severe, rigid, dark Severe, grey Coarse reticular
colored pattern

Microscopic Hyalen membranes Disintegration in barriers- Fibrosis,

Edema edema Macrophages and
Neutrophils Alveol type II proliferation Lymphocytes
Alveolar damage Myofibroblast infiltration Matrix organisation
Neutrophiles Emphysematous
Alveoler collapse changes
Epithelial apoptosis
Fibroproliferation
Vascular Local trombus Capillary loss Miyointimal thickening
structure Pulmonary hypertension Vascular structure
malformation
 Normal alveolus and ARDS acute
phase
Alveolocapillary unit
• Capillary endothelium
• Endothelial basal membrane
• İnterstitial area
• Epithelial basal membrane
• Alveolar epithelium (Type1
and Type2)

Type I % 90
Type II % 10
Surfactant production
Ion change
Change to type-1
epithelium
 Acute phase-Clinic

•  Acute onset respiratory failure

•  Refractory hypoxemia
•  Bilateral infiltraions are assymetric and patchy
–  Can not be differentiated from cardiac edema radiologically

•  Pulmonary effusion
•  Alveolar consolidaton and emhysema in CT
•  Widespread inflammation throughout the lungs
Subacute- Fibroproliferative Phase
(~7-21 days)

–  Collagenous fibrosis
–  Microcystic honeycomb pattern
–  Strain related bronchiectasy
–  Artererial distortion
 Radiography and Tomography

A B

C D

A-Exudative phase- Diffuse bilateral alveolar oppacities as alveolary edema

B-Fibroproliferatifve phase- Fibrosis related reticular opacities
C-Exudative phase Alveolar opacities are more intense in dependant areas. Curser shows thickened
interlobular septum.Bilateral severe plevual effusion
D-Fibroproliferatifve phase Reticular opacities,ground-glass appearance, bulla
Fibrosis/Resolution Stage
Restoration and Recovery

•  Progressive decrease in hypoxemia

•  Recovery in pulmonary compliance
•  Restoration of radiological findings
•  Pulmonary function is nearly normal in 6-12
months
 Restorational Mechanisms
•  Regression in edema
•  Tailing the proteins off
•  Resolution of neutrophilic inflammation
•  Resolution of fibrotic changes
•  Apoptosis
–  Type 2 cell hyperplasia recovery
–  Diferentiation of type-1
–  Clearing of PNL’s from the alveoli
ARDS-Complications
§  Barotrauma-volutrauma
§  Fragile lung tissue can easily rupture
§  Pneumothorax→intrapleural air→lung collapse
§  Bacterial infections
§  Diagnose is problematic depending on previous
radiological findings

§  Organ dysfunction
§  Liver, kidney, brain, immune system
§  Blood transfusion, trombocyte replacement
§  Delirium/ICU psychosis
§  Agitation, confusion, disorientation
Ventilator induced lung injury
ü  Volutrauma
(overdistension of alveoli)
ü  Atelectotrauma
(cyclic collapsibility of atelectatic units)
ü  Biotrauma
(local inflammation)→Translocation
45 cm H20 Normal 45 cm H20
5 min 20 min
Treatment
•  Standard supportive treatment
–  Treating predisposing factors
–  Fluid and hemodynamic balance
–  nutrition

•  Optimising oxygenization with MV

–  Lung protective ventilation
–  Pharmacologic treatment
–  Antiinflammatory treatment

•  Preventing Complications
–  Barotrauma
–  VIP
–  MODS, neuropathy-myopathy
Classical Mechanical Ventilation in
ARDS-Lung Protective Strategies
•  Non toxic FiO2 levels
•  PEEP level for adequate PaO2

Ø  Low tidal volume

Ø  High PEEP levels
Ø  Prone position
Ø  Recruitment maneuver
Oxygenisation and Gas Exchange

–  4-6 ml/kg tidal volume,

–  <30 cmH2O plato pressure
–  Permissive hypercapnia (PaCO2<65 mmHg)
and acidosis (pH>7.20)
–  Prone (in severe cases)
–  PEEP titration
–  Sedation and pauses
–  Fowler position
Lung Protective Ventilation Preferred in
ARDSNet
Ventilator mode Volume control
Tidal volume (ml/kg) 6 (due to Pplato)
Pplat (cm/H2O) <30
Respiratory rate/dk 6-35
İ:E ratio 1:1-1:3
PaO2 55-80
SpO2 %88-95
PEEP (cmH2O) 5-24
Role of Prone Position
•  Leads heart reposition in thorax
•  Helps better ventilation/perfusion synchrony
•  Elevates arterial oxygene level

•  Potential mechanisms
–  ↑ End-expiratory volume
–  Regional changes in ventilation
 Recruitment
•  Providing higher airway pressure for a while in
order to restore athelectatic alveoli
–  PEEP, CPAP, Pressure controlled mechanical
ventilation, gaspingmaneuver, prone position,
Inverse ratio ventilation IRV, high frequency
ventilation

•  Primary ARDS, is less recruitable than secondary

•  Late phase ARDS is less recruitable than early
•  Closure of recruited alveoli should be restrained
Pharmacologic agents and mechanisms
of acting
Therapotic agents
İNO
Prosteocyclin and PGE1
(systemic and inhalation)
Almitrine (with NO)
Beta adrenergic
agonists(terbutaline, dopamin)
Phosphodiesterase inhibitors
(pentoxifiylline)
ANP
Mechanisms of acting
Pulmonary vasodilatation
(ventilating areas)
Vasodilatation
(antiinflammatory effect)
Pulmonary vasocontraction
(NO effect is limited to alveoli)
Alveolar resorption ↑
Decreasing vasocontraction
(cAMP ↑)
Decreasing vasocontraction
(cAMP ↑)
 Antinflammatory treatment
•  Glucocorticoid therapy !!!(Late phase)
•  NSAI
•  Complement cascade inhibitors
•  Adhesion molecule inhibitors(Antibodies)
•  Granulocyte response modulators
•  Antiprostanoids(ketaconasole)
•  Cytokine antagonists
•  Coagulation-Fibrinolysis cascade inhibitors(AT III, aPC)
•  Protease inhibitors(anti-elastase, metalloproteazse
inhibitors)
•  Antioxidants
–  NAC, glutation, vit E, dimethylthiyourea and antioxidan
enzymes (SOD, catalase)
Non-Conventional Treantments in
Severe ARDS
•  Prone
•  HFOV
•  ECMO
ü  Provides better oxygenisation

Salvage therapy ECLS-ECMO

ü  For hypoxemia and respiratory acidosis
ü  O2 transfer and CO2 elimination with extracorporeal
treatment
Fluid Restriction
•  Alveolar fluid overload depending on elevated
vascular permeability
•  Independent risk factors
–  Positive fluid balance
–  Elevated CVP
CVP ≤ 4 mmHg
PAOP ≤ 8 mmHg

Corticosteroids
•  There is less or none effect on acute stage
•  Results about late stage effects are controversial

Neuromuscular blockage
•  May be used for a while if severe
hypoxemia occurs
 Results
•  Pulmonary edema developing due to elevation
in lung capillary permeability
•  The most important causes: sepsis, pneumonia,
aspiration and multitrauma
•  Acute onset respiratory failure
•  15% in critically ill patient popullation
•  Mortality 35-50%
•  Frequent in ICU’s but oftenly misdiagnosed
 Results
•  ARDS is a mortal respiratory failure
•  Supportive interventions are fundemental
•  Effective therapies are limited depending on
complexity of pathogenesis
•  Mechanical ventilation support and supportive
interventions are main treatment modalities
•  There is no spesific beneficial treatment except lung
protective mechanical ventilation