Acute Respiratory

Distress Syndrome
David Sweet
 CASE
 GF, is a 57 yo male who presents to SPH with a one
week history of feeling unwell. His wife states that
he was having intermittent fevers, general feelings of
malaise and dry cough. Over the last 24 hours he has
become progressively unwell with more severe cough
and mild confusion. At 8 AM when he refused to get
off the couch and his lips looked blue; GFs wife
called the ambulance. When probed wife states has
had decrease oral intake and occasional diarrhea over
the last 48hrs.
 Case
 PMHx:
 EtOH
 Prev pancreatitis in 2004
 HTN
 BPH
 Raynauds syndrome
 Prev episode of stable VT with negative angio and
EP studies for inducible VT 4 months previous.
 He had a UTI 1 months ago.
 Case
 Social: Lives in apt complex with his wife and his pet
parrot. Has two children not living at home.
Currently doing home renovations.
 Meds: norvasc, amiodarone, thiazide. avodart
 Allergies: nil
 Case
 Upon arrival to the Emergency room he was in
obvious respiratory distress with RR=40 and Sats
85% on double flow non-rebreather. He was
intubated by the emergency physician using
etomidate and succinylcholine. His blood pressure
dropped post intubation requiring phenylephrine and
has now received 2 L of NS. As you are standing in
the Emergency Dept, you are consulted immediately
as there is a septic patient coming though the doors
(88 yo DNR that is hypotensive and you hear the EP
ask for dopamine…….sigh).
 Case
 The EP tells you that he has ordered blood work and a ABG.
You go to the patients bedside. He is just being placed on the
ventilator by the RT. He is stated as “stable” by the bedside
nurse, Sats 96 on Fio2=1.00, 110/54, 130, temp 36.2, and is
dyssynchronous with the Vent. You have a excellent resident
who immediately takes over bedside management. Orders
another L of NS, ensures BC have been drawn and asks for
moxifloxacin to be given. Orders a CXR, sedates the patient.
Places an arterial line, IJ central line and continues resuscitating
him.
 Case
 His physical exam reveals crackles in his bases
bilaterally. His skin is mottled and cold with
no rash. Neuro (no meningeal signs prev to
intubation), CV, abd, genital, ext exam in non-
contributory.
 Initial CXR shows bilateral basilar infiltrate.
 ECG= NS tachy.
 Case
 Hb 150, Hct 0.55 WCC 18.2, Neut 12.3 Plat
79
 Film – few schistocyes, toxic granulation.
 INR 1.4, PTT 42, Fib 2.78
 Na 134, K 4.4, Cl 107, HCO3 13, Urea 18.8,
creat 178
 CK 508, Trop <0.1 LDH 540
 Albumin 20, Lactate 8.1
 Case
 ABG pre intubation sent by RT:
 pH=7.22, CO2=27, PaO2=98, HCO3=13, Base
excess= neg 16.
 New ABG returns as you are looking at the
computer (post intubation):
 ABG= pH=7.11, PaCO2=38, PaO2=105,
HCO3=12, Base excess=neg 17. FiO2=1.00
 Case
 Questions:
1) What is the differential diagnosis? Are there any clues in the
story to the etiology? What is the most likely diagnosis?
2) Based on the laboratory/ABG results what concurrent issues
are present in this disorder? What is the likely precipitants in
this case?
3) Any further investigations?
4) What treatments would you recommend now? Do you agree
with the abx choice?
5) What initial ventilator settings would you have this patient on?
 Case
 The resident feels this is a pneumonia and comments
that it likely meets criteria for ARDS. A medical
student then speaks up and asks “what is ARDS”?
6. What is the Definition of ARDS?
7. What is the Epidemiology of ARDS?.
8. What is the Pathophysiology/Clinical Stages and
likely causes of ARDS.?
 ARDS
 During 1960s, with widespread use of PPV a
distinct form of bilateral lung disease noted.
 Coined “Shock Lung” in trauma patients in
Viet Nam surgical hospitals.
 Then referred as Adult Respiratory Distress
Syndrome.
 Currently described as Acute Respiratory
Distress Syndrome.
Bernard, GR. Acute Respiratory Distress Syndrome: A Historical Perspective. Am J Respir Crit Care Med
2005; 172:798
What defines ARDS?
 Definitions
 For more than 20 yrs there was lack of a
uniformed description of ARDS.
 1994 American-European Consensus
Conference on ARDS issued the following
definitions for:
1)ALI= Acute lung injury
2)ARDS= Acute Respiratory Distress Syndrome
Bernard, G, Artigas, A, Carlet, J, et al. The American-European consensus conference on ARDS: Definitions,
mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818.
 Definitions
 ALI:
 Bilateral radiographic inflitrates
 PaO2/FiO2 between 201 and 300 regardless
of level of PEEP
 No clinical evidence for elevated left atrial
pressure. If measured, the pulmonary capillary
wedge pressure is 18 mmHg or less
 Definitions
 ARDS:
 Bilateral radiographic inflitrates
 PaO2/FiO2 less than 200 regardless of level
of PEEP
 No clinical evidence for elevated left atrial
pressure. If measured, the pulmonary capillary
wedge pressure is 18 mmHg or less
 Definitions
 By definition is ACUTE.
 Typically will develop over 4-48 hrs and will
persist for days to weeks.
 Some equate with the pathophysiologic entity
of increased capillary permeability. This is
discouraged as there are other
pathophysiologic mechanisms in ARDS.
 Definitions
 Early pathologic features of ARDS are generally described
as diffuse alveolar damage (DAD). There is minimal
alveolar septal thickening, hyperplasia of pneumocytes, and
eosinophilic hyaline membranes present.

Beskow, CO, Drachenberg, CB, Bourquin, PM, et al. Diffuse alveolar damage. Morphologic features in bronchoalveolar lavage
fluid. Acta Cytol 2000; 44:640.
Epidemiology
 Epidemiology
 ALI=
- Age-adjusted incidence of 86 per 100,000 person-
years
Mortality of 39%

 ARDS=
- Age-adjusted incidence of 64 per 100,00 person-years
Mortality of 41%
**190,600 cases of ALI in US each year, which
associated with 74,500 deaths.
Rubenfeld, GD, Caldwell, E, Peabody, E, et al. Incidence and outcomes of acute lung injury. N Engl J Med
2005; 353:1685.
 Epidemiology
 Intensive Care Units:
 10-15% of admitted patients meet criteria for ARDS
 20% of mechanically ventilated patients meet criteria
for ARDS
 Mortality rate varies on the basis of underlying cause,
most dying of MOF rather than resp. insufficiency.
 Large trials suggest overall mortality of ARDS ranges
from 25-58%.
Frutos-Vivar, F, Nin, N, Esteban, A. Epidemiology of acute lung injury and acute respiratory distress syndrome.
Curr Opin Crit Care 2004; 10:1
Maccallum, NS, Evans, TW. Epidemiology of acute lung injury. Curr Opin Crit Care 2005; 11:43.
Pathophysiology
 Pathophysiology
 In healthy lung, a tight regulation on
movement of fluid to maintain dry alveoli and
a small amount of interstitial fluid.
 In lung injury this regulation is lost. There is
excess fluid in both interstitium and alveoli.
 Results in impaired gas exchange, dec
compliance, and increased pulmonary arterial
pressures.
 Pathophysiology
 Normal pulmonary capillary endothelium is
selectively permeable; serum protein remains
intravascular, fluid crosses the membranes
under control of:
1) Hydrostatic forces
2) Osmotic forces

George, RB, Chesson, AL, Rennard, SI. Functional anatomy of the respiratory system. In: George, RB, Light, RW, Matthay, MA, et
al (Eds), 3rd ed, Chest Medicine. Essentials of Pulmonary and Critical Care Medicine, Williams & Wilkins, Baltimore,
1995, p. 3
 Pathophysiology
 The Starling equation describes the forces that
direct fluid movement. Simplified version of
the equation is:
 Q=K * [(Pmv – Ppmv) – rc (mv – pmv)]
Q= net transvascular flow
K= permeability
Pmv= hydrostatic pressure in lumen
Ppmv= hydrostatic pressure in perimicrovascular space
Rc= reflection coefficient of capillary barrier
Mv= oncotic pressure of circ
Pmv= oncotic pressure of perimicrovasc comp
 Pathophysiology
 The balance of equation usually allows small
amounts of fluid into interstitium but 3 mech
prevent alveolar edema.
1) Retained intravascular protein
2) Interstitial lymphatics can return large
quantities of fluid to circulation
3) Tight junctions between alveolar epithelial
cells
 Pathophysiology
 Clinical ARDS is result of inflammatory injury to
alveoli producing DAD.
 Lungs are very vulnerable to injury b/c they receive
the entire CO and as pro-inflammatory mediators
(TNF, IL-1, IL-6, IL-8) released into blood stream the
lungs feel their full effect.
 Additionally, neutrophils are recruited to the lungs,
become activated and release reactive oxygen species
and proteases which damage endothelium and alveoli.
 Pathophysiology
 As a result, the normal barriers to alveolar edema are
lost.
1) Protein escapes vascular space, oncotic gradient lost.
2) Fluid pours into interstitium and overwhelms the
lymphatics.
3) Air spaces fill with bloody, proteinaceous edema
fluid and debris from degenerating cells.
4) Functional surfactant is lost, resulting in alveolar
collapse.
Ware, LB, Matthay, MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute
respiratory distress syndrome. Am J Respir Crit Care Med 2001; 163:1376.
 Pathophysiology
 Consequences:
1) Impaired gas exchange= V/Q mismatching and
shunting.
2) Dec lung compliance= Low compliance is due to
stiffness of poorly or nonaerated lung more so than
changes in PV characteristics of residual fxning
lung units. (Baby lung)
3) Pulmonary HTN= present in up to 25% of Px with
ARDs. Multifactorial. RV dysfunction associated
with inc risk of death!
Monchi, M, Bellenfant, F, Cariou, A, et al. Early predictive factors of survival in the acute respiratory distress syndrome. A
multivariate analysis. Am J Respir Crit Care Med 1998; 158:1076
Clinical Stages
 Clinical Stages
 ARDs progresses through three relatively discrete
pathologic stages.
1) Exudative stage: DAD, in 1st week progresses to
2) Proliferative stage: characterized by resolution of
pulmonary edema and proliferation of type II alveolar
cells, squamous metaplasia, interstitial infiltration by
myofibroblasts, and early deposition of collagen.
3) Fibrotic stage: obliteration of normal lung
architecture, diffuse fibrosis, and cyst formation.
Tomashefski, JFJ. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990; 11:593
 Clinical Stages
 Initial Course (exudative phase):
 Usually symptoms predominated by cause of
ARDs (eg abd pain from pancreatitis, fever
and shock from sepsis)
 Pulmonary dysfunction develops within 24-48
hrs of inciting event.
 Worsening tachypnea, dyspnea, hypoxemia
and diffuse crackles on exam.
 Clinical Stages
 Labs non-specific. May show inc WBC, DIC
and lactic acidosis.
 ABG= acute resp alkalosis, inc DAaO2, severe
hypoxemia
 CXR= Bilateral patchy infiltrates, does not
need to be widespread or severe opacification.
 CT= generally demonstrates patchy abn with
inc density in dependent lung zones.
 Clinical Stages
 Proliferative stage:
 Oxygenation tends to improve somewhat over first
few days as edema resolves, most patients remain
ventilator-dependent due to:
1) Continued hypoxemia
2) High minute vent requirements (Classically the
Dead Space may begin to increase at this stage and
ventilation may become more of an issue)
3) Poor compliance
Gattinoni, L, Bombino, M, Pelosi, P, et al. Lung structure and function in different stages of severe adult respiratory distress
syndrome. JAMA 1994; 271:1772
 Clinical Stages
 CXR= Densities become less dense as edema
resolves, interstitial infiltrates remain.
 May start to develop interstitial emphysema
and lung cysts.
 At this point may become dominated by
complications such as barotrauma, nosocomial
infection or dev of MODS. (discussed later)
 Clinical Stages
 Fibrotic Stage:
 Will see progressive increasing airway
pressures, progressive pulmonary HTN and a
honeycomb appearance on CXR
Etiology
 Causes and predisposing conditions
 Traditionally conceptualized as a pattern of injury that
does not differ significantly depending upon cause.
 Now called in question with revolution of CT scan.
 Additionally studies have found more severe
reductions in lung compliance and less responsiveness
to PEEP in ARDS from a pulmonary process than
those with extrapulmonary precipitant.

Gattinoni, L, Pelosi, P, Suter, P, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease:
Different syndromes. Am J Respir Crit Care Med 1998; 158:3.
Tugrul, S, Akinci, O, Ozcan, PE, et al. Effects of sustained inflation and postinflation positive end-expiratory pressure in acute
respiratory distress syndrome: focusing on pulmonary and extrapulmonary forms. Crit Care Med 2003; 31:738.
 Abbreviated list of conditions
associated with ARDS
 Sepsis
 Aspiration
 Infectious pneumonia
 Severe trauma
 Surface burns
 Multiple blood
transfusions
 Leukoagglutin reactions
 Pancreatitis
 Drug overdose
 Near drowning
 Smoke inhalation
 Following bone marrow
transplantation
 Drug reaction
 Venous air embolism
 Amniotic fluid embolism
 Neurogenic pulmonary edema
 Acute eosinophilic pneumonia*
 Bronchiolitis obliterans
organizing pneumonia (BOOP)*
 Miliary tuberculosis*
 Cardiopulmonary bypass
 Pulmonary contusion
 Multiple fractures
 Following upper airway
obstruction
 Causes and predisposing conditions
 Sepsis: most common cause
 Risk of developing ARDS with sepsis may be
especially high in patients with alcoholism.
 One prospective study analyzed the incidence of
ARDS in 220 Px with septic shock.
 70% in chronic alcohol abusers
 31% in non-alchohol abusers
 ? Proposed mechanism= dec levels of glutathione in
epithelial lining, predispose to oxidative injury.
Doyle, RL, Szaflarski, N, Modin, GW, et al. Identification of patients with acute lung injury. Predictors of mortality. Am J Respir Crit Care Med 1995; 152:1818.

Moss, M, Bucher, B, Moore, FA, et al. The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 1996; 2
 Causes and predisposing conditions
 Trauma: Several mechanism can lead to ARDS
1) Bilateral lung contusions
2) Fat embolism: 12-24 hrs after injury, less common
now as fractures are immobilized prior to transfer.
3) Sepsis
4) Massive tissue injury
 ALI and ARDS contribute to length of critical
illness, these disorders don not appear to inc risk of
death. In comparison to other causes of ARDS,
trauma-related is associated with better prognosis.
Rubenfeld, GD, Caldwell, E, Peabody, E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353:1685.
 Causes and predisposing conditions
 Transfusion related
 More than 15 pRBCs is an important risk factor even
without trauma.
 Transfusion of smaller volumes of pRBCs may also
increase risk of developing ARDS and inc mortality
in Px with established ARDS.
 TRALI: even one unit of plasma-containing blood
can result in TRALI. FFP, plts, pRBCs all
implicated. Symptoms become apparent within 6
hours.
Gong, MN, Thompson, BT, Williams, P, et al. Clinical predictors of and mortality in acute respiratory distress syndrome: potential
role of red cell transfusion. Crit Care Med 2005; 33:1191.
Khan, H, Belsher, J, Yilmaz, M, et al. Fresh-frozen plasma and platelet transfusions are associated with development of acute lung
injury in critically ill medical patients. Chest 2007; 131:1308.
 Causes and predisposing conditions
 Toxicological causes?:
1) ASA
2) Opioids
3) Phenothiazines
4) TCAs
5) Also idosyncratic rxn to protamine,
nitrofuantoin, chemotherapeutics, contrast
material
 Case
 The resident also states that the chest X-ray looks very
similar to previous cases of pulmonary edema that she
has seen. She asks you if there are any diagnostic tests
and evidence that can help you determine if this is
ARDS vs cardiogenic pulmonary edema? (Aside from
clinical exam)
Cardiogenic pulmonary
edema vs ARDS
 Diagnosis
 During first several days ARDS will resemble
acute cardiogenic pulmonary edema in both a
clinical and radiographic sense.
 Distinction usually made from clinical
circumstances associated with onset but
occasionally additional diagnostic tests may help.
1) BNP
2) Echo
3) PAC
 Diagnosis
 BNP:
 May be helpful in distinguishing ARDS from
hemodynamic pulmonary edema.
 A level below 100 pg/ml indicates heart failure unlikely.
 A higher level is not helpful. On study looking at 24 px
with Severe Sepsis or Septic Shock and 51 px with
acute heart failure found that values not significantly
different.
Rubenfeld, GD, Caldwell, E, Granton, J, et al. Interobserver variability in applying a radiographic definition for ARDS. Chest 1999; 116:1347.
Rudiger, A, Gasser, S, Fischler, M, et al. Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with
severe sepsis, septic shock, and acute heart failure. Crit Care Med 2006; 34:2140.
 Diagnosis
 Echocardiography:
 Most commonly used test to distinguish
questionable cardiogenic component of ARDS.
 Can detect LV dysfunction, severe aortic or
mitral valve abnormalities, estimation of
diastolic dysfuction and volume overload.
 Interpretation may be difficult in the presence of
over/under resuscitation, renal failure, sepsis
induced myocardial dysfunction, PPV.
 Diagnosis
 Pulmonary artery catheterization (PAC):
 Classically clinicians would look for a wedge
> 18 mmHg. Need to be interpreted with
caution in the face of patients on high levels of
PPV and PEEP.
 Also, it is estimated that as many as 20% of px
with ARDS have concomitant LV dysfxn.
Ware, LB, Matthay, MA. Clinical practice. Acute pulmonary edema. N Engl J Med 2005; 353:2788.
Montgomery, A, Stager, M, Carico, C, et al. Causes of mortality in patients with the adult respiratory distress
syndrome. Am Rev Respir Dis 1985; 132:485.
 Diagnosis
 Therefore, the dx cannot be made easily when
the wedge pressure is elevated.
 More useful to follow the wedge pressure with
treatment and how infiltrates and hypoxemia
change with treatment.
 If the infiltrates and hypoxemia do not
improve appreciable within 24-48 hrs after
normalization of wedge pressure more likely
ARDS has occurred as well.
 Diagnosis
 Additionally, PAC has never been shown to
confer benefit in ARDS.
 Recent multi-center trail (FACTT) found no
improvement in survival or organ function, but
more complications in PAC group vs CVC
monitoring.

Wheeler, AP, Bernard, GR, Thompson, BT, et al. Pulmonary-artery versus central venous catheter to guide
treatment of acute lung injury. N Engl J Med 2006; 354:2213.
 Case
 The patient is moved to the ICU. The patient receives EGDT
and you modify the antibiotic choices. Over the next 24 hrs the
patient receives 9L of crystalloid and colloid. Currently on 20
ug/min of Levophed, ScvO2 has always been greater than 70%
and dobutamine was never used nor was transfusion. A Stat
ECHO on arrival reveals a mildly reduced EF (40%) but no wall
motion abn and RV is mildly dilated and PA systolic is 45.
Arrival CXR to the ICU shows worsening bilateral infiltrates
and you make the decision to do early bronchoscopy/BAL.
 10. Your resident asks how bronchoscopy is going to help you
management?
 Bronchoscopy in ARDs
 Useful tool if cannot determine etiology from history.
 Able to visualize airways and perform
bronchoalveolar lavage.
 Occult aspiration= see acute inflammation localized
to dependent regions and see food material.
 DAH= finding of frothy blood in airways and
increasing bloody returns with recurrent lavage. Find
hemosiderin-laden macrophages on microscopy.
 Bronchoscopy in ARDs
 Gram stain= Can identify organisms and
cellular components.
 Culture and staining= look for aerobic
bacteria, mycobacteria, legionella
pneumophila, pneumocystis, viruses.
 Cytologic preps examined for eosinophils,
viral inclusion bodies and cancer.
 Others= eg) foamy macrophages seen with
BOOP and amiodarone toxicity.
 Case
 During bronchoscopy you find moderate amounts of
secretions and no bloody returns. Initial gram stain
only shows neutrophils, negative for foamy
macrophages. hemosiderin-laden macrophages and
few esinophils.
 Case
 11. Your fantastic senior
fellow then states there
are several clinical
syndromes that present
with inflammatory
prodrome and acute
respiratory failure. They
have specific treatments
and prognosis, therefore
should be considered.
 Case
1) Diffuse alveolar hemorrage syndromes
(DAH)
2) Acute interstitial pneumonia (Hammer-Rich)
3) Idiopathic acute eosinophilic pneumonia
4) Cryptogenic organizing pneumonia
Briefly describe each of these entities with
respect to symptoms, diagnosis and treatment!
DAH
 DAH
 Is included in the differential of hypoxia with
bilateral infiltrates.
 Hemopysis will be absent in 33% of cases.
 Is defined by injury to alveolar-capillary
basement membrane and bleeding into
alveolar spaces.
Collard, HR, Schwarz, MI. Diffuse alveolar hemorrhage. Clin Chest Med 2004; 25:583
 DAH
 A variety of diseases are associated with the
development of diffuse alveolar hemorrhage
syndrome.
 All fit within one of three histological
patterns
1) Pulmonary capillaritis
2) Bland pulmonary hemorrhage
3) Diffuse alveolar damage
 DAH
Pulmonary Capillaritis
 Systemic vasculitides:
- Wegener's granulomatosis
- Microscopic polyangiitis
- Henoch-Schoenlein purpura
 Collagen vascular
diseases:
- Systemic lupus
erythematosus
- Polymyositis
- Rheumatoid arthritis
- Scleroderma
 DAH
Bland pulmonary hemorrhage
- Goodpasture's syndrome
- Systemic lupus
erythematosus
- Post bone marrow transplant
- Severe coagulopathies
- Mitral stenosis
- Penicillamine,
nitrofurantoin,
amiodarone
 DAH
Diffuse alveolar damage
 ARDS and its causes
 DAH
 Clinical presentation:
 Onset is often abrupt or of short duration (<7
days)
 Cough, fever and dyspnea and may present in
extremis requiring PPV.
 May have constellation of new alveolar
infiltrates, falling hgb and hemorragic fluid on
sequential bronchoalveolar lavage
DAH
 DAH
 CXR:
- Diffuse, bilateral, patchy, basal consolidation
on chest radiograph (sparing the apex)
- Resembles pulmonary edema but normal heart
size can be clue.
 CT:
- alveolar densities with sparing of peripheral
lung fields
 DAH
 A number of diseases that cause DAH are also
associated with pulmonary-renal syndrome.
 Usually cause a focal segmental necrotizing
glomerulonephritis.
 Will see elevated creatinine and abn urinalysis
(red blood cells, white blood cells, red and
white cell casts.)
 DAH
 As previously mentioned in DAH will see
progressive hemorrhagic return with BAL.
 Will also see hemosiderin-laden macrophages,
which may be demonstrated by prussian blud
staining.
 Additionally, specific diagnosis/etiology can
be made from specific auto-antibodies or
lung/kidney/skin biopsy.
 DAH
 Many of the possible diagnosis are treated with
either corticosteroids, immunosuppressive
therapy or plasmapheresis.
 Therefore must think of these diagnosis in the
setting of ARDS.
 Failure to treat in the settting of acute hypoxic
respiratory failure may significantly worsen
prognosis.
Schwarz, MI, Mortenson, RL, Colby, TV, et al. Pulmonary capillaritis. The association with progressive irreversible airflow
limitation and hyperinflation. Am Rev Respir Dis 1993; 148:507
Acute Interstitial
Pneumonia
Hamman-Rich Syndrome
 Acute Interstitial Pneumonia
 Rare and fulminate form of lung injury
described by Hamman and Rich in 1935.
 Occurs in previously healthy individuals
without a history of lung disease who present
within days to weeks following onset of
symptoms.
 Similar in presentation to ARDS, and likely is a
subset of idiopathic ARDS.
Hamman, L, Rich, AR. Fulminating diffuse interstitial fibrosis of the lungs. Trans Am Clin Climatol Assoc 1935; 51:154
Hamman, L, Rich, AR. Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp 1944; 74:177
 Acute Interstitial Pneumonia
 Exact mechanism of damage to pulmonary
endothelium unknow.
 Likely neutrophil-mediated.
 Results in damage of alveolar walls, inc
alveolar capillary permeability, interstitial
edema, intralveolar haline membranes.
 As with ARDS after initial insult also have a
fibroblast proliferation phase
 Acute Interstitial Pneumonia
 Most patients over age of 40.
 Usually begins with a prodromal illness lasting 7-14
days prior to presentation.
 Fever, cough and shortness of breath.
 Labs nonspecific.

 Primack, SL, Hartman, TE, Ikezoe, J, et al. Acute interstitial pneumonia:

Radiographic and CT findings in nine patients. Radiology 1993; 188:817
 Acute Interstitial Pneumonia
 CXR= diffuse, bilateral air-space opacification.
 CT= A combination of ground-glass attenuation,
airspace consolidation, traction bronchiectasis, and
architectural distortion
 The extent of ground-glass attenuation and traction
bronchiectasis increases with disease duration.
 Acute Interstitial Pneumonia
 Diagnosis is based upon two findings:
1) Presence of a clinical syndrome of idiopathic
ARDS.
2) Pathologic confirmation.
 Thus a open or thoracoscopic lung biopsy is
required to confirm the diagnosis.
 Acute Interstitial Pneumonia
 AIP should be distiguished from two other
forms of idiopathic interstitial pneumonia:
1) Usual interstitial pneumonia (UIP)
2) Desquamative interstitial pneumonia (DIP)
 These both have a more subacute/chronic
presentations and therefore are not included
in differential of a acute ARDS picture.
Vourlekis, JS, Brown, KK, Cool, CD, et al. Acute interstitial pneumonitis. Case series and review of the literature. Medicine
(Baltimore) 2000
UIP
DIP
 Acute Interstitial Pneumonia
 Treatment:
 Mainly supportive care.
 Mech vent is often required.
 Currently unclear if steroid therapy is effective.
 Mortality is high (>60%), and majority die within 6
months of presentation.
 If survive usual do so with complete recovery of lung
function.
Vourlekis, JS, Brown, KK, Cool, CD, et al. Acute interstitial pneumonitis. Case series and review of the literature. Medicine (Baltimore) 2000; 79:369
 Idiopathic Acute
Eosinophilic Pneumonia
(AEP)
 Idiopathic Acute Eosinophilic
Pneumonia
 First described as a cause of respiratory failure in 1989.
 Etiology: Unknown, some feel is an acute
hypersensitivity reaction to unidentified inhaled antigen
in otherwise healthy people.
 Several reports people have been involved in unusual
outdoor activities just prior to illness.
 Temporal relationship noticed to recent onset of
cigarette smoking.
Philit, F, Etienne-Mastroianni, B, Parrot, A, et al. Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med 2002; 166:1235
Miki, K, Miki, M, Nakamura, Y, et al. Early-phase neutrophilia in cigarette smoke-induced acute eosinophilic pneumonia. Intern Med
2003; 42:839
 Idiopathic Acute Eosinophilic
Pneumonia
 Ages of 20 and 40.
 Begins with acute febrile illness of less than 3
weeks duration; most less than 7 days.
 Malaise, myalgias, night sweats,
nonproductive cough and dyspnea are present
in almost every patient.
 O/E= fever (often high) and tachypnea,
bilateral basilar crackles.
 Idiopathic Acute Eosinophilic
Pneumonia
 Labs: generally elevated WBCs with neutrophilic
leukocytosis.
 With progression of disease the eosinophil fraction becomes
markedly elevated.
 CXR= bilateral diffuse mixed alveolar and reticular opacities
are seen. Bilateral effusions are often present (if tap will have
marked eosinophilia with high pH.)
 CT= bilateral, random, and patchy group-glass or reticular
opacities. In height of disease will have peripheral ground-
glass opacities along the bronchovascular bundles.
Hayakawa, H, Sato, A, Toyoshima, M, et al. A clinical study of idiopathic eosinophilic pneumonia. Chest 1994; 105:1462
Ogawa, H, Fujimura, M, Matsuda, T, et al. Transient wheeze. Eosinophilic bronchobronchiolitis in acute eosinophilic pneumonia.
Chest 1993; 104:493
Idiopathic Acute Eosinophilic
Pneumonia
 Idiopathic Acute Eosinophilic
Pneumonia
 BAL is useful in making the diagnosis.
 Often show a very high (>25%) and total
number of eosinophils.
 The proportions of BAL lymphocytes and
neutrophils are also frequently increased.
 Rarely will need to do open lung biopsy.
Philit, F, Etienne-Mastroianni, B, Parrot, A, et al. Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med 2002;

166:1235
 Idiopathic Acute Eosinophilic
Pneumonia
 Treatment:
 Spontaneous improvement has been reported.
 Uniformly respond to IV and oral
corticosteroid therapy.
 Response is often dramatic, occurring within
12 to 48 hours, and there is no relapse
following withdrawl of the steroids.
 Cryptogenic
Organizing Pneumonia
Idiopathic BOOP
 Cryptogenic Organizing Pneumonia
 Distinct clinical entity with features of pneumonia.
 Due to proliferation of granulation tissue within small
airways (proliferative bronchiolitis) and alveolar
ducts, chronic inflammation in surrounding alveoli.
 Pathogenesis remains unknown.
 Abnormal vascuar endothelial growth factor and
matrix metalloproeinase regulation.

Choi, KH, Lee, HB, Jeong, MY, et al. The role of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in cryptogenic organizing
pneumonia. Chest 2002; 121:1478
Cryptogenic Organizing Pneumonia
Cryptogenic Organizing Pneumonia
 Presents in the 40s and 50s
 May have had symptoms for up to month or
more before presentation.
 Mimics CAP.
 Heralded by flu-like illness (fever, malaise,
fatigue, and cough). Also may have weight
loss.
 Labs= Inc WBC, Inc ESR, Inc CRP.
 Cryptogenic Organizing Pneumonia
 CXR= bilateral, diffuse alveolar opacities with
normal lung volumes. May be peripherally located.
 The infiltrates may also be migratory and recurrent.
 CT= patchy air-space consolidation, ground-glass
opacities, small nodular opacities, and bronchial wall
thickening and dilation.
 More often in the periphery and lower lung zones.
Davison, AG, Heard, BE, McAllister, WAC, Turner-Warwick, MEH. Cryptogenic organizing pneumonitis. Q J Med 1983; 52:382
Ujita, M, Renzoni, EA, Veeraraghavan, S, et al. Organizing pneumonia: perilobular pattern at thin-section CT. Radiology 2004;

232:757
 Cryptogenic Organizing Pneumonia
 Diagnosis:
 BAL is very helpful: Classically a “mixed cellular
pattern”
 Similar to hypersensitivity pneumonitis. Proportion
of macrophages is lower, lymphocytes, neutrophils
and eosinophils are higher.
 Foamy macrophages
 Occasionally, mast cells and plasma cells
King, TE Jr, Mortenson, RL. Cryptogenic organizing pneumonia. The North American experience. Chest 1992; 102:8S
 Cryptogenic Organizing Pneumonia
 An open biopsy or thoracoscopic lung biopsy
is suggested to confirm diagnosis.
 Need generous amount of lung tissue.
 Important to provide pathologist with adequate
clinical information to guide search for
specific lesions and to rule out other possible
causes that have similar pathologic picture.
Miyagawa, Y, Nagata, N, Shigematsu, N. Clinicopathological study of migratory lung infiltrates. Thorax 1991; 46:233
Cryptogenic Organizing Pneumonia
 Treatment:
 Supportive
 Corticosteroid pulse then taper.
 Some who cant tolerate steroids or deteriorate
are treated with cyclophophamide.
 Prognosis= 2/3 recover in weeks to months.
1/3 will have persistant disease. May relapse.
 Case
 The patient then slowly deteriorates from an
oxygenation point of view and after a brief
period of a FiO2 of 0.60 is now requiring 0.80.
The CXR has now blossomed into severe
bilateral infiltrates. A CT scan was performed
and shows a diffuse bilateral groundglass
appearance with consolidation in the dorsal
aspects of the lung.
 Case
 The urin output has picked up and the creatinine is
dropping. You are currently on a volume control
ventilation (6cc/kg, rate=28, plat are 28, PEEP=7 nil
autoPEEP). ABG: pH=7.35, PaCo2=35, PaO2=75
HCO3=20.

12) She questions if the amount of fluid she has given the
patient and if this is detrimental? Is there any evidence
to how we should manage the fluid balance in Px with
ARDS?
Fluid management in
ARDS
 Fluid management in ARDS
 Pulmonary edema in ARDS is directly related to
increased vascular permeability but the quantity
depends on hydrostatic pressure.

Mitchell, JP, Schuller, D, Calandrino, FS, et al. Improved outcome based on fluid management in critically ill patients requiring pulmonary artery
catheterization. Am Rev Respir Dis 1992; 145:990
 Fluid management in ARDS
 Thus, even in px who are not overloaded a
conservative strategy approach may be beneficial.
 Fluid management in ARDS
 RCT, n=1000
 Conservative group=CVP <4 mmHg, PAOP< 8
mmHg. (Unable to obtain in study)
 Liberal group= CVP 10-14, PAOP 14-18.
 Fluid balance= -136 cc vs 6992 cc
 Fluid management in ARDS
 Vent free days= 15 vs 12 (p=0.001)
 ICU free days= 13 vs 11 (p=0.001)
 60 day mortality 25.5% vs 28.4% (p=0.30)
 Fluid management in ARDS
 Important to know
1) Needed to be out of shock for 12 hrs before
diuretics given.
2) Requiring dialysis was contraindication to
the study
3) Average time to study entry was 43 hours.
 Study found no difference between
prevalence of shock or need for renal
replacement therapy once randomized.
 Fluid management in ARDS
 Can we incorporate this into our practice?
 Likely we should attempt a conservative
strategy of fluid management in select px with
ARDS or ALI.
 Attempt goals of CVP <4 and PAOP < 8 (may
be difficult to obtain.)
 Must be balanced with EGDT and early phases
of sepsis when fluid replacement is crucial.
 Fluid management in ARDS
 Simplified algorithm for conservative fluid
management.
 Case
 13. The fellow asks the resident if there is anything else
we can do with conventional ventilation or the PEEP.
 14. What are the primary mechanisms of Ventilator
induced lung injury (VILI)?
 15. What is the concept of “Baby Lung”?
 16. Do you have a strategy to determining the “Best
PEEP”?
 17. Is there any evidence for higher

PEEP and Open Lung ventilation

(not including oscillators)
 Mechanical Ventilation
 Mechanical Ventilation is the corner stone of
supportive therapy ARDS management.
 Primary issue in ARDS is that it is a
heterogeneous disease process within the lungs.
 Much of the lungs is so consolidated it cannot
be recruited to participate in gas exchange.
 Therefore, the effective lung being ventilated is
much smaller than usual. This is the concept of
“baby lung”.
Fan, E, Needham, DM, Stewart, TE. Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA 2005; 294:2889
 Mechanical Ventilation
 Additionally, different areas of lung have different
“time constants”
 What are time constants?
 Different physiologic properties pertaining to their
compliance, inflation and deflation times relative to
each other.
 Therefore, at a set driving pressure and PEEP, some
areas will never inflate while others will open and
close cyclically and still others will be continuously
distended and damaged.
 Mechanical Ventilation
 Last 15 years there has been a growing
appreciation of ventilator-related morbidity
and Ventilator Induced Lung Injury (VILI).
 Clinicians strive to determine the optimal
modes of ventilation to reduce VILI and
improve survival.
 Mechanical Ventilation
 Primary mechanisms of VILI are felt to be
barotrauma and biotrauma.
 Barotrauma= High airway/alveolar pressure
results in air migrating into extrapulmonary
compartments (discuss later).
 Biotrauma= Both tidal hyperinflation and
cyclic atelectasis.
Terragni, PP, Rosboch, G, Tealdi, A, et al. Tidal Hyperinflation during Low Tidal Volume Ventilation in Acute
Respiratory Distress Syndrome. Am J Respir Crit Care Med 2007; 175
 Mechanical Ventilation
 What is tidal hyperinflation and cyclic
atelectasis?
 Tidal hyperinflation= over-inflation of aerated
lung units.
 Cyclic atelectasis= areas of diseased lung
appear to collapse and open cyclically with
each breath. This places stress and damages
adjacent lung that remains open.
 Mechanical Ventilation
 Key protective modalities/ideologies are

1) Low tidal volume ventilation (ARDSnet ARMA

study) and the idea of the “baby lung”.
2) Use of PEEP and open lung ventilation to improve
hypoxemia and limit cyclic atelectasis.

Fan, E, Needham, DM, Stewart, TE. Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA 2005; 294:2889
 Mechanical Ventilation
 Clinical value of low tidal volume ventilation
“clearly” demonstrated in ARDSnet study.

 ARMA (originally called KARMA….know why?)

 Mechanical Ventilation
 RCT of 861 patients.
 6 cc/kg IBW and Plat
<30cm H2O
 12 cc/kg IBC and Plat
<50cm H2O
 Stopped early at interim
analysis b/c of
significant lower
mortality (31 vs
40 % p=0.007).
 Mechanical Ventilation
 Issues:
1) Was study control group tidal volume
inappropriate high? (studies showed no true
standard of care!)
2) Practice Misalignment?
 Mechanical Ventilation
 Issues:
3) People fear that low tidal volume will result in more
discomfort, therefore inc sedation?
- Secondary analysis of one ARDSnet center showed
neither inc dose nor duration of sedation.
4) Hypercapnia does occur when attempting to use low
tidal volume ventilation! Is this safe?
- Multiple studies have shown that modest, permissive
hypercapnia is safe!
Kahn JM et al. Low tidal volume ventilation does not increase sedation use ni patients with acute lung injury. Crit Care Med 2005; 33:766-771
Laffey JG et al. Permissive hypercapnia role in protective lung ventilation strategies. Intensive Care Med 2004; 30247-356.
PEEP and Open Lung
Ventilation
 PEEP and Open Lung Ventilation
 Rational behind PEEP= Preventing subsequent
recollapse of difficult to recruit lung units.
 Several benefits:
1) Improve V/Q matching.
2) Alveoli will not have to repeatedly construct
surfactant monolayer, and this improves compliance.
3) Prevent cyclic atalectasis.
 Overall goal is to improve oxygenation and reduce
the levels of required FiO2 to less toxic levels.
Plotz FB, Slutsky AS, van Vught AJ, Heijnen CJ. Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses.

Intensive Care Med. 2004;30:1865-1872

 PEEP and Open Lung Ventilation
 
 PEEP and Open Lung Ventilation
 3 basic approaches to setting appropriate
level of PEEP.
1) Visual- variety of radiologic, nuc med, CT
tech to determine amount of recruitable and
over distended lung…..currently not readily
available.
2) Mechanical- using pressure-volume
relationships….not easy to capture regional
variations within lung. Tech challenging.  
 PEEP and Open Lung Ventilation
3) Gas-exchange approaches- use FiO2, PaO2
or calculated shunt fraction to target and adjust
PEEP.  
 Many of the PEEP studies (such as ALVEOLI
by ARDSnet) use predetermined algorithms
based on this idea.
PEEP and Open Lung Ventilation
 PEEP and Open Lung Ventilation
 ALVEOLI (ARDSnet group) N=549
 RCT of aggressive PEEP (12-24 cm H2O) vs
conservative PEEP (5-24 cm H2O) approach guided by
gas exchange.
 All low tidal volume
 PEEP and Open Lung Ventilation
Successfully achieved different levels of PEEP
High PEEP Low PEEP
Day 1 14.7 8.9
Day 3 12.9 8.5
Day 7 12.9 8.4
 PEEP and Open Lung Ventilation
 Aggressive strategy
improved gas exchange,
atalectasis and
compliance, the plateau
pressue was higher but
the mortality was
unchanged.   
 P = 0.48
If hi PEEP reduced atelectasis more,
why didn’t outcomes improve?
 Maybe it really did
- Sig imbalances in age and P/F favored low PEEP,
adjustments showed “trends” for hi PEEP
- Might “recruitable” subgroups benefit?
 But maybe it didn’t
- Benefits of more recruitment countered by
overdistention elsewhere
- In setting of low VT and recruitment of “easy”
alveoli, further recruitment of “tough” alveoli adds
little benefit (prevent cyclic injury, allow fixed)
 PEEP and Open Lung Ventilation
 In 2007, two additional, large RCTs studying
aggressive vs conservative PEEP were
completed and preliminary analysis reported.
 Canadian/Australian/Saudi Arabian Lung
Open Ventilation Study (LOVS)
 French ExPress study.
Meade MO, Cook DJ, Arabi Y, et al. A multinational randomized controlled trial of a lung open ventilation strategy in ALI/ARDS -- preliminary results. Am
J Respir Crit Care Med. 2007;A507
Mercat A, Richard JC, Brochard L, et al. Comparison of two strategies for setting PEEP in ALI/ARDS (ExPress study). Am J Respir Crit Care Med.

2007;A507
 PEEP and Open Lung Ventilation
 In both the new trials:   ALVEOLI LOVS ExPress

N 583 983 767

1) Higher vent-free days and
       
better compliance in the Aggressive
15 cm H2O* 13 cm H2O* 15 cm H2O*
aggressive PEEP group. PEEP

PaO2/FiO2 222 mm Hg* 187 mm Hg* 218 mm Hg*

2) No mortality benefit. Pplat 27 cm H2O* 30 cm H2O* 27 cm H2O*

3) Non significant subgroup Mortality 27% 36% 28%

benefit in sickest        

patients.  Conservative
PEEP
8 cm H2O* 9 cm H2O* 7 cm H2O*

??? What will meta-analysis PaO2/FiO2 168 mm Hg* 149 mm Hg* 150 mm Hg*

show?  Pplat 24 cm H2O* 25 cm H2O* 21 cm H2O*

Mortality 25% 40% 31%

 PEEP and Open Lung Ventilation
 So……how should we manage our PEEP?
 Thoughts?
 Use enough PEEP to reduce FiO2 to 0.6 or
less while still keeping your plat <30 (after
maximizing your MAP). If unable to do
this…..think about tech (ie HFOV.)
 There is association between higher PEEP and
barotrauma.
 PEEP and Open Lung Ventilation
 What about recruitment maneuvers in the
ALVEOLI study?
 First 80 patients in the High PEEP group were
randomized to recruitment maneuvers vs sham
maneuvers.
 Resulted in only small and transient increases
in PaO2….therefore was discontinued.
 Case
 The patient continues to deteriorate and is now on
inverse ratio PC ventilation (2:1) with a PEEP of 18.
The PaO2 is 68 on FiO2 of 0.80. Hemodynamically
they have actually improved and are requiring only
10 of levophed. They are currently deeply sedated on
propofol and fentenyl and you gain no benefit from
paralysis. There is adequate urin output and the
creatine and lactate have returned to normal. Your
BAL cultures comes back negative viral, bacterial
and fungal.
 Case
 18.Your resident asks if there is anything else we can do
in this situation and if there are any other treatments?
(Your fellow comments on the fact we don’t have a
diagnosis!)
 19. What is the role of lung biopsy in ARDS

I Love
Meduri!!!!!!!!
Lung biopsy in ARDS
 Lung Biopsy
 In general, reserved for carefully selected
patients with ARDs of unclear etiology.
 Suspected Dx of CA, DAH, cryptogenic
organizing pneumonitis, undiagnosis
underlying lung disease such as sarcoidosis,
acute interstitial pneumonia (Hamman-Rich
Syndrome).
Patel, SR, Karmpaliotis, D, Ayas, NT, et al. The role of open-lung biopsy in ARDS. Chest 2004; 125:197
Papazian, L, Thomas, P, Bregeon, F, et al. Open-lung biopsy in patients with acute respiratory distress syndrome. Anesthesiology
1998; 88:935
 Lung Biopsy
 Considered reasonably safe 
 Retrospective review of 57 px with ARDS mean
PaO2/FiO2 ratio of 145 mmHg that received open
lung biopsy.
 Major complication rate=7% (death, hemothorax,
new dialysis), no deaths from procedure.
 Overall complication rate=39% (most air leaks)
 Results of biopsy resulted in additional tx in 60% and
withdrawl of unnecessary tx in 37%.
Patel, SR, Karmpaliotis, D, Ayas, NT, et al. The role of open-lung biopsy in ARDS. Chest 2004; 125:197 .
 Case
 20. Your Fellow is also a believer of Meduri and asks
if we should start steroids? How do you interpret the
literature? what is the best evidence currently?
 21. Your fellow then sheepishly brings up nitric and
pronation. What is the current evidence for these
therapeutic maneuvers?
 22. What are the potential harms with proning and
NO.
 23. Is there currently any role for the use oscillation?
What is the current evidence for oscillation?
Corticosteroids in
ARDS
 Corticosteroids in ARDS
 Studied extensively in ARDS.
 There are clear roles in situations when ARDS
has been precipitated by a steroid-responsive
process (AEP).
 Uncertain how they should be used in other
cases of ARDS.

Davis, WB, Wilson, HE,Wall, RL. Eosinophilic alveolitis in acute respiratory failure. A clinical marker for a non-infectious
etiology. Chest 1986; 90:7
 Corticosteroids in ARDS
 Empirically used for ARDS in 70s and early
80s.
 Used less after several studies found that they
had no benefit and may cause harm.
 In the last several years we have seen many new
studies re-looking at steroids in ARDS.
Weigelt, JA, Norcross, JF, Borman, KR, et al. Early steroid therapy for respiratory failure. Arch Surg 1985; 120:536

Luce, JM, Montgomery, AB, Marks, JD, et al. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury
and improving mortality in patients with septic shock. Am Rev Respir Dis 1988; 138:62
Bernard, GR, Luce, JM, Sprung, CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J
Med 1987; 317:1565
Corticosteroids in ARDS
 Corticosteroids in ARDS
 Recent studies have looked more at the use of steroids
in late ARDS.
 Best and largest study to date is the ARDSnet groups
study.

Steinberg, KP, Hudson, LD, Goodman, RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354:1671
 Corticosteroids in ARDS
 Double Blind RCT
 180 px with persistent ARDS to receive either
methylprednisolone or placebo for 21 days.
 Persistent ARDS= ongoing disease 7 to 28 days after onset.
 No diff in 60 day mortality (29.2% vs 28.6%) or 180 day
mortality (31.5% vs 31.9%)
 Corticosteroids in ARDS
 Px randomized 7-13 days, steroid caused a nonstatistically
significant reduction in 60 day mortality (27% vs 36%) and
180 day mortality (27% vs 39%).
 Px randomized more than 14 days after onset; inc 60 day
mortality (35% vs 8%) and 180 day mortality (44% vs 12%)
 Steroids inc ventilator free days, shock free days, oxygenation,
lung compliance, and blood pressure but also inc
neuromuscular weakness.
 Px in steroid group had a significant inc in reintubation (9% vs
28% p=0.006) as the steroids were stopped post
extubation….did they not find mortality benefit because of
this?
 Based on this trial corticosteroids cannot be recommended in
early or late ARDS.
 Corticosteroids in ARDS
 Recently Meduri revisited steroid use in Early ARDS.
 Double blind RCT. N= 91 in 2:1 ratio.
 Early ARDS (<72 hrs).
 Compared to previous studies, this study gave steroids
in lower doses and for longer duration.
 Corticosteroids in ARDS
 Reduced mech vent,
length of ICU stay, ICU
mortality (21% vs 43%)
….too good to be true?
 Needs repetition and
confirmation before can
be advised!
NO
 NO
 Conceptually NO is a local vasodilator.
 Several well done studies have looked at NO.
 One Multicenter RCT assigned 385 px with
moderate/severe ARDS to placebo vs NO at 5 ppm.
 Induced short-term improvement and oxygenation;
however, no improvement in duration of mech vent,
28 day mortality, or one year survival.

Taylor, RW, Zimmerman, JL, Dellinger, RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury. A randomized controlled trial. JAMA
2004; 291:1603
 NO
 Another multicenter double blind RCT N=177
 Used increasing concentrations of inhaled NO
or placebo.
 Improved oxygenation modestly but was not
sustained.
 No difference in 28 day mortality (not
powered for this).
Dellinger, RP, Zimmerman, JL, Taylor, RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress
syndrome: Results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med 1998; 26:15
 NO
 In addition, meta-analysis of 10 RCTs (1237 px)
 Comparing inhaled NO vs placebo or
conventional Tx.
 NO did not improve mortality, duration of MV,
or ventilator free days.
 It did increase P/F ratio on first day of tx, but
there was no effect on mean pulmonary arterial
pressure.
Adhikari, NK, Burns, KE, Friedrich, JO, et al. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic
review and meta-analysis. BMJ 2007; 334:779
 NO
 Need to keep in mind that there are some potential harms.
1) May produce toxic radicals (unknown if worse than high
FiO2).
2) Methemoglobin and NO2 may inc when high does of NO
are given, and these should both be watched.
3) Inhaled NO have immunosuppressant properties then could
in theory in risk of infection.
4) NO can cuase DNA strand breaks and base alteration.
Eichacker, PQ. Inhaled nitric oxide in adult respiratory distress syndrome: Do we know the risks versus benefits? [editorial]. Crit Care Med 1997; 25:563
Adhikari, NK, Burns, KE, Friedrich, JO, et al. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis.
BMJ 2007; 334:779
Greene, JH, Klinger, JR. The efficacy of inhaled nitric oxide in the treatment of acute respiratory distress syndrome. An evidence-based medicine approach.
Crit Care Clin 1998; 14:387
Weinberger, B, Laskin, DL, Heck, DE, Laskin, JD. The toxicology of inhaled nitric oxide. Toxicol Sci 2001; 59:5
 NO
 Current recommendation?
 What do you think?
 Can be used as a temporizing measure in the
face of profound hypoxia?
 Can be used as a bridge while attempting
recruitment?
Prone Ventilation
 Prone Ventilation
 Mechanisms of action:
 More homogeneous Ppl
gradient in ventrodorsal and
cephalocaudal planes.
 Increased FRC and V/Q
matching.
 Improved bronchial drainage.
 Improved aerosol delivery.
 Abdomen is unsupported.
Pelosi, P, Brazzi, L, Gattinoni, L. Prone position in acute respiratory distress syndrome.
Eur Respir J 2002; 20:1017
 Prone Ventilation
 Efficacy: Two primary outcomes that have been
studied are oxygenation and mortality.
 Oxygenation:
 Originally reported to improve in case series in the
70s.
 Prospective studies have now shown that prone
position will increase oxygenation in 60-80% of Px.
 Some will maintain improved oxygenation even
after return to supine.
Piehl, MA, Brown, RS. Use of extreme position changes in acute respiratory failure. Crit Care Med 1976; 4:13
Papazian, L, Gainnier, M, Marin, V, et al. Comparison of prone positioning and high-frequency oscillatory ventilation in
patients with acute respiratory distress syndrome. Crit Care Med 2005; 33:2162
Chatte, G, Sab, JM, Dubois, JM, et al. Prone position in mechanically ventilated patients with severe acute respiratory failure.
Am J Respir Crit Care Med 1997; 155:473
Fridrich, P, Krafft, P, Hochleuthner, H, Mauritz, W. The effects of long-term prone positioning in patients
with trauma-induced adult respiratory distress syndrome. Anesth Analg 1996; 83:1206
 Prone Ventilation
 Additionally, patients whose oxygenation improves during trial of
prone positioning tend to improve each time prone positioning
repeated.

Chatte, G, Sab, JM, Dubois, JM, et al. Prone position in mechanically ventilated patients with severe acute respiratory failure. Am J Respir Crit Care Med 1997;
155:473
Fridrich, P, Krafft, P, Hochleuthner, H, Mauritz, W. The effects of long-term prone positioning in patients with trauma-induced adult
respiratory distress syndrome. Anesth Analg 1996; 83:1206
 Prone Ventilation
 Mortality: Published studies have not shown a
survival advantage!!
 RCT, N=304 with ALI/ARDS randomized to
supine vent or six hours prone daily for 10 days.
Improved PaO2/FiO2 but not 10-day, ICU, 6
months mortality.
 Risk of complications similar.
 Post-hoc suggest dec 10 day mort in sickest Px with
PaO2/FiO2 < 88 (23.1% vs 47.2%)
 ?? Relatively short duration of proning, used low
levels of PEEP and Vt of >10cc/kg
Gattinoni, L, Tognoni, G, Pesenti, A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N
Engl J Med 2001; 345:568
 Prone Ventilation
 Another RCT, N=791 with ALI randomized to supine
vs prone for 8 hr/day (most got only 4 days worth)
 Inc PaO2/FiO2 for first 28 days (p<0.001), but no
change 28 day (32.4% vs 31.5%), 90 day mortality
(43.4% vs 42.2%) or duration of Mech Vent.
 Statistically significant inc in complications.
- Selective intubation (p=0.01)
- ETT obstruction (p=0.002)
- Pressure sores (p=0.005)
Guerin, C, Gaillard, S, Lemasson, S, et al. Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial.
JAMA 2004; 292:2379
 Prone Ventilation
 More recent well designed trial by Mancebo.
 Multicenter RCT, N=136 with ARDS. Randomized
to supine vs “high dose” prone vent. Both groups had
standardized ventilation and weaning strategy.
 Px proned were that way for average of 17 hrs a day
for mean of 10 days.
 Improved mortality (43% vs 58% p=0.12)
 Multivariate analysis found that supine position was
independent predictor of mortality!
Mancebo, J, Fernandez, R, Blanch, L, et al. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2006;
173:1233
 Prone Ventilation
 Predicting Benefit based on physiology:
 Px with early diffuse lung injury with edematous lungs
and dependent collapse respond best to prone position.
 Px with anterior predominance of infiltrates or injury
with marked consolidation or fibrosis do not!
 Therefore, Px with an extrapulmonary cause of ARDS
and diffuse disease are more likely to benefit!
 Additionally, Px with inc IAP and poor chest wall
compliance may benefit.
Lim, CM, Kim, EK, Lee, JS, et al. Comparison of the response to the prone position between pulmonary and extrapulmonary acute respiratory distress syndrome. Intensive Care
Med 2001; 27:477
Mure, M, Glenny, RW, Domino, KB, Hlastala, MP. Pulmonary gas exchange improves in the prone position with abdominal
distension. Am J Respir Crit Care Med 1998; 157:1785
 Prone Ventilation
 Contraindications:
 Spinal instability
 Hemodynamic and cardiac rhythm disturbances
 Multiple trauma
 Pregnancy
 Raised intracranial pressure
 Abdominal surgery
Curley, MA. Prone positioning of patients with acute respiratory distress syndrome: a systematic review. Am J Crit Care 1999;

8:397
 Prone Ventilation
 Complications:
 Nerve compression
 Crush injury
 Venous stasis
 Airway security
 Pressure sores
 Dislodging vascular catheters
 Retinal damage
 Prone Ventilation
 Conclusions:
 Improve oxygenation but not mortality.
 May benefit the sickest ARDS Px if used early and for
prolonged periods (? Px with diffuse, non-pulmonary
ARDS).
 Think about in people with high abd pressures and non-
compliant chest walls.
 May attempt if goals of lung-protective vent are not
being met, if there is persistent acidosis or tissue
hypoxia despite standard ventilation.
 Another study showed improved oxygenation with
HFOV post proning!!
High-frequency
Ventilation
 High-frequency Ventilation
 Proposed as alternate form of lung protective
ventilation.
 Theoretically could prevent overdistention and cyclic
atelectasis.
 Combines very high respiratory rates with tidal
volumes that are smaller than the anatomic dead space.
 Multiple mechanisms of gas transport.

Wunsch, H, Mapstone, J. High-frequency ventilation versus conventional ventilation for treatment of acute lung injury and acute respiratory distress syndrome. Cochrane Database
Syst Rev 2004; :CD004085
High-frequency Ventilation
 High-frequency Ventilation
 4 basic types:
1) High-frequency positive
pressure ventilation.
2) High-frequency jet
ventilation (HFJV)
3) High-frequency oscillatory
ventilation (HFOV)
4) High-frequency percussive
ventilation (FFPV)
** We only use HFOV and is
what will be discussed!
 High-frequency Ventilation
 Vt is employed using a oscillatory pump.
 Set the MAP (which is higher than
conventional ventillarion) by adjusting flow
rate and expiratory back pressure.
 The ventilator then oscillates around this MAP
and avoids low end-expiratory pressures and
high peak pressures.
 High-frequency Ventilation
 Optimize oxygenation by manipulating MAP
and FiO2.
 Optimize ventilation by adjusting amplitude
(Vt), frequency, or introduction of a cuff leak.
 Primarily studied in children and neonates.
 Several non-randomized trials showed
improvements in oxygenation but not mortality.
Derdak, S, Mehta, S, Stewart, TE, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a
randomized, controlled trial. Am J Respir Crit Care Med 2002; 166:801
 High-frequency Ventilation
 Multicenter RCT, N=148, HFOV vs PCV (6-10cc/kg)
 MAP was higher in HFOV group compared to PCV
(expected)
 HFOV group showed earlier improvements in
PaO2/FiO2 (<16 hours, p=0.0008). This did not last
longer than 24 hours.
 30 day mortality rate was lower in HFOV but no stat.
sig. (37% vs 52%, p=0.10)
 Control group had higher tidal volumes than
recommended (8 +/- 2 ml/kg)
Derdak, S, Mehta, S, Stewart, TE, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled
trial. Am J Respir Crit Care Med 2002; 166:801
 High-frequency Ventilation
 Another RCT, N=61 with ARDS, HFOV vs
conventional.
 Improvement in oxygenation but not in mortality.
 But trial was small and had poor recruitment, early
termination, and unequal oxygenation index in groups
after randomization.
 Both of these trials enrolled Px before the benefits of
low tidal volume ventilation were know!
Bollen, CW, van Well, TJ, Sherry, T, et al. High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory
distress syndrome: a randomized controlled trial (ISRCTN24242669). Crit Care, 2005, 9:430
 High-frequency Ventilation
 Risks of barotrauma and hemodynamic
compromise with high frequency are
comparable to conventional ventilation.
 We are currently waiting for the results of
the OSCILLATE trial!
Demory, D, Michelet, P, Arnal, JM, et al. High-frequency oscillatory ventilation following prone positioning
prevents a further impairment in oxygenation. Crit Care Med 2007; 35:106
Gluck, E, Heard, S, Patel, C, et al. Use of ultrahigh frequency ventilation in patients with ARDS:
A preliminary report. Chest 1993; 103:1413
 Other contraversial treatments
 ECMO= CAESAR study (?positive) to be
presented at SCCM
 Partial liquid ventilation= Negative, not
recommended
 Current multicenter phase II trial looking at
APC in ALI (expected to finish 2008)
 GM-CSF
 Aerosolized B-agonist therapy in ALI/ARDS.
 ECCO2R (Novalung)
 Other contraversial treatments
 Also know about:
 IRV
 APRV
 Currently found to have short-term
physiologic benefits but b/c lack of RCT not
recommended for routine use at this time.
Complications of
ARDS
 Complications
 Primary complications:
1) Barotrauma
2) Nosocomial infection
3) MOF
4) DVT
5) Untoward effects from sedation and paralysis
 Barotrauma
 When air escapes the alvolar space and migrates into
the extrapulmonary compartments.
 Includes pneumothorax, interstitial emphysema, SC
emphysema, pneumomediastinum,
pneumoperitoneum and air embolism.
 In one study specifically looking at barotrauma in
100 ARDS Px:
 13% of ARDS Px.
 Directly contributed to death in less than 2%.
Schnapp, LM, Chin, DP, Szaflarski, N, et al. Frequency and importance of barotrauma in 100 patients with acute lung injury. Crit
Care Med 1995; 23:272
 Barotrauma
 In another study of 84 Px with ARDS mortality
rates were:
 66% in Px with pneumothorax.
 46% in Px without pneumothorax.
 In different study looking at 725 Px with ARDS
there was no significant difference in mortality
among Px with and without barotrauma.
Gattinoni, L, Bombino, M, Pelosi, P, et al. Lung structure and function in different stages of severe adult respiratory distress
syndrome. JAMA 1994; 271:1772
Weg, JG, Anzueto, A, Balk, RA, et al. The relation of pneumothorax and other air leaks to mortality in the acute respiratory distress
syndrome. N Engl J Med 1998; 338:341
 Barotrauma
 Currently unclear if results from high airway
pressures or is simply a marker of severe lung injury.
 Retrospective analysis of ARDSnet trial found that
peak, mean, plateau and driving pressures do not
seem to correlate with risk of pneumothorax.
 They did find that higher levels of PEEP associated
with increased risk of barotrauma.

Eisner, MD, Thompson, BT, Schoenfeld, D, et al. Airway pressures and early barotrauma in patients with acute lung injury and acute respiratory distress
syndrome. Am J Respir Crit Care Med 2002; 165:978
Outcome
 Outcome
 Survival has improved for Px with ARDS, with
mortality decreasing from 67% in 1990 to 30% in 2006.
 Likely related to improved supportive care and
ventilatory strategies.
 One study suggests that the improved mortality is
limited to Px with ARDS and no sepsis (eg Trauma
related ARDS)
Wheeler, AP, Bernard, GR, Thompson, BT, et al. Pulmonary-artery versus central venous catheter to guide
treatment of acute lung injury. N Engl J Med 2006; 354:2213
Wiedemann, HP, Wheeler, AP, Bernard, GR, et al. Comparison of two fluid-management strategies in acute lung
injury. N Engl J Med 2006; 354:2564
Stapleton, RD, Wang, BM, Hudson, LD, et al. Causes and timing of death in patients with ARDS. Chest 2005;
128:525
 Outcomes
 Survivors may have abnormalities in pulmonary
function and exercise endurance, which can persist
for years (no changes with low tidal volume vent).
 In addition, impaired neurocognitive function and
quality of life have been reported two years after
acute illness.

Neff, TA, Stocker, R, Frey, HR, et al. Long-term assessment of lung function in survivors of severe ARDS. Chest 2003; 123:845
Orme, J Jr, Romney, JS, Hopkins, RO, et al. Pulmonary function and health-related quality of life in survivors of acute respiratory
distress syndrome. Am J Respir Crit Care Med 2003; 167:690
Hopkins, RO, Weaver, LK, Collingridge, D, et al. Two-Year Cognitive, Emotional, and Quality-of-Life Outcomes in Acute
Respiratory Distress Syndrome. Am J Respir Crit Care Med 2005; 171:340
 Outcomes
 Factors that are correlated with abnormal
lung fxn one year after recovery:
1) Duration of PPV
2) Lowest static thoracic compliance
3) Mean PA pressure
4) Requiring FiO2 >0.6 for more than 24 hrs.
 Outcomes
 Factors correlating with better functional
outcome at one year:
1) Absence of steroid treatment
2) Absence of illness acquired during ICU stay
3) Rapid resolution of lung injury

Herridge, MS, Cheung, AM, Tansey, CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003; 348:683
Elliott, CG, Rasmusson, BY, Crapo, RO, et al. Prediction of pulmonary function abnormalities after adult respiratory distress
syndrome (ARDS). Am Rev Respir Dis 1987; 135:634
Ghio, AJ, Elliott, CG, Crapo, RO, et al. Impairment after adult respiratory distress syndrome. An evaluation based on American
Thoracic Society recommendations. Am Rev Respir Dis 1989; 139:1158
Conclusions
 Conclusions
 ARDS common entity in the ICU.
 Think about other diagnosis that can present
like ARDS.
1) DAD
2) AIP
3) IAEP
4) ICP
 Conclusion
 Use bronchoscopy/BAL early.
 Think about lung biopsy if diagnosis uncertain.
 Low tidal volume, optimize PEEP for now.
 NO as a bridge?
 Proning in specific cases.
 Say no to drugs! (steroids)
 Watch for OSCILLATE/ CEASAR