Acute Respiratory
Distress Syndrome
Alice Gray, MD
Duke University Medical Center
March 21, 2007
Objectives
Define ARDS and describe the
pathological process
 Know causes of ARDS, and differential
diagnosis
 Understand specific challenges in
mechanical ventilation of patients with
ARDS
 Understand treatment strategies and
evidence behind them

ARDS
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First described 1967 by Ashbaugh and colleagues
Severe lung injury characterized by noncardiogenic pulmonary edema, decreased lung
compliance, refractory hypoxemia
1994 Consensus Definition
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Acute onset (<2 weeks)
Bilateral infiltrates on chest xray
PCWP ≤18mmHg or lack of evidence of left atrial
hypertension
Acute lung injury if PaO2/FiO2 ≤300
ARDS if PaO2/FiO2 ≤200
Epidemiology
Incidence of acute lung injury (ALI): 17.978.9 cases per 100,000 person-years
 Incidence of acute respiratory distress
syndrome (ARDS): 13.5-58.7 cases per
100,000 person-years
 Approx 9% of ICU beds in US

N Engl J Med. 2005;353:1685-93. Am J Respir Crit Care Med. 1999;159:1849-61.
Most common causes ARDS
Pneumonia (34%)
 Sepsis (27%)
 Aspiration (15%)
 Trauma (11%)

Pulmonary contusion
 Multiple fractures

ARDSnet NEJM 2000:342:1301-8.
Causes of ARDS
NEJM 2000;342,18:1334-1349
Risk factors for ARDS
Preexisting lung disease
 Chronic alcohol use
 Low serum pH
 Sepsis
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
40% of patients with sepsis develop
ARDS
Differential diagnosis
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Pulmonary edema from left
heart failure
Diffuse alveolar
hemorrhage
Acute eosinophilic
pneumonia
Lupus pneumonitis
Acute interstitial pneumonia
Pulmonary alveolar
proteinosis
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BOOP or COP
Hypersensitivity
pneumonitis
Leukemic infiltrate
Drug-induced pulmonary
edema and pneumonitis
Acute major pulmonary
embolus
Sarcoidosis
Interstitial pulmonary
fibrosis
Excluding other diagnoses
Echo
 Central venous catheter
 Bronchoscopy with bronchoalveolar
lavage (to eval for hemorrhage, AEP,
etc)
 Chest CT

Acute (Exudative) Phase
Rapid onset respiratory failure in patient
at risk for ARDS
 Hypoxemia refractory to oxygen
 Chest xray resembles cardiogenic
pulmonary edema

Bilateral infiltrates worse in dependent
lung zones, effusions
 Infiltrates may be asymmetric

Acute Phase - Radiographs
NEJM 2000;342,18:1334-1349
Pathological findings
Diffuse alveolar damage
 Neutrophils, macrophages, erythrocytes
 Hyaline membranes
 Protein-rich edema in alveolar spaces

Acute (Exudative) Phase
Alveolar Filling
Expansion of
interstitium with
macrophages and
inflammation
Hyaline
Membranes
Fibroproliferative Phase
Persistent hypoxemia
 Fibrosing alveolitis
 Increased alveolar dead space
 Decreased pulmonary compliance
 Pulmonary hypertension

From obliteration of capillary bed
 May cause right heart failure

Fibroproliferative phase
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Chest xray shows linear opacities consistent with
evolving fibrosis
Pneumothorax in 10-13% of patients
CT: diffuse interstitial opacities and bullae
Histologically, fibrosis, mesenchymal cells,
vascular proliferation, collagen and fibronectin
accumulation
Can start 5-7 days after symptom onset
Not present in every patient with ARDS, but does
portend poorer prognosis
Fibroproliferative phase
NEJM 2000;342,18:1334-1349
Fibrosing alveolitis
NEJM 2000;342,18:1334-1349.
Recovery phase

Gradual resolution of hypoxemia
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Hypoxemia improves as edema resolves via active
transport Na/Cl, aquaporins
Protein removal via endocytosis
Re-epithelialization of denuded alveolar space with
type II pneumocytes that differentiate into type I cells
Improved lung compliance
Chest xray and CT findings resolve
PFTs improve, often normalize
Management of ARDS

Treat underlying illness

Sepsis, etc
Nutrition
 Supportive care
 DVT prophylaxis
 GI prophylaxis
 Medications

Complications in Managing
ARDS patients

Mechanical ventilation causes:

Overdistention of lungs (volutrauma)
• Further damaging epithelium
• Increased fluid leak, indistinguishable from ARDS damage

Barotrauma
• Rupture alveolar membranes
• Pneuomothorax, pneumomediastinum

Sheer stress
• Opening/closing alveoli
• Inflammatory reaction, cytokine release
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Oxygen toxicity

Free radical formation
ARDS Network
NIH-funded consortium of 10 centers,
24 hospitals, 75 intensive care units
 Goal to design large RCTs to
determine effective treatments
 Key ARDSnet studies:

Ventilator volumes
 Steroids
 PEEP
 Volume management/PA catheter

Pulmonary artery catheters
Often used to help evaluate for cardiogenic
pulmonary edema
 SUPPORT trial (retrospective study) first
raised doubts about utility
 Two multicenter RCTs confirmed lack of
mortality benefit of PA catheters in ARDS
(ARDSnet FACTT)
 Monitoring CVP equally effective, so PAC not
recommended in routine management

JAMA. 1996;276:889-97. N Engl J Med. 2006:354:2213-24
Ventilator management –
ARDSnet protocol
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861 patients randomized to Vt 10-12 mg/kg ideal
body weight and plateau pressure ≤50cmH2O vs
Vt 6-8 mg/kg IBW and plateau pressure ≤30cm
H2O
KEYS
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Low tidal volumes – 6-8mL/kg ideal body weight
Maintain plateau (end-inspiratory) pressures <30cm
H20
Permissive hypercapnia and acidosis
Decreased mortality by 22%
NEJM 2000;342:1301-8.
ARDSnet Tidal Volume
Study
NEJM 2000;342:1301-8.
Positive End-Expiratory
Pressure (PEEP)

Titrate PEEP to decrease FiO2

Goal sat 88% with FiO2 <60%
• Minimize oxygen toxicity
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PEEP can improve lung recruitment and decrease
end-expiratory alveolar collapse (and therefore
right-to-left shunt)
Can also decrease venous return, cause
hemodynamic compromise, worsen pulmonary
edema
ARDSnet PEEP trial of 549 patients show no
difference in mortality or days on ventilator with
high vs low PEEP
NEJM 2004:351(4):327-336
Other Ideas in Ventilator
Management

Prone positioning

May be beneficial in certain subgroup, but
complications including pressure sores
• RCT of 304 patients showed no mortality benefit

High-frequency oscillatory ventilation
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In RCT, improved oxygenation initially, but results not
sustained after 24 hours, no mortality benefit
ECMO

RCT of 40 adults showed no benefit
JAMA 1979;242:2193-6. Am J Respir Crit Care Med. 2002;166:801-8
Drug therapy
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Agents studied:
Corticosteroids
 Ketoconazole
 Inhaled nitric oxide
 Surfactant
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No benefit demonstrated
Steroids in ARDS
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Earlier studies showed no benefit to early use steroids,
but small study in 1990s showed improved
oxygenation and possible mortality benefit in late stage
ARDSnet trial (Late Steroid Rescue Study “LaSRS” –
“lazarus”) of steroids 7+ days out from onset of ARDS
180 patients enrolled, RCT methylprednisolone vs
placebo
Overall, no mortality benefit

Steroids increased mortality in those with sx >14 days
JAMA 1998;280:159-65, N Engl J Med 2006;354:1671-84
Steroids in ARDS
N Engl J Med 2006;354:1671-84
Other drugs in ARDS
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Ketoconazole
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Surfactant
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ARDSnet study of 234 patients, ketoconazole did NOT
decrease mortality, duration of mechanical ventilation or
improve lung function
Multicenter trial, 725 patients with sepsis-induced
ARDS, surfactant had no effect on 30-day survival, ICU
LOS, duration of mechanical ventilation or physiologic
function
Inhaled Nitric oxide

177 patients RCT, improved oxygenation, but no effect
on mortality of duration of mechanical ventilation
N Engl J Med. 1996;334:1417-21. Crit Care Med. 1998;26:15-23.
Fluid management
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“Dry lungs are happy lungs”
ARDSnet RCT of 1000 patients (FACTT),
Conservative vs liberal fluid strategy using CVP or
PAOP monitoring to guide, primary outcome:
death. Conservative fluids
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Improved oxygenation
More ventilator-free days
More days outside ICU
No increase in shock or dialysis
No mortality effects
ARDSnet Fluid Management
NEJM 2006;354:2564-75.
Keys to management
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Treat underlying illness
Supportive care
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Low tidal volume ventilation
Nutrition
Prevent ICU complications
•
•
•
•
•
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Stress ulcers
DVT
Nosocomial infections
Pneumothorax
No routine use of PA catheter
Diuresis/avoidance of volume overload
Give lungs time to recover
Survival and Long Term
Sequelae
Traditionally mortality 40-60%
 May be improving, as mortality in more
recent studies in range 30-40%
 Nonetheless survivors report decreased
functional status and perceived health
 79% of patients remember adverse events in
ICU
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29.5% with evidence of PTSD
1 year after ARDS survival
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Lung Function:
 FEV1 and FVC were normal; DLCO minimally reduced
 Only 20% had mild abnormalities on CXR
Functionally:
 Survivors’ perception of health was <70% of normals
in:
• Physical Role: Extent to which health limits physical activity
• Physical Functioning: Extent to which health limits work
• Vitality: Degree of energy patients have


6 minutes walk remained low
Only 49% had returned to work
NEJM 2003: 348: 683-693
Summary
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ARDS is a clinical syndrome characterized by
severe, acute lung injury, inflammation and scarring
Significant cause of ICU admissions, mortality and
morbidity
Caused by either direct or indirect lung injury
Mechanical ventilation with low tidal volumes and
plateau pressures improves outcomes
So far, no pharmacologic therapies have
demonstrated mortality benefit
Ongoing large, multi-center randomized controlled
trials are helping us better understand optimal
management
References
Rubenfeld GD, et al. Incidence and outcomes of acute lung injury N Engl J Med.
2005;353:1685-93.
Luhr OR, et al. Incidence and mortality after acute respiratory failure and acute respiratory
distress syndrome in Sweden, Denmark, and Iceland. The ARF study group. Am J
Respir Crit Care Med. 1999;159:1849061,
Bersten AD et al. Australian and New Zealand Intensive Care Society Clinical Trials Group.
Incidence and mortality of acute lung injury and the acute respiratory distress syndrome
in three Australian states. Am J Respir Crit Care Med. 2002;165:443-8.
Connors AF Jr, et al. The effectiveness of right heart catheterization in the initial care of
critically ill patients. SUPPORT investigators. JAMA. 1996;276:889-97.
Richard C, et al. Early use of the pulmonary artery catheter and outcomes in patients with
shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA.
2003;290:2713-20.
Wheeler AP, et al. Pulmonary-artery versus central venous catheter to guide treatment of
acute lung injury. N Engl J Med. 2006:354:2213-24.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung
injury and the acute respiratory distress syndrome. The Acute Respiratory Distress
Syndrome Network. N Engl J Med. 2000;342:1301-8.
National Heart, Lung and Blood Institues Acute Respiratory Distress (ARDS) Clinical Trials
Network. Comparison of two fluid-management strategies in acute lung injury. N Enlg J
Med. 2006;354:2564-75.
Kollef, MH, Schuster DP. The acute respiratory distress syndrome. N Engl J Medicine
1995;332(1):27-37.
References
Ketoconazole for early treatment of acute lung injury and acute respiratory distress
syndrome: a randomized controlled trial. JAMA. 2000;283:1995-2002.
Anzueto A, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory
distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group.
N Engl J Med. 1996;334:1417-21.
Dellinger RP et al. Effects of inhaled nitric oxide in patients with acute respiratory distress
syndrome: results of randomized phase II trial. Inhaled Nitric Oxide in ARDS Study
Group. Crit Care Med. 1998;26:15-23.
Zapol WM, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A
randomized prospective study. JAMA 1979;242:2193-6.
Derdak S, et al. High-frequency oscillatory ventilation for adult respiratory distress syndrome:
a randomized controlled trial. Am J Respir Crit Care Med. 2002;166:801-8.
Bernard GR, et al. High-dose steroids in patients with the adult respiratory distress
syndrome. N Engl J Med. 1987;317:1565-70.
Steinberg KP, et al. Efficacy and safety of corticosteroids for persistent acute respiratory
distress syndrome. N Engl J Med. 2006:354:1671-84.
Ware LB, MA Matthay. The acute respiratory distress syndrome. N Engl J Med
2000;342:1334-49.
Meduri GU et al. Effect of prolonged methylprednisolone therapy in unresolving acute
respiratory distress syndrome: a randomized controlled trial. JAMA 1998;280:159-65.
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS)
Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute
respiratory distress syndrome. N Engl J Med 2006;354:1671-84.