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

First described 1967 by Ashbaugh and colleagues

Severe lung injury characterized by noncardiogenic pulmonary edema, decreased lung
compliance, refractory hypoxemia
1994 Consensus Definition
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

40%

of patients with sepsis develop

ARDS

Differential diagnosis

Pulmonary edema from left

heart failure
Diffuse alveolar hemorrhage
Acute eosinophilic
pneumonia
Lupus pneumonitis
Acute interstitial pneumonia
Pulmonary alveolar
proteinosis

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
Membran
es

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

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

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

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

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
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

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

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

Agents studied:
Corticosteroids
Ketoconazole
Inhaled

nitric oxide
Surfactant

No benefit demonstrated

Steroids in ARDS

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

Ketoconazole
ARDSnet

study of 234 patients, ketoconazole did NOT

decrease mortality, duration of mechanical ventilation or
improve lung function

Surfactant
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

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
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

Treat underlying illness

Supportive care
Low

tidal volume ventilation

Nutrition
Prevent ICU complications

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

29.5%

with evidence of PTSD

1 year after ARDS survival

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

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.