ards gray
TRANSCRIPT
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 non-
cardiogenic 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): 17.9-78.9 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 contusionMultiple 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 edemaBilateral infiltrates worse in dependent
lung zones, effusionsInfiltrates 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
Expansion of interstitium with macrophages and inflammation Hyaline
Membranes
Alveolar Filling
Fibroproliferative Phase
Persistent hypoxemia Fibrosing alveolitis Increased alveolar dead space Decreased pulmonary compliance Pulmonary hypertension
From obliteration of capillary bedMay 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 illnessSepsis, 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 volumesSteroidsPEEPVolume 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:CorticosteroidsKetoconazoleInhaled nitric oxideSurfactant
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
ICU29.5% 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.