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Acute Respiratory Distress Syndrome

Alice Gray, MD

Duke University Medical Center

March 21, 2007

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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

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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

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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.

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Most common causes ARDS

Pneumonia (34%) Sepsis (27%) Aspiration (15%) Trauma (11%)

Pulmonary contusionMultiple fractures

ARDSnet NEJM 2000:342:1301-8.

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Causes of ARDS

NEJM 2000;342,18:1334-1349

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Risk factors for ARDS

Preexisting lung disease Chronic alcohol use Low serum pH Sepsis

40% of patients with sepsis develop ARDS

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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

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Excluding other diagnoses

Echo Central venous catheter Bronchoscopy with bronchoalveolar

lavage (to eval for hemorrhage, AEP, etc)

Chest CT

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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

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Acute Phase - Radiographs

NEJM 2000;342,18:1334-1349

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Pathological findings

Diffuse alveolar damage Neutrophils, macrophages, erythrocytes Hyaline membranes Protein-rich edema in alveolar spaces

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Acute (Exudative) Phase

Expansion of interstitium with macrophages and inflammation Hyaline

Membranes

Alveolar Filling

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Fibroproliferative Phase

Persistent hypoxemia Fibrosing alveolitis Increased alveolar dead space Decreased pulmonary compliance Pulmonary hypertension

From obliteration of capillary bedMay cause right heart failure

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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

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Fibroproliferative phase

NEJM 2000;342,18:1334-1349

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Fibrosing alveolitis

NEJM 2000;342,18:1334-1349.

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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

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Management of ARDS

Treat underlying illnessSepsis, etc

Nutrition Supportive care DVT prophylaxis GI prophylaxis Medications

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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

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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

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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

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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.

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ARDSnet Tidal Volume Study

NEJM 2000;342:1301-8.

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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

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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

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Drug therapy

Agents studied:CorticosteroidsKetoconazoleInhaled nitric oxideSurfactant

No benefit demonstrated

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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

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Steroids in ARDS

N Engl J Med 2006;354:1671-84

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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.

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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

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ARDSnet Fluid Management

NEJM 2006;354:2564-75.

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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

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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

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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

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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

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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.

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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.