Acute respiratory distress syndrome (ARDS)

Essential Evidence

Updated: 2019-12-03

Overall Bottom Line

  • Brain natriuretic peptide (BNP) is helpful in differentiating acute respiratory distress syndrome (ARDS) from cardiogenic pulmonary edema. SORT C
  • In patients with indeterminate levels of BNP, echocardiogram or pulmonary artery catheterization may be required to make the diagnosis of ARDS. SORT C
  • Ventilatory strategies using lower tidal volumes (6 mL/kg) and lower airway pressures (end-expiratory plateau pressure of <30 cm H2O) have been associated with lower mortality from ARDS and have decreased the length of time required for mechanical ventilation. SORT A
  • There is some evidence that corticosteroids can reduce mortality and time on the ventilator. SORT B

Background

Background

ARDS is a severe manifestation of acute lung injury (ALI). ALI is defined as a syndrome of acute and persistent lung inflammation with increased vascular permeability. 16

Incidence

  • A prospective multicenter cohort study indicated that ALI was more common than previously thought, with an age-adjusted incidence of 86.2 per 100,000 patient years and a mortality of 38%.
  • Extrapolation of these data suggests 190,600 cases of ALI per year, associated with 74,000 deaths. 15

Other Impact

  • Among ICU patients, 10% to 15% of all patients meet criteria for ARDS, and up to 20% of intubated patients meet criteria for ARDS.

Causes of the Condition

  • Sepsis (the most common cause of ARDS)
  • Aspiration of gastric contents
  • Infectious pneumonia
  • Severe trauma and surface burns
  • Massive blood transfusion
  • Transfusion-related lung injury (TRALI)
  • Relief of upper airway obstruction
  • Lung or bone marrow (and stem cell) transplantation
  • Drug overdose (aspirin, cocaine, opioids, phenothiazines, tricyclic antidepressants)
  • Idiosyncratic drug reactions (protamine, nitrofurantoin, many chemotherapeutic agents)

Pathophysiology

  • The exudative phase is the initial pathologic state, which is characterized by diffuse alveolar damage due to inflammatory injury. This is manifest by proteinaceous fluid in the alveoli and functional loss of surfactant leading to alveolar collapse. The consequences of this lung injury are impaired gas exchange, decreased pulmonary compliance, and pulmonary hypertension.
  • The proliferative phase occurs over the first week as there is resolution of alveolar edema and the hyperplasia of type II pneumocytes, interstitial myofibroblasts, and deposition of interstitial collagen.
  • The fibrotic phase is a third phase not seen in all patients and is characterized by disruption of lung architecture, diffuse lung fibrosis, and cyst formation.

Diagnosis

Diagnosis

Bottom Line

  • Patients with bilateral pulmonary infiltrates and a PaO2/FIO2 ratio of less than 200 mm Hg should be given a test for BNP. SORT C [calculator]1
  • A BNP of less than 200 makes the diagnosis of ARDS more likely, whereas a BNP of greater than 1200 makes the diagnosis of cardiogenic pulmonary edema more likely. SORT C [calculator]1
  • BNP levels between 200 and 1200 are not useful in distinguishing between ARDS and cardiogenic pulmonary edema. [calculator]1 In this case a transthoracic echocardiogram or pulmonary artery catheter may be required for the diagnosis. SORT C

Differential Diagnosis

DiagnosisFeatures
Cardiogenic pulmonary edemaIf the BNP is less than 100 (or <200 if the glomerular filtration rate [GFR] is <60 mL/min), congestive heart failure is unlikely.
Diffuse alveolar hemorrhage syndromesBloody fluid is obtained from bronchoalveolar lavage (BAL).
Acute interstitial pneumonia (Hamman-Rich syndrome)This is a rare, fulminant lung disease that is essentially indistinguishable from ARDS; it occurs in patients most often over fifty with no prior lung disease.
Idiopathic acute eosinophilic pneumoniaEosinophils are recovered from BAL, peripheral eosinophilia is inconsistently present, and a dramatic response to corticosteroids is seen.
Lymphangitic carcinomatosisThis is most commonly from leukemia or lymphoma but can also be seen in solid tumors.

Diagnostic Criteria

  • ALI is characterized by three clinical features: (1) bilateral radiographic infiltrates; (2) PaO2/FIO2 between 200 and 300 mm Hg regardless of positive end-expiratory pressure (where FIO2 is expressed as between 0.21 and 1.0); and (3) there is no clinical evidence for an elevated left atrial pressure. If measured, the pulmonary capillary wedge pressure is less than 18 mm Hg.
  • The definition of ARDS is the same as that of ALI except that the hypoxia is worse, with a PaO2/FIO2 of 200 mm Hg or less. 16

Using the History and Physical

  • Acute onset of dyspnea is the hallmark of ARDS.
  • Cyanosis is seen if oxygen desaturation is present.
  • Look for risk factors for ARDS including those producing direct lung injury (ie, aspiration, diffuse pneumonia, toxic gas inhalation) and those conditions associated with indirect injury (sepsis, shock, acute pancreatitis, drug overdose, and severe nonthoracic trauma).
  • Use the physical examination to help exclude the probability of an ARDS "mimic" such as congestive heart failure (CHF; look for jugular venous distention [JVD], S3, acute heart murmur); however, ancillary diagnostic studies are commonly needed for precise diagnosis.

Selecting Diagnostic Tests

  • There is no single "gold standard" diagnostic test for ARDS. Instead, a combination of tests, including clinical impression, CXR, BNP, echocardiography, and occasionally pulmonary artery catheterization has been used to make a diagnosis of ARDS.
  • In patients with acute respiratory failure and bilateral infiltrates, a very low BNP 1 level helps rule in ARDS (LR = 4.6), and a very high BNP (>1200 pg/mL) makes the diagnosis of cardiogenic pulmonary edema (CPE) more likely (LR = 6.52). Intermediate levels of BNP (200-1200 pg/mL) are not helpful in differentiating ARDS from CPE. [calculator]1
  • Transthoracic echocardiography that shows significant aortic or mitral valve dysfunction or severe left ventricular systolic dysfunction makes CPE a more likely diagnosis than ARDS. However, CPE may be present with normal ventricular function in the setting of acute myocardial ischemia or diastolic dysfunction.
  • When the diagnosis remains uncertain following clinical evaluation, BNP, and transthoracic echocardiogram, placement of a pulmonary artery catheter is a reasonable option. If the pulmonary capillary wedge pressure is greater than 18 mm Hg, some degree of CPE is present. Interpretation of the pulmonary capillary wedge pressure can be misleading in patients on very high levels of positive end-expiratory pressure (PEEP).
  • If a pulmonary artery catheter is required for diagnostic purposes, it should be removed as soon as feasible.

Approach to the Patient

Diagnostic Tests

Treatment

Treatment

Bottom Line

  • Mechanical ventilation using lower tidal volumes (6 mL/kg) resulted in decreased mortality and fewer days requiring mechanical ventilation. SORT A [poem]14
  • High-frequency oscillation and ECMO do not reduce hospital and 30-day mortality due to ARDS compared to conventional mechanical ventilation. [poem]22 SORT B [cochrane]13
  • In patients receiving low tidal volumes (6 mL/kg) and an end-inspiratory plateau-pressure limit of 30 cm of water, outcomes are similar whether lower or higher levels of PEEP are used. SORT B 2
  • There is no clearly effective specific pharmacotherapy at the present time. SORT B [poem]14 [cochrane]30
  • There is some evidence that methylprednisolone 1 mg/kg/d by continuous intravenous infusion increased the number of patients breathing without the ventilator at 7 days (NNT = 4) and reduced ICU mortality (NNT = 5). SORT B 11

Drug Therapy

  • A Cochrane review of 48 RCTs (n=6299) found insufficient evidence that any pharmacotherapy reduces mortality in adults with ARDS. [cochrane]30
  • A meta-analysis of five RCTs found no mortality benefit to exogenous pulmonary surfactant in adults with ARDS. 4
  • A meta-analysis of 12 RCTs with 1237 patients found no benefit to inhaled nitric oxide in ARDS. 3
  • A recent RCT consisting of 91 patients randomized patients to methylprednisolone 1 mg/kg/d by continuous intravenous infusion or placebo. In the treated patients, 54% were breathing without the ventilator at 7 days compared with 25% of control patients (NNT = 4) and had a lower ICU mortality (20.6% vs. 42.9%; NNT = 5). Prior studies had generally shown no benefit to early or late administration of corticosteroids; however, in these previous studies higher doses of corticosteroids had been used (as high as methylprednisolone 30 mg/kg/d). 11
  • An RCT of 540 patients with ARDS found no benefit from simvastatin therapy. 19
  • A Cochrane review identified only 2 studies with 81 patients of aerosolized prostacyclins, and was unable to draw conclusions regarding their efficacy. [cochrane]24

Managing the Hospitalized Patient

  • Most patients with ARDS will require mechanical ventilation. Patients with ARDS should be ventilated with lower tidal volumes (6 mg/kg), and end-expiratory plateau pressure should be maintained at 30 cm H2O or less. ("lung protective ventilation strategy").
  • When patients are ventilated with a strategy using low tidal volumes (6 mL/kg) and a goal end-expiratory plateau pressure of 30 cm H2O or less, clinical outcomes are similar whether lower or higher levels of PEEP are used. 2
  • A Cochrane review of lung protective ventilation identified 6 trials with 1297 patients and found significant reductions in 28 day mortality (RR 0.74, 95% CI 0.61 - 0.88) and hospital mortality (RR 0.80, 95% CI 0.69 - 0.92) .
  • Prone positioning improves oxygenation in most patients with ARDS 10 and was demonstrated in one RCT to reduce 28- and 60-day mortality compared to supine positioning (NNT = 6). [poem]17 A subsequent systematic review confirmed the mortality benefit of prone positioning, espeically for patients with severe hypoxemia. [poem]18
  • Extracorporal membrane oxygenation (ECMO) did not significantly reduce 60-day mortality in a RCT of 249 patients with severe ARDS. [poem]22
  • Using lung recruitment maneuvers to titrate positive end-expiratory pressure (PEEP) increases barotrauma, pneumothorax, and deaths compared with the standard low PEEP strategy. [poem]21
  • A Cochrane review of recruitment maneuvers identified a reduction in ICU mortality based on 5 poor quality randomized trials (RR 0.83, 95% CI 0.72 - 0.97), but no effect on in-hospital mortality, 28 day mortality or barotrauma. [cochrane]23
  • Continuous monitoring by pulmonary artery catheter (PAC) does not improve survival or organ function and is associated with more complications compared with central venous catheter-directed therapy. 9
  • Two studies with 401 patients evaluated partial liquid ventilation (PLV) for adults with ARDS and found no net benefit. [cochrane]25There was insufficient evidence regarding PLV in children. [cochrane]26
  • A Cochrane review of 10 RCTs with 1850 patients compared high frequency oscillatory with conventional mechanical ventilation, and found no benefit in terms of mortality. One study found increased mortality in the HFO group. [cochrane]27
  • A randomized trial with 1006 patients with moderate to severe ARDS compared early, continuous neuromuscular blockade with usual care. It was halted early for futility. 28

Prognosis

Prognosis

Bottom Line

  • Mortality from ARDS has dropped from 67% in 1990 to 25% to 30% at present. SORT B 7 8
  • Most deaths in patients with ARDS are not due to lung disease but are from sepsis and multiple organ system failure. SORT B 6
  • Survivors of ARDS may show pulmonary gas exchange abnormalities, neurocognitive abnormalities, and decreased quality of life for at least 2 years after the acute illness. SORT B 5
  • Survivors of ARDS from 12 hospitals that participated in the ARDS Network randomized trials had substantial impairments in physical functioning at 6 and 12 months; higher average corticosteroid doses and longer intensive care unit stays were associated with worse outcomes. 20
  • Elevated levels of IL-18 were associated with worse prognosis. 29

References and Links

References and Links

Author

Jennifer L. Good, MD, Associate Director Altoona Family Physicians, Department of Internal Medicine, Altoona Regional Health System

Editors

Kenny Lin, MD, MPH, Professor of Family Medicine, Georgetown University
Linda French, MD, Professor and Chair, Department of Family Medicine, University of Toledo
Gary Ferenchick, MS, MD, Professor of Medicine, Michigan State University

References

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  2. Brower RG, Lanken PN, MacIntyre N, et al.; National Heart, Lung, and Blood Institute ARDS, Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-336.
  3. Adhikari NK, Burns KE, Friedrich JO, Granton JT, Cook DJ, Meade MO. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 2007;334:779.
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  9. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; 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;354:2213-2224.
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    [cochrane]
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  19. McAuley DF, Laffey JG, O'Kane CM, Perkins GD, Mullan B, Trinder TJ, Johnston P, Hopkins PA, Johnston AJ, McDowell C, McNally C; HARP-2 Investigators, Irish Critical Care Trials Group. Simvastatin in the acute respiratory distress syndrome. N Engl J Med 2014;371:1695–1703.
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  22. Combes A, Hajage D, Capellier G, Demoule A, Lavoué S, Guervilly C, Da Silva D, Zafrani L, Tirot P, Veber B, Maury E, Levy B, Cohen Y, Richard C, Kalfon P, Bouadma L, Mehdaoui H, Beduneau G, Lebreton G, Brochard L, Ferguson ND, Fan E, Slutsky AS, Brodie D, Mercat A, EOLIA Trial Group, REVA, and ECMONet. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med 2018;378:1965–1975.
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  24. Afshari A, Bastholm Bille A, Allingstrup M. Aerosolized prostacyclins for acute respiratory distress syndrome (ARDS). Cochrane Database of Systematic Reviews 2017, Issue 7. Art. No.: CD007733. DOI: 10.1002/14651858.CD007733.pub3.
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    [cochrane]
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    [cochrane]
  27. Sud S, Sud M, Friedrich JO, Wunsch H, Meade MO, Ferguson ND, Adhikari NK. High-frequency oscillatory ventilation versus conventional ventilation for acute respiratory distress syndrome. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD004085. DOI: 10.1002/14651858.CD004085.pub4.
    [cochrane]
  28. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, Gong MN, Grissom CK, Gundel S, Hayden D, Hite RD, Hou PC, Hough CL, Iwashyna TJ, Khan A, Liu KD, Talmor D, Thompson BT, Ulysse CA, Yealy DM, Angus DC. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med 2019;380:1997–2008.
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    [cochrane]

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