Source: Chaudhuri D, Sasaki K, Karkar A, et al. Corticosteroids in COVID-19 and non-COVID-19 ARDS: a systematic review and meta-analysis. Intensive Care Med. 2021;47(5):521-537

Study Population: 18 trials comprising 2,826 critically ill patients with ARDS (COVID-19 and non-COVID-19)

Efficacy Endpoints:

Mortality

Duration of mechanical ventilation

Intensive care unit and hospital length of stay

Harm Endpoints:

Gastrointestinal bleeding

Neuromuscular weakness

Nosocomial infection

Narrative: Acute respiratory distress syndrome (ARDS) is a disabling lung condition associated with noncardiogenic pulmonary edema and capillary endothelial injury.1 Commonly accepted definitions require an acute condition with bilateral pulmonary infiltrates, severe hypoxemia, and noncardiogenic pulmonary edema.2^, 3 Up to 10% of patients admitted to an intensive care unit and 23% of mechanically ventilated patients are affected by ARDS, with a mortality rate approaching 45%.1^, 4^, 5 Current guidelines recommend corticosteroids in early, moderate-to-severe ARDS,6^, 7 and recent randomized controlled trials (RCTs) have suggested that corticosteroids may benefit patients with ARDS,8^, 9 including those suffering from COVID.10 The review summarized here, by Chaudhuri et al.,11 included RCTs evaluating corticosteroids for critically ill adults with non-COVID– or COVID-associated ARDS. The authors included studies of ARDS where the condition was strictly defined as well as subgroups of mechanically ventilated subjects with COVID on the assumption such patients are highly likely to be experiencing ARDS. Outcomes included mortality, duration of mechanical ventilation, intensive care unit length of stay, and hospital length of stay. Harm outcomes included opportunistic infections, muscle weakness, and gastrointestinal bleeding. The authors also conducted trial sequential analysis for the primary outcome of mortality.

The review identified 18 relevant RCTs (n = 2,826).11 Of these, 10 utilized strict ARDS criteria (eight non-COVID and two COVID). Eight trials used methylprednisolone, six hydrocortisone, and four dexamethasone. Two started corticosteroids >7 days after the diagnosis, whereas the other 16 initiated corticosteroids during the first 7 days. Eight trials administered ≤7 days of therapy, while 10 provided ≥10 days. Ten RCTs were double-blinded and utilized a placebo control, while eight were nonblinded and used standard care as a control group.

Overall, corticosteroids were associated with statistically lower mortality in adult patients with presumed ARDS (relative risk [RR] = 0.8; 95% confidence interval [CI] = 0.7 to 0.95, absolute risk reduction [ARR] = 8.8%, NNT = 12, n = 2,740), reduced length of mechanical ventilation (mean difference 4 days fewer; 95% CI = 2.5 to 5.5 days), and reduced hospital length of stay (8 days fewer; 95% CI = 3.1–13 days). In subgroup analysis of studies using a strict definition of ARDS corticosteroids were associated with lower mortality in non-COVID illnesses (RR = 0.7, 95% CI = 0.5 to 0.9, ARR = 12.6%, NNT = 8, n = 1,317). Patients receiving corticosteroids for >7 days also demonstrated lower mortality (RR = 0.7, 95% CI = 0.6 to 0.9, ARD = 11.2%, NNT = 9, n = 2,044). No statistical difference was seen, however, in the subgroup of patients with COVID (RR = 0.9, 95% CI = 0.8 to 1.1). No clinically relevant harms were noted.

The authors’ trial sequential analyses found data are inadequate to establish a benefit concerning mortality with corticosteroids. They calculate 4,690 subjects would be required for the difference found here to be considered significant (the meta-analysis included 2,740 subjects).11^, 12

Caveats: Beyond inadequate power there are important limitations to any findings suggested by these data. First, while this analysis included 18 RCTs, only 10 used a strict definition for ARDS, although findings were similar for those that did and did not. Second, the etiology of ARDS in the included studies varied significantly, including trauma, sepsis, pneumonia, aspiration, blast injury, post-operation, multiple transfusions, and drug reactions. While the statistical effect on mortality seemed somewhat consistent across trials, these are major sources of clinical heterogeneity. Moreover, corticosteroid types, doses, timing of initiation, and duration of therapy varied substantially. Unfortunately, while the authors performed many subgroup and sensitivity analyses in an effort to address these issues, the overwhelming heterogeneity in these data means (1) different disease states are being analyzed together and (2) determining an ideal agent, dose, timing, or duration is not possible. It should also be noted just one of eight COVID studies and two of eight non-COVID studies found a benefit with corticosteroids, while 13 were negative.

Finally, major sources of bias affect a preponderance of included trials. Perhaps most importantly only half used a placebo and doubleblinding, and two more were rated “high risk of bias” for other reasons.

Based on the presented evidence, we have assigned a color recommendation of yellow (data inadequate) for use of corticosteroids in critically ill patients with ARDS. Further data preferably from larger, more rigorous trials, performed in well-defined populations, are needed.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

Author: Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD

Published/Updated: March 15, 2022