Steroids for sepsis and ARDS: this eternal controversy remains with COVID-19
Authors: Jean Carlet, Didier Payen, Steven M Opal
Journal: The Lancet (2020)

In the past 50 years, the potential benefit of corticosteroids in treating sepsis or acute respiratory distress syndrome (ARDS) has been evaluated in many randomised controlled trials (RCTs). Corticosteroids have contradictory effects on mortality, leading to a profound and still active controversy. Low doses of corticosteroids have been shown to decrease mortality from septic shock in patients who also receive mineralocorticoids.1Annane D Renault A Brun-Buisson C et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (548) Google Scholar However, the effect of corticosteroids has been negative in other studies.2Venkatesh B Finfer S Cohen J et al.Adjunctive glucocorticoids therapy in patients with septic shock.N Engl J Med. 2018; 378: 797-808Crossref PubMed Scopus (618) Google Scholar In one RCT,3Vilar J Ferrando C Martinez D et al.Dexamethasone treatment for ARDS: a multicentric randomized controlled trial.Lancet Respir Med. 2020; 8: 267-276Summary Full Text Full Text PDF PubMed Scopus (723) Google Scholar corticosteroids were efficacious for ARDS of various origin. This modest hope for corticosteroids has been heightened from findings in patients with severe COVID-19. Most of the initial therapeutic studies of corticosteroids for COVID-19 have been of very poor quality. The RECOVERY trial was one of the most robust studies.4The RECOVERY Collaborative GroupDexamethasone in hospitalized patients with COVID-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Crossref Scopus (7056) Google Scholar In this large, open-labelled RCT, 2104 patients treated with corticosteroids were compared with 4321 patients receiving standard therapy. The study used different compounds, at different time courses, and in patients with COVID-19 symptoms of varying severity. Corticosteroids (dexamethasone, 6 mg per day) caused a moderate but significant 11% reduction in mortality. Mortality was significantly reduced in patients who were mechanically ventilated (29%) or received oxygen (11%), but not in patients without any respiratory failure. These results were considered credible proof of corticosteroid efficacy, particularly by WHO, which announced prematurely that corticosteroid was the gold standard for treating severe COVID-19.5Lamontagne F Agoritsas T Macdonald H A living WHO guideline on drugs for COVID-19.BMJ. 2020; 370m3379Crossref PubMed Scopus (466) Google Scholar However, the methodology in this study was very questionable, in particular (but not only) because no severity markers were recorded, making highly questionable the comparability of the two treatment groups at the time of study inclusion. Results of four additional studies have since been published,6The WHO Rapid Evidence Appraisal for COVID-19 therapies (REACT) working groupAssociation between systemic corticosteroids administration and mortality among critically ill patients with Covid-19: a meta-analysis.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1056/JAMAoa2021436Crossref Scopus (1679) Google Scholar, 7Dequin PF Heming N Meziani F et al.Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.16761Crossref Scopus (334) Google Scholar, 8The Writing Committee for REMAP-CAP InvestigatorsEffect of hydrocortisone on mortality and organ support in patients with severe COVID-19.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.17022Crossref Scopus (570) Google Scholar, 9Tomasini BM Maia IS Cavalcati AB et al.Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.17021Crossref Scopus (865) Google Scholar one of which was a meta-analysis promoted by WHO.6The WHO Rapid Evidence Appraisal for COVID-19 therapies (REACT) working groupAssociation between systemic corticosteroids administration and mortality among critically ill patients with Covid-19: a meta-analysis.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1056/JAMAoa2021436Crossref Scopus (1679) Google Scholar In this meta-analysis of pooled data from seven studies, corticosteroids were associated with a decrease in mortality from severe COVID-19. However, this effect disappeared when data from the RECOVERY trial4The RECOVERY Collaborative GroupDexamethasone in hospitalized patients with COVID-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Crossref Scopus (7056) Google Scholar were excluded from the meta-analysis, suggesting an overweight of these data in the meta-analysis. The substantial heterogeneity within the remaining six trials limits the validity of the interpretation of the meta-analysis results. Furthermore, in the RECOVERY trial,4The RECOVERY Collaborative GroupDexamethasone in hospitalized patients with COVID-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Crossref Scopus (7056) Google Scholar various compounds and dosages of corticosteroids were used. Among the three other studies,7Dequin PF Heming N Meziani F et al.Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.16761Crossref Scopus (334) Google Scholar, 8The Writing Committee for REMAP-CAP InvestigatorsEffect of hydrocortisone on mortality and organ support in patients with severe COVID-19.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.17022Crossref Scopus (570) Google Scholar, 9Tomasini BM Maia IS Cavalcati AB et al.Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.17021Crossref Scopus (865) Google Scholar the CAPE COVID study7Dequin PF Heming N Meziani F et al.Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.16761Crossref Scopus (334) Google Scholar was stopped after publication of the RECOVERY trial4The RECOVERY Collaborative GroupDexamethasone in hospitalized patients with COVID-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Crossref Scopus (7056) Google Scholar results. In CAPE COVID,7Dequin PF Heming N Meziani F et al.Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.16761Crossref Scopus (334) Google Scholar a well designed study that enrolled 149 patients with severe COVID-19, no benefit of corticosteroids was found. In the REMAP trial,8The Writing Committee for REMAP-CAP InvestigatorsEffect of hydrocortisone on mortality and organ support in patients with severe COVID-19.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.17022Crossref Scopus (570) Google Scholar which included 903 treated patients, hydrocortisone (40 mg intravenous every 6 h) significantly reduced mortality from severe COVID-19 by 26%. Although not double-blinded, REMAP was the first robust trial to show a very clear-cut positive effect on mortality. The CoDEX trial,9Tomasini BM Maia IS Cavalcati AB et al.Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial.JAMA. 2020; (published online Sept 2.)https://doi.org/10.1001/jama.2020.17021Crossref Scopus (865) Google Scholar with an excellent methodology, included 299 patients with mild or severe ARDS. Corticosteroids significantly increased ventilator-free days during the first 28 days, but there was no benefit on 28-day mortality or length of stay in intensive care units, both tested as secondary endpoints. Finally, in Metcovid,10Jeronimo CMP Leano-Farias ME Almeida Val FF et al.Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a randomised, double-blind, phase iib, placebo-controlled trial.Clin Infect Dis. 2020; (published online Aug 12.)https://doi.org/10.1093/cid/ciaa1177Crossref Scopus (283) Google Scholar a large phase 2b double-blind RCT with 416 patients with COVID-19, corticosteroids had no effect on mortality. The above scientific limits and the contradicting results of the various studies ought to impose caution before adoption of corticosteroids as the master drug to save lives from COVID-19 (appendix). Although the medical community and citizens worldwide are impatient for efficient therapies, enthusiasm after the first positive results should be tempered until studies with a better design are completed, demonstrating clearly the efficacy of corticosteroids. We do not think there is any equipoise or ethical problem in planning further double-blind RCTs. We declare no competing interests. Download .pdf (.1 MB) Help with pdf files Supplementary appendix