Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Abstract

Importance: Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option.

Objective: To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure.

Design, setting, and participants: Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board.

Interventions: Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73).

Main outcomes and measures: The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay.

Results: The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment.

Conclusions and relevance: In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.

Trial registration: ClinicalTrials.gov Identifier: NCT02517489.

Figure 1.. Study Flow of the CAPE COVID Trial

Randomization was stratified by center and use of mechanical ventilation at the time of inclusion. CAPE COVID indicates Community-Acquired Pneumonia: Evaluation of Corticosteroids in Coronavirus Disease; COVID-19, coronavirus disease 2019; ICU, intensive care unit. ^aOne patient had aspiration of gastric content associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Five patients had hospital-acquired SARS-CoV-2 infection, which was misinterpreted as a criterion of noninclusion.

Figure 2.. Nosocomial Infections Cumulative Incidence

Cumulative proportion of patients who have had at least 1 nosocomial infection. Nosocomial infections were defined when they were diagnosed by the clinician in charge and antibiotic treatment was prescribed. All patients were observed to death or 28 days (the patient who withdrew consent being censored on the last reported date). HR indicates hazard ratio.