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.
In this randomized clinical trial that was terminated early, hydrocortisone, compared with placebo, did not significantly reduce the rate of treatment failure, defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy, on day 21 among critically ill patients with COVID-19. In addition, hydrocortisone, compared with placebo, did not significantly reduce the proportion of patients receiving mechanical ventilation on day 21.
The primary end point was deemed to be relevant both at the individual level and at the population level, by combining a clinically robust criterion (mortality) with criteria indicative of constraint resources utilization in a pandemic context. This outcome was also consistent with outcomes used in trials of corticosteroids in non-ICU patients with community-acquired pneumonia, namely speeding recovery and shortening hospital stays.25 The failure rate was initially estimated to be 30% in the control group, with substantial uncertainty at the beginning of the epidemic. The observed rate of the primary outcome in the placebo group was much higher than expected (50.7% cases vs 30.0%).
The trial was terminated prematurely after the press release of the dexamethasone trial. According to those findings, dexamethasone may reduce mortality on day 28 in mechanically ventilated patients and, to a lesser extent, in oxygen-dependent patients.The DSMB therefore recommended stopping the trial after 149 patients of the planned maximum of 290 had been enrolled. This trial is therefore likely underpowered. The observed difference in the post hoc outcome of proportion of deaths at day 21 was not statistically significant; however, the finding was consistent with the reduced mortality observed with dexamethasone in the subgroup of mechanically ventilated patients.A dose of 6 mg of dexamethasone is approximatively equivalent to 160 mg of hydrocortisone, very close to the initial daily dose used in this trial.
In severe community-acquired pneumonia, meta-analysis of the few available randomized trials suggest a reduction in mortality in patients treated with corticosteroids; however, these findings need to be confirmed. In previous outbreaks of coronavirus pneumonia, the lack of high-quality trials precluded any conclusions regarding the use of corticosteroids in severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS).In these reports, increased rates of adverse effects with corticosteroids, related to the use of high doses, have been observed.Clearance of viral RNA may be decreased by corticosteroids in SARS and MERS,but this effect has not been proven for COVID-19, and its clinical relevance is uncertain. In influenza pneumonia, despite the absence of randomized trials and conflicting results from observational studies, it has been suggested that corticosteroids may increase the risk of death. In patients with COVID-19, the risk of worsening the viral diffusion in the body, worsening the cytotoxic effect of the virus, or both is uncertain. However, the observed numerically lower rate of deaths in hydrocortisone-treated patients in this trial is reassuring in this regard. Most of the patients were included more than 1 week after the onset of their symptoms. It is possible that the peak of viral excretion occurs earlier in the course of COVID-19 and that the deterioration leading to ICU hospitalization is related to the deregulation of the pulmonary inflammatory response. The favorable effect of dexamethasone was more likely in patients treated after 7 days from onset of symptoms compared with those treated earlier.
In this trial, hydrocortisone therapy was not associated with an increase in the rate of secondary infections, a concerning risk with corticosteroids, especially in mechanically ventilated patients with ventilator-associated pneumonia.
This study has several limitations. First, the trial was stopped early and lacked power. Second, while this study was embedded within an existing trial, it had not been planned to record certain data relevant to COVID-19, such as the prevalence of hypertension. Third, the COVID-19 pandemic context has not, to date, allowed for the capture and analysis of all the data provided for in the parent protocol. Fourth, diagnosis of nosocomial infections was not adjudicated; however, the double-blind nature of the trial suggests that the comparison of the rate of secondary infections between the 2 groups may still be valid.
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.
Reference & Source information: https://jamanetwork.com/
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