Original Investigation 

July 5, 2022

High-Dose Dexamethasone and Oxygen Support Strategies in Intensive Care Unit Patients With Severe COVID-19 Acute Hypoxemic Respiratory Failure: The COVIDICUS Randomized Clinical Trial

Lila Bouadma, Armand Mekontso-Dessap, Charles Burdet, et al

JAMA Intern Med. Published online July 5, 2022. doi:10.1001/jamainternmed.2022.2168

Key Points

Question  What are the effects of high-dose vs low-dose dexamethasone on 60-day time to all-cause mortality, and oxygenation strategies vs standard oxygen support on 28-day time to fulfilling invasive mechanical ventilation (IMV) criteria in patients with COVID-19 and severe acute hypoxemic respiratory failure (AHRF)?

Findings  In this randomized clinical trial among 546 patients with COVID-19 and severe AHRF, no difference was observed in 60-day mortality according to dexamethasone dose or in 28-day cumulative need for IMV according to oxygenation strategy.

Meaning  These findings suggest that in patients with COVID-19 and AHRF, high-dose dexamethasone or different oxygenation strategies did not significantly modify 60-day mortality or 28-day requirement for IMV criteria.

Abstract

Importance  The benefit of high-dose dexamethasone and oxygenation strategies vs standard of care for patients with severe acute hypoxemic respiratory failure (AHRF) caused by COVID-19 pneumonia is debated.

Objectives  To assess the benefit of high-dose dexamethasone compared with standard of care dexamethasone, and to assess the benefit of high-flow nasal oxygen (HFNo₂) or continuous positive airway pressure (CPAP) compared with oxygen support standard of care (o₂SC).

Design, Setting, and Participants  This multicenter, placebo-controlled randomized clinical trial was conducted in 19 intensive care units (ICUs) in France from April 2020 to January 2021. Eligible patients were consecutive ICU-admitted adults with COVID-19 AHRF. Randomization used a 2 × 3 factorial design for dexamethasone and oxygenation strategies; patients not eligible for at least 1 oxygenation strategy and/or already receiving invasive mechanical ventilation (IMV) were only randomized for dexamethasone. All patients were followed-up for 60 days. Data were analyzed from May 26 to July 31, 2021.

Interventions  Patients received standard dexamethasone (dexamethasone-phosphate 6 mg/d for 10 days [or placebo prior to RECOVERY trial results communication]) or high-dose dexamethasone (dexamethasone-phosphate 20 mg/d on days 1-5 then 10 mg/d on days 6-10). Those not requiring IMV were additionally randomized to o₂SC, CPAP, or HFNo₂.

Main Outcomes and Measures  The main outcomes were time to all-cause mortality, assessed at day 60, for the dexamethasone interventions, and time to IMV requirement, assessed at day 28, for the oxygenation interventions. Differences between intervention groups were calculated using proportional Cox models and expressed as hazard ratios (HRs).

Results  Among 841 screened patients, 546 patients (median [IQR] age, 67.4 [59.3-73.1] years; 414 [75.8%] men) were randomized between standard dexamethasone (276 patients, including 37 patients who received placebo) or high-dose dexamethasone (270 patients). Of these, 333 patients were randomized among o₂SC (109 patients, including 56 receiving standard dexamethasone), CPAP (109 patients, including 57 receiving standard dexamethasone), and HFNo₂ (115 patients, including 56 receiving standard dexamethasone). There was no difference in 60-day mortality between standard and high-dose dexamethasone groups (HR, 0.96 [95% CI, 0.69-1.33]; P = .79). There was no significant difference for the cumulative incidence of IMV criteria at day 28 among o₂ support groups (o₂SC vs CPAP: HR, 1.08 [95% CI, 0.71-1.63]; o₂SC vs HFNo₂: HR, 1.04 [95% CI, 0.69-1.55]) or 60-day mortality (o₂SC vs CPAP: HR, 0.97 [95% CI, 0.58-1.61; o₂SC vs HFNo₂: HR, 0.89 [95% CI, 0.53-1.47]). Interactions between interventions were not significant.

Conclusions and Relevance  In this randomized clinical trial among ICU patients with COVID-19–related AHRF, high-dose dexamethasone did not significantly improve 60-day survival. The oxygenation strategies in patients who were not initially receiving IMV did not significantly modify 28-day risk of IMV requirement.

Trial Registration  ClinicalTrials.gov Identifier: NCT04344730; EudraCT: 2020-001457-43.