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Randomized Controlled Trial
. 2022 Sep 1;182(9):906-916.
doi: 10.1001/jamainternmed.2022.2168.

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  1   2 , Armand Mekontso-Dessap  3   4 , Charles Burdet  2   5 , Hamid Merdji  6   7 , Julien Poissy  8   9 , Claire Dupuis  2   10 , Christophe Guitton  11 , Carole Schwebel  12 , Yves Cohen  13   14   15 , Cedric Bruel  16 , Mehdi Marzouk  17 , Guillaume Geri  18   19   20 , Charles Cerf  21 , Bruno Mégarbane  22   23 , Pierre Garçon  24 , Eric Kipnis  25   26 , Benoit Visseaux  27 , Naima Beldjoudi  28 , Sylvie Chevret  29 , Jean-François Timsit  1   2 ; COVIDICUS Study Group
Collaborators, Affiliations
Randomized Controlled Trial

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 et al. JAMA Intern Med. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mekontso-Dessap reported receiving grants from Addmedica, Baxter, Ferring, Fisher Paykel, and Philips and personal fees from Air Liquide outside the submitted work. Dr Burdet reported receiving personal fees from Da Volterra and Mylan Pharmaceuticals outside the submitted work. Dr Poissy reported receiving personal fees from Gilead and Pfizer outside the submitted work. Dr Geri reported receiving personal fees from BD outside the submitted work. Dr Cerf reported receiving personal fees from MSD and Getinge outside the submitted work. Dr Kipnis reported receiving personal fees from Pfizer, MSD, and LFB Biomédicament and serving as a consultant for Merck outside the submitted work. Dr Visseaux reported receiving grants and personal fees from Qiagen and personal fees from Gilead, BioMérieux, and Sanofi outside the submitted work. Dr Timsit reported serving as a consultant for Beckton-Dickinson, French Ministry of Health, Gilead, Medimmune , Merck, Pfizer, and Shinogi and receiving grants from Thermo Fisher Scientific, Merck, and Pfizer and personal fees from Merck, Pfizer, Shionogi, Gilead, and Thermo Fisher Scientific outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Recruitment Flowchart
aConsent withdrawal occurred before the date of day 60 of follow-up in no patients receiving standard of care oxygen (o2SC), 8 patients receiving continuous positive airway pressure (CPAP), and 1 patient receiving high-flow nasal oxygen (HFNo2) in the non–invasive mechanical ventilation (IMV) group. In patients with IMV or contraindication to any 1 o2 support strategy, 3 patients withdrew consent. These patients were censored at the date of consent withdrawal. DXM indicates dexamethasone; ICU, intensive care unit.
Figure 2.
Figure 2.. Primary End Points of Both Interventions
A. Standard dexamethasone (DXM) included 37 patients who received placebo DXM then dexamethasone-phosphate 6 mg/d for days 1 to 10; high-dose DXM was dexamethasone-phosphate 20 mg/d for days 1 to 5, then 10 mg/d for days 6 to 10. CPAP indicates continuous positive airway pressure; HFNo2, high-flow nasal oxygen; and o2SC, oxygen standard of care.
See this image and copyright information in PMC

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