Lila Bouadma1,2, Armand Mekontso-Dessap3,4, Charles Burdet2,5, Hamid Merdji6,7, Julien Poissy8,9, Claire Dupuis2,10, Christophe Guitton11, Carole Schwebel12, Yves Cohen13,14,15, Cedric Bruel16, Mehdi Marzouk17, Guillaume Geri18,19,20, Charles Cerf21, Bruno Mégarbane22,23, Pierre Garçon24, Eric Kipnis25,26, Benoit Visseaux27, Naima Beldjoudi28, Sylvie Chevret29, Jean-François Timsit1,2. 1. Medical and Infectious Diseases Intensive Care Unit, Bichat-Claude Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 2. Infection, anti-microbien, modélisation, évolution, Université de Paris U1137, Paris, France. 3. Medical Intensive Care Unit, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, Créteil, France. 4. East-Paris Créteil University, Institut national de la santé et de la recherche médicale, Institut Mondor de Recherche Biomédicale, Cardiovascular and Respiratory Manifestations of Acute Lung Injury and Sepsis, Créteil, France. 5. Epidemiology, Biostatistics and Clinical Research Department, Bichat-Claude Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 6. Intensive Care Unit, New Civil Hospital, Strasbourg University Hospital, Strasbourg, France. 7. Institut national de la santé et de la recherche médicale, UMR 1260, Federation of Traditional Medicine of Strasbourg, University of Strasbourg, Strasbourg, France. 8. Intensive Care Unit, Centre hospitalier universitaire de Lille, Lille, France. 9. UniversityLille, Institut national de la santé et de la recherche médicale U1285, Centre national de la recherche scientifique, UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France. 10. Intensive Care Unit, Gabriel Montpied Hospital, CHU de Clermont-Ferrand, Clermont-Ferrand, France. 11. Medical and Surgical Intensive Care Unit, Le Mans Hospital, Le Mans, France. 12. Medical Intensive Care Unit, CHU Grenoble-Alpes, Grenoble, France. 13. Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Avicenne Hospital, Group Hospitalier Paris Seine Saint-Denis, Bobigny, France. 14. UFR Santé Médecine et Biologie Humaine, Université Sorbonne Paris Nord, Bobigny, France. 15. Institut national de la santé et de la recherche médicale, U942, Paris, France. 16. Medical and Surgical Intensive Care Unit, Paris Saint-Joseph Hospital Network, Paris, France. 17. Intensive Care Unit, Centre Hospitalier de Bethune-Beuvry, Bethune, France. 18. Medical Intensive Care Unit, Ambroise Paré University Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France. 19. Institut national de la santé et de la recherche médicale, UMR 1018, Paris-Saclay University - Université de Versailles Saint-Quentin-en-Yvelines, France. 20. FHU SEPSIS, Paris, France. 21. Intensive Care Unit, Foch Hospital, Suresnes, France. 22. Department of Medical and Toxicological Critical Care, Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 23. Université de Paris, Institut national de la santé et de la recherche médicale, UMRS-1144, Paris, France. 24. Medical and Surgical Intensive Care Unit, Grand Hôpital de l'Est Francilien site Marne-la-Vallée, Jossigny, France. 25. Surgical Critical Care, Department of Anesthesiology and Critical Care, CHU Lille, Lille, France. 26. University Lille, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, Institut Pasteur de Lille, U1019, UMR 9017, Center for Infection and Immunity of Lille, Lille, France. 27. Virology Department, Bichat-Claude Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 28. Epidemiology and Clinical Research Department, GH Paris-Nord Val de Seine, Assistance Publique-Hôpitaux de Paris, Paris, France. 29. Department of Biostatistics and Medical Informatics, Institut national de la santé et de la recherche médicale, UMR 1153, Saint Louis Hospital, University of Paris, Paris, France.
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.
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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