Marie W Munch1, Sheila N Myatra2, Bharath Kumar Tirupakuzhi Vijayaraghavan3, Sanjith Saseedharan4, Thomas Benfield5, Rebecka R Wahlin6, Bodil S Rasmussen7, Anne Sofie Andreasen8, Lone M Poulsen9, Luca Cioccari10, Mohd S Khan11, Farhad Kapadia12, Jigeeshu V Divatia2, Anne C Brøchner13, Morten H Bestle14, Marie Helleberg15, Jens Michelsen16, Ajay Padmanaban3, Neeta Bose17, Anders Møller18, Kapil Borawake19, Klaus T Kristiansen20, Urvi Shukla21, Michelle S Chew22, Subhal Dixit23, Charlotte S Ulrik24, Pravin R Amin25, Rajesh Chawla26, Christian A Wamberg27, Mehul S Shah28, Iben S Darfelt29, Vibeke L Jørgensen30, Margit Smitt31, Anders Granholm1, Maj-Brit N Kjær1, Morten H Møller1, Tine S Meyhoff1, Gitte K Vesterlund1, Naomi E Hammond32,33, Sharon Micallef32, Abhinav Bassi34, Oommen John34,35, Anubhuti Jha34, Maria Cronhjort6, Stephan M Jakob10, Christian Gluud36,37, Theis Lange38, Vaijayanti Kadam4, Klaus V Marcussen18, Jacob Hollenberg6, Anders Hedman6, Henrik Nielsen7, Olav L Schjørring7, Marie Q Jensen1, Jens W Leistner1, Trine B Jonassen1, Camilla M Kristensen1, Esben C Clapp1, Carl J S Hjortsø1, Thomas S Jensen1, Liv S Halstad1, Emilie R B Bak1, Reem Zaabalawi1, Matias Metcalf-Clausen1, Suhayb Abdi1, Emma V Hatley1, Tobias S Aksnes1, Emil Gleipner-Andersen1, Arif F Alarcón6, Gabriel Yamin6, Adam Heymowski6, Anton Berggren6, Kirstine La Cour9, Sarah Weihe9, Alison H Pind9, Janus Engstrøm36, Vivekanand Jha32,34,35,39, Balasubramanian Venkatesh32,40, Anders Perner1,32. 1. Department of Intensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 2. Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India. 3. Apollo Hospitals, Chennai, India. 4. SL Raheja Hospital, Mumbai, India. 5. Department of Infectious Diseases, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark. 6. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden. 7. Aalborg University Hospital, Aalborg University, Aalborg, Denmark. 8. Department of Anaesthesia and Intensive Care, Copenhagen University Hospital, Herlev-Gentofte Hospital, Herlev, Denmark. 9. Department of Anaesthesia and Intensive Care, Zealand University Hospital, Koege, Denmark. 10. Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 11. Rajendra Institute of Medical Sciences, Ranchi, India. 12. Hinduja Hospital, Mahim, Mumbai, India. 13. Department of Anaesthesia and Intensive Care, Kolding Hospital, Kolding, Denmark. 14. Department of Anaesthesia and Intensive Care, Copenhagen University Hospital, North Zealand, Hilleroed, Denmark. 15. Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 16. Department of Anaesthesia and Intensive Care, Odense University Hospital, Odense, Denmark. 17. Gotri General Hospital, Gujarat, India. 18. Department of Anaesthesia and Intensive Care, Slagelse Hospital, Slagelse, Denmark. 19. Vishwaraj Hospital, Pune, India. 20. Department of Anaesthesia and Intensive Care, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark. 21. Symbiosis University Hospital and Research Centre, Lavale, India. 22. Department of Anaesthesia and Intensive Care Medicine, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden. 23. Sanjeevan Hospital, Pune, India. 24. Department of Respiratory Diseases, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark. 25. Bombay Hospital Institute of Medical Sciences, Mumbai, India. 26. Indraprastha Apollo Hospital, New Delhi, India. 27. Department of Anaesthesia and Intensive Care, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark. 28. Sir H. N. Reliance Foundation Hospital and Research Centre, Mumbai, India. 29. Department of Anaesthesia and Intensive Care, Herning Hospital, Herning, Denmark. 30. Department of Thoracic Anaesthesia, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 31. Department of Neurointensive Care, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 32. The George Institute for Global Health, University of New South Wales, Sydney, Australia. 33. Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, Sydney, Australia. 34. The George Institute for Global Health, New Delhi, India. 35. Prasanna School of Public Health, Manipal Academy of Medical Sciences, Manipal, India. 36. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region, Copenhagen University Hospital, Rigshospitalet, Denmark. 37. Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense. 38. Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark. 39. School of Public Health, Imperial College, London, England. 40. Department of Intensive Care, Wesley Hospital, Brisbane, Australia.
Abstract
Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.
Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.
Authors: Bharath Kumar Tirupakuzhi Vijayaraghavan; Ena Gupta; Nagarajan Ramakrishnan; Abi Beane; Rashan Haniffa; Nazir Lone; Nicolette de Keizer; Neill K J Adhikari Journal: PLoS One Date: 2022-05-05 Impact factor: 3.240
Authors: Elisabetta Caiazzo; Asma O M Rezig; Dario Bruzzese; Armando Ialenti; Carla Cicala; John G F Cleland; Tomasz J Guzik; Pasquale Maffia; Pierpaolo Pellicori Journal: Pharmacol Res Date: 2021-12-31 Impact factor: 7.658
Authors: Brit Long; Summer Chavez; Brandon M Carius; William J Brady; Stephen Y Liang; Alex Koyfman; Michael Gottlieb Journal: Am J Emerg Med Date: 2022-03-26 Impact factor: 4.093