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Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19The CoDEX Randomized Clinical Trial

Educational Objective
To understand the effects of Dexamethasone on days alive and ventilator-free in patients with moderate or severe COVID-19
1 Credit CME
Key Points

Question  In patients with coronavirus disease 2019 (COVID-19) and moderate or severe acute respiratory distress syndrome (ARDS), does intravenous dexamethasone plus standard care compared with standard care alone increase the number of days alive and free from mechanical ventilation?

Findings  In this randomized clinical trial that included 299 patients, the number of days alive and free from mechanical ventilation during the first 28 days was significantly higher among patients treated with dexamethasone plus standard care when compared with standard care alone (6.6 days vs 4.0 days).

Meaning  Intravenous dexamethasone plus standard care, compared with standard of care alone, resulted in a statistically significant increase in the number of days alive and free of mechanical ventilation over 28 days.

Abstract

Importance  Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients.

Objective  To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19–associated ARDS.

Design, Setting, and Participants  Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients.

Interventions  Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148).

Main Outcomes and Measures  The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.

Results  A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, −1.16; 95% CI, −1.94 to −0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events.

Conclusions and Relevance  Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.

Trial Registration  ClinicalTrials.gov Identifier: NCT04327401

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Article Information

Corresponding Author: Luciano C. P. Azevedo, MD, PhD, Hospital Sirio-Libanes, Rua Prof Daher Cutait, 69, 01308-060, São Paulo, Brazil (luciano.azevedo@hsl.org.br).

Accepted for Publication: August 20, 2020.

Published Online: September 2, 2020. doi:10.1001/jama.2020.17021

Author Contributions: Drs Tomazini and Azevedo had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Mr Damiani conducted and is responsible for the data analysis.

Concept and design: Tomazini, Maia, Cavalcanti, Berwanger, Veiga, Lopes, Bueno, Baldassare, Damiani, Lisboa, Zampieri, Fernandes, Morais, Zung, Machado, Azevedo.

Acquisition, analysis, or interpretation of data: Tomazini, Cavalcanti, Berwanger, Rosa, Veiga, Avezum, Lopes, Bueno, Silva, Baldassare, E. Costa, Moura, Honorato, A. Costa, Damiani, Lisboa, Kawano-Dourado, Olivato, Righy, Amendola, Roepke, D. Freitas, Forte, F. Freitas, Melro, Junior, Machado, Azevedo.

Drafting of the manuscript: Tomazini, Berwanger, Veiga, Bueno, Baldassare, Kawano-Dourado, Junior, Machado, Azevedo.

Critical revision of the manuscript for important intellectual content: Tomazini, Maia, Cavalcanti, Berwanger, Rosa, Veiga, Avezum, Lopes, Bueno, Silva, Baldassare, E. Costa, Moura, Honorato, A. Costa, Damiani, Lisboa, Kawano-Dourado, Zampieri, Olivato, Righy, Amendola, Roepke, D. Freitas, Forte, F. Freitas, Fernandes, Melro, Morais, Zung, Machado, Azevedo.

Statistical analysis: Tomazini, Berwanger, Bueno, Damiani, Lisboa.

Obtained funding: Berwanger, Bueno, Baldassare, Lisboa, Morais, Zung, Azevedo.

Administrative, technical, or material support: Tomazini, Rosa, Bueno, Silva, Baldassare, Moura, Honorato, A. Costa, Lisboa, Righy, Roepke, Fernandes, Junior, Morais, Zung, Azevedo.

Supervision: Tomazini, Maia, Veiga, Avezum, Bueno, Baldassare, E. Costa, Moura, Zampieri, Roepke, Fernandes, Junior, Machado, Azevedo.

Conflict of Interest Disclosures: Dr Tomazini reported receiving support from Aché pharmaceutical. Dr Maia reported receiving nonfinancial support from Aché Laboratórios Farmacêuticos. Dr Cavalcanti reported receiving grants from Bayer, Bactiguard, Johnson & Johnson, do Brasil, Hemaclear, Hillrom, and Pfizer. Dr Berwanger reported receiving grants from AstraZeneca, Novartis, Servier, Bayer, Amgen, and Boehringer-Ingelheim. Dr Lopes reported receiving personal fees from Bayer, Boehinger Ingleheim, Daiichi Sankyo, Merck, and Portola; grants and personal fees from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Portola, and Sanofi. Ms Bueno reported receiving personal fees from Endpoint Health. Dr Silva reported receiving support from Aché Laboratórios Farmacêuticos. Mrs Baldassare reported receiving grants from Aché Laboratórios Farmacêuticos. Dr Moura reported receiving personal fees from Hospital Sírio-Libanês. Dr A. Costa reported receiving grants from Pfizer. Dr Fernandes reported receiving grants from Hospital Sírio Libanês and from Aché Laboratórios Farmacêuticos S.A. Mr Morais reported receiving personal fees and other support from Aché Laboratórios Farmacêuticos. Dr Zung reported receiving personal fees from Aché Laboratórios Farmacêuticos. Dr Machado reported receiving support from Laboratórios Farmacêuticos. Dr Azevedo reported receiving grants from Aché Laboratórios and personal fees from Pfizer and Halex-Istar. No other disclosures were reported.

Funding/Support: This trial was funded and supported by the Coalition COVID-19 Brazil. The Laboratórios Farmacêuticos provided the study drug, distribution logistics, and insurance for the study patients.

Role of the Funder/Sponsor: Laboratórios Farmacêuticos had no role in the design and conduct of the study. The Coalition COVID-19 Brazil was responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Site Investigators: All in Brazil: Hospital Vila Santa Catarina, São Paulo: Adriano José Pereira, Guilherme Benfatti Olivato, Natalie Botelho Borges, and Ana Lucia Neves; Instituto Estadual do Cérebro, Rio de Janeiro: Cássia Righy, Pedro Kurtz, Ricardo Turon, and Marília Gomes e Silva; Hospital do Câncer de Barretos, Barretos: Cristina Prata Amendola, Luciana Coelho Sanches, Luis Henrique Simões Covello, and André Luiz Tosello Penteado; UTI Emergências Cirúrgicas e Trauma–HCFMUSP, São Paulo: Bruno M. Tomazini, Roberta Muriel Longo Roepke, and Estevão Bassi; UTI Respiratória–HCFMUSP, São Paulo: Eduardo Leite Vieira Costa, Marcelo Britto Passos Amato, Daniela Helena Machado de Freitas, and Carlos R. Carvalho; Hospital São Paulo, Universidade Federal de São Paulo–UNIFESP, São Paulo: Flavia Ribeiro Machado, Flávio Geraldo Rezende Freitas, Maria Aparecida de Souza, and Fernando José da Silva Ramos; UTI 09DN–HCFMUSP: Daniel Neves Forte, José Mauro Vieira Júnior, Sâmia Yasin Wayhs, Veridiana Schulz Casalechi, and Ricardo Antônio Bonifácio Moura; Hospital Estadual Mario Covas–FMABC, Santo André: Caio Cesar Ferreira Fernandes, Marcelo Rodrigues Bacci, Antônio Carlos Palandri Chagas, and Desirè Carlos Callegari; Hospital Samaritano, São Paulo: Livia Maria Garcia Melro, Yuri de Albuquerque Pessoa dos Santos, Anderson Roberto Dallazen, and Daniel Curitiba Marcellos; Hospital Evangélico de Vila Velha, Vila Velha: Gedealvares Francisco de Souza Júnior, Ana Carolina Simões Ramos, and Gláucia Gleine Souza Ferraz; Hospital Unimed Vitória, Vitória: Eliana Bernadete Caser and Danilo Hugo Brito Figueiredo; UTI da Disciplina de Emergências Clínicas—HCFMUSP: Bruno Adler Maccagnan Pinheiro Besen and Leandro Utino Taniguchi; Hospital Naval Marcílio Dias, Rio de Janeiro: Vicente Cés de Souza Dantas, Priscilla Alves Barreto, and Orlando Farias Jr; Hospital São José, Criciúma: Felipe Dal Pizzol and Cristiane Ritter; Hospital Israelita Albert Einstein, São Paulo: Otávio Berwanger, Remo H. M. Furtado, Thiago D. Correia, and Ary Serpa Neto; Hospital das Clínicas da Faculdade de Medicina de Botucatu–UNESP, Botucatu: Marina Politi Okoshi, Suzana Erico Tanni, and Aparecido Rios Queiroz; UTI Bloco Cirúrgico IV–HCFMUSP, São Paulo: Carlos Eduardo Pompilio and José Otto Reusing Jr; Hospital Sepaco, São Paulo: Flávio Geraldo Rezende de Freitas, Antônio Tonete Bafi, and Fernanda Regina de Campos Radziavicius; Hospital Municipal Dr. Moysés Deutsch (M’Boi Mirim), São Paulo: Felipe Maia de Toledo Piza, Airton L. O. Manoel, Niklas S. Campos; Hospital Regional Hans Dieter Schmidt, Joinville: Conrado Roberto Hoffmann Filho and Iara Caravajal Hoffmann; Unidade de Terapia Intensiva Cirúrgicas da Divisão de Anestesiologia–HCFMUSP, São Paulo: Luiz Marcelo Sá Malbouisson and Thiago Tavares dos Santos; Casa de Saúde Santa Marcelina, São Paulo: Luiz Relvas and Bruno Nunes Rodrigues; Beneficência Portuguesa, São Paulo: Viviane Cordeiro Veiga and Agnes Cohen Lisboa; Hospital Estadual Jayme dos Santos Neves, Serra: Priscila Aquino and Vinícius Santana Nunes; Hospital da Mulher do Recife, Recife: Mario Diego Teles Correia and Giselle Matias de Carvalho; Hospital Universitário de Maringá, Maringá: Sergio Yamada; Hospital do Coração, São Paulo: Alexandre Biasi Cavalcanti and Leticia Kawano-Dourado; UTI da Divisão de Anestesia–HCFMUSP, São Paulo: Pedro Vitale Mendes and João Manoel Silva Junior; Hospital Alemão Oswaldo Cruz, São Paulo: José Victor Gomes Costa and David J. B. Machado; Hospital Maternidade São Vicente de Paulo, Barbalha: Meton Soares De Alencar Filho and Jussara Alencar Arraes; Unimed Cariri, Juazeiro do Norte: Thales Anibal leite Barros Agostinho and Sérgio de Araújo; Santa Casa de Misericórdia de Passos, Passos: Priscila Freitas das Neves Gonçalves; Instituto do Coração (Incor)–FMUSP, São Paulo: Alexandre de Matos Soeiro; Hospital Baía Sul, Florianópolis: Israel Silva Maia and Ana Cristina Burigo; Hospital Sírio-Libanês, São Paulo: Bruno M. Tomazini and Luciano Cesar Pontes de Azevedo; Hospital Nereu Ramos, Florianópolis: Israel Silva Maia and Cassio Zandonai; Hospital Moinhos de Vento, Porto Alegre: Regis G. Rosa; Hospital de Brasília, Brasília: Rodrigo Santos Biondi; and UTI da Gastroenterologia–HCFMUSP, São Paulo: Rodolpho Augusto de Moura Pedro.

Trial Coordinating Center: Bruno Martins Tomazini, Flavia R. Bueno, Maria Vitoria A. O. Silva, Franca P. Baldassare, Eduardo Leite V. Costa, Ricardo A. B. Moura, Michele Honorato, Andre N. Costa, Camila S. J. C. Sampaio, Luciano CP Azevedo; Hospital Sirio-Libanes, São Paulo, Brazil.

Executive Committee: Luciano C. P. Azevedo, MD, PhD; Alexandre B. Cavalcanti, MD, PhD; Regis G. Rosa, MD, PhD; Alvaro Avezum, MD, PhD; Viviane C. Veiga, MD, PhD; Renato D. Lopes, MD, PhD; Flávia R. Machado, MD, PhD; and Otavio Berwanger, MD, PhD.

Steering Committee: Luciano C. P. Azevedo, MD, PhD; Alexandre B. Cavalcanti, MD, PhD; Regis G. Rosa, MD, PhD; Alvaro Avezum, MD, PhD; Viviane C. Veiga, MD, PhD; Renato D. Lopes, MD, PhD; Flávia R Machado, MD, PhD; Otavio Berwanger, MD, PhD; Fernando G. Zampieri, MD, PhD; Letícia Kawano-Dourado, MD, PhD; Thiago Lisboa, MD, PhD; Israel S. Maia, MD, MSc; Remo Furtado, MD, PhD; Henrique Fonseca, MD, PhD; Ary Serpa-Neto, MD, PhD; Thiago Correa, MD, PhD; Cláudio Galvão, MD, PhD; Leonardo R. Ferraz, MD, PhD; Guilherme Schettino, MD, PhD; Luiz V. Rizzo, MD, PhD; Maicon Falavigna, MD, PhD; Eduardo Leite Vieira Costa, MD, PhD; Bruno M. Tomazini, MD; Danielle Leão, MD, PhD; João Prats, MD, PhD; Philip Scheinberg MD, PhD; André Gobatto, MD, PhD; Cintia Grion, MD, PhD; Felipe Dal Pizzol, MD, PhD; Fernando A. Bozza, MD, PhD; Flavio G. R. Freitas, MD, PhD; Glauco Westphal, MD, PhD; Hugo Urbano, MD; Rodrigo Biondi, MD; and Rodrigo C. Figueiredo, MD.

Affiliations of the Executive Committee and Steering Committee: Hospital Sirio-Libanes, São Paulo, Brazil: Azevedo, Tomazini, and Eduardo Costa; Disciplina de Emergências Clínicas, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil: Azevedo; Brazilian Research in Intensive Care Network (BRICNet), Brazil: Azevedo, Cavalcanti, Rosa, Veiga, Machado, Zampieri, Lisboa, Maia, Gobatto, Grion, Dal Pizzol, Bozza, Freitas, Westphal, Urbano, Biondi, and Figueiredo; Hcor Research Institute, São Paulo, Brazil: Cavalcanti, Zampieri, Kawano-Dourado, Lisboa, and Maia; Hospital Moinhos de Vento, Porto Alegre, Brazil: Rosa and Falavigna; Hospital Alemão Oswaldo Cruz, São Paulo, Brazil: Avezum; BP–A Beneficência Portuguesa de São Paulo, São Paulo, Brazil: Veiga; Brazilian Clinical Research Institute, São Paulo, Brazil: Lopes; Duke University Medical Center-Duke Clinical Research Institute, Durham, North Carolina: Lopes; Anesthesiology, Pain, and Intensive Care Department, Federal University of São Paulo, São Paulo, Brazil: Machado and Freitas; and Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil: Berwanger, Furtado, Fonseca, Serpa-Neto, Correa, Galvão, Ferraz, Schettino, and Rizzo.

Data Monitoring and Safety Committee: Monash University, Melbourne, Australia; Carol Hodgson, PhD, FACP, BappSc(PT) Mphil PGDip(Cardio); Michael Bailey, BSc(Hons), MSc, PhD; University of Michigan, Ann Arbor: Theodore John Iwashyna, MD.

Disclaimer: This study was performed on behalf of the Coalition COVID-19 Brazil Group.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank all the multidisciplinary teams in the participating centers for their support in following the study interventions in the challenging context of the COVID-19 pandemic.

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  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
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