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Visual Abstract. Effect of Dexamethasone on Ventilator-Free Days Among Patients With COVID-19
Effect of Dexamethasone on Ventilator-Free Days Among Patients With COVID-19
Figure 1.  Flow of Patients in the Coronavirus Dexamethasone (CoDEX) Trial
Flow of Patients in the Coronavirus Dexamethasone (CoDEX) Trial

Abbreviations: COVID-19, coronavirus disease 2019; Pao2:Fio2 partial pressure of arterial oxygen to the fraction of inspired oxygen ratio, COPD, chronic obstructive pulmonary disease.

Figure 2.  Ventilator-Free Days at 28 Days
Ventilator-Free Days at 28 Days

The dashed lines represent patients who died (assigned 0 ventilator-free days), and solid lines show the cumulative frequency of patients who were receiving mechanical ventilation all 28 days (at the 0 ventilator-free days tick mark) and then the cumulative frequency of patients who no longer required the ventilator for an increasing number of days.

Table 1.  Baseline Characteristicsa
Baseline Characteristicsa
Table 2.  Study Outcomes
Study Outcomes
Table 3.  Adverse Events
Adverse Events
1.
Zhu  N, Zhang  D, Wang  W,  et al; China Novel Coronavirus Investigating and Research Team.  A novel coronavirus from patients with pneumonia in China, 2019.   N Engl J Med. 2020;382(8):727-733. doi:10.1056/NEJMoa2001017PubMedGoogle Scholar
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World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19. Posted March 11, 2020. Accessed March 25, 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020
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Richardson  S, Hirsch  JS, Narasimhan  M,  et al; and the Northwell COVID-19 Research Consortium.  Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.   JAMA. 2020;323(20):2052-2059. doi:10.1001/jama.2020.6775PubMedGoogle Scholar
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Ackermann  M, Verleden  SE, Kuehnel  M,  et al.  Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.   N Engl J Med. 2020;383(2):120-128. doi:10.1056/NEJMoa2015432PubMedGoogle Scholar
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Moore  JB, June  CH.  Cytokine release syndrome in severe COVID-19.   Science. 2020;368(6490):473-474. doi:10.1126/science.abb8925PubMedGoogle Scholar
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Qin  C, Zhou  L, Hu  Z,  et al.  Dysregulation of Immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China.   Clin Infect Dis. 2020;71(15):762-768. doi:10.1093/cid/ciaa248PubMedGoogle Scholar
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Rhen  T, Cidlowski  JA.  Antiinflammatory action of glucocorticoids—new mechanisms for old drugs.   N Engl J Med. 2005;353(16):1711-1723. doi:10.1056/NEJMra050541PubMedGoogle Scholar
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Steinberg  KP, Hudson  LD, Goodman  RB,  et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.  Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.   N Engl J Med. 2006;354(16):1671-1684. doi:10.1056/NEJMoa051693PubMedGoogle Scholar
11.
Villar  J, Ferrando  C, Martínez  D,  et al; Dexamethasone in ARDS Network.  Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.   Lancet Respir Med. 2020;8(3):267-276. doi:10.1016/S2213-2600(19)30417-5PubMedGoogle Scholar
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Lee  N, Allen Chan  KC, Hui  DS,  et al.  Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients.   J Clin Virol. 2004;31(4):304-309. doi:10.1016/j.jcv.2004.07.006PubMedGoogle Scholar
13.
Arabi  YM, Mandourah  Y, Al-Hameed  F,  et al; Saudi Critical Care Trial Group.  Corticosteroid Therapy for critically ill patients with Middle East respiratory syndrome.   Am J Respir Crit Care Med. 2018;197(6):757-767. doi:10.1164/rccm.201706-1172OCPubMedGoogle Scholar
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Ni  YN, Chen  G, Sun  J, Liang  BM, Liang  ZA.  The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis.   Crit Care. 2019;23(1):99. doi:10.1186/s13054-019-2395-8PubMedGoogle Scholar
15.
Horby  P, Lim  WS, Emberson  JR,  et al; RECOVERY Collaborative Group.  Dexamethasone in hospitalized patients with Covid-19—preliminary report.   N Engl J Med. Published online July 7, 2020. doi:10.1056/NEJMoa2021436PubMedGoogle Scholar
16.
Tomazini  BM, Maia  IS, Bueno  FR,  et al.  COVID-19–associated ARDS treated with DEXamethasone (CoDEX): study design and rationale for a randomized trial.   Rev Bras Ter Intensiva. Published online July 28, 2020. . http://rbti.org.br/imagebank/pdf/RBTI-0226-20-en-para-site-16.07.pdfGoogle Scholar
17.
Ranieri  VM, Rubenfeld  GD, Thompson  BT,  et al; ARDS Definition Task Force.  Acute respiratory distress syndrome: the Berlin definition.   JAMA. 2012;307(23):2526-2533. doi:10.1001/jama.2012.5669PubMedGoogle Scholar
18.
Harris  PA, Taylor  R, Minor  BL,  et al; REDCap Consortium.  The REDCap consortium: building an international community of software platform partners.   J Biomed Inform. 2019;95:103208. doi:10.1016/j.jbi.2019.103208PubMedGoogle Scholar
19.
Annane  D, Pastores  SM, Rochwerg  B,  et al.  Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients, I: Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017.   Crit Care Med. 2017;45(12):2078-2088. doi:10.1097/CCM.0000000000002737PubMedGoogle Scholar
20.
Béduneau  G, Pham  T, Schortgen  F,  et al; WIND (Weaning according to a New Definition) Study Group and the REVA (Réseau Européen de Recherche en Ventilation Artificielle) Network ‡.  Epidemiology of weaning outcome according to a new definition: the WIND Study.   Am J Respir Crit Care Med. 2017;195(6):772-783. doi:10.1164/rccm.201602-0320OCPubMedGoogle Scholar
21.
World Health Organization. COVID-19 therapeutic trial synopsis. Draft February 18, 2020. Accessed July 28, 2020. https://www.who.int/blueprint/priority-diseases/key-action/COVID-19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf
22.
Cavalcanti  AB, Suzumura  ÉA, Laranjeira  LN,  et al; Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators.  Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial.   JAMA. 2017;318(14):1335-1345. doi:10.1001/jama.2017.14171PubMedGoogle Scholar
23.
Lehmann  EL, D'Abrera  HJM.  Nonparametrics: Statistical Methods Based on Ranks. Holden-Day; 1975.
24.
Blenkinsop  A, Parmar  MK, Choodari-Oskooei  B.  Assessing the impact of efficacy stopping rules on the error rates under the multi-arm multi-stage framework.   Clin Trials. 2019;16(2):132-141. doi:10.1177/1740774518823551PubMedGoogle Scholar
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Neto  AS, Barbas  CSV, Simonis  FD,  et al; PRoVENT; PROVE Network investigators.  Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study.   Lancet Respir Med. 2016;4(11):882-893. doi:10.1016/S2213-2600(16)30305-8PubMedGoogle Scholar
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Ferrando  C, Suarez-Sipmann  F, Mellado-Artigas  R,  et al; COVID-19 Spanish ICU Network.  Clinical features, ventilatory management, and outcome of ARDS caused by COVID-19 are similar to other causes of ARDS.   Intensive Care Med. Published online July 31, 2020. doi:10.1007/s00134-020-06192-2PubMedGoogle Scholar
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Moreno  RP, Metnitz  PG, Almeida  E,  et al; SAPS 3 Investigators.  SAPS 3—from evaluation of the patient to evaluation of the intensive care unit, II: development of a prognostic model for hospital mortality at ICU admission.   Intensive Care Med. 2005;31(10):1345-1355. doi:10.1007/s00134-005-2763-5PubMedGoogle Scholar
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Metnitz  PG, Moreno  RP, Almeida  E,  et al; SAPS 3 Investigators.  SAPS 3—from evaluation of the patient to evaluation of the intensive care unit, I: objectives, methods and cohort description.   Intensive Care Med. 2005;31(10):1336-1344. doi:10.1007/s00134-005-2762-6PubMedGoogle Scholar
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Grasselli  G, Greco  M, Zanella  A,  et al; COVID-19 Lombardy ICU Network.  Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.   JAMA Intern Med. Published online July 2020. doi:10.1001/jamainternmed.2020.3539PubMedGoogle Scholar
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Wang  Y, Lu  X, Li  Y,  et al.  Clinical course and outcomes of 344 intensive care patients with COVID-19.   Am J Respir Crit Care Med. 2020;201(11):1430-1434. doi:10.1164/rccm.202003-0736LEPubMedGoogle Scholar
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Zhou  F, Yu  T, Du  R,  et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.   Lancet. 2020;395(10229):1054-1062. . doi:10.1016/S0140-6736(20)30566-3PubMedGoogle Scholar
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Cao  B, Gao  H, Zhou  B,  et al.  Adjuvant corticosteroid treatment in adults with influenza A (H7N9) viral pneumonia.   Crit Care Med. 2016;44(6):e318-e328. doi:10.1097/CCM.0000000000001616PubMedGoogle Scholar
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    Original Investigation
    Caring for the Critically Ill Patient
    September 2, 2020

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

    Author Affiliations
    • 1Hospital Sírio-Libanês, São Paulo, Brazil
    • 2Departamento de Cirurgia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
    • 3HCor Research Institute, São Paulo, Brazil
    • 4Brazilian Research in Intensive Care Network (BRICNet), São Paulo, Brazil
    • 5Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil
    • 6Hospital Moinhos de Vento, Porto Alegre, Brazil
    • 7BP–A Beneficência Portuguesa de São Paulo, São Paulo, Brazil
    • 8International Research Center, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil
    • 9Brazilian Clinical Research Institute, São Paulo, Brazil
    • 10Duke University Medical Center, Duke Clinical Research Institute, Durham, North Carolina
    • 11UTI Respiratória, Instituto do Coração (Incor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
    • 12Departamento de Cardiopneumologia, Instituto do Coração (Incor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
    • 13Hospital de Clinicas de Porto Alegre, Rio Grande do Sul, Brazil
    • 14Hospital Vila Santa Catarina, São Paulo, Brazil
    • 15Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
    • 16Laboratorio de Medicina Intensiva, Instituto Nacional de Infectologia, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
    • 17Barretos Cancer Hospital, Barretos, Brazil
    • 18Intensive Care Unit, AC Camargo Cancer Center, São Paulo, Brazil
    • 19UTI 09DN, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
    • 20Anesthesiology, Pain, and Intensive Care Department, Federal University of São Paulo, São Paulo, Brazil
    • 21Hospital Mario Covas, FMABC, Santo Andre, Brazil
    • 22Hospital Samaritano Paulista, São Paulo, Brazil
    • 23Hospital Evangélico de Vila Velha, Vila Velha, Brazil
    • 24Aché Laboratórios Farmacêuticos, São Paulo, Brazil
    • 25Disciplina de Emergências Clínicas, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
    JAMA. Published online September 2, 2020. doi:10.1001/jama.2020.17021
    Visual Abstract. Effect of Dexamethasone on Ventilator-Free Days Among Patients With COVID-19
    Effect of Dexamethasone on Ventilator-Free Days Among Patients With COVID-19
    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

    Introduction

    Three months after the emergence of the coronavirus disease 2019 (COVID-19)1 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the World Health Organization declared it a pandemic.2 Estimates have suggested that up to 12% of patients hospitalized with COVID-19 have required invasive mechanical ventilation,3,4 with the majority developing acute respiratory distress syndrome (ARDS).5 Diffuse alveolar damage with hyaline membranes,6 hallmarks of ARDS, have been found on pulmonary histological examination of patients with COVID-19. Furthermore, an uncontrolled inflammatory state is frequent with COVID-197,8 and may contribute to multiorgan failure in these patients. Corticosteroids might exert an effect in controlling this exacerbated response.9

    Several trials evaluated the role of corticosteroids for non–COVID-19 ARDS with conflicting results.10,11 Observational studies of other viral diseases suggested that corticosteroids might increase viral load in patients with SARS-CoV12 and Middle East respiratory syndrome (MERS).13 A meta-analysis identified an association between corticosteroids and higher mortality among patients with influenza.14 Findings from a randomized clinical trial involving patients with COVID-19 indicated that the use of dexamethasone decreased mortality in hospitalized patients requiring supplemental oxygen or mechanical ventilation.15

    The COVID-19 Dexamethasone (CoDEX) randomized clinical trial was conducted to evaluate the efficacy of intravenous dexamethasone in patients with moderate to severe ARDS due to COVID-19. The hypothesis was that dexamethasone would increase the number of days alive and free from mechanical ventilation during the first 28 days.

    Methods
    Study Design and Oversight

    We conducted an investigator-initiated, multicenter, randomized, open-label, clinical trial in 41 intensive care units (ICUs) in Brazil. The trial protocol (Supplement 1) and the statistical analysis plan were submitted for publication before the first interim analysis16 (Supplement 2). The study was approved at the Brazilian Health Regulatory Agency, the Brazilian National Commission for Research Ethics, and all ethics committees at the participating sites. Written or oral informed consent was obtained before randomization from each patient’s legal representative. The trial was overseen by an external and independent data and safety monitoring committee (DSMC).

    Patients

    Patients were enrolled who were at least 18 years old, had confirmed or suspected COVID-19 infection (eMethods in Supplement 3), and were receiving mechanical ventilation within 48 hours of meeting criteria for moderate to severe ARDS with partial pressure of arterial blood oxygen to fraction of inspired oxygen (Pao2:Fio2)ratio of 200 or less. An ARDS diagnosis was made according to the Berlin Definition criteria.17 Exclusion criteria were pregnancy or active lactation, known history of dexamethasone allergy, corticosteroid use in the past 15 days for nonhospitalized patients, use of corticosteroids during the present hospital stay for more than 1 day, indication for corticosteroid use for other clinical conditions (eg, refractory septic shock), use of immunosuppressive drugs, cytotoxic chemotherapy in the past 21 days, neutropenia due to hematological or solid malignancies with bone marrow invasion, consent refusal, or expected death in the next 24 hours (Figure 1). During the study period we refined some of the inclusion and exclusion criteria. Full details are provided in Supplement 3.

    Trial Procedures

    Randomization was performed through an online web-based system18 using computer-generated random numbers and blocks of 2 and 4, unknown to the investigators, and was stratified by center. The group treatment was disclosed to the investigator only after all information regarding patient enrollment was recorded in the online system (eMethods in Supplement 3).

    Eligible patients were randomly assigned in a 1:1 ratio to receive dexamethasone 20 mg intravenously once daily for 5 days, followed by 10 mg intravenously once daily for additional 5 days or until ICU discharge, whichever occurred first, plus standard care. Patients in the control group received standard care only. Physicians, patients, and individuals who assessed the outcomes were not blinded for the assigned treatment. Each study center was encouraged to follow the best practice guidelines and their institutional protocol for the care of critically ill patients with COVID-19. All clinical interventions, such as use of antibiotics, ventilatory strategy, laboratory testing, and hemodynamic management were left at the discretion of the ICU team for both groups.

    Protocol adherence was assessed daily until day 10. Unjustified corticosteroid use or use for treating ARDS or COVID-19 in the control group was not recommended and considered a protocol deviation. The use of nonstudy corticosteroids was permitted in the control group for usual ICU indications, such as bronchospasm and refractory septic shock.19 Additionally, any dexamethasone dosage change or early interruption in the intervention group was considered a protocol violation.

    Clinical and Laboratory Data

    Data on demographic characteristics, physiological variables, corticosteroid use before randomization, timing from ARDS diagnosis to randomization, insulin use for hyperglycemia, and other clinical and laboratory data were collected. Use of neuromuscular blocking agents, prone positioning, and extracorporeal membrane oxygenation (ECMO) were collected daily through day 14. Use of mechanical ventilation and other oxygen supportive therapies (high-flow nasal cannula, noninvasive positive pressure ventilation, and use of supplemental oxygen) were collected daily through 28 days. Diagnosis of new infections were reported daily through day 28. Individual patient data on infections were adjudicated by a blinded investigator (eMethods in Supplement 3). Patients were followed up for 28 days after randomization or until hospital discharge, whichever occurred first.

    Outcomes

    The primary outcome was ventilator-free days during the first 28 days, defined as the number of days alive and free from mechanical ventilation for at least 48 consecutive hours.20 Patients discharged from the hospital before 28 days were considered alive and free from mechanical ventilation at 28 days. Nonsurvivors at day 28 were considered to have no ventilator-free days. More details on the definitions are provided in the eMethods section of Supplement 3.

    Prespecified secondary outcomes were all-cause mortality during 28 days, clinical status of patients at day 15 using a 6-point ordinal scale adapted from the World Health Organization R&D Blueprint expert group21—(1) not hospitalized, (2) hospitalized, not requiring supplemental oxygen, (3) hospitalized, requiring supplemental oxygen, (4) hospitalized, requiring noninvasive ventilation or nasal high-flow oxygen therapy, (5) hospitalized, requiring invasive mechanical ventilation or ECMO, and (6) death; ICU-free days during the first 28 days; mechanical ventilation duration at 28 days; and Sequential Organ Failure Assessment (SOFA) scores, which range from 0 to 24, with higher scores indicating greater dysfunction, at 48 hours, 72 hours, and 7 days. For post hoc analyses, we evaluated the components of ventilator-free days during the first 28 days, the cumulative proportions of the 6-point ordinal scale at 15 days, and the outcome of discharge from hospital alive within 28 days. For patients who died, the number of ventilator-free days was 0; for patients who were alive, the ventilator-free days were the days they did not require mechanical ventilation.

    Statistical Analysis

    No reliable data were available at the trial design to allow for an accurate sample size calculation. Therefore, we used data from a multicenter randomized trial of non–COVID-19 ARDS in Brazil22 for our sample size calculation. We originally estimated a 2-sided α level of .05 and power of 80% to detect a difference of 3 ventilator-free days between groups; assuming a mean of 8 (SD, 9) ventilator-free days in the control group, 290 patients had to be enrolled. Before the first interim analysis, without any study data review and after discussing the protocol with the DSMC, the study steering committee decided to increase the sample size to 350 patients based on necessary adjustments regarding the uncertainty about the normality of the distribution of ventilator-free days. Thus, the original sample size was increased by 15% based on the Pitman asymptotic relative efficiency23 to preserve study power.

    Two preplanned interim analyses for efficacy and safety evaluation after 96 and 234 patients with complete follow-up were programmed. The stopping rule for safety was P < .01 and for efficacy P < .001 (Haybittle–Peto boundary).24 There was no adjustment in the final threshold for statistical significance for sequential analysis.

    To estimate treatment effects on the primary outcome, a generalized linear model was used with 0-1 inflated beta-binomial distribution, with center as random effect and adjusted for age and the Pao2:Fio2 ratio at randomization. The effect size was estimated as mean difference and its respective 95% confidence interval.

    The all-cause mortality rate at 28 days was analyzed using a mixed Cox model, with centers as the random effects. The treatment effect on the SOFA score at 48 hours, 72 hours, and 7 days after randomization was analyzed by a linear mixed model with patients as random effects adjusted for the baseline SOFA score. For the clinical status of patients, if the proportional odds assumption was met, a mixed ordinal logistic regression was used. All secondary outcomes were adjusted for age and the Pao2:Fio2 ratio to increase statistical power and improve the efficiency of the analysis. Further details on model assumptions and model fit are provided in the eMethods section of Supplement 3. Adverse events are expressed as counts and percentages and compared between groups using the χ2 test.

    All patients were included in the primary analysis. There was no loss to follow-up, and data on the primary outcome, mortality within 28 days, clinical status at day 15, ICU-free days at 28 days, and mechanical ventilation duration were available for all patients. Missing values on individual SOFA components were imputed as normal (eMethods in Supplement 3). We assessed the consistency of the primary analysis results through prespecified sensitivity analyses considering the per-protocol population, patients who received corticosteroids vs patients who did not (as-treated population), patients with confirmed COVID-19, and patients with confirmed or probable COVID-19 (eMethods in Supplement 3).

    We performed prespecified subgroup analysis on the primary outcome testing interactions for age (<60 and ≥60 years), Pao2:Fio2 ratio (≤100 and >100), symptoms duration at randomization (≤7 and >7 days), Simplified Acute Physiology Score III (SAPS III) (<60 and ≥60), position at randomization (prone or supine), and use of vasopressor at randomization (eMethods in Supplement 3).

    Patients were analyzed according to their randomization groups, and no adjustments for multiplicity were performed. Thus, the results of secondary outcomes and subgroup analyses should be interpreted as exploratory. A 2-sided P value of less than .05 was considered statistically significant. All analyses were performed using the R software version 4.0.2 (R Core Team).

    Early Trial Termination

    On June 25, 2020, the DSMC discussed the implications of the results of the dexamethasone group in the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial,15 stating that given the study results,15 it was no longer ethical to continue the trial, which led to the recommendation to stop the trial. This recommendation was accepted by the CoDEX Steering Committee on June 25, 2020 (eMethods in Supplement 3).

    Results
    Patients

    From April 17 to June 23, 2020, 299 patients were randomized. Of the enrolled patients, 151 were randomly assigned to receive dexamethasone and 148 to the control group (Figure 1).

    Baseline characteristics were well balanced between groups (Table 1; eTable 1 in Supplement 3), including severity of ARDS and the use of rescue therapies at randomization. Remdesivir was not available in Brazil during the trial period. Only 1 patient received lopinavir-ritonavir treatment. Other therapeutic strategies such as tocilizumab and convalescent plasma were limited and not widely available.

    Interventions

    Only 1 patient in the intervention group did not receive any dexamethasone. The rate of dexamethasone use within 10 days was 94.8 per 100 patient-days (eTable 2 in Supplement 3). The median duration of dexamethasone treatment was 10 days (interquartile range [IQR], 6-10 days). In the standard care group, 52 patients (35.1%) received at least 1 dose of corticosteroids, of whom 38 (73.1%) had other established clinical indications for corticosteroid use. The use of corticosteroids in 14 patients (9.4%) was considered a protocol deviation, and the rate of corticosteroid use within 10 days was 16.5 per 100 patient-days (eTable 3 in Supplement 3).

    Primary Outcome

    The mean number of days alive and free from mechanical ventilation during the first 28 days was significantly higher in the dexamethasone group than in the standard care group (6.6; 95% CI, 5.0-8.2 days vs 4.0; 95% CI, 2.9-5.4 days; difference, 2.26; 95% CI, 0.2-4.38; P = .04) (Table 2; eFigure 1 in Supplement 3). The cumulative frequency of ventilator-free days according to study group is shown in Figure 2.

    Secondary Outcomes and Adverse Events

    There was no significant difference in all-cause mortality at 28 days (56.3% in the dexamethasone group vs 61.5% the standard care group; hazard ratio, 0.97; 95% CI, 0.72 to 1.31; P = .85), in the 6-point ordinal scale at day 15 (median, 5; IQR, 3-6 for the dexamethasone group vs median, 5; IQR, 5-6 for standard care group; odds ratio [OR], 0.66; 95% CI, 0.39 to 1.13; P = .07), ICU-free days at 28 days (mean, 2.1; 95% CI, 1.0 to 4.5 days for the dexamethasone group vs mean, 2.0; 95% CI, 0.8 to 4.2 days for the standard care group; difference, 0.28; 95% CI, −0.49 to 1.02; P = .50), and mechanical ventilation duration (12.5; 95% CI, 11.2 to 13.8 days for the dexamethasone group vs 13.9, 95% CI, 12.7 to 15.1 days for the standard care group; difference, −1.54; 95% CI, −3.24 to −0.12; P = .11). The mean SOFA score at 7 days was significantly lower in the treatment group (6.1; 95% CI, 5.5 to 6.7 for dexamethasone vs 7.5; 95% CI, 6.9 to 8.1 for standard care; difference, −1.16; 95% CI, −1.94 to −0.38; P = .004) (Table 2).

    Both groups had a comparable need for insulin use for hyperglycemia: 47 patients (31.1%) in the dexamethasone group vs 42 (28.4%) in the standard care group. The number of new diagnoses of infection until day 28 was 33 (21.9%) vs 43 (29.1%). Twelve patients (7.9%) in the dexamethasone group had bacteremia vs 14 (9.5%) in the standard care group. Five patients (3.3%) had serious adverse events vs 9 (6.1%) (Table 3; eTable 4 in Supplement 3).

    Subgroup and Exploratory Analyses

    In subgroup analyses, tests for interaction were not statistically significant for subgroups defined by age (P = .21), Pao2:Fio2 ratio (P = .73), SAPS III (P = .75), time since symptom onset (P = .12), position at randomization (P = .89), and vasopressor use at randomization (P = .81) (eFigure 2 in Supplement 3).

    The post hoc analyses showed no significant difference of the intervention in the components of the primary outcome or in the outcome of discharged alive within 28 days (eTable 6 in Supplement 3). Patients in the dexamethasone group had significantly lower cumulative probability of having died or being mechanically ventilated at day 15 (categories 5-6 on the 6-point scale) than the standard care group (67.5% vs 80.4%; OR, 0.46; 95% CI, 0.26 to 0.81; P = .01) (eTable 6 and eFigure 3 in Supplement 3). In the sensitivity analyses for the primary outcome of ventilator-free days, the treatment effect was not significantly different in the as-treated analysis. The mean number of ventilator-free days was 5.8 (95% CI, 4.6 to 7.3) among 203 patients in the dexamethasone group vs 4.1 (95% CI, 2.6 to 5.5) among 96 patients in the standard care group, for a mean difference of 2.38 (95% CI, −0.6 to 3.32; P = .16). In the per-protocol analysis, the mean number of ventilator-free days among dexamethasone group was 6.4 (95% CI, 5.1 to 8.1) among 125 patients vs 4.1 (95% CI, 2.6 to 5.5) among 96 patients in the standard care group for a difference of 2.36 (95% CI, −0.15 to 4.56; P = .06). The main results remained statistically significant among patients with confirmed COVID-19 in the dexamethasone group, which had a mean number of ventilator-free days of 6.8 (95% CI, 5.4 to 8.4) among 144 patients vs 3.9 (95% CI, 2.7 to 5.1) among 142 patients in the standard care group for a difference of 2.7 (95% CI, 0.8 to 4.74; P = .01). Among the patients with confirmed or probable COVID-19, the mean number of ventilator-free days was 6.6 (95% CI, 5.3 to 8.2) among 151 patients vs 4.1 (95% CI, 2.9 to 5.2) among 147 patients for a difference of 2.38 (95% CI, 0.48 to 4.33; P = .02) (eTable 7 in Supplement 3).

    Discussion

    In this randomized clinical trial involving 299 adults with moderate or severe ARDS due to COVID-19, dexamethasone plus standard care compared with standard care alone significantly increased the number of days alive and free of mechanical ventilation during the first 28 days. Dexamethasone was not associated with increased risk of adverse events in this population of critically ill COVID-19 patients.15

    This trial included only patients with COVID-19 and moderate or severe ARDS and provided laboratory, physiological, and adverse events data on the use of corticosteroids in this population. The ventilator-free days criterion was chosen as the primary outcome because it comprises both mortality and ventilation duration in surviving patients. The number of days alive and free from mechanical ventilation at 28 days was significantly lower than reported in other trials of non–COVID-19 ARDS,10,11,25 but consistent with COVID-19 ARDS studies, confirming the disease severity.26 The difference between groups of 2.26 days was lower than the effect size of 3 days used in the sample size calculation. This reduction is relevant in the context of a pandemic, in which an inexpensive, safe, and widely available intervention like dexamethasone increases even modestly the number of ventilator-free days and may reduce the risk of ventilatory complications, ICU length of stay, and burden to the health care system.

    Mortality rates were high and not significantly different between groups, in contrast with the RECOVERY trial of dexamethasone in patients hospitalized for COVID-1915 and a trial of dexamethasone in patients with non-COVID-19 ARDS.11 The high mortality rate might be explained by several factors. The patients had a high risk of death as shown by the low mean Pao2:Fio2 ratio and mean SAPS III score of 70, which represents a mortality risk of 70.9% in South America.27,28 In a previous randomized clinical trial, moderate to severe ARDS not caused by COVID-19 had an elevated mortality rate in Brazil of 52%,22 and recent data collected by Brazilian Association of Critical Care demonstrated mortality rates of 66% to 70% for ventilated patients with COVID-19 in Brazilian ICUs.29 This may be explained by the pandemic and its burden to the health care system, especially in a country with limited resources like Brazil. However, even in high-income countries the mortality rate in ventilated patients with COVID-19 might range from 54% to 88%.30-32 This mortality rate may be similar to that of other low and middle-income countries and is important to consider when translating the scientific evidence to clinical practice. In this sense, the results of this trial expand those of the RECOVERY trial15 by showing that corticosteroids were effective even when the baseline mortality rate was high.

    The dexamethasone dose was chosen based on a previous11 trial showing the benefit of dexamethasone to patients with non–COVID-19 ARDS. Previous data suggest that high doses of corticosteroids (the equivalent of 30 mg/d of dexamethasone) in viral pneumonia may be associated with unfavorable outcomes.33 However, there are no currently available data from patients with COVID-19 to determine if higher doses are harmful. In the present study, the number of adverse events, new infections, and the use of insulin were comparable in both groups, in line with previous studies that did not demonstrate an augmented risk of adverse events with corticosteroids in non-COVID-19 ARDS.10,11,19

    This trial has several strengths. Bias was controlled by ensuring allocation concealment, all patients were analyzed according to their randomization group, and follow-up was complete. Also, adverse events data regarding corticosteroid use among patients with COVID-19 were provided, along with detailed data on ventilatory parameters, ARDS treatment, and laboratory and physiological variables.

    Limitations

    This study has several limitations. First, it was an open-label trial due to time constraints of producing placebo in a pandemic scenario with an urgent need for reliable and randomized data. Second, 35% of the patients in the control group received corticosteroids during the study period, possibly related to the open-label design, the disease severity of the patients, and other diverse indications for corticosteroid use in critical care.19 However, the use of corticosteroids in the control group would have biased the results toward the null, and the study identified a benefit of the intervention on the primary outcome. Third, the open-label design and investigator-reported data on adverse events and infections may have led to bias in the description of these events. Fourth, the trial was underpowered for important secondary outcomes like mortality and the study was interrupted before the original sample size was obtained due to external evidence of benefit, and the obtained sample size was limited to demonstrate benefits in secondary outcomes.

    Conclusions

    In 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 increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.

    Section Editor: Derek C. Angus, MD, MPH, Associate Editor, JAMA (angusdc@upmc.edu).
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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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