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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

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