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 | Critical Care Medicine | JAMA | JAMA Network
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A conversation with Jonathan A. C. Sterne, MA, MSc, PhD, of the University of Bristol, Todd W. Rice, MD, MSc, of Vanderbilt University, and Janet V. Diaz, MD, of the World Health Organization (WHO) on the latest research supporting the use of hydrocortisone and dexamethasone for treatment of COVID-19 ARDS. Recorded September 2, 2020.

In a randomized trial conducted in 2020-2021 of patients with COVID-19 and severe hypoxemia, 12 mg of dexamethasone did not statistically significantly reduce the number of days patients were alive without life support at 28 days compared with 6 mg of dexamethasone. In this video, Sheila Myatra, MD (Homi Bhabha National Institute, Mumbai, India), Balasubramanian Venkatesh, MD (The George Institute for Global Health, Sydney, Australia) and Anders Perner, MD, PhD (Rigshospitalet, Copenhagen, Denmark) present findings from the COVID STEROID 2 Trial at a Critical Care Reviews livestream presentation on October 21, 2021. An oral editorial, author reply to the oral editorial, a Q&A session, and a panel discussion follow. Click the related article link for full trial details....

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    1 Comment for this article
    The right decision to stop, or another casualty of preprint publication? The dangers of putting all the eggs in one basket
    Shyan Goh, MBBS FRACS | Private
    Despite only just 51 patients away from the minimum number for CoDEX RCT, the researchers' decision to stop the trial on 25 June 2020 would have been made on what RECOVERY data was available then, the preprint on 22 June 2020 (the final published version (in NEJM) from the RECOVERY group was not published until July 17 2020). The CAPE COVID trial (1) was halted on 3 July 2020, but their last study enrollment actually occured on 1 June 2020 and a RECOVERY press release was available only from 16 June.

    What CoDEX had shown is that IV dexamethasone
    plus standard care is associated with increased 28 day survival and days free of mechanical ventilation.

    Unlike RECOVERY, mortality rates between IV dexamethasone plus standard care vs standard care only are not significantly different. Perhaps this is due to inadequate numbers recruited for the trial. But it could also very well be related to different population, or nuances in ICU and ventilation criteria (no matter how defined it appears to be) such that mortality rates of standard care only for patients requiring invasive ventilation in CoDEX is 50% higher than RECOVERY trial (61% vs 41% -Ref 2).

    What does it mean?

    Despite the initial enthusiasm of the success of dexamethasone shown by the RECOVERY, the variation in mortality rates across different populations cannot be discounted and high expectations of applicability of RECOVERY conclusion may have to be curbed until further studies can corroborate them across the world.

    Judging by the wave of optimism, this may never happen.

    As a clinician I want dexamethasone to work, but wishing a result should not interfere with the vigour of the scientific method we rely on as an evidence base.


    1. https://jamanetwork.com/journals/jama/fullarticle/2770276
    2. https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
    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. 2020;324(13):1307-1316. 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.


    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