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
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.207.129.82. Please contact the publisher to request reinstatement.

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.

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 ScholarCrossref
2.
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
3.
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 ScholarCrossref
4.
Docherty  AB, Harrison  EM, Green  CA,  et al; ISARIC4C investigators.  Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.   BMJ. Published online May 22, 2020. doi:10.1136/bmj.m1985PubMedGoogle Scholar
5.
Grasselli  G, Zangrillo  A, Zanella  A,  et al; COVID-19 Lombardy ICU Network.  Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy.   JAMA. 2020;323(16):1574-1581. doi:10.1001/jama.2020.5394PubMedGoogle ScholarCrossref
6.
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 ScholarCrossref
7.
Moore  JB, June  CH.  Cytokine release syndrome in severe COVID-19.   Science. 2020;368(6490):473-474. doi:10.1126/science.abb8925PubMedGoogle ScholarCrossref
8.
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 ScholarCrossref
9.
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 ScholarCrossref
10.
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 ScholarCrossref
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 ScholarCrossref
12.
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 ScholarCrossref
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 ScholarCrossref
14.
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 ScholarCrossref
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 ScholarCrossref
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 ScholarCrossref
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 ScholarCrossref
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 ScholarCrossref
25.
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 ScholarCrossref
26.
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
27.
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 ScholarCrossref
28.
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 ScholarCrossref
29.
Uso de Supporte na Unidade de Principais Desfechos—Internaçõis em UTI Adulto com Desfecho Hospitalar Atribuísdo. UTIs Brasileiras. Updated August 19, 2020. Accessed July 31, 2020. http://www.utisbrasileiras.com.br/sari-covid-19/benchmarking-covid-19/
30.
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
31.
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 ScholarCrossref
32.
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 ScholarCrossref
33.
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 ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    EXPAND ALL
    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.

    Reference

    1. https://jamanetwork.com/journals/jama/fullarticle/2770276
    2. https://www.nejm.org/doi/full/10.1056/NEJMoa2021436
    CONFLICT OF INTEREST: None Reported
    READ MORE
    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.

    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

    ×