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

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.

Conflict of interest statement

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.

Figures

Figure 1.. 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

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.