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September - 2020

   

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Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19

B Tomazini, I Maia, A Cavalcanti, et al for the CoDEX Randomised Clinical Trial JAMA, 2020, online Sept 2020

Comment

There is a lot to review regarding corticosteroids and COVID-19;

This trial, performed in 41 Brazilian ICUs evaluated the efficacy of intravenous dexamethasone in patients with moderate to severe ARDS due to COVID-19. The details;

  • Adults, receiving MV <48hrs, mod-severe ARDS (PF <200), confirmed or suspected COVID
  • Analysis plan: 
    • Estimated 2-sided α level of .05, power of 80% to detect difference of 3 VFDs between groups; assuming a mean of 8 VFDs in control, required 290 patients, increased to 350 patients after 1st DSMC
    • Stopped June 25 due to RECOVERY trial at 299 patients. 
  • Interventions
    • Dexamethasone 20mg IV daily for 5 days, 10mg IV daily 5 days or ICU discharge
    • Placebo
    • 95% received therapy and median duration 10-days in Dex group, 35% in standard group recipe at least 1-dose Dex, of which 73% had other indication.
  • Primary outcome: 
    • Days alive and free from MV during the 1st day 28 
    • 6.6 vs 4.0 days (diff, 2.26; 95%CI, 0.2-4.38; P = .04)
  • Secondary outcomes
    • No difference all-cause mortality, clinical status at day 15 using 6-point ordinal scale, ICU free days, hospital etc.
    • 28-d all cause mortality 56.3% vs 61.5%, p=0.31
  • Subgroup and exploratory analyses
    • confirmed COVID-19 patients,  dexamethasone group, had mean VFDs 6.8 (95%CI, 5.4 to 8.4) among 144 patients vs 3.9 (95% CI, 2.7 to 5.1) among 142  the standard care group, difference of 2.7 (95% CI, 0.8 to 4.74; P = .01)
    • confirmed or probable COVID-19, mean VFDs  6.6 (95% CI, 5.3 to 8.2) among 151 patients vs 4.1 (95% CI, 2.9 to 5.2) among 147 standard care for diff of 2.38 (95%CI, 0.48 to 4.33; P = .02)

Overall this RCT of 299 adults with mod-severe ARDS due to COVID-19 reported increased days alive and are free from mechanical ventilation during first 28-days with dexamethasone compared to standard care.  Trial was stopped early due to RECOVERY, and 35% of standard care arm received corticosteroids during study.

 

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.

September


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