Critical Care, Critical Care Alert, COVID-19

Critical Care Alert: Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Critical Care Alert

Article
Sterne JA, Murthy S, Diaz JV, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 10.1001/jama.2020.17023.

Background
The SARS-CoV-2 (coronavirus 2019, COVID-19) pandemic has led to unprecedented disruption throughout the world.  The medical community has been flooded with case reports, pre-prints, small retrospective studies and conflicting dialogues through social media and journals.  The lack of prospective RCTs months after the pandemic has left millions infected has left clinicians uncertain on best practices for patients.  

Steroids have been used extensively by clinicians throughout the pandemic.  The prior DEXA-ARDS(2), ADRENAL(3) and APPROACHSS(4) trials have provided evidence that steroids are beneficial in ARDS, and sepsis.  However, it was unclear what the role of steroids were in this novel disease.  The RECOVERY(5) trial was a landmark trial showing the benefits of steroids in COVID patients in respiratory failure.  There were many other trials throughout the world examining the role of steroids in COVID that were stopped early due to the resounding results of the RECOVERY trial.  A working group by the World Health Organization (WHO) developed a protocol to perform a meta-analysis of these prospective trials examining the role of steroids for SARS-CoV-2.

Objective
Study investigators aimed to determine if the administration of systemic corticosteroids was associated with reduced 28-day mortality in critically ill patients with coronavirus disease 2019 (COVID-19)

Design
Prospective meta-analysis comprised of pooled data from 7 clinical trials investigating corticosteroid use in critically ill patients with COVID-19

Trial Selection
Inclusion Criteria: 

  • Listed with clinicaltrials.gov, Chinese Clinical Trial Registry or EU Clinical Trials Registrar
  • Listed between December 31, 2019 and Apri 6, 2020
  • Trials must have examined interaction of corticosteroids and COVID-19

Of the 16 trials identified, 7 were excluded and 2 not included for lack of consent/reply.

Primary Outcome

  • All-cause mortality up to 30 days after randomization (shorter terms accepted if 30 days not available

Secondary Outcomes

  • Serious adverse events

 

Key Results
Total number of patients included in analysis: 1703

Primary Outcomes

  • Death reported in 222/678 patients randomized to corticosteroids
  • Death reported in 435/1025 patients randomized to usual care or placebo.
  • The overall OR was 0.66 (95% CI, 0.53-0.82; P < .001) for all-cause mortality comparing corticosteroids with usual care or placebo
  • The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo
  • The fixed-effect summary OR  for the association with mortality was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone  compared with usual care or placebo.
  • The OR for the association with mortality was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone  compared with usual care or placebo.

Secondary Outcomes (adverse events): 

  • 64 adverse events among 354 patients in the steroid group
  • 80 adverse events among the 342 patients  in the usual care/placebo groups

Strengths

  • Large number of critically ill patients
  • Meta-analysis
  • 6/7 of studies involved were considered “low-risk” for potential bias

Limitations

  • Poor estimation in comparison between low-dose and high-dose corticosteroids with respect to all-cause mortality
  • Could not estimate optimal duration of treatment or dose
  • Limited data on adverse events available; mixed languages between studies
  • RECOVERY trial accounted for >50% of the weight of primary meta-analysis

EM Take-Aways
Use of corticosteroids in critically ill patients, including those with COVID-19 was shown to be associated with a lower 28-day all-cause mortality. Greater than 50% of the weight of this determination was appropriated to the RECOVERY trial, which demonstrated, among other findings, a 12% absolute risk reduction in death among patients receiving low-dose dexamethasone who were on invasive mechanical ventilation. The lack of synthesis of this data into recommendations of dosage and duration of treatment makes these findings less user-friendly, but point towards overall mortality benefits.


References

  1. Sterne JA, Murthy S, Diaz JV, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 10.1001/jama.2020.17023.
  2. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797-808.
  3. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-18.
  4. Meduri GU, Siemieniuk RAC, Ness RA, Seyler SJ. Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS. J Intensive Care. 2018;6(1):53.
  5. Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. The Lancet Resp Med. 2020 Mar 1;8(3):267-76.

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