In this episode, I’ll discuss the dose of dexamethasone for patients with COVID-19.
Current recommendations are for a daily dose of 6 mg dexamethasone for up to 10 days in patients with severe and critical COVID-19. This dose was not determined by a dose-finding study, rather it was the single-dose selected by the RECOVERY trial authors. However higher doses have been studied in patients with COVID-19, and a meta-analysis suggests there may be a benefit to going beyond 6 mg.
Recently published in JAMA was a multicenter, randomized clinical trial looking at the Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia.
1000 patients were randomized 1:1 to 12 mg/day of intravenous dexamethasone or 6 mg/day of intravenous dexamethasone for up to 10 days. All patients had confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation.
The authors concluded that
Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.
The adjusted mean difference was 1.3 days in favor of the higher dose group however the 95% confidence interval included zero, and the p-value for this difference was outside the range of statistical significance at 0.07. In order to ensure adequate trial size, the trial design allowed up to 4 days of dexamethasone use before enrollment. This however may have reduced the effect of the intervention because in some patients the intervention period could have been only 6 days. Despite this, the study had 85% power to demonstrate a relative reduction of 15% in 28-day mortality.
An accompanying editorial published in the same issue of JAMA focuses on the subgroup of patients who were not receiving IL-6 receptor antagonists at baseline. These patients may have had an improvement from the higher dose of dexamethasone, and the editorialists argue that in resource-limited settings where steroid access is plentiful but IL-6 inhibitors are unavailable, the consequences of a type II error are of greater importance than a type I error and the results raise the strong possibility that treatment outcomes for COVID-19 may be improved further by the use of higher doses of glucocorticoids.
Unless further data becomes available, higher doses of dexamethasone beyond 6 mg do not appear warranted as long as access to IL-6 inhibitors is plentiful.
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