High- Versus Low-Dose Dexamethasone for the Treatment of COVID-19-Related Acute Respiratory Distress Syndrome: A Multicenter, Randomized Open-Label Clinical Trial

Abstract

To determine whether high-dose dexamethasone increases the number of ventilator-free days (VFD) among patients with acute respiratory distress syndrome (ARDS) caused by COVID-19.

Design

Multicenter, randomized, open-label, clinical trial.

Participants

Consecutive patients with confirmed COVID-19-related ARDS were enrolled from June 17, 2020, to March 27, 2021, in four intensive care units (ICUs) in Argentina

Intervention

16 mg of dexamethasone intravenously daily for five days followed by 8 mg of dexamethasone daily for five days or 6 mg of dexamethasone intravenously daily for 10 days.

Main Outcome and Measures

The primary outcome was ventilator-free days during the first 28 days. The secondary outcomes were all-cause mortality at 28 and 90 days, infection rate, muscle weakness, and glycemic control in the first 28 days.

Results

Data from 98 patients who received at least one dose of dexamethasone were analyzed. The trial was prematurely terminated due to low enrollment rate. At 28 days after randomization, there was no difference between high- and low-dose dexamethasone groups in VFD (median, 0 [interquartile range [IQR] 0-14] vs. 0 [IQR 0-1] days; P = .231), or in the mean duration of mechanical ventilation (19 ± 18 vs. 25 ± 22 days; P = .078). The cumulative hazard of successful discontinuation from mechanical ventilation was increased by the high-dose treatment (adjusted sub-distribution hazard ratio: 1.84; 95% CI: 1.31 to 2.5; P < .001). None of the prespecified secondary and safety outcomes showed a significant difference between treatment arms.

Conclusions

Among patients with ARDS due to COVID-19, the use of higher doses of dexamethasone compared with the recommended low-dose treatment did not show an increase in VFD. However, the higher dose significantly improved the time required to liberate them from the ventilator

SciScore for 10.1101/2021.09.15.21263597: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Ethics	IRB: The study was approved at the Research Ethics Committee of CEMIC (Buenos Aires, Argentina) and by the Argentine Society of Intensive Care Medicine (SATI) Ethics Committee. Consent: Either a written or an electronic informed consent (REDCap electronic consent framework) was obtained from the legal representative of each patient.
Sex as a biological variable	The exclusion criteria were pregnant or breastfeeding women, terminal disease, therapeutic limitation, severe immunosuppression, chronic treatment with glucocorticoids, participation in another randomized clinical trial, prior use of dexamethasone for COVID-19 (> 5 days), or consent refusal (e-Methods Supplement 2).
Randomization	Study Design and Oversight: We conducted an investigator-initiated, multicenter, randomized, open-label clinical trial in four intensive care units (ICUs) in Argentina.
Blinding	The investigators who assessed the outcomes were not blinded for the assigned treatment.
Power Analysis	Statistical Analysis: No reliable data on ARDS caused by COVID-19 were available at the trial design to allow for an accurate sample size calculation.

Table 2: Resources

Software and Algorithms
Sentences	Resources
Trial Procedures: Treatment allocation was performed through an online web-based system (REDCap) 16 using a permuted random block sequence stratified by center.	REDCap suggested: (REDCap, RRID:SCR_003445)

Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

This study has many limitations. First, it is an open-label study. A double-blind design would be desirable but, given the urgent need for evidence required by the pandemic, we were unable to do it differently. Nevertheless, we believe that our data may provide some useful and interesting findings. Second, the early and unplanned termination of the study due to poor accrual after nine months indicates a failure in our trial process. The reasons for this premature termination were related to the fast-changing dynamics of the pandemic and were not anticipated by us during the trial design. The smaller size probably reduced the power of our study to detect differences in the VFD and other secondary outcomes. Third, the lack of shared procedures for liberation from mechanical ventilation in this multicenter open-label trial produces a potential bias. However, international guidelines commonly used were suggested. Finally, the investigators reported the results and conducted the analysis. Nevertheless, to prevent bias, the analysis was conducted as planned at the writing of the protocol, following such procedures after the termination of the data recollection.

Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

Identifier	Status	Title
NCT04395105	Terminated	Dexamethasone for COVID-19 Related ARDS: a Multicenter, Rand…

Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

Results from JetFighter: We did not find any issues relating to colormaps.

Results from rtransparent:

Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
No protocol registration statement was detected.

Results from scite Reference Check: We found no unreliable references.

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