An Exploratory Reanalysis of the Randomized Trial on Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome

Objectives: In the Acute Respiratory Distress Syndrome Network randomized controlled trial, methylprednisolone treatment was associated with increased return to mechanical ventilation with partial loss of early improvements. We hypothesize a causal relationship between protocol-driven rapid discontinuation of methylprednisolone post extubation and return to mechanical ventilation. To explore this possibility, we investigated the timing that events occurred in each treatment arm during active treatment intervention (efficacy) and after stopping therapy. Design and Settings: Retrospective intention-to-treat analysis of multicenter randomized controlled trial. Patients and Interventions: Patients were randomized to methylprednisolone (2 mg/kg/d) or placebo (89 vs 91). The target sample size was reduced post hoc and provided 80% power for an optimistic 50% mortality reduction. Measurements and Main Results: Findings are reported as methylprednisolone versus placebo. By day 28, fewer patients died before achieving extubation (15.7% vs 25.3% and risk ratio, 0.62; 95% CI, 0.34–1.13), more achieved successful extubation (71.9% vs 49.5% and risk ratio, 1.45; CI, 1.14–1.85), time to successful extubation was shorter (hazard ratio, 2.05; CI, 1.42–2.96), and more were discharged alive from the ICU (65.2% vs 48.3%; risk ratio, 1.35; CI, 1.04–1.75). After treatment discontinuation, more methylprednisolone-treated patients returned to mechanical ventilation (26.6% vs 6.7%; risk ratio, 3.98; CI, 1.24–12.79)—consistent with reconstituted systemic inflammation in the presence of adrenal suppression. Participants returning to mechanical ventilation without reinstitution of methylprednisolone had increased risk of ventilator dependence and mortality. Despite loss of early benefits, methylprednisolone was associated with sizable and significant improvements in all secondary outcomes and reduction in serious complications (shock and severe infections). Conclusions: During active intervention, methylprednisolone was safe and effective in achieving disease resolution. Our findings support rapid glucocorticoid discontinuation post extubation as likely cause of disease relapse. Gradual tapering might be necessary to preserve the significant improvements achieved during methylprednisolone administration. Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government. The contents of this commentary do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Funding for the respective trials was disclosed in the original publications. None of the sponsors had any role in the design and conduct of the study, the collection, management, analysis and interpretation of the data, the preparation, review, or approval of the report, or the decision to submit the manuscript for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Dr. Meduri wrote the study and wrote the first draft of the report with the assistance of Ms. Bridges. Ms. Bridges standardized definitions and prepared the dataset. Drs. Siemieniuk and Kocak did the statistical analysis and collaborated in writing the article. All authors reviewed and approved the final report. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Supported, in part, by the resources and use of facilities at the Memphis Veterans Administration Medical Center. Dr. Meduri disclosed that this material is the result of work supported with the resources and use of facilities at the Memphis Veterans Administration Medical Center. He disclosed off-label product use of prolonged methylprednisolone treatment in acute respiratory distress syndrome (ARDS). Dr. Siemieniuk disclosed off-label product use of corticosteroids for ARDS. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: gmeduri@uthsc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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