Reference: N Engl J Med. 2023 May 25;388(21):1931
Practice Point: High-dose hydrocortisone should be strongly considered as an addition to standard treatment for adults with severe community-acquired pneumonia.
EBM Pearl: Nearly without fail, “Table 1” in published trials conveys a plethora of information about what types of patients may benefit from an intervention (external validity) as well as any important baseline differences between groups (internal validity).
As many folks in the US will gather with family and friends for Thanksgiving this week, it’s likely that some will be expressing gratitude that a loved one survived a scary stay in the ICU and is there to celebrate. That might be thanks to high-dose hydrocortisone.
In the US, 1.5 million people are hospitalized for community-acquired pneumonia each year, making it the leading cause of death from infection. A trial recently published in NEJM evaluated the addition of IV hydrocortisone to standard care for the treatment of adults in France admitted to an ICU with severe pneumonia. Investigators found a significant (2-fold) reduction in 28-day mortality, among improvements in other secondary outcomes. The trial was expertly designed and executed with randomization and allocation concealment, an appropriate control, and double-blinding. Due to differing pharmacodynamics of glucocorticoids, patients with septic shock were excluded, as were patients with pneumonia caused by influenza due to safety concerns of glucocorticoids in those patients.
A total of 800 adults were enrolled from 2015-2020. Enrollment was halted at the beginning of the COVID pandemic and a second interim analysis delayed until 2021, at which point the trial was stopped for benefit before the planned 1146 participants had been achieved. In addition to other appropriate treatments such as antibiotics and supportive care, patients were randomized to received either placebo or IV hydrocortisone 200 mg daily for either 4 or 7 days based on preset criteria indicating clinical improvement, followed by a taper for a total treatment duration of 8 or 14 days. About 25% of patients had comorbid COPD, 25% had diabetes, and about 6% were immunosuppressed. None of these patients had COVID (that they know of). These patients were sick: nearly half required mechanical ventilation and about 10% received pressors. The trial drug was initiated within 24 hours of meeting preset severity criteria, which occurred at a median of about 15 days after ICU admission in both groups.
At 28 days, death had occurred in 6.2% (CI 3.9%-8.6%) of patients in the hydrocortisone group and 11.9% (CI 8.7%-15.1%) in the placebo group. At 90 days, mortality was 9.3% and 14.7%, respectively. Patients in the hydrocortisone group were also significantly less likely to need pressors or mechanical ventilation if not already receiving those treatments at enrollment. There were no significant differences in adverse events including ICU-acquired infections and GI bleeds, although patients in the hydrocortisone group were more likely to receive higher doses of insulin (median 36 vs. 21 units per day).
It’s not often that we review a trial that demonstrates a clear, practice-changing benefit with very few opportunities to poke holes in the methodology. We are thankful for that this week. We also appreciate the thoughtful design of this trial, which considered previous trials of other glucocorticoids including methylprednisolone that did not demonstrate as clear a benefit, and chose to study a steroid with a different balance of mineralocorticoid and glucocorticoid effects. Based on the best available evidence, hydrocortisone (specifically) should be strongly considered for patients with severe pneumonia without fear that it will worsen their condition.
For more information, see the topic Community-acquired Pneumonia in Adults in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Associate Editor at DynaMed.