From Pages to Practice

By Robert Smyth, MD, MSc

Published April 27, 2023


The perennial question of whether to use glucocorticoids to treat patients with community acquired pneumonia (CAP) continues to consume hours of discussion in intensive care units (ICUs). Pneumonia elicits an inflammatory response in the lung, which left unchecked, can lead to a deleterious decline in pulmonary function and oxygenation. Glucocorticoids reduce inflammation, and in theory, should improve patient outcomes. Most recent randomized trials and meta-analyses indicate that glucocorticoids reduce the need for mechanical ventilation in patients with CAP but do not show a clear mortality benefit. The 2019 guidelines from the Infectious Diseases Society of America/American Thoracic Society do not recommend routine use of glucocorticoids for treatment of CAP, except in patients with concurrent refractory septic shock.

To evaluate whether hydrocortisone treatment reduces mortality in adult patients admitted to an ICU for severe CAP, researchers conducted the Community-Acquired Pneumonia: Evaluation of Corticosteroid (CAPE COD) trial. In this double-blind, randomized, placebo-controlled superiority trial, 800 patients admitted to the ICU with severe CAP were randomized to receive hydrocortisone (continuous intravenous dose of 200 mg daily) or placebo for 4 days. The hydrocortisone dose was tapered over 4 to 10 days based on clinical improvement. In all cases, treatment was discontinued at discharge from the ICU.

By day 28, 25 of 400 patients (6.2%) in the hydrocortisone group had died versus 47 of 395 patients (11.9%) in the placebo group (absolute difference, −5.6 percentage points; 95% CI, −9.6 to −1.7; P=0.006). Among patients who were not mechanically ventilated at baseline, 40 of 222 patients (18.0%) in the hydrocortisone group underwent endotracheal intubation versus 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86).

The positive results and large effect size of this trial suggest a mortality benefit from hydrocortisone in patients with severe CAP. However, it is unclear whether continuous infusions of hydrocortisone are equal to the norm of using divided doses and whether all glucocorticoids have the same effect at equivalent doses. Furthermore, from a practical standpoint, the U.S. currently has a shortage of hydrocortisone. Whether the results of this study will change current guidelines remains to be seen. For now, these results sway me to consider hydrocortisone treatment for ICU patients with severe CAP, unless contraindicated.

Read the following NEJM Journal Watch summary for more details of this study.

Lower Mortality in Patients Treated with Hydrocortisone for Severe Community-Acquired Pneumonia

Patricia Kritek, MD, reviewing Dequin P-F et al. N Engl J Med 2023 Mar 21

Are corticosteroids beneficial for patients with community-acquired pneumonia (CAP)? Earlier this year, a randomized, controlled trial of patients with severe CAP showed no benefit for steroids (Intensive Care Med 2022; 48:1009.). Just last month, a meta-analysis of 16 randomized trials also showed no effect on mortality (NEJM JW Gen Med Apr 15 2023 and Chest 2023; 163:484). Interestingly though, the meta-analysis showed that patients treated with corticosteroids were less likely to need intubation.

French investigators randomized 800 patients who were admitted to the intensive care unit with severe CAP to receive hydrocortisone (intravenous 200 mg daily) or placebo. Patients began treatment within 24 hours of developing severe CAP and were treated for 4 days and then tapered over 4 or 10 days depending on clinical improvement. About one quarter of patients were intubated at enrollment, and 40% were receiving high-flow nasal cannula oxygen. No standardized microbiologic investigation was done.

This trial began prior to the pandemic, and enrollment was halted in March 2020. Mortality at 28 days was significantly lower with hydrocortisone than with placebo (6% vs. 12%); this benefit persisted at 90 days. The hydrocortisone group was also less likely to require mechanical ventilation and less likely to develop shock. Hyperglycemia was more common in patients treated with hydrocortisone, but other adverse events were similar between groups.

COMMENT: Completely reconciling this body of literature is hard, but it seems that glucocorticoids lower the need for mechanical ventilation in patients with severe CAP — an outcome that reasonably could drive a mortality benefit. It will be interesting to see how the guidelines evolve, given that they currently recommend steroids only in CAP patients with septic shock (NEJM JW Gen Med Dec 1 2019 and Am J Respir Crit Care Med 2019; 200:45). I will have a lower threshold to administer hydrocortisone to patients admitted to the ICU with severe CAP.

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Robert Smyth, MD, MSc, is a 2022–2023 NEJM Editorial Fellow. He is currently an Assistant Professor of computational biomedicine at the Boston University School of Medicine.