Adding hydrocortisone therapy to standard therapy lowered the risk of death within 28 days in adults with severe community-acquired pneumonia (CAP) in the intensive care unit (ICU), according to study findings published in The New England Journal of Medicine.
More than 1.5 million adults in the US are hospitalized annually with CAP, which was the ninth leading cause of death in the US in 2019. Researchers sought to determine whether early treatment with hydrocortisone reduced 28-day mortality among patients with severe community-acquired pneumonia admitted to an ICU. In addition to the mortality outcome, researchers also evaluated initiation of vasopressor therapy by day 28 and endotracheal intubation rates.
This phase 3, randomized, double-blind, controlled trial (Community-Acquired Pneumonia: Evaluation of Corticosteroids; ClinicalTrials.gov Identifier: NCT02517489) was conducted at 31 French centers from October 2015 to March 2020 by members of the Clinical Research in Intensive Care and Sepsis/Trial Group for Global Evaluation and Research in Sepsis Network. The trial included 795 adult patients admitted to a participating ICU with severe community-acquired pneumonia. Patients with septic shock, pneumonia caused by influenza, or with a do-not-intubate order were excluded.
Severe pneumonia was defined by either: (1) initiation of the oxygen through high-flow nasal cannula with a ratio of partial pressure of arterial oxygen to inspired fraction of oxygen (PaO2/FIO2) of less than 300, with a FIO2 of at least 50%; (2) initiation of mechanical ventilation (invasive or noninvasive) with positive end-expiratory pressure of at least 5cm of water; (3) an estimated PaO2/FIO2 ratio of less than 300 for patients wearing a nonrebreathing mask; or (4) a score of more than 130 on the Pulmonary Severity Index.
All patients received standard care (antibiotics and supportive care) and were randomly assigned to additionally receive hydrocortisone (n=400; median age 67 years; 29.8% women) or placebo (n=395; median age 67 years; 31.4% women). Participant comorbidities included diabetes (about 23%), chronic obstructive pulmonary disease (24%), and immunosuppression (6%).
Death occurred by day 28 in 25 of the 400 patients (6.2%; 95% CI, 3.9%-8.6%) receiving intravenous hydrocortisone (200 mg daily for either 4 or 8 days, based on clinical improvement, followed by tapering for a total of 8 or 14 days). Death occurred by day 28 in 47 of 395 patients (11.9%; 95% CI, 8.7%-15.1%) in the placebo group. The between group absolute difference was -5.6 percentage points (95% CI, -9.6 to -1.7; P =.006).
Vasopressor therapy was initiated by day 28 among patients not already receiving this therapy at baseline in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25%) in the placebo group (hazard ratio [HR], 0.59; 95% CI, 0.43-0.82).
Endotracheal intubation (among patients not undergoing mechanical ventilation at baseline) was performed by day 28 in 40 of 222 (18%) patients in the hydrocortisone group and in 65 of 220 patients (29.5%) in the placebo group (HR, 0.59; 95% CI, 0.40-0.86).
Cumulative incidence of invasive mechanical ventilation before day 28 (among patients who had received no invasive ventilation at baseline) was 19.5% in the hydrocortisone group and 27.7% in the placebo group (HR, 0.69; 95% CI, 0.50-0.94).
With respect to between-group differences, the researchers reported no differences in frequency of hospital-acquired infections or frequency of gastrointestinal bleeding. However, during the first week of treatment, patients in the hydrocortisone group received higher daily doses of insulin.
Overall, 169 adverse events were recorded in 151 of the 795 study participants: 70 in the hydrocortisone group, and 99 in the placebo group.
Significant study limitations include a lower-than-predicted control group mortality (11.9% vs 27% predicted), implying lower severity of illness in that cohort; lack of identification of pathogens for 44.9% of participants; and a sample size that was smaller than anticipated due to the advent of the COVID-19 pandemic.
“We found that early treatment with hydrocortisone reduced 28-day mortality among patients who had been admitted to the ICU with severe community-acquired pneumonia,” researchers concluded. They noted results appeared to be consistent across important subgroups. They wrote “Our data do not indicate any particular safety issues, including no between-group difference in the occurrence of hospital-acquired infections.”
Dequin PF, Meziani F, Quenot JP, et al.; CRICS-TriGGERSep Network. Hydrocortisone in severe community-acquired pneumonia. N Engl J Med. Published online March 21, 2023. doi:10.1056/NEJMoa2215145