Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial

Abstract

Background: Authors of recent meta-analyses have reported that prolonged glucocorticoid treatment is associated with significant improvements in patients with severe pneumonia or acute respiratory distress syndrome (ARDS) of multifactorial etiology. A prospective randomized trial limited to patients with sepsis-associated ARDS is lacking. The objective of our study was to evaluate the efficacy of hydrocortisone treatment in sepsis-associated ARDS.

Methods: In this double-blind, single-center (Siriraj Hospital, Bangkok), randomized, placebo-controlled trial, we recruited adult patients with severe sepsis within 12 h of their meeting ARDS criteria. Patients were randomly assigned (1:1 ratio) to receive either hydrocortisone 50 mg every 6 h or placebo. The primary endpoint was 28-day all-cause mortality; secondary endpoints included survival without organ support on day 28.

Results: Over the course of 4 years, 197 patients were randomized to either hydrocortisone (n = 98) or placebo (n = 99) and were included in this intention-to-treat analysis. The treatment group had significant improvement in the ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen and lung injury score (p = 0.01), and similar timing to removal of vital organ support (HR 0.74, 95 % CI 0.51-1.07; p = 0.107). After adjustment for significant covariates, day 28 survival was similar for the whole group (HR 0.80, 95 % CI 0.46-1.41; p = 0.44) and for the larger subgroup (n = 126) with Acute Physiology and Chronic Health Evaluation II score <25 (HR 0.57, 95 % CI 0.24-1.36; p = 0.20). With the exception of hyperglycemia (80.6 % vs. 67.7 %; p = 0.04), the rate of adverse events was similar. Hyperglycemia had no impact on outcome.

Conclusions: In sepsis-associated ARDS, hydrocortisone treatment was associated with a significant improvement in pulmonary physiology, but without a significant survival benefit.

Trial registration: ClinicalTrials.gov identifier NCT01284452 . Registered on 18 January 2011.

Keywords: ARDS; Glucocorticoid treatment; Hydrocortisone; Randomized trial; Septic shock; Severe sepsis.

Fig. 1

Flow diagram of the progress of the trial

Fig. 2

a Changes in ratio of partial pressure of oxygen in arterial blood fraction of inspired oxygen (PaO₂/FiO₂) over the course of 7 days and on day 14. In comparison with the placebo group, the hydrocortisone group had a significantly higher PaO₂/FiO₂ ratio by day 3 (p = 0.03) and throughout the observation period. b Changes in Lung Injury Score over the course of 7 days and on day 14. In comparison with the placebo group, the hydrocortisone group had a significantly lower Lung Injury Score by day 3 (p = 0.003) and throughout the observation period

Fig. 3

a Kaplan-Meier estimate of time to removal of organ support by treatment arm after adjustment by Cox regression analysis for Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Lung Injury Score. Continuous line corresponds to the placebo group, and dashed line corresponds to the hydrocortisone group. b Kaplan-Meier curve illustrates the probability of survival at 60 days based on APACHE II score <25 vs. ≥25. Continuous line corresponds to the subgroup with APACHE II score <25 (blue = hydrocortisone, red = placebo). Dashed line corresponds to the subgroup with APACHE score ≥25 (blue = hydrocortisone, red = placebo). After adjustment for the presence of vasopressor-dependent shock and Lung Injury Score, in the subgroup with APACHE score <25 (n = 126), the HR for probability of survival at 28 days was 0.57 (95 % CI 0.24–1.36; p = 0.20), and at 60 days it was 0.69 (95 % CI 0.36–1.31; p = 0.25). In the subgroup with APACHE II score ≥25 (n = 71), the HR for probability of survival at 28 days was 1.05 (95 % CI 0.49–2.23; p = 0.60), and at 60 days it was 0.97 (95 % CI 0.50–1.88; p = 0.92)