A Multinational Randomized Trial of Mega-Dose Esomeprazole as Anti-Inflammatory Agent in Sepsis

OBJECTIVES: Proton pump inhibitors have dose-dependent immunomodulatory effects. We tested the hypothesis that mega-dose esomeprazole therapy would reduce organ dysfunction in patients with sepsis or septic shock. DESIGN: A multinational, randomized, double-blind, placebo-controlled clinical trial. SETTING: Seventeen ICUs or emergency departments in three countries. PATIENTS: Adult patients with sepsis or septic shock. INTERVENTIONS: Mega-dose (1024 mg) esomeprazole or placebo over a 72-hour period. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mean daily Sequential Organ Failure Assessment (SOFA) score to day 10. Secondary outcomes included antibiotics-free days, ICU-free days at day 28, and all-cause mortality. We also conducted a mechanistic study of the in vitro effects of esomeprazole in sepsis. We randomized 307 patients and assigned 148 to esomeprazole and 159 to placebo. Mean age was 71 years; 166 patients (54%) had septic shock and median SOFA score at randomization was 7. The median mean daily SOFA score in the first 10 days post-randomization was 5 (interquartile range [IQR], 3-9) in the esomeprazole group and 5 (IQR, 3-8) in the placebo group (risk difference, 0.1; 95% CI, -0.8 to 1.0; p > 0.99). No differences were observed in secondary outcomes. Monocytes isolated from patients' peripheral blood and activated with a toll-like receptor agonist exhibited a pro-inflammatory phenotype, which was not affected by esomeprazole therapy. CONCLUSIONS: Among patients with sepsis or septic shock, mega-dose esomeprazole did not reduce organ dysfunction or other patient-related or biological secondary outcomes.