High dose esomeprazole as an anti-inflammatory agent in sepsis: Protocol for a randomized controlled trial

Background: Sepsis is caused by dysregulated immune responses due to infection and still presents high mortality rate and limited efficacious therapies, apart from antibiotics. Recent evidence suggests that very high dose proton pump inhibitors might regulate major sepsis mediators' secretion by monocytes, which might attenuate excessive host reactions and improve clinical outcomes. This effect is obtained with doses which are approximately 50 times higher than prophylactic esomeprazole single daily administration and 17 times higher than the cumulative dose of a three day prophylaxis. We aim to perform a randomized trial to investigate if high dose esomeprazole reduces organ dysfunction in patients with sepsis or septic shock. Methods: This study, called PPI-SEPSIS, is a multicenter, randomized, double blind, placebo-controlled clinical trial on critically ill septic patients admitted to the emergency department or intensive care unit. A total of 300 patients will be randomized to receive high dose esomeprazole (80 mg bolus followed by 12 mg/h for 72 h and a second 80 mg bolus 12 h after the first one) or equivolume placebo (sodium chloride 0.9%), with 1:1 allocation. The primary endpoint of the study will be mean daily Sequential Organ Failure Assessment (SOFA) score over 10 days. Secondary outcomes will include antibiotic-free days, single organ failure severity, intensive care unit-free days at day 28, and mortality. Discussion: This trial aims to test the efficacy of high dose esomeprazole to reduce acute organ dysfunction in patients with septic shock. Trial registration: This trial was registered on ClinicalTrials.gov with the trial identification NCT03452865 in March 2018.