Sivelestat Sodium in the Treatment of Patients with Acute Respiratory Distress Syndrome Combined with Systemic Inflammatory Response Syndrome

Abstract

Objectives: Neutrophil elastase (NE) plays an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). Sivelestat sodium, an NE inhibitor, has been approved in Japan for the treatment of patients with ARDS combined with systemic inflammatory response syndrome (SIRS). This trial was designed to evaluate the role of sivelestat sodium in mild to moderate ARDS combined with SIRS. Methods: We conducted a multicentre, double blind, randomized, placebo controlled trial enrolling patients diagnosed with mild to moderate ARDS combined with SIRS admitted within 72 hours of ARDS onset (clinicaltrials.gov,NCT04909697). Patients were randomized in a 1:1 fashion to sivelestat or placebo. Trial drugs were administrated as a 24 hour continuous intravenous infusion at a rate of 0.2 mg/kg/h for 5 days. The primary outcome was PaO2/FiO2 ratio change on day 3 after randomization, which was defined as (PaO2/FiO2 ratio on day 3 baseline PaO2/FiO2 ratio)/baseline PaO2/FiO2 ratio. Results: The study was stopped early at the recommendation of an independent Data and Safety Monitoring Board, which noted a between group difference in mortality. A total of 162 patients were randomized, of whom 81 were assigned to receive sivelestat sodium and 81 placebo. On day 3, the PaO2/FiO2 ratio improved by 36% in the sivelestat group compared to 3% in the placebo group (difference, 0.27; 95% CI, 0.13 to 0.41, p<0.001). In addition, The invasive mechanical ventilation free days within 28 days was significantly longer in the sivelestat sodium group compared to the placebo group (median 26.9 days vs. 21.0 days, p = 0.004). The Kaplan Meier curves showed a significant reduction in 90 day mortality in patients receiving sivelestat compared to those not receiving sivelestat (hazard ratio, 0.51; 95% CI, 0.26 to 0.99; log rank p = 0.044). Conclusion: In patients with mild to moderate ARDS combined with SIRS, sivelestat sodium may improve oxygenation on day 3, increase invasive mechanical ventilation free days, and was associated with improved survival.