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). 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 41% in the sivelestat group compared to 16% in the placebo group (difference, 0.25; 95% CI, 0.10 to 0.40, p=0.001). In addition, the duration of invasive mechanical ventilation was significantly shorter in the sivelestat group compared to the placebo group (median 104.0 hours versus 170.3 hours, p=0.006). 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; p=0.044). Conclusion: In patients with mild to moderate ARDS combined with SIRS, sivelestat sodium may improve oxygenation on day3, shorten the duration of mechanical ventilation, and was associated with reduced 90 day mortality.