Sivelestat and Incidence of Acute Respiratory Distress Syndrome After Cardiovascular Surgery: A Randomized Clinical Trial.

Abstract

Acute respiratory distress syndrome (ARDS) represents a frequent and serious complication after cardiovascular surgery. Although sivelestat, a specific neutrophil elastase inhibitor, has demonstrated therapeutic potential in preliminary studies, the evidence remains limited by methodological constraints of observational designs and underpowered studies. To evaluate the efficacy of sivelestat vs placebo in reducing the incidence of postoperative ARDS and associated complications among patients undergoing major cardiovascular procedures. This single-center, randomized, placebo-controlled clinical trial conducted at a tertiary care academic medical center om China enrolled 424 participants between February 15, 2024, and April 16, 2025, with a 90-day postoperative follow-up period. Participants were consecutive patients scheduled for cardiovascular surgery, including coronary artery bypass grafting, valve surgeries, ascending aortic reconstruction, combined procedures, congenital heart defect repairs, and cardiac tumor resections. Participants were randomly allocated (1:1) to receive either continuous intravenous sivelestat (0.2 mg/kg/h), initiated immediately on intensive care unit (ICU) admission postoperatively and continued for up to 7 days or until ICU discharge; or volume-matched 0.9% sodium chloride placebo administered on an identical schedule. The primary outcome was the incidence of ARDS. Secondary outcomes included serial measurements of inflammatory biomarkers, including interleukin 6 and interleukin 8, tumor necrosis factor, systemic immune-inflammation index, and serum neutrophil elastase, on postoperative days 1, 3, 5, and 7, along with ARDS-related clinical outcomes including death, pneumonia, and reintubation. Analysis was performed on an intention-to-treat basis. Among 424 randomized patients, 382 completed the trial (mean [SD] age, 62.9 [6.2] years; 210 male [55.0%]). Adverse events monitored for safety did not differ between groups. The sivelestat group had significantly lower rates of ARDS (16.8% [32 of 190] vs 31.2% [60 of 192]; P < .001), and 90-day mortality (1.1% [2 of 190] vs 5.2% [10 of 192]; P = .02). Postoperative inflammatory biomarkers, including neutrophil elastase and interleukin 6, were significantly reduced in the sivelestat group. In this single-center, randomized, placebo-controlled clinical trial of patients undergoing cardiovascular surgery, sivelestat significantly reduced ARDS incidence and 90-day all-cause mortality. Sivelestat attenuated neutrophil-driven inflammation by dynamically suppressing neutrophil elastase and reducing key downstream biomarkers. These preliminary findings suggest sivelestat may be a pharmacologic option to mitigate ARDS in cardiovascular procedures. ClinicalTrials.gov Identifier: NCT06276569.