Importance: 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.
Objective: To evaluate the efficacy of sivelestat vs placebo in reducing the incidence of postoperative ARDS and associated complications among patients undergoing major cardiovascular procedures.
Design, setting, and participants: 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.
Interventions: 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.
Main outcomes and measures: 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.
Results: 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.
Conclusion and relevance: 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.
Trial registration: ClinicalTrials.gov Identifier: NCT06276569.