Efficacy and safety of sivelestat in sepsis-induced acute respiratory distress syndrome: an updated meta-analysis based on disease severity and treatment strategy subgroups

Objective Sivelestat sodium hydrate is a selective neutrophil elastase inhibitor that attenuates neutrophil-mediated alveolar–capillary injury and is used in some East Asian countries for acute lung injury/ARDS. We evaluated the efficacy and safety of sivelestat in sepsis-induced acute respiratory distress syndrome (ARDS) and explored whether disease severity, baseline mortality risk, and treatment background modify the mortality effect. Methods We searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science, CNKI, Wanfang, and ClinicalTrials.gov from database inception to August 27, 2026. Eligible studies were adult studies of sepsis-induced ARDS comparing a sivelestat-containing regimen with an otherwise comparable regimen without sivelestat. COVID-19-only cohorts, non-septic ARDS, mixed-etiology studies without a separable sepsis subgroup, and comparisons in which both groups received sivelestat were excluded. The primary outcome was all-cause mortality; secondary outcomes included P/F ratio, duration of mechanical ventilation, ICU length of stay, organ-function scores, inflammatory markers, and adverse events. Mortality was pooled as odds ratios (ORs) using a random-effects model with restricted maximum likelihood; Hartung–Knapp intervals were used for the primary and study-design analyses. This review was prospectively registered in PROSPERO. Results Fourteen studies were eligible for qualitative synthesis, and 10 studies (943 patients) provided extractable 2 × 2 mortality data. Deaths occurred in 73/431 patients receiving sivelestat and 125/512 controls. Sivelestat was associated with lower mortality (OR=0.55, 95% CI 0.36–0.84; I 2 = 0%). The signal persisted in randomized trials (OR=0.37, 95% CI 0.16–0.86; I 2 = 0%). Study-level point estimates appeared more favorable in cohorts with baseline P/F < 100 mmHg and control mortality >30%; however, interaction tests were not statistically significant and severity analyses were ecological. Leave-one-out analyses were stable. Egger testing did not detect significant small-study asymmetry ( P = 0.197), although power was limited. Baseline-stratified treatment effects by IL-6, PCT, CRP, or neutrophil elastase were unavailable for quantitative effect-modification analyses. Conclusions In an updated and etiologically strict evidence synthesis, sivelestat was associated with lower mortality in sepsis-induced ARDS, including in randomized trials. Severe hypoxemia and high baseline risk remain plausible enrichment factors, but current aggregate evidence is insufficient to support a validated phenotype-guided prescribing rule. Co-intervention reporting was sparse, and residual confounding by prone positioning, sedation, neuromuscular blockade, and steroid background cannot be excluded. Systematic Review Registration PROSPERO CRD420261541158.