Nebulized Heparin in Adults With Acute Respiratory Failure: A Meta-Analysis of Randomized Trials

OBJECTIVES: Dysregulated pulmonary coagulation and inflammation is a hallmark of respiratory failure in various etiologies. Excessive fibrin deposition contributes to alveolar collapse, impaired gas exchange, and progression to pulmonary fibrosis. Nebulized heparin can mitigate these coagulation and inflammation disturbances. Although several randomized controlled trials have explored its effects, results remain inconsistent and limited by small patient populations. We conducted a random-effects meta-analysis to calculate the risk ratio (RR) and 95% CIs. DATA SOURCES: We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for randomized controlled trials comparing nebulized unfractionated heparin to standard care or placebo in adult patients with respiratory failure either invasively mechanical ventilated or not. The primary outcome was all-cause mortality at the longest follow-up. STUDY SELECTION: We included randomized clinical trials enrolling adult patients with respiratory failure, comparing nebulized heparin vs. standard care or placebo, and reporting at least one clinical outcome, including all-cause mortality. DATA EXTRACTION: Two independent investigators extracted data on trial design, setting, etiology of respiratory failure, heparin dosing regimens, follow-up duration, and outcomes. Discrepancies were resolved by consensus. DATA SYNTHESIS: We identified 16 studies (787 receiving nebulized heparin, 833 control). Six (38%) were multicenter, five focused on COVID-19, 12 enrolled ICU patients, and dosing clustered around 25,000 international units (IUs) three times a day (~75,000 IU/d for ~10 d). At the longest follow-up, nebulized heparin reduced all-cause mortality vs. control (110/645 [17.1%] vs. 157/711 [22.1%]; RR, 0.79; 95% CI, 0.66-0.95; with ten studies included). Nebulized heparin was also associated with more ventilation-free days by day 28 (mean difference, +4.85; 95% CI, 1.47-8.24). Major bleeding was rare (1.1 vs. 0.7%; RR, 1.48; 95% CI, 0.42-5.18), while no minor bleeding or heparin-induced thrombocytopenia was reported. CONCLUSIONS: Nebulized unfractionated heparin may improve survival in patients with respiratory failure without increasing adverse events.