Inhaled Heparin to Shorten Antibiotic Duration in Ventilator‐Associated Pneumonia: A Randomized Double‐Blind Controlled Trial

ABSTRACT Background and Aims Prolonged antibiotic therapy in ventilator‐associated pneumonia (VAP) contributes to antimicrobial resistance. Inhaled heparin has pleiotropic anti‐inflammatory and mucolytic properties. This trial evaluated whether adjunctive nebulized heparin reduces antibiotic duration in VAP using a procalcitonin (PCT)‐guided discontinuation algorithm. Methods In this single‐center, double‐blind, randomized controlled trial, 82 mechanically ventilated adults with VAP (CPIS ≥ 6) were assigned to standard care plus nebulized heparin (10,000 IU every 6 h) or placebo (sterile distilled water). Both groups followed a PCT‐guided antibiotic discontinuation algorithm (≤ 0.2 µg/L or ≥ 90% reduction from peak, plus clinical stability). Primary outcome: antibiotic duration (days). Secondary outcomes: duration of mechanical ventilation, ICU/hospital length of stay (LOS), serial CPIS, CRP, PCT, SOFA, APACHE II, adverse events, and 28‐day mortality rate. Results Antibiotic duration was significantly shorter with heparin (mean difference −3.2 days; 95% CI: −4.8 to −1.6; p < 0.001). Baseline characteristics were similar except for higher mean APACHE II in the control group (18.8 vs. 15.2). After adjusting for baseline APACHE II imbalance, the treatment effect remained significant (adjusted mean difference −2.9 days; 95% CI: −4.5 to −1.3; p = 0.001). Heparin also reduced duration of mechanical ventilation (mean difference −1.47 days; p = 0.01), ICU LOS (− 3.5 days; p = 0.02), and hospital LOS (− 4.1 days; p = 0.01). CPIS and CRP improved more rapidly in the heparin group (group×time interaction p < 0.05). No major bleeding or heparin‐related adverse events occurred. Conclusion Adjunctive nebulized heparin (40,000 IU/day) significantly shortens antibiotic duration and improves clinical recovery in VAP without increasing adverse events. However, given the single‐center design and modest sample size, our results require confirmation in future multicenter trials with optimum heparin doses and comprehensive biomarker panels to better elucidate the mechanisms of action and establish the definitive role of inhaled heparin in antimicrobial stewardship.