Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis

Pulmonary coagulopathy is a characteristic feature of lung injury including ventilator-induced lung injury. The aim of this individual patient data meta-analysis is to assess the effects of nebulized anticoagulants on outcome of ventilated intensive care unit (ICU) patients. A systematic search of PubMed (1966-2014), Scopus, EMBASE, and Web of Science was conducted to identify relevant publications. Studies evaluating nebulization of anticoagulants in ventilated patients were screened for inclusion, and corresponding authors of included studies were contacted to provide individual patient data. The primary endpoint was the number of ventilator-free days and alive at day 28. Secondary endpoints included hospital mortality, ICU- and hospital-free days at day 28, and lung injury scores at day seven. We constructed a propensity score-matched cohort for comparisons between patients treated with nebulized anticoagulants and controls. Data from five studies (one randomized controlled trial, one open label study, and three studies using historical controls) were included in the meta-analysis, compassing 286 patients. In all studies unfractionated heparin was used as anticoagulant. The number of ventilator-free days and alive at day 28 was higher in patients treated with nebulized heparin compared to patients in the control group (14 [IQR 0-23] vs. 6 [IQR 0-22]), though the difference did not reach statistical significance (P = 0.459). The number of ICU-free days and alive at day 28 was significantly higher, and the lung injury scores at day seven were significantly lower in patients treated with nebulized heparin. In the propensity score-matched analysis, there were no differences in any of the endpoints. This individual patient data meta-analysis provides no convincing evidence for benefit of heparin nebulization in intubated and ventilated ICU patients. The small patient numbers and methodological shortcomings of included studies underline the need for high-quality well-powered randomized controlled trials.