title: Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis.
abstract: 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.
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Department of Intensive Care, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. g.j.glas@amc.uva.nl.
authors.forename: Gerie J
authors.initials: GJ
authors.lastname: Glas
authors.affiliation: Department of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil.|Department of Critical Care Medicine, Faculdade de Medicina do ABC, Santo André, Brazil.|Program of Post-Graduation, Research and Innovation, Faculdade de Medicina do ABC, Santo André, Brazil.
authors.forename: Ary
authors.initials: A
authors.lastname: Serpa Neto
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Department of Intensive Care, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Horn
authors.affiliation: Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: Amalia
authors.initials: A
authors.lastname: Cochran
authors.affiliation: Department of Intensive Care, St. Vincent's Hospital, Melbourne, Australia.
authors.forename: Barry
authors.initials: B
authors.lastname: Dixon
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, James A. Haley Veteran's Hospital, University of South Florida, Tampa, FL, USA.
authors.forename: Elamin M
authors.initials: EM
authors.lastname: Elamin
authors.affiliation: Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Faraklas
authors.affiliation: Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Dissanaike
authors.affiliation: Department of Critical Care Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA.|Department of Emergency Medicine, West Virginia University, Morgantown, WV, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Miller
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Department of Intensive Care, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
keywords: Administration; Anticoagulants; Heparin; Humans; Inhalation; Intensive care; Mechanical ventilation