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Introduction
Unfractionated heparin (UFH) is an inexpensive naturally occurring sulphated glycosaminoglycan [1] which promotes mucociliary clearance [2] , decreases sputum viscidity [2] , displays antibacterial effects on common respiratory pathogens [3] , and has anti-inflammatory properties [4] . Clinical applications have been reported in airway burns [5] and respiratory conditions where there is a significant sputum production or airway inflammation [6] . With these therapeutic effects, the potential role of UFH in preventing and treating lung infections including ventilator-associated pneumonia (VAP) remains insufficiently investigated.
Nebulized administration to maximize drug concentrations in the epithelium of the airway may also enhance effectiveness. Indeed, UFH is simple and safe to administer by ventilator nebulizer with less than 1% of a 90,000 unit dose found in blood [7] . Doses of 30,000 units twice daily are not associated with significant changes in the coagulation profile [8] . Furthermore, recent work exploring the clinical role of nebulized UFH has demonstrated an 18% increase in ventilator free days in critically ill patients at risk of developing acute respiratory distress syndrome (ARDS) [9] .
With this strong theoretical background supporting the potential beneficial effects of nebulized UFH, we performed a feasibility Phase-2b double-blind, multicenter, randomized controlled trial in patients receiving mechanical ventilation (MV) to investigate the effectiveness of Inhaled Prophylactic Heparin In the preVention and treAtment of Pneumonia (IPHIVAP). Primary study endpoints were the incidence, severity and time to develop VAP. The incidence of ventilator associated complications (VAC), rate of resolution of pneumonia, and incidence and time to bacterial airway colonization were secondary endpoints.
Materials and methods
Study population
Patients aged >=18years who had received less than 24hours of invasive MV at the time of enrolment and commencement of study drug but were likely to require invasive MV for more than 48hours were eligible for study inclusion. Patient exclusions included pregnancy, patients with treatment limitations or who were moribund, contraindications to subcutaneously administered heparin, systemic anticoagulation at enrolment and previous enrolment in the study. Routine subcutaneous thromboembolism prophylaxis (<= 15,000 units of unfractionated heparin per day or equivalent) and low dose heparin to prevent clotting of continuous renal replacement therapies were permitted.
Randomization
The study was coordinated from the Burns, Trauma and Critical Care Research Centre of the University of Queensland. Secure...