Abstract
IntroductionAnimal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. No human studies have been undertaken to date. We assessed the feasibility, safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI.MethodsAn open label phase 1 trial of four escalating doses of nebulised heparin was performed. A total of 16 ventilated patients with ALI were studied. The first group was administered a total of 50,000 U/day, the second group 100,000 U/day, the third group 200,000 U/day and the fourth group 400,000 U/day. Assessments of lung function included the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction. Monitoring of anticoagulation included the activated partial thromboplastin time (APTT) and the thrombin clotting time. Bronchoalveolar lavage fluid was collected and the prothrombin fragment and tissue plasminogen activator levels were assessed. Analysis of variance was used to compare the effects of dose.ResultsNo serious adverse events occurred for any dose. The changes over time for the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction levels were similar for all doses. A trend to increased APTT and thrombin clotting time levels was present with higher doses (P = 0.09 and P = 0.1, respectively). For the highest dose, the APTT reached 64 seconds; following cessation of nebulised heparin, the APTT fell to 39 seconds (P = 0.06). In bronchoalveolar lavage samples a trend to reduced prothrombin fragment levels was present with higher doses (P = 0.1), while tissue plasminogen activator levels were similar for all doses.ConclusionAdministration of nebulised heparin to mechanically ventilated patients with ALI is feasible. Nebulised heparin was not associated with any serious adverse events, and at higher doses it increased APTT levels. Larger trials are required to further investigate the safety and efficacy of nebulised heparin. In these trials due consideration must be given to systemic anticoagulant effects.Trial registrationAustralian Clinical trials registry ACTRN12606000388516.
Highlights
Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation
The changes over time for the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction levels were similar for all doses
A trend to increased activated partial thromboplastin time (APTT) and thrombin clotting time levels was present with higher doses (P = 0.09 and P = 0.1, respectively)
Summary
Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. Safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI. Acute lung injury (ALI) is a serious clinical problem. Estimates are that 190,600 cases of ALI develop in the United States each year, which are associated with 74,500 deaths and 3.6 million hospital days [1]. The 28-day mortality for ALI is 32% [2]. ALI is characterised by the rapid onset of respiratory distress in the setting of an inflammatory insult to the lungs [3,4]. Inflammatory insults include sepsis, trauma, hypotension, cardiopulmonary bypass, pancreatitis, aspiration and multiple transfusions. Septic insults are by the commonest cause of ALI. Pneumonia triggers 30% of cases, and sepsis elsewhere in the body causes 32% of cases [2]
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