A phase 1 trial of nebulised heparin in acute lung injury

Abstract

Introduction: Animal 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.

Methods: An 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.

Results: No 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.

Conclusion: Administration 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 registration: Australian Clinical trials registry ACTRN12606000388516.

Figure 1

Changes in arterial to inspired oxygen ratio with nebulised heparin dosage. Percentage change from baseline in the arterial to inspired oxygen ratio (P_aO₂/F_iO₂) (mean ± standard deviation).

Figure 2

Changes in lung compliance with nebulised heparin dosage. Percentage change from baseline in the lung compliance over time for each dose (mean ± standard deviation).

Figure 3

Changes in alveolar dead space fraction with nebulised heparin dosage. Percentage change from baseline in the alveolar dead space fraction (ADSF) (mean ± standard deviation).

Figure 4

Changes in activated partial thromboplastin time with nebulised heparin dosage. Upper: Change in the activated partial thromboplastin time (APTT) over time. The last dose of heparin was given at 36 hours for all groups except the 400,000 U/day group, in which it was administered at 42 hours (mean levels; P = 0.06, comparison of 46-hour and 58-hour timepoints in the 400,000 U/day group). Lower: APTT at baseline and following the final dose of nebulised heparin (P = 0.09, analysis of variance comparison by dose, mean and standard deviation).

Figure 5

Changes in thrombin clotting time with nebulised heparin dosage. Upper: Change in the thrombin clotting time (TCT) over time. The last dose of heparin was given at 36 hours for all groups except the 400,000 U/day group, in which it was administered at 42 hours (mean levels). Lower: TCT at baseline and following the final dose of nebulised heparin (P = 0.1, analysis of variance comparison by dose, mean and standard deviation).

Figure 6

Comparison of prothrombin fragment levels in bronchoalveolar fluid with nebulised heparin dosage. Comparison of prothrombin fragment (PTF) levels in bronchoalveolar fluid. Levels were assessed at baseline and following the final dose of nebulised heparin (P = 0.1, analysis of variance comparison by dose, mean and standard deviation).

Figure 7

Comparison of tissue plasminogen activator levels in bronchoalveloar fluid with nebulised heparin dosage. Comparison of tissue plasminogen activator (t-PA) levels in bronchoalveloar fluid. Levels were assessed at baseline and following the final dose of nebulised heparin (mean and standard deviation).