A phase 1 trial of nebulised heparin in acute lung injury

Barry Dixon , John D Santamaria and Duncan J Campbell

Critical Care 2008, 12:R64doi:10.1186/cc6894


Published:	6 May 2008

Abstract (provisional)

Introduction

Animal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. To date no human studies have been undertaken. We assessed the feasibility, safety and potential anti-coagulant effects of administration of nebulised heparin to patients with ALI.

Methods

An open label phase 1 trial of 4 escalating doses of nebulised heparin. A total of 16 ventilated patients with ALI were studied. The first group was administered a total of 50,000 U/day, the second 100,000 U/day, the third 200,000 U/day and the fourth 400,000 U/day. Assessments of lung function included the arterial to inspired oxygen ratio (PaO2/FiO2), lung compliance and the alveolar dead space fraction. Monitoring of anti-coagulation included the activated partial thromboplastin time (APTT) and the thrombin clotting time (TCT). Bronchoalveolar lavage (BAL) fluid was collected and prothrombin fragment (PTF) and tissue plasminogen activator (t-PA) 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, lung compliance and the alveolar dead space fraction levels were similar for all doses. A trend to increased APTT and TCT levels was present with higher doses (p = 0.09 and 0.1, respectively). For the highest dose the APTT reached 64 seconds and following cessation of nebulised heparin fell to 39 seconds (p = 0.06). In BAL samples a trend to reduced PTF levels was present with higher doses (p = 0.1), while t-PA levels were similar for all doses.

Conclusions

Administration of nebulised heparin to mechanically ventilated patients with ALI is feasible. It was not associated with any serious adverse events and at higher doses 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 anti-coagulant effects. Trial registration: Australian Clinical trials registry ACTRN12606000388516