TISSUE PLASMINOGEN-ACTIVATOR CEREBROVASCULAR THROMBOLYSIS IN RABBITS IS DEPENDENT ON THE RATE AND ROUTE OF ADMINISTRATION

Background and Purpose: The main aim of our study was to assess the cerebrovascular thrombolytic efficacy of different tissue plasminogen activator treatment protocols with Doppler ultrasound. Methods: We occluded one internal carotid artery in 48 New Zealand White rabbits with whole blood emboli. Five minutes later the rabbits were assigned to receive one of the following tissue plasminogen activator protocols: 1) intravenous square-wave infusion in a total dose of 10 mg/kg, 2) intravenous constant infusion in a total dose of 10 mg/kg, 3) intravenous square-wave infusion in a total dose of 3 mg/kg, or 4) regional intra-arterial square-wave infusion in a total dose of 3 mg/kg. Blood flow velocities in the internal carotid arteries were continuously monitored during the study with Doppler ultrasound. Results: In all 12 animals treated with a 10-mg/kg square-wave intravenous tissue plasminogen infusion, internal carotid artery blood flow was reestablished within 2 hours (57.9 +/- 33.3 minutes) after the initiation of treatment, whereas this was the case for only six (50%) of the 12 animals treated with a constant 10-mg/kg intravenous tissue plasminogen activator infusion (p < 0.05, Fisher's exact test). Internal carotid artery blood flow was restored within 2 hours (33.5 +/- 40.4 minutes) in all animals treated with a regional intra-arterial tissue plasminogen infusion in a total dose of 3 mg/kg and in only three (50%) of the six animals treated with the same dosage intravenously (p < 0.05, signed rank test). Conclusions: The thrombolytic efficacy of tissue plasminogen activator in the rabbit cerebral vasculature was superior when the same intravenous dose was given as a square-wave rather than a constant infusion and when the drug was given as a regional intra-arterial infusion rather than intravenously.