Delayed Tissue-Plasminogen Activator Therapy in a Rabbit Model of Thromboembolic Stroke

Abstract

THIS STUDY INVESTIGATED the efficacy and safety of delayed therapy with tissue-plasminogen activator (t-PA) in a rabbit model of thromboembolic stroke. The t-PA therapy was started 3, 4, or 5 hours after autologous clot embolization. New Zealand rabbits were randomized to receive a 2-hour intravenous infusion of either t-PA (6.3 mg/kg) or a saline solution (0.9% saline) after an autologous clot had embolized the anterior cerebral circulation. Regional cerebral blood flow (rCBF), intracranial pressure (ICP), and infarct size were measured to determine the effects of the delayed administration of the t-PA after intracranial embolization. Additionally, the following physiological parameters were monitored throughout the protocol: mean arterial pressure, hematocrit, arterial blood gases, glucose, and core and brain temperatures. All animals were studied for 4 hours after the administration of the t-PA or control solution; thus, the duration of each experiment was 7, 8, or 9 hours after autologous clot embolization. In control animals, brain infarct size and final ICP values were directly related to the length of time studied after clot embolization; among control animals, the largest infarct size and greatest rise in ICP were seen 9 hours after embolization. The start of the t-PA therapy 3 hours after clot embolization was associated with a trend toward smaller mean brain infarct size (31.6 ± 6.4% [n = 10] versus 44.2 ± 8.6% [n = 10] of the infarcted hemisphere; the mean ± the standard error of the mean) and a significantly lower mean ICP (15.5 ± 2.8 versus 22.0 ± 3.1 mm Hg, P= 0.02). A trend toward restoration of rCBF was also noted with the t-PA therapy given 3 hours after embolization. No benefit was noted for any parameter studied (ICP, infarct size, or rCBF) with further delay to the t-PA therapy (4 or 5 h). In the group receiving t-PA 4 hours after embolization, ICP (measured 8 h after embolization) was significantly higher (31.3 ± 5.2 versus 21.6 ± 2.6 mm Hg, P= 0.01), although no significant difference in ICP was detected between the two groups at 9 hours after embolization. In this rabbit model of thromboembolic stroke, the administration of t-PA 3 hours after autologous clot embolization was associated with a reduction in brain injury. Despite significant clot lysis by t-PA in all groups, no benefit was noted when the t-PA therapy was delayed longer (4–5 h after embolization); no return of rCBF was noted in the t-PA group at 9 hours after embolization.