DELAYED TISSUE-PLASMINOGEN ACTIVATOR THERAPY IN A RABBIT MODEL OF THROMBOEMBOLIC STROKE

THIS STUDY INVESTIGATED the efficacy and safety of delayed therapy wit h tissue-plasminogen activator (t-PA) in a rabbit model of thromboembo lic stroke. The t-PA therapy was started 3, 4, or 5 hours after autolo gous 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 ante rior cerebral circulation. Regional cerebral blood flow (rCBF), intrac ranial 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 wer e monitored throughout the protocol: mean arterial pressure, hematocri t, 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, bra in infarct size and final ICP values were directly related to the leng th 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 emboli zation was associated with a trend toward smaller mean brain infarct s ize (31.6 +/- 6.4% [n = 10] versus 44.2 +/- 8.6% [9 = 10] of the infar cted hemisphere; the mean +/- the standard error of the mean) and a si gnificantly 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 af ter embolization, ICP (measured 8 h after embolization) was significan tly higher (31.3 +/- 5.2 versus 21.6 +/- 2.6 mm Hg, P = 0.01), althoug h 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 embo lization was associated with a reduction in brain injury. Despite sign ificant clot lysis by t-PA in all groups, no benefit was noted when th e t-PA therapy was delayed longer (4-5 h after embolization); no retur n of rCBF was noted in the t-PA group at 9 hours after embolization.