Effect of intra-arterial tissue plasminogen activator and urokinase on autologous arterial emboli in the cerebral circulation of rabbits [corrected].

Abstract

We conducted a randomized, blinded controlled trial to test the efficacy of fibrinolytic therapy with tissue plasminogen activator and urokinase in the treatment of acute embolic stroke. Embolic stroke was simulated in rabbits by injecting three 0.5x0.5 mm fragments of autologous arterial thrombus harvested from a traumatized auricular artery. Thirty minutes after embolization the rabbits were blindly treated with tissue plasminogen activator (n=21), urokinase («=20), or 0.9% saline (n=20). At 6 hours the rabbits were sacrificed, and the cerebral vasculature was inspected for the location and number of emboli

Influence of tissue plasminogen activator and heparin on cerebral ischemia in a rabbit model.

“…The absence of hemorrhagic change in the ischemic areas of the brains of our rabbits accords with the findings of Benes et al 6 (using rabbits treated with a 1 mg t-PA bolus 30 minutes after embolization, then 1 mg/kg/hr infusion for 2 hours and killed 6 hours later) and of Chehrazi et al 22 (dosage as above and killed immediately after completion of treatment), as well of Slivka and Pulsinelli 29 (whose animals survived 30 hours after receiving a single bolus of streptokinase 1 hour postembolization). These latter authors also found that hemorrhagic transformation of the stroke was common when treatment was delayed for 24 hours with 7-9 hours' subsequent survival.…”

“…27 Thus, although the use of arterial thrombus in our model somewhat complicated the experimental procedure, we, like others, 6 ' 23 considered this to be acceptable because the resulting emboli more closely resembled those found in humans than if we had employed emboli prepared from clotted venous blood. However, whereas Benes et al 6 injected t-PA directly into the previously embolized ICA, which presumably produced a very high concentration of t-PA at the site of embolism, we gave t-PA by the intravenous route, on the basis that the highly sophisticated interventional neuroradiological techniques for thrombolysis, such as those described by Zeumer et al, 24 are unlikely to be available for most stroke victims in the immediate future.…”

“…However, the thrombi used in these studies were in most instances <24 hours old and all were "red" thrombi prepared by preclotting autologous or heterologous venous blood. In the study reported here, which in many respects follows the methods reported by Benes et al 6 and Rigamonte et al, 23 the emboli were prepared from white thrombus at least 2 days old since this is the embolic material that is regularly found in human cerebral embolism. However, unlike the two last-mentioned groups, we administered t-PA by intravenous infusion rather than by direct intracarotid injection since direct intra-arterial therapy in humans 24 requires special expertise and equipment.…”

“…6 - 23 Under short-term intravenous anesthesia comprising a mixture of ketamine, xylazine, and acetylpromazine, the central artery of the pinna was punctured using an 18-gauge needle 1.5 cm long. Through this was introduced into the arterial lumen the stylet of a 22-gauge spinal needle 10 cm long, the tip of which had been roughened and slightly bent.…”

Variations in the anatomy of the rabbit cervical carotid artery.

“…After we began following the internal carotid artery to the skull base and occluding the occipital artery when it rose from the internal carotid, the incidence of ischemic injury in control animals increased to 85%. 2 We prefer to use temporary vessel clips to exclude the occipital artery from the experimental field. When this is accomplished, the embolic material will be consistently directed into the cerebral circulation, thereby minimizing experimental variability.…”