COMPARISON OF INTRATHECAL ADMINISTRATION OF UROKINASE AND TISSUE-PLASMINOGEN ACTIVATOR ON SUBARACHNOID CLOT AND CHRONIC VASOSPASM IN A PRIMATE MODEL

SAFETY AND EFFICACY of the thrombolytic agent urokinase (URO) in the elimination of subarachnoid clot and prevention of chronic vasospasm was compared with tissue-type plasminogen activator (rt-PA) in a blind, randomized placebo-controlled trial. Twenty monkeys were randomly assigned to one of five groups of four. Each group underwent baseline cerebral angiography followed by bilateral craniectomy and experimental subarachnoid hemorrhage. An Ommaya reservoir was inserted on the right side with its catheter placed into the ipsilateral subarachnoid space. Twenty-four hours later, depending upon group assignment, the animals received 100,000 IU URO, 200,000 IU URO, 1 mg rt-PA, 2 mg rt-PA, or the equivalent volume of normal saline (control group). On Day 7, angiography was repeated and the animals were killed. One animal died as a result of complications during the baseline angiography, presumably due to blood loss and prolonged anesthesia, and a replacement animal was obtained. No animals demonstrated any delayed neurological deficits. The study demonstrated that a single intracisternal bolus injection of rt-PA, 2.0 mg in 2 ml sterile water, or URO, 200,000 IU in 2 ml sterile water, 24 hours after induction of experimental subarachnoid hemorrhage in primates, was equally effective in thrombolysing ipsilateral clot, but neither dosage prevented angiographic vasospasm. Vasospasm occurred bilaterally in all groups. Whereas gross subarachnoid clot was found bilaterally in all animals in the placebo group and both smaller-dose URO and rt-PA groups, right-sided subarachnoid clot was virtually absent and left-sided clot reduced in both higher-dose URO and rt-PA groups. Intrathecal URO in the dosage used had no apparent adverse effect on the animal's neurological condition or the histological appearance of the cerebral cortex, pia, arachnoid, or ependyma. No clear difference between rt-PA and URO emerged in this study at the dosages and timing of administration employed. Presumably larger dosages, given earlier or more often, would be required to completely lyse the bilateral clots and prevent vasospasm.