The long-term effect of recombinant tissue-plasminogen-activator (rt-PA) on edema formation in a large-animal model of intracerebral hemorrhage

Abstract

Hematoma puncture, fibrinolysis, and aspiration of the liquefied clot is a promising new treatment strategy for large intracerebral hemorrhages (ICH). Characteristics of the cellular injury and neuronal and glial cell death associated with ICH and the administration of fibrinolytic agents still need to be defined. We developed a porcine model to study the histopathological effects of recombinant tissue-Plasminogen-Activator (rt-PA) on perihematomatous cell integrity. In 20 pigs, lobar hematomas were induced by intracranial pressure (ICP)-controlled injections of 7.6 ± 1.6 ml of autologous blood into the white matter of the right frontal hemisphere. In nine animals, the clots were lysed with rt-PA, thereby facilitating aspiration 2 h after hematoma induction. In 11 control pigs, the hematoma resorption followed its natural course. The rate of hematoma reduction and edema formation over 10 days was evaluated on planimetry of the MRI data and correlated to the histopathological changes found at autopsy. Although rt-PA significantly accelerated clot resolution compared to controls ( p< 0.02), the increase of perihematomatous edema volume within 10 days was not significantly ameliorated in rt-PA-treated animals compared to controls on MRI. The extent of inflammatory infiltrates on histology was more pronounced in animals treated with rt-PA. In conclusion, despite significant reduction in the size of the hematoma clot liquefication with rt-PA and aspiration invokes a substantial inflammatory response when studied after 10 days and does not result in a reduction of the perihematomatous edema.