Pigs

Our group has developed and extensively studied the pathophysiology, pathochemistry, and treatment of ICH in a porcine white-matter (lobar ICH) model (17) (reviews in Refs. 20 and 21). The advantages of using the pig for an ICH model include its large gyrated brain and large amount of hemispheric white matter, its relatively low cost, and its noncompanion animal status. The pig's large brain enables the production of hematoma volumes up to approximately 3 cc by slowly (10-15 mins) infusing autologous arterial blood through a plastic catheter into the frontal white matter. We have used this model to investigate ICH pathophysiology and pathochem-istry, edema development, the role of blood components, and metabolism (18,20,63) (reviews in Refs. 21 and 64). The large hematoma volumes that can be generated in this model make it useful to investigate studies of neurosurgical clot evacuation (19,65 ).

This lobar ICH model in the pig is clinically relevant for several reasons: (i) bleeds into the white matter are common in human ICH and occur with almost similar frequency to basal ganglia bleeds (66) ; (i i) lobar ICH is the most frequent hemorrhage site in the young (67) ; (iii) white-matter damage is an important contributor to long-term morbidity following ICH

(68,69). Because white matter is more vulnerable to vasogenic edema development than is gray matter (70), this model is especially applicable for studying edema-associated injury.

Studies in the porcine ICH model have demonstrated the important role of clot formation, retraction, and plasma protein accumulation in perihematomal edema development (17,20). The importance of coagulation in animal models is translatable to patients who developed ICH after thrombolytic treatment but failed to develop significant edema despite large intracerebral masses (71). Although whole blood is responsible for the majority of the hematoma's mass effect, infusions of packed red cells alone fail to generate perihematomal edema. As described above, nonclotting blood also produces minimal perihematomal edema in both rat and porcine models. Thus, these results support the conclusion that the early and substantial perihema-tomal edema that follows ICH does not result from the mass effect and potentially reduced perfusion that are induced by the hematoma. Rather, the findings suggest that this very early edema results primarily from the coagulation cascade and clot retraction. The cellular elements of the hematoma are concentrated at the core as clotting proceeds. The fluid/serum components of the whole blood are extruded to the perimeter (72). Interestingly, it was recently reported (73) that increased rates of water diffusion measured in the perihematomal region by diffusion-weighted MRI in ICH patients suggested that this edema development is plasma derived. These results also are consistent with the experimental and human ICH studies, which show relatively more early edema in the setting of normal coagulation compared with the lesser edema seen in the setting of anticoagulants or thrombolytics (71 ).

This porcine ICH model has been especially useful for clot evacuation studies. We have demonstrated that early (3.5 hr) clot aspiration after rtPA-induced lysis markedly reduced (by >70%) both clot volume and perihematomal edema and protected the BBB at 24 hr following ICH (19). This reduction in clot volume, achieved with rtPA liquification of the clot, was significantly (>37%) greater than the reduction obtained by mechanical aspiration without rtPA. Lastly, we have used the porcine ICH model to test the Possis AngioJet rheolytic thrombectomy catheter (74). This surgical clot removal study showed that the device was very effective for rapidly removing intracerebral hematomas, producing an average 61% decrease in clot volumes in approximately 30 sec. Other treatments studied in this model include inhibiting heme oxygenase by a metalloporphyrin (13 ).

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