The most frequently used species for experimental ICH studies has been the rat, and the most commonly injected site has been the basal ganglia. Some of the earliest ICH studies in rat, conducted in the mid-to-late 1980s, examined relationships between mass effect, perihemato-mal blood flow, and ICP (27-31). In addition, microballoons were employed to examine the relationships between mass volumes, elevations of ICP, and local perfusion (32). Overall, investigators concluded that perihematomal blood flow was markedly reduced in their model. Based on their findings, it was suggested that ischemia was responsible for secondary damage after ICH (reviews in Refs. 33 and 34).

However, not all investigators have concluded that ischemia is responsible for perihematomal tissue injury after ICH. Although initial ischemia of 20% to 30% below baseline has been noted in a rat model, recovery of flow and hyperemia in the hours following ICH were described (35). More recently, Yang et al. measured local cerebral blood flow (CBF) using [14C]-iodoantipyrine (25). They reported that CBF was reduced to 50% of control at 1 hr after ICH, returned to control values by 4 hr, but then decreased to <50% of control in the subacute phase between 24 and 48 hr. They concluded that although some degree of ischemia occurs in the early minutes to a few hours following ICH, the degree of ischemia is neither severe nor the basis for the development of perihematomal edema (25). Furthermore, in human ICH (36,37), Positron Emission Tomography studies demonstrated that, although blood flow might be reduced, this reduction is coupled with a reduction in metabolism in perihematomal tissue; therefore, cerebral ischemia is not present.

Some investigators have reported that hyperemia is present following ICH in rats (30), and we observed hyperemia in our porcine ICH model (20,38). A recent report that increased glucose metabolism in perihematomal rat brain in the early hours after ICH is due to glutamate receptor activation (10) might explain the hyperemia and the marked increases in perihemato-mal lactate previously reported in a porcine ICH model (18 ).

Studies in rats over the past decade have established that activation of the coagulation cascade and specific plasma proteins are required for both acute and delayed development of perihematomal edema. The plasma protein thrombin, when infused into brain, produces edema that is comparable to that generated by infusions of whole blood (39). The importance of the coagulation cascade in ICH-induced perihematomal edema formation was demonstrated both in rat and in porcine ICH models (40). Heparinized blood infusions generated very little edema when compared to infusions of unheparinized blood. As demonstrated in models in which packed red cells alone were infused (40), the contribution by erythrocytes to edema formation is delayed. Red cells infused into the basal ganglia in rats did not produce a dramatic increase in edema until 3 days postinfusion (40) . In contrast, infusions of lysed autologous erythrocytes into the rat brain produced marked edema 24 hr after infusion. In the rat model, whereas hemoglobin infusions produce severe edema, packed erythrocytes do not. Similarly, in a porcine ICH model, lysed blood causes severe brain edema and death, presumably as a result of high concentrations of released hemoglobin (41).

Complement activation and membrane attack-complex formation also appear to contribute to perihematomal edema formation, as N-acetylheparin, which inhibits complement activation, diminished this edema (42). Importantly, these results in an animal ICH model suggest that the complement system could be targeted for future ICH treatment.

Lastly, studies in a rat cortical ICH model demonstrate the additional toxicity of hemorrhage, as compared to cerebral ischemic insults (43). These investigators showed that extravasated whole blood causes a greater degree of cell death and inflammation than do ischemic lesions of similar size (44 ).

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