Metabolic Distress in the perihematomal tissue Intracerebral hemorrhage is crucially important neurologic emergency with high societal impact (Sacco 1994;Qureshi 2001;Broderick 2007). The pathophysiology of intracerebral hemorrhage ca,n be considered to consist of two phases. The first phase includes immediate necrosis of the brain cells in the hemorrhage core due to the acute bleed and early hemorrhagic expansion. It is now clear that hematoma enlargement contributes to deterioration in a subset of patients. Brott and colleagues (1997) reported hematoma expansion in 26% of patients within 1 hour of the initial CT and overall in 38% of patients within 20 hours. These findings are in accord with those of Kazui (1996) who reported an overall expansion rate of 20% in their series. Mayer et al (2005) demonstrated that hemorrhagic expansion occurs within 4 hours of onset. While the use factor Vila did not result in improved clinical outcome, hemorrhagic expansion was reduced (Mayer - oral presentation American Academy of Neurology meeting, 2007). It may be that prevention of hemorrhagic expansion is not enough, and that the metabolic distress surrounding the hemorrhage, due to edema or other mechanisms, must be relieved in order to improve outcome. The second phase is the slowly ensuing damage to perihematomal tissue due to mass effect, excitotoxic edema, and progressive neurotoxicity resulting from iron, thrombin, blood breakdown products, free radical formation, protease activation and inflammation (Gong 2000;Lee 1997;Wu 2002;Xi and Hoff 2006). These mechanisms lead to metabolic distress and subsequent damage in the perihematomal tissue which is progressive over time (Gebel 2002a, 2002b), perhaps through alteratiion of selected genetic pathways. We hypothesize that early removal of blood avoids the subsequent damage from progressive brain edema that occurs in the days following ICH. The slowly ensuing damage to the perihematomal tissue is complex and involves multiple mechanisms that are in one way or another linked to the presence of the mass of collected blood and progressive edema. It is recognized that perihematomal ischemia per se does not exist in experimental models (Qureshi 1999), however, sophisticated animal studies measuring blood flow, cerebral oxygen extraction, oxygen consumption, glucose utilization, and lactate production have demonstrated that metabolism is disturbed in the perihematomal tissue (Nath1987). Similar work in humans, using positron emission tomography (PET), demonstrated symmetrically reduced blood flow in both hemispheres in 12 patients imaged within 7-28 hours of onset. (Zazulia and Diringer 2001). In a recent study, Powers and colleagues also demonstrated that autoregulation of CBF was preserved in 14 patients with acute ICH during pharmacologic blood pressure reductions of mean arterial pressure of 15%. The same research group found disproportionately reduced focal perihematomal CBF, but no focal increase in oxygen extraction fraction, suggesting that the low perilesional CBF values reflected metabolic dysfunction (Powers 2001), as has been confirmed by mitochondrial respiration experiments on biopsied human mitochondria (Kim-Han 2006). Our group has demonstrated two independent findings that the perihematomal tissue is in a state of metabolic distress due to the hematoma. The first is the MRI finding of a rim of perihematomal decrease in ADC values in a subset of patients evaluated within 6 hours of symptom onset (Kidwell 2001). In our initial 5- year study period, we confirmed these findings demonstrating that 30% of patients have a rim of ADC reduction (see Preliminary Studies below). Of note, this rim of tissue bioenergetic compromise was not associated with focal perihematomal decreased blood flow and was not associated with the extent and severity of perihematomal edema. The second finding is that perihematomal microdialysis glutamate and lactate/pyruvate values are elevated for many days after ICH. Reduction of hematoma volume, through the use of stereotactic thrombolysis, resulted in normalization of glutamate values but not lactate/pyruvate values. This suggests that evacuation of hematoma can improve this metabolic distress (Miller 2006;Vespa 2006). We have validated microdialysis lactate/pyruvate ratio to be a robust marker of impaired oxidative metabolism (Vespa 2005). We have a considerable experience with human cerebral microdialysis and have demonstrated the safety and utility of this technique in determining sequential changes in brain metabolism after traumatic brain injury and intracerebral hemorrhage (Vespa 1998;Vespa 2003;Vespa 2006;Vespa 2007). We propose that endoscopic surgery will result in improvement in the metabolic state of the perihmatomal region, and we intend to measure this response using microdialysis and MRI in this study.
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