Repeat positron emission tomographic studies in transient middle cerebral artery occlusion in cats: Residual perfusion and efficacy of postischemic reperfusion

Abstract

The wider clinical acceptance of thrombolytic therapy for ischemic stroke has focused more attention on experimental models of reversible focal ischemia. Such models enable the study of the effect of ischemia of various durations and of reperfusion on the development of infarctions. We used high- resolution positron emission tomography (PET) to assess cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMR(glc)) before, during, and up to 24 h after middle cerebral artery occlusion (MCAO) in cats. After determination of resting values, the MCA was occluded by a transorbital device. The MCA was reopened after 30 min in five, after 60 min in 11, and after 120 min in two cats. Whereas all cats survived 30-min MCAO, six died after 60-min and one after 120-min MCAO during 6-20 h of reperfusion. In those cats surviving the first day, infarct size was determined on serial histologic sections. The arterial occlusion immediately reduced CBF in the MCA territory to <40% of control, while CMRO2 was less affected, causing an increase in OEF. Whereas in the cats surviving 24 h of reperfusion after 60- and 120-min MCAO, OEF remained elevated throughout the ischemic episode, the initial OEF increase had already disappeared during the later period of ischemia in those cats that died during the reperfusion period. After 30-min MCAO, the reperfusion period was characterized by a transient reactive hyperemia and fast normalization of CBF, CMRO2, and CM R(gle) and no or only small infarcts in the deep nuclei were found in histology. After 60- and 120- min MCAO, the extent of hyperperfusion was related to the severity of ischemia, decreased CMRO2 and CMR(gle) persisted, and cortical/subcortical infarcts of varying sizes developed. A clear difference was found in the flow/metabolic pattern between surviving and dying cats: In cats dying during the observation period, extended postischemic hyperperfusion accompanied large defects in CMRO2 and CMR(gle), large infarcts developed, and intracranial pressure increased fatally. In those surviving the day after MCAO, increased OEF persisted over the ischemic episode, postischemic hyperperfusion was less severe and shorter, and the perfusional and metabolic defects as well as the final infarcts were smaller. These results stress the importance of the severity of ischemia for the further course after reperfusion and help to explain the diverging outcome after thrombolysis, where a relation between the residual flow and the effectiveness of reperfusion was also observed.