Early postischemic hyperperfusion: Pathophysiologic insights from positronemission tomography

Early postischemic hyperperfusion (EPIH) has long been documented in animal stroke models and is the hallmark of efficient recanalization of the occlu ded artery with subsequent reperfusion of the tissue (although occasionally it may be seen in areas bordering the hypoperfused area during arterial oc clusion). In experimental stroke, early reperfusion has been reported to bo th prevent infarct growth and aggravate edema formation and hemorrhage, dep ending on the severity and duration of prior ischemia and the efficiency of reperfusion, whereas neuronal damage with or without enlarged infarction a lso may result from reperfusion (so-called "reperfusion injury"). In humans , focal hyperperfusion in the subacute stage (i.e., more than 48 hours afte r onset) has been associated with tissue necrosis in most instances, but re garding the acute stage, its occurrence, its relations with tissue metaboli sm and viability, and its clinical prognostic value were poorly understood before the advent of positron emission tomography (PET), in part because of methodologic issues. By measuring both CBF and metabolism, PET is an ideal imaging modality to study the pathophysiologic mechanism of EPIH. Although only a few PET studies have been performed in the acute stage that have sy stematically assessed tissue and clinical outcome in relation to EPIH, they have provided important insights. In one study, about one third of the pat ients with first-ever middle cerebral artery (MCA) territory stroke studied within 5 to 18 hours after symptom onset exhibited EPIH. Tn most cases, EP IH affected large parts of the cortical MCA territory in a patchy fashion, together with abnormal vasodilation (increased cerebral blood volume), "lux ury perfusion" (decreased oxygen extraction fraction), and mildly increased CMRO2, which was interpreted as postischemic rebound of cellular metabolis m in structurally preserved tissue. In that study, the spontaneous outcome of the tissue exhibiting EPIH was good, with late structural imaging not sh owing infarction. This observation was supported by another PET study, whic h showed, in a few patients, that previously hypoperfused tissue that later exhibited hyperperfusion after thrombolysis did not undergo frank infarcti on at follow-up. In both studies, clinical outcome was excellent in all pat ients showing EPIH except one, but in this case the hyperperfused area coex isted with an extensive area of severe hypoperfusion and hypometabolism. Th ese findings from human studies therefore suggest that EPIH is not detrimen tal for the tissue, which contradicts the experimental concept of "reperfus ion injury" but is consistent with the apparent clinical benefit from throm bolysis. However, PET studies per Formed in the cat have shown that althoug h hyperperfusion was associated with prolonged survival and lack of histolo gic infarction when following brief (30-minute) MCA occlusion, it often was associated with poor outcome and extensive infarction when associated with longer (60-minute) MCA occlusion. It is unclear whether this discrepancy w ith human studies reflects a shorter window for tissue survival after strok e in cats, points to the cat being more prone to reperfusion injury, or ind icates that EPIH tends not to develop in humans after severe or prolonged i schemia because of a greater tendency for the no-reflow phenomenon, for exa mple. Nevertheless, the fact that the degree of hyperperfusion in these cat studies was related to the severity of prior flow reduction suggests that hyperperfusion is not detrimental per se. Preliminary observations in temporary MCA occlusion in baboons suggest that hyperperfusion developing even after 6 hours of occlusion is mainly cortic al and associated with no frank infarction, as in humans. Overall, therefor e, PET studies in both humans and the experimental animal, including the ba boon, suggest that hyperperfusion is not a key factor in the development of tissue infarction and that it may be a harmless phenomenon when it occurs in the acute setting. However, an important issue that needs to be resolved by future studies with respect to EPIH relates to the possible occurrence of selective neuronal loss, as opposed to pannecrosis, in the previously hy perperfused tissue.