Effects of glucose and PaO2 modulation on cortical intracellular acidosis,NADH redox state, and infarction in the ischemic penumbra

Background and Purpose-During focal cerebral ischemia, the ischemic penumbr a or border-zone regions of moderate cortical blood flow reductions have a heterogeneous development of intracellular cortical acidosis. This experime nt tested the hypotheses that (1) this acidosis is secondary to glucose uti lization and (2) this intracellular acidosis leads to recruitment of potent ially salvageable tissue into infarction. Methods-Brain pH(i), regional cortical blood now, and NADH redox state were measured by in vivo fluorescent imaging, and infarct volume was assessed b y triphenyltetrazolium chloride histology. Thirty fasted rabbits divided in to 6 groups of 5 each were subjected to 4 hours of permanent focal ischemia in the presence of hypoglycemia (approximate to 2.8 mmol/L), moderate hype rglycemia (approximate to 11 mmol/L), and severe hyperglycemia (>28 mmol/L) under either normoxia or moderate hypoxia (Pa-O2 approximate to 50 mm Hg). Results-Preischemic hyperglycemia led to a more pronounced intracellular ac idosis and retardation of NADH regeneration than in the hypoglycemia groups under both normoxia and moderate hypoxia in the ischemic penumbra. For exa mple, 4 hours after ischemia, brain pH, in the severe hyperglycemia/normoxi a group measured 6.46, compared with 6.84 in the hypoglycemia/normoxia grou p (P<0.01), and NADH fluorescence measured 173% compared with 114%. Infarct volume in the severe hyperglycemia/normoxia group measured 35.1+/-6.9% of total hemispheric volume, compared with 13.5+/-4.2% in the hypoglycemia/nor moxia group (P<0.01). Conclusions-Hyperglycemia significantly worsened both cortical intracellula r brain acidosis and mitochondrial function in the ischemic penumbra. This supports the hypothesis that the evolution of acidosis in the ischemic penu mbra is related to glucose utilization. Furthermore, the observation that h ypoglycemia significantly decreased infarct size supports the postulate tha t cortical acidosis leads to recruitment of ischemic penumbra into infarcti on.