Background and Purpose-During focal cerebral ischemia, the ischemic penumbra or border-zone regions of moderate cortical blood flow reductions have a heterogeneous development of intracellular cortical acidosis. This experiment tested the hypotheses that (1) this acidosis is secondary to glucose utilization and (2) this intracellular acidosis leads to recruitment of potentially salvageable tissue into infarction. Methods-Brain pH i , regional cortical blood flow, and NADH redox state were measured by in vivo fluorescent imaging, and infarct volume was assessed by triphenyltetrazolium chloride histology. Thirty fasted rabbits divided into 6 groups of 5 each were subjected to 4 hours of permanent focal ischemia in the presence of hypoglycemia (Ϸ2.8 mmol/L), moderate hyperglycemia (Ϸ11 mmol/L), and severe hyperglycemia (Ͼ28 mmol/L) under either normoxia or moderate hypoxia (PaO 2 Ϸ50 mm Hg). Results-Preischemic hyperglycemia led to a more pronounced intracellular acidosis and retardation of NADH regeneration than in the hypoglycemia groups under both normoxia and moderate hypoxia in the ischemic penumbra. For example, 4 hours after ischemia, brain pH i in the severe hyperglycemia/normoxia group measured 6.46, compared with 6.84 in the hypoglycemia/normoxia group (PϽ0.01), and NADH fluorescence measured 173% compared with 114%. Infarct volume in the severe hyperglycemia/normoxia group measured 35.1Ϯ6.9% of total hemispheric volume, compared with 13.5Ϯ4.2% in the hypoglycemia/normoxia group (PϽ0.01). Conclusions-Hyperglycemia significantly worsened both cortical intracellular brain acidosis and mitochondrial function in the ischemic penumbra. This supports the hypothesis that the evolution of acidosis in the ischemic penumbra is related to glucose utilization. Furthermore, the observation that hypoglycemia significantly decreased infarct size supports the postulate that cortical acidosis leads to recruitment of ischemic penumbra into infarction. (Stroke. 1999;30:160-170.)

Several hours after an hypoxic-ischemic injury to the developing brain, hyperemia, then seizures, edema, and infarction can develop. The roles of nitric oxide (NO) synthesis and excitotoxin accumulation during these later phases of injury are not known. The time course of extracellular levels of amino acids within the parasagittal parietal cortex were measured with microdialysis during and for 3 d after 30 min of cerebral ischemia in nine chronically instrumented near-term fetal sheep (119-133 d). Cortical electroencephalographic (EEG) activity and extracellular space (ECS) were quantified simultaneously with real-time spectral analysis and cortical impedance measurements, respectively. Amino acid concentrations were measured using HPLC. During ischemia, citrulline (by-product of NO synthesis), glutamate, glycine, and gamma-aminobutyric acid (GABA) concentrations rose to 147 +/- 18%, 180 +/- 20%, 290 +/- 50% and 4800 +/- 1300% of baseline respectively (p < 0.05). The excitotoxic index ([glutamate] x [glycine]/[GABA]) decreased to 15 +/- 8%. Upon reperfusion, the cytotoxic edema and amino acid accumulation largely resolved within 1 h, and the EEG was depressed. Citrulline began to rise again by 4 h (p < 0.05), reaching a maximum (273 +/- 21%) at 32 +/- 2 h. Seizure activity developed at 7 +/- 2 h, and impedance plus the excitotoxic index then rose progressively and peaked at 32 +/- 2 h (480 +/- 170%). At 72 h, there was severe neuronal loss and laminar necrosis within the parasagittal cortex. These data suggest that, several hours after a severe hypoxicischemic injury, NO synthesis increased, then seizures arose, and edema developed concomitantly with the accumulation of excitotoxins.

To determine the effect of suppression of epileptiform activity that develops after hypoxic-ischemic injury in the immature brain, chronically instrumented near-term fetal sheep (119-133 days) were subjected to 30 minutes of complete cerebral ischemia: 6 were given a 0.3-mg/kg bolus of MK-801 at 6 hours after the insult followed by continuous infusion of 1 mg/kg over the next 36 hours, and were compared to 6 control sheep. Electrocorticographic activity and edema within the parasagittal region of the cortex were quantified with real-time spectral analysis and impedance measurements, respectively. Histological outcome was assessed 72 hours later. The intense epileptiform activity seen from 9 +/- 2 to 30 +/- 3 hours in the control group was completely suppressed in the MK-801-treated group. The onset of secondary cortical edema was delayed from 9.4 +/- 1.1 hours to 14.8 +/- 0.7 hours (p < 0.01). Neuronal damage was reduced, particularly in the lateral cortex and hippocampus (p < 0.05). Infarction of the parasagittal cortex was not prevented. These results suggest that N-methyl-D-aspartate-mediated epileptiform activity that develops after a global hypoxic-ischemic insult worsens neuronal outcome in the immature brain.

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Background and Purpose-Perinatal hypoxic-ischemic injuries can trigger a cascade of events leading to delayed deterioration and cell death several hours later. The objective of this study was to characterize the cerebral blood flow responses and the changes in extracellular glucose and lactate during the delayed phases of injury and to determine their relationships with the pathophysiological events after hypoxic-ischemic injury. Methods-Two groups of near-term chronically instrumented fetal sheep were subjected to 30 minutes of cerebral hypoperfusion. In the first group, regional cerebral blood flow was measured over the next 24 hours with radiolabeled microspheres. In the second, cortical extracellular glucose and lactate were measured by microdialysis. Parietal electrocorticographic activity and cortical impedance were recorded continuously in both groups, and the extent of neuronal loss was determined histologically at 72 hours after injury. Results-Cerebral blood flow was transiently impaired in the cortex during reperfusion, whereas during the delayed phase, there was a marked increase in cerebral blood flow. The severity of cortical neuronal loss was related to the degree of hypoperfusion in the immediate reperfusion period and inversely related to the magnitude of the delayed hyperperfusion. Cortical extracellular lactate was elevated after injury, and both glucose and lactate secondarily increased during the delayed phase of injury. Conclusions-The delayed phase is accompanied by a period of hyperperfusion that may protect marginally viable tissue.