The relationship between cerebral blood flow (CBF) and the evolution of brain edema was investigated in an experimental model of perinatal hypoxic-ischemic brain damage. Seven-d postnatal rats were subjected to unilateral common carotid artery ligation followed by 3 h of hypoxia with 8% oxygen at 37 degrees C. This insult produces neuronal necrosis and/or infarction only in the cerebral hemisphere ipsilateral to the arterial occlusion in the majority of animals; hypoxia alone produces no damage. CBF, measured by the indicator diffusion technique using iodo[14C]-antipyrine, and tissue water content were determined concurrently in both cerebral hemispheres at specific intervals during recovery from cerebral hypoxia-ischemia. Water contents in the ipsilateral cerebral hemisphere were 89.1, 89.6, 89.7, 91.0, and 88.3% at 30 min, 4 h, 24 h, 3 d, and 6 d, respectively (p less than 0.001); whereas the percent tissue water in the contralateral hemisphere was unchanged from values in nonligated, hypoxic control rats (87.7%). CBF was similar in both cerebral hemispheres at 30 min, 4 h, and 24 h of recovery (50-65 mL/100 g/min) and not different from age-matched controls. At 3 and 6 d, CBF in the ipsilateral cerebral hemisphere was 30 and 26% of the contralateral hemisphere and 23 and 29% of the control animals, respectively (p less than 0.001). No inverse correlation existed between the changes in brain water content and CBF at any interval until 6 d of recovery. Thus, an early hypoperfusion does not follow perinatal cerebral hypoxia-ischemia, as occurs in adults.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary: The brain damage that evolves from perinatal cerebral hypoxia-ischemia may involve lingering distur bances in metabolic activity that proceed into the recov ery period. To clarify this issue, we determined the car bohydrate and energy status of cerebral tissue using en zymatic, fluorometric techniques in an experimental model of perinatal hypoxic-ischemic brain damage. Seven-day postnatal rats were subjected to unilateral common carotid artery ligation followed by 3 h of hypoxia with 8% oxygen at 37°C. This insult is known to produce tissue injury (selective neuronal necrosis or infarction) predominantly in the cerebral hemisphere ipsilateral to the carotid artery occlusion in 92% of the animals. Rat pups were quick-frozen in liquid nitrogen at 0, 1, 4, 12, 24, or 72 h of recovery; littermate controls underwent neither ligation nor hypoxia. Glucose in both cerebral hemi spheres was nearly completely exhausted during hypoxia ischemia, with concurrent increases in lactate to 10 mmoU kg. During recovery, glucose promptly increased above control values, suggesting an inhibition of glycolytic flux, as documented in the ipsilateral cerebral hemisphere by measurement of glucose utilization (CMRg1c) at 24 h. Tis sue lactate declined rapidly during recovery but remained slightly elevated in the ipsilateral hemisphere for 12 h.Cerebral hypoxia-ischemia is a frequent accom paniment to high-risk pregnancy and labor, and oc casionally culminates in brain damage with its as sociated neurologic impairment (F enichel, 1983;Volpe, 1987;Vannucci, 1989). The pathophysio- Abbreviations used: 2-DG, 2-deoxyglucose; MCA, middle ce rebral artery; NMR, nuclear magnetic resonance; PCA, perchlo ric acid; P-Cr, phosphocreatine. 227Phosphocreatine (P-Cr) and ATP in the ipsilateral cere bral hemisphere were 14 and 26% of control (p < 0.001) at the end of hypoxia-ischemia; total adenine nUcleotides (A TP + ADP + AMP) also were partially depleted (-46%). During the first hour of recovery, mean P-Cr was replenished to within 90% of baseline, whereas mean ATP was incompletely restored to 68-81 % of control (p < 0.05). Individual ATP and total adenine nucleotide values were >2 SD below control levels in 17/24 (71%) brains at all intervals of recovery. Both ATP and total adenine nu cleotides were inversely correlated with tissue water con tent, reflecting the extent of cerebral edema. No major alterations in the high-energy phosphate reserves oc curred in the contralateral cerebral hemisphere either during or following hypoxia-ischemia. Thus, following perinatal cerebral hypoxia-ischemia, ATP and total ade nine nUcleotides never recover completely in brains un dergoing damage but rather are permanently depleted to levels that reflect the severity of tissue injury. Recovery of P-Cr to near normal levels can occur despite evolving brain damage. The findings have relevance to the assess ment of asphyxiated newborn humans using magnetic res onance spectroscopy.

ABSTRACT. The 2-deo~y-['~C]-glucose (2-DG) method of Sokoloff was used to assess regional cerebral glucose utilization (CGU) in the immature rat. The 7-d postnatal rats received 2.5 pCi 2-DG subcutaneously, after which blood was collected for measurement of plasma glucose and 2-DG activity at intervals up to 90 min. The brains of the 90-min rat pups either were frozen for analysis of glucose concentration and chromatographic separation of 2-DG and 2-DG-6-phosphate or for ['4C]-autoradiography. A lumped constant of 0.55 was calculated from plasma and brain glucose levels of 6.4 and 1.62 mmol/L.kg, respectively. Of the [I4C] activity in brain, 75.6% was in the 2-DG-6-phosphate fraction; this percent was substituted for Kl", K2*, and K3" in the Sokoloff equation. Cerebral hemispheric CGU (n = 6) averaged 11.4 + 1.5 wmo1/100 g/min, 1/10 the value of adult rat brain. Rates in 16 brain structures (n = 10) ranged from 7.8 (frontal white matter) to 16.9 (cerebellum) pmo1/100 g/min. During hypoxiaischemia (unilateral common carotid artery ligation combined with exposure to 8% oxygen), the lumped constant increased to 1.04, and 99% of 2-DG was converted to 2-DG-6-phosphate. Increases in CGU occurred in all eight structures of the cerebral hemisphere ipsilateral to the carotid artery occlusion (n = 9), ranging from 287% (frontal white matter) to 445% (striatum) of control values (p < 0.05). Relatively comparable elevations in CGU (234-435% of control) occurred in the contralateral cerebral hemisphere, which were not significantly different from those of the ipsilateral hemisphere. The relatively proportionate increases in regional CGU of the two cerebral hemispheres, only one of which sustains tissue injury, suggest interhemispheric differences in the extent to which glucose is metabolized via anaerobic glycolysis to maintain cellular energy production. The investigation demonstrates the feasibility of measuring regional CGU in the small laboratory animal, which is applicable to a variety of physiologic and pathologic situations. (Pediatr Res 26: 208-214,1989) Abbreviations CGU, cerebral glucose utilization rCGU, regional CGU 2-DG, 2-deoxyglucose 2-DG-6-P, 2-deoxyglucose-6-phosphate s.c., ~ubcutaneous LC, lumped constant -P, high-energy phosphate bond The 2-DG technique, as originally developed by Sokoloff et al. (I), has become an established procedure to measure rCGU in adult animals. The method has been used in numerous species under a variety of physiologic and pathologic situations (2). Furthermore, the method provides the theoretical and practical basis for the measurement of rCGU in humans, including infants and children, using positron emission tomography (3, 4). Although rCGU has been determined in large perinatal animals (5-7), a systematic investigation of its applicability to the small laboratory animal has yet to be accomplished. We here describe a feasibility study to measure rCGU, using 2-DG, in the immature rat; and we have used the technique to ascertain the nature and extent of alterations in regional...