MODEST HYPOTHERMIA PRESERVES CEREBRAL ENERGY-METABOLISM DURING HYPOXIA-ISCHEMIA AND CORRELATES WITH BRAIN-DAMAGE - A P-31 NUCLEAR-MAGNETIC-RESONANCE STUDY IN UNANESTHETIZED NEONATAL RATS

Recent studies have shown that mild to moderate (modest) hypothermia d ecreases the damage resulting from hypoxic-ischemic insult (HI) in the immature rat. To determine whether suppression of oxidative metabolis m during HI is central to the mechanism of neuroprotection, P-31 nucle ar magnetic resonance (NMR) spectroscopy was used to measure high ener gy metabolites in 7-d postnatal rats under conditions of modest hypoth ermia during the M. The rats underwent unilateral common carotid arter y ligation followed by exposure to hypoxia in 8% oxygen for 3 h. Envir onmental temperature was decreased by 3 or 6 degrees C from the contro l temperature, 37 degrees C, which reliably produces hemispheric damag e in over 90% of pups. The metabolite parameters and tissue swelling ( edema) at 42 h recovery varied very significantly with the three tempe ratures. Tissue swelling was 26.9, 5.3, and 0.3% at 37, 34, and 31 deg rees C, respectively. Core temperature and swelling were also measured , with similar results, in parallel experiments in glass jars. Multisl ice magnetic resonance imaging, histology, and triphenyltetrazolium ch loride staining confirmed the fairly uniform damage, confined to the h emisphere ipsilateral to the ligation. The NMR metabolite levels were integrated over the last 2.0 h out of 3.0 h of HI, and were normalized to their baseline for all surviving animals (n = 25). ATP was 47.9, 6 9.0, and 83.0% of normal, whereas the estimator of phosphorylation pot ential (phosphocreatinine/inorganic phosphorus) was 16.9, 27.8, and 42 .6% of normal at 37, 34, and 31 degrees C, respectively. There was a s ignificant correlation of both phosphocreatinine/inorganic phosphorus (p < 0.0001) and ATP levels (p < 0.0001) with brain swelling. Abnormal brain swelling and thus damage can be reliably predicted from a thres hold of these metabolite levels (p < 0.0001). Thus for all three tempe ratures, a large change in integrated high energy metabolism during HI is a prerequisite for brain damage. With a moderate hypothermia chang e of 6 degrees C, where there is an insufficient change in metabolites , there is no subsequent HI brain damage, In general, treatment for HI in our 7-d-old rat model should be aimed at preserving energy metabol ism.