To test the hypothesis that acute hyperglycemia reduces changes in cell membrane structure and function during cerebral hypoxia in the newborn, brain cell membrane Na+, K+-ATPase activity and levels of membrane lipid peroxidation products were measured in four groups of anesthetized, ventilated newborn piglets: normoglycemia/normoxia (control, group 1,n= 12), hyperglycemia/normoxia (group 2,n= 6), untreated hypoxia (group 3,n= 10), and hyperglycemia/hypoxia (group 4,n= 7). Hyperglycemia (blood glucose concentration 20 mmol/L) was induced using the glucose clamp technique. The hyperglycemic glucose clamp was maintained for 90 min before onset of hypoxia and throughout the period of hypoxia. Cerebral tissue hypoxia was induced in groups 3 and 4 by reducing fraction of inspired oxygen for 60 min and was documented by a decrease in the ratio of phosphocreatine to inorganic phosphate as measured using31P-nuclear magnetic resonance spectroscopy. Blood glucose concentration during hypoxia in hyperglycemic hypoxic animals was 20.7 ± 1.2 mmol/L, compared with 10.3 ± 1.7 mmol/L in untreated hypoxic piglets (p< 0.05). Peak blood lactate concentrations were not significantly different between the two hypoxic groups (8.4 ± 2.8 mmol/Lversus7.8 ± 1.6 mmol/L). In cerebral cortical membranes prepared from the untreated animals, cerebral tissue hypoxia caused a 25% reduction in Na+,K+-ATPase activity compared with normoxic controls and an increase in conjugated dienes and fluorescent compounds, markers of lipid peroxidation. In contrast, Na+,K+-ATPase activity and levels of lipid peroxidation products in hyperglycemic hypoxic animals were not significantly different from the values in control normoxic animals. These data suggest that in the newborn piglet model acute hyperglycemia reduces hypoxia-induced brain cell membrane dysfunction.