Mapping of the consequences of bilirubin exposure in the immature rat: local cerebral metabolic rates for glucose during moderate and severe hyperbilirubinemia.

The regional cerebral metabolic consequences of bilirubin intoxication are not well known. With the quantitative autoradiographic [14C]2-deoxyglucose (2DG), we studied the effect of moderate or severe bilirubin infusion on local cerebral metabolic rates for glucose utilization (LCMRglcs) in 10 (P10) and 21 day-old (P21) rats. After an 80 or 160 mg/kg loading dose of bilirubin administered over 15 min, the speed of bilirubin infusion was reduced to 32 or 64 mg/kg/h for the following 105 min, for moderate or severe intoxication, respectively. This infusion protocol led to plasma bilirubin concentrations of 100-200 nmol/ml (moderate intoxication) or 200-300 nmol/ml (severe intoxication). Cerebral bilirubin concentration was 10 nmol/g at P10 and undetectable at P21 in moderate hyperbilirubinemia while it reached 22-34 nmol/g at both ages during severe hyperbilirubinemia. At P10, bilirubin infusion, moderate or severe, induced significant decreases in LCMRglcs in 17 and 15 brain regions of the 24 studied, respectively. At P21, moderate hyperbilirubinemia induced a decrease in LCMRglcs in only 2 regions, auditory cortex and auditory nerve. Conversely, at that age, severe bilirubin intoxication led to significant decreases in LCMRglcs in all regions studied. These results demonstrate that metabolic changes induced by bilirubin are directly correlated to its entry into the brain which occurs without any alteration in the blood-brain barrier. Indeed, the effects of the dye are quite discrete during moderate hyperbilirubinemia at P21 when no bilirubin is detectable in the brain while they are massive during severe hyperbilirubinemia at P21 and at both levels of intoxication at P10 when bilirubin has entered the brain in measurable amounts.