Brainstem bilirubin toxicity in the newborn primate may be promoted and reversed by modulating PCO2.
The auditory brainstem response (ABR) was monitored during infusion of bilirubin in six ventilated newborn rhesus monkeys (138-145 d gestation) while acute changes in pH were produced by varying inspired CO2. Prolonged respiratory acidosis without bilirubin infusion produced minimal changes in the ABR (one animal). CO2 exposure, usually initiated when the bilirubin level reached approximately 20 mg/dL, decreased arterial pH to values ranging from 6.85 to 7.10. ABR changes, including prolongation of the wave II-IV peak to peak intervals and decreased wave amplitudes, first developed 2-4 h after initial exposure to CO2. Total and unbound bilirubin levels at this time ranged from 376 to 564 mumol/L (22-33 mg/dL) and 38 to 65 nmol/L (2.5-3.8 micrograms/dL), respectively. Correction of respiratory acidosis produced partial to complete reversal of ABR changes within 3 to 20 min. Reexposure to CO2 immediately reproduced the ABR abnormality. Production and reversal of the abnormal ABR was obtained through two to three cycles in three animals. Thus, when the brainstem bilirubin level was near the threshold for toxicity, the effect of changes in PCO2 on the ABR were immediate, suggesting that auditory pathway toxicity is initially mediated by a reversible pH-dependent bilirubin-membrane complex. In contrast to humans, in monkeys auditory toxicity appeared to be a late manifestation of bilirubin toxicity, inasmuch as all monkeys were obtunded and apneic 30-70 min before ABR abnormalities appeared. Notwithstanding these limitations, the results support the hypothesis that bilirubin toxicity can be both promoted and reversed by modulating brain pH.
Wennberg
R P
RP
Department of Pediatrics, University of California, Davis 95616.
Gospe
S M
SM
Rhine
W D
WD
Seyal
M
M
Saeed
D
D
Sosa
G
G
D000142:Acidosis, Respiratory / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000378:metabolism / Q000494:pharmacology*; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology; D002245:Carbon Dioxide; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000503:physiopathology; D008253:Macaca mulatta
D002245:Carbon Dioxide; D001663:Bilirubin