Effect of extreme hypercapnia on hypoxic-ischemic brain damage in the immature rat

Abstract

To ascertain the effect of extreme hypercapnia on perinatal hypoxic-ischemic brain damage, 7-d-postnatal rats were exposed to unilateral common carotid artery occlusion followed by hypoxia with 8% oxygen combined with 3, 12, or 15% carbon dioxide (CO2) for 2 h at 37 degrees C. Survivors underwent neuropathologic examination at 30 d of postnatal age, and their brains were characterized as follows: 0 = normal; 1 = mild atrophy; 2 = moderate atrophy; 3 = cystic infarct with external dimensions <3 mm; and 4 = cystic infarct with external dimensions >3 mm. The width of the cerebral hemisphere ipsilateral to the carotid artery occlusion also was determined on a posterior coronal section and compared with that of the contralateral hemisphere to ascertain the severity of cerebral atrophy/cavitation. CO2 tensions averaged 5.08, 11.1, and 13.2 kPa in the 3, 12, and 15% CO2-exposed animals, respectively, during hypoxia-ischemia (HI). Neuropathologic results showed that immature rats exposed to 3 and 12% CO2 had similar severities of brain damage. In contrast, rat pups exposed to HI combined with 15% CO2 were significantly more brain damaged than littermates exposed to 3% CO2. Specifically, eight of 14 animals exposed to 15% CO2 showed cystic infarcts (grades 3 and 4), whereas none of 14 littermates exposed to 3% CO2 developed cystic infarcts (p < 0.01). Analyses of coronal width ratios at each CO2 exposure provided results comparable with those of the gross neuropathology scores. Cerebral blood flow (CBF), measured at 90 min of HI, was lowest in those immature rats exposed to 15% CO2 compared with control (p = 0.04), with higher values in those rat pups exposed to 3 and 12% CO2. The findings indicate that 7-d-postnatal rats exposed to HI with superimposed 12% CO2 are neither less nor more brain damaged than littermates exposed to 3% CO(2) (normocapnia). In contrast, animals exposed to 15% CO2 are the most brain damaged of the three groups. Presumably, extreme hypercapnia produces more severe cardiovascular depression than is seen in animals subjected to lesser degrees of hypercapnia; the cardiovascular depression, in turn, leads to greater cerebral ischemia and ultimate brain damage.