Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: An experimental study in the immature rat

Background and Objective. Clinical investigations suggest that premature infants who require mechanical ventilation from respiratory distress syndrome are at increased risk for periventricular leukomalacia if hypocapnia occurs during respiratory management. The question remains as to the contribution of hypocapnia to hypoxic-ischemic brain damage and whether or not hypercapnia is neuroprotective. Methods. Seven-day postnatal rats underwent unilateral common carotid artery ligation followed thereafter by exposure to systemic hypoxia with 8% oxygen (O₂) combined with either 0, 3, 6, or 9% carbon dioxide (CO₂) for 2.5 hours at 37°C. Survivors underwent neuropathologic examination at 30 days of postnatal age, and their brains were categorized as follows: 0 = normal; 1 = mild atrophy; 2 = moderate atrophy; 3 = atrophy with cystic cavitation <3 mm; 4 = cystic cavitation >3 mm of the cerebral hemisphere ipsilateral to the carotid artery ligation. The width of the ipsilateral hemisphere also was determined on a posterior coronal section and compared with that of the contralateral hemisphere to ascertain the severity of cerebral atrophy/cavitation. Data were analyzed by linear models. Results. CO₂ tensions averaged 26, 42, 54, and 71 mm Hg in the 0, 3, 6, and 9% CO₂ exposed animals, respectively, during systemic hypoxia. Blood O₂ tensions during hypoxia were not different among the four groups and averaged 34.7 mm Hg. Neuropathologic results showed that 30/38 (79%) rats exposed to 3% CO₂ showed either no or mild brain damage compared with 13/33 (39%) controls (0% CO₂). Cystic cavitation occurred in only four CO₂ exposed rat pups compared with 14 controls (P = .001). At 6% CO₂ exposure, all of 20 rat pups showed either no damage or mild atrophy compared with controls (P < .001); and at 9% CO₂ exposure, 19/23 (83%) rat pups showed no or mild damage compared with controls (P < .001). The data also showed that the greatest reduction in brain damage occurred in immature rats exposed to 6% CO₂ with slightly less protection at 9% CO₂ (P = .012), the latter comparable with the severity of brain damage sustained by animals inhaling 3% CO₂. Analyses of coronal width ratios at each CO₂ exposure provided results comparable with those of the gross neuropathology scores. Conclusions. The results indicate that in an immature rat model normocapnic cerebral hypoxia-ischemia is associated with less severe brain damage than in hypocapnic hypoxia-ischemia and that mild hypercapnia is more protective than normocapnia. The findings in an experimental model merit further animal investigations as well as a clinical reappraisal of the ventilatory management of sick newborn human infants.