A Combination of Mild Hypothermia and Sevoflurane Affords Long-Term Protection in a Modified Neonatal Mouse Model of Cerebral Hypoxia-Ischemia

Infant brain injury from hypoxia-ischemia (HI) can lead to life-long impairment, but protective strategies are lacking. Short-term but not long-term protection has been demonstrated in the Rice-Vannucci neonatal brain ischemia model (RVM) by volatile anesthetic administration before HI, while exposure during HI has not been tested. In the current study, we evaluated a combination of sevoflurane and mild hypothermia as a protective approach during HI, both short- and long-term, by introducing intubation and mechanical ventilation to the RVM.The right common carotid artery was ligated in 10-day-old mice during brief sevoflurane anesthesia, followed by a 2-hour recovery with the dam. Littermates were then randomized to either: HI spontaneously breathing 10% oxygen for 60 minutes (the classical RVM); HI-Protect mild hypothermia and orotracheal intubation and mechanical ventilation with 3.5% sevoflurane in 10% oxygen for 60 minutes; or Room Air spontaneously breathing room air for 60 minutes. In a nonsurviving cohort, cerebral oxygenation was monitored in the area at risk and the contralateral hemisphere during HI or HI-Protect using visible-light spectroscopy (Spectros Corp). Mean arterial blood pressure and heart rate were measured. Arterial blood gases were obtained. Right/left brain hemispheric weight ratios and brain damage scores were determined 1 week after HI. In another group, learning and behavior were assessed in young adulthood (9 weeks) using spontaneous locomotion, Morris water maze, and apomorphine injection.During HI, ipsilateral and contralateral brain oxygenation, arterial blood pressures, blood gases, and glucose levels were similar in both ischemic groups, while heart rate was slower in the HI-Protect group. One week after ischemia, brain hemispheric weight ratios and injury scores in several brain regions were significantly worse after HI, compared with HI-Protect. Nine weeks after HI, Morris water maze hidden platform and reversal platform escape latencies, measures of spatial memory function, were superior after HI-Protect, compared with HI (P0.0001). HI-Protect animals demonstrated significantly less circling behavior after an apomorphine challenge (P0.0001), a measure of striatal integrity.To test the neuroprotective effects of volatile anesthetics during neonatal brain ischemia, we developed a modification of the RVM. By using mechanical ventilation and endotracheal intubation, sevoflurane administration during HI was survivable. The combination of sevoflurane administration and mild hypothermia during HI conferred not only short-term structural, but also long-term functional protection, compared with littermates treated according to the RVM. These findings warrant further studies to improve neurological outcome in critically ill infants.