Abstract:

Perinatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal death and disability. Therapeutic hypothermia significantly reduces death and major disability associated with HIE; however, many infants still experience lifelong disabilities to movement, sensation and cognition. Clinical guidelines, based on strong clinical and preclinical evidence, recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours, with a target brain temperature of 33.5 ± 0.5°C for infants with moderate to severe HIE. The clinical guidelines also recommend that infants be rewarmed at a rate of 0.5°C per hour, but this is not based on strong evidence. There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with HIE. Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia. In this review, we evaluate the evidence for the optimal start time, duration and depth of hypothermia, and whether the rate of rewarming after treatment affects brain injury and neurological outcomes.

Key words: hypoxia-ischemia, hypoxic-ischemic encephalopathy, therapeutic hypothermia, neuroprotection, therapeutic strategies, randomized controlled trials, animal models, fetal sheep, piglets