The effects of adding prophylactic phenobarbital to therapeutic hypothermia in the term-equivalent hypoxic-ischemic rat.

BackgroundHypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Therapeutic hypothermia (TH) is the only available intervention, but neuroprotection is incomplete and variable. Seizures are common in infants with HIE undergoing TH and may worsen outcome. Phenobarbital (PB) is sometimes added, although use of prophylactic PB is controversial in the neonate. We hypothesize that prophylactic PB will not reduce, and may enhance, the neuroprotective effects of TH on brain injury and motor outcomes in the postnatal day 10 (P10) hypoxic-ischemic (HI) rat.MethodsP10 rat pups were subjected to unilateral HI and 4 h recovery with: normothermia (N); hypothermia (TH); and hypothermia with phenobarbital (TH+PB). Brain damage was assessed longitudinally at 24 h and 2 weeks using brain magnetic resonance imaging and 12 weeks using histochemical analysis. Motor function was assessed with the beam walk and cylinder tests.ResultsTH and TH+PB induced neuroprotection, as measured by global brain damage score and improved motor function. Exploratory analyses suggest that TH+PB may confer enhanced protection, especially to the extent of damage.ConclusionProphylactic PB with TH is not deleterious and may provide additional long-term neuroprotection, including improvement of motor outcomes following HI in the term-equivalent, neonatal rat.

Therapeutic hypothermia and hypoxia-ischemia in the term-equivalent neonatal rat: characterization of a translational preclinical model.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity in survivors. Therapeutic hypothermia (TH) is the only available intervention, but the protection is incomplete. Preclinical studies of HIE/TH in the rodent have relied on the postnatal day (P) 7 rat whose brain approximates a 32-36 wk gestation infant, less relevant for these studies. We propose that HIE and TH in the term-equivalent P10 rat will be more translational. METHODS: P10-11 rat pups were subjected to unilateral hypoxia-ischemia (HI) and 4 h recovery in normothermic (N) or hypothermic (TH) conditions. Brain damage was assessed longitudinally at 24 h, 2 wk, and 12 wk. Motor function was assessed with the beam walk; recognition memory was measured by novel object recognition. RESULTS: Neuroprotection with TH was apparent at 2 and 12 wk in both moderately and severely damaged animals. TH improved motor function in moderate, but not severe, damage. Impaired object recognition occurred with severe damage with no evidence of protection of TH. CONCLUSION: This adaptation of the immature rat model of HI provides a reproducible platform to further study HIE/TH in which individual animals are followed up longitudinally to provide a useful translational preclinical model.