BackgroundHypoxic-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 week gestation infant, less relevant for these studies. We propose that HIE and TH in the term-equivalent P10 rat will be more translational.MethodsP10–11 rat pups were subjected to unilateral hypoxia-ischemia (HI) and 4 hours recovery in normothermic (N) or hypothermic (TH) conditions. Brain damage was assessed longitudinally at 24 hours, 2 and 12 weeks. Motor function was assessed with the beam walk; recognition memory was measured by novel object recognition.ResultsNeuroprotection with TH was apparent at 2 and 12 weeks 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.ConclusionThis adaptation of the immature rat model of HI provides a reproducible platform to further study HIE/TH in which individual animals are followed longitudinally to provide a useful translational preclinical model.

Neonatal encephalopathy resulting from HI (hypoxia-ischaemia) continues to be a significant cause of mortality and morbidity in infants and children, affecting 1-2/1000 live term births and up to 60% of pre-term births. In order to understand the pathophysiology of this insult, as well as design therapeutic interventions, it is important to establish a relevant animal model for pre-clinical studies. One of the most frequently used models of HI-induced brain damage in immature animals is the unilateral carotid ligation/hypoxia model, initially developed in our laboratory more than 30 years ago. The original model employed the postnatal day 7 rat, whose brain is representative of that of a late gestation, pre-term [32-36 weeks GA (gestational age)] human infant. We, and others, have employed this model to characterize the pathophysiological, biochemical/energetic and neuropathological events following HI, as well as the determination of the unique characteristics of the immature brain that define its vulnerability to, and outcome from, HI. In defining the cascade of events following HI, it has become possible to identify potential targets for intervention and neuroprotection. Currently, the only available therapeutic intervention for neonatal encephalopathy in the term asphyxiated infant is therapeutic hypothermia, although this must be initiated within 6 h of birth and is at best partially effective in moderately injured infants. Ongoing pre-clinical studies are necessary to determine the basis for the partial protection afforded by hypothermia as well as the design of adjunct therapies to improve the outcome. The present review highlights the importance of using a well-characterized and relevant animal model to continue to pursue translational research in neuroprotection for the infant brain.

Purpose To determine whether birth weight less than1,500 grams is a relevant guideline indicating the need for examination for retinopathy of prematurity (ROP) when gestational age at birth is 30 or more completed weeks. Design A retrospective observational cohort study. Methods 266 infants in a single institutional neonatal intensive care unit (NICU), whose gestational age at birth was 30 or more weeks but whose birth weight was less than 1,500 grams, were examined according to published guidelines. Infants with lethal congenital anomalies or major ocular abnormalities were excluded. Outcomes were vascularization in retinal zone III without a prior need for treatment, or ROP warranting treatment. Results A study outcome was reached by 212 infants. Two hundred and eleven (99.5%) became vascularized through zone III without needing treatment. Only 1 (0.5%) required treatment for ROP. The 95% confidence interval for the occurrence rate of ROP requiring treatment in this cohort was 0.01 to 2.60%. Conclusion Our results suggest that the occurrence rates of ROP requiring treatment in infants with gestational age 30 or more weeks and birth weight less than 1,500 grams is very low, and could indicate the need to revise examination guidelines for this subgroup of infants.

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