Defining the optimal temperature for newborn hypothermic neuroprotection and effect of sodium/proton exchanger blockade

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Brain damage due to a transient shortage of oxygen and blood supply during birth leads to death or severe permanent disability in around 1-2 per 1000 infants born in the UK, and is a major cause of childhood disability around the world. Until recently no treatment given after birth has been shown to improve the outcome, but evidence is now accumulating that mild cooling may be an effective protective treatment. In addition, new research suggests that the brain alkalosis that occurs immediately after HI is damaging to the brain and that mild acidosis and prevention of the alkaline overshoot reduces brain damage. Amiloride, a drug used to treat water imbalance in patients, maintains mild brain acidosis and prevents the alkaline overshoot. We propose to study 2 questions: (1) What is the optimal temperature for neuroprotection and is it the same for moderate and severe HI insults? We will compare delayed whole body cooling to either 33oC or 35oC from 2-26 hours after resuscitation. (2) Does amiloride administered immediately after HI reduce the extent of brain injury and is this effect additive when hypothermia is also applied? A well-characterised experimental animal model of brain injury will be used and the changes in brain energy levels and number of cells dying at 48 hours will be compared. These results will guide the clinical application of cooling and one other neuroprotective therapy in newborn infants, ensuring that treatment is applied in the most effective manner and tailored to the individual needs of each patient. Translating the results from this study to the clinical setting is likely to improve neurodevelopmental outcome in a large number of infants worldwide.