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

在英国，每1000名婴儿中约有1-2名因出生时短暂缺氧和供血不足而导致脑损伤，导致死亡或严重永久性残疾，这是世界各地儿童残疾的主要原因。直到最近，还没有证据表明出生后给予的治疗可以改善结果，但现在越来越多的证据表明，轻度冷却可能是一种有效的保护性治疗。此外，新的研究表明，HI后立即发生的脑水肿会损害大脑，轻度酸中毒和预防碱性过冲可减少脑损伤。阿米洛利是一种用于治疗患者水分失衡的药物，可维持轻度脑酸中毒并防止碱性过冲。我们拟研究两个问题：（1）神经保护的最佳温度是多少？中度和重度HI损伤的最佳温度是否相同？我们将在复苏后2-26小时内将延迟全身冷却与33 ℃或35 ℃进行比较。(2)HI后立即给予阿米洛利是否能减少脑损伤的程度？当同时应用低温时，这种效果是否是累加的？将使用表征良好的脑损伤实验动物模型，并将比较脑能量水平的变化和48小时时死亡的细胞数量。这些结果将指导冷却和其他神经保护疗法在新生儿中的临床应用，确保以最有效的方式应用治疗，并根据每个患者的个体需求进行定制。将这项研究的结果转化为临床环境可能会改善全球大量婴儿的神经发育结果。

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.