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

在英国，出生期间短暂的氧气和血液供应不足导致的脑损伤会导致大约1-2名出生的婴儿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预后，但现在越来越多的证据表明，温和降温可能是一种有效的保护性治疗。此外，新的研究表明，HI后立即发生的脑碱中毒会对大脑造成损害，轻度酸中毒和防止碱性过激可以减少大脑损伤。阿米洛利是一种用于治疗患者水分失衡的药物，它可以维持轻微的脑酸中毒，防止碱性超标。我们建议研究两个问题：(1)神经保护的最适温度是多少？中度和重度HI侮辱的最适温度是否相同？我们将比较复苏后2-26小时延迟的全身降温与33oC或35oC。(2)缺氧缺血后立即给予阿米洛利是否减轻了脑损伤的程度，当同时应用低温时，这种影响是否增加？我们将使用一个典型的脑损伤实验动物模型，并比较48小时内大脑能量水平和死亡细胞数量的变化。这些结果将指导降温和另一种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人需求量身定做。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.