Cerebral edema in pediatric ketoacidosis

描述（由申请人提供）：糖尿病酮症酸中毒（DKA）发生在25-40%的新发1型糖尿病儿童中，并以每年约8%的比率发生在已确诊的糖尿病儿童中。脑水肿（CE）是儿童DKA最常见的严重并发症，占DKA发作的1-5%。CE死亡率高（20-90%），是儿童中最常见的与糖尿病相关的死亡原因。dka相关CE的生理机制尚不清楚。我们小组先前的研究表明，CE风险最大的儿童是那些表现出严重脱水和严重低碳酸血症的儿童。这些与CE最密切相关的危险因素表明，中枢神经系统灌注不足可能是CE发病的一个重要因素。本小组对DKA患儿和DKA动物模型的初步研究支持这样的假设，即未经治疗的DKA期间脑灌注不足可能在导致CE中起核心作用，并且在这种情况下可能发生血脑屏障（BBB）高分泌NaCI和水。我们假设；(1) DKA刺激血脑屏障对NaCI和水的运输，(2)阻断NaCI运输的药物干预将减少DKA期间水肿的形成，(3)快速恢复脑灌注的药物干预将导致DKA相关的脑代谢异常更快地正常化。在目前的提案中，我们旨在确定布美他尼（一种通过血脑屏障运输NaCl的特异性抑制剂）和甘露醇（一种增强脑灌注的渗透剂）这两种干预措施是否可以预防或改善DKA中的CE，以及这些药物是否可以改善与DKA相关的脑代谢异常。我们计划在DKA患儿和DKA动物模型中进行平行研究，比较药物干预（布美他尼、甘露醇和地塞米松）对水肿形成、脑灌注和脑代谢的影响。在人类和动物研究中，我们将使用磁共振（MR）成像方法（质子和磷酸盐磁共振光谱，扩散加权成像和灌注加权成像）来研究这些干预措施。初步的动物研究将提供关于预防或改善DKA患儿CE的最佳治疗方案的信息。这一初步的动物数据将为预防DKA患儿CE的干预措施的随机临床试验奠定基础，这将是该研究的主要焦点。

DESCRIPTION (provided by applicant): Diabetic ketoacidosis (DKA) occurs in 25-40% of children with new onset of type 1 diabetes, and occurs in children with established diabetes at a rate of approximately 8% per year. Cerebral edema (CE) is the most common serious complication of DKA in children, occurring in 1-5% of DKA episodes. CE has a high mortality rate (20-90%) and is the most common diabetes-related cause of death in children. The physiological mechanisms responsible for DKA-related CE are not understood. Previous studies by our group demonstrated that children at greatest risk for CE are those who present with greater dehydration and greater hypocapnia. The identification of these risk factors as those most strongly associated with CE suggests that central nervous system hypoperfusion may be an important factor in the pathogenesis of CE. Preliminary studies by our group in children with DKA and in an animal model of DKA support the hypothesis that cerebral hypoperfusion during untreated DKA may play a central role in causing CE and that hypersecretion of NaCI and water by the blood-brain barrier (BBB) may occur in this setting. We hypothesize that; (1) DKA results in stimulation of transport of NaCI and water by the BBB, (2) pharmacological interventions which block NaCI transport will decrease edema formation during DKA, (3) pharmacological interventions which rapidly restore cerebral perfusion will lead to more rapid normalization of cerebral metabolic abnormalities associated with DKA. In the current proposal, we aim to determine whether two interventions, bumetanide (a specific inhibitor of NaCl transport by the BBB), and mannitol (an osmotic agent which enhances cerebral perfusion) prevent or ameliorate CE in DKA and whether these agents improve cerebral metabolic abnormalities associated with DKA. We plan to conduct parallel studies in children with DKA and in an animal model of DKA to compare the effects of pharmacological interventions (bumetanide, mannitol and dexamethasone) on edema formation, cerebral perfusion and cerebral metabolism. In both the human and animal studies, we will use magnetic resonance (MR) imaging methods, (proton and phosphate MR spectroscopy, diffusion weighted imaging and perfusion weighted imaging) to study these interventions. Initial animal studies will provide information regarding the optimal treatment protocol to prevent or ameliorate CE in children with DKA. This initial animal data will form the basis for a randomized clinical trial of interventions for the prevention of CE in children with DKA which will be the main focus of the study.