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%的速度发生在确诊糖尿病儿童中。脑水肿（CE）是儿童DKA最常见的严重并发症，发生在1-5%的DKA发作中。CE的死亡率很高（20-90%），是儿童中最常见的糖尿病相关死亡原因。DKA相关CE的生理机制尚不清楚。我们小组以前的研究表明，CE风险最大的儿童是那些存在严重脱水和严重低碳酸血症的儿童。将这些风险因素确定为与CE最密切相关的风险因素表明，中枢神经系统灌注不足可能是CE发病机制中的一个重要因素。我们小组在DKA儿童和DKA动物模型中的初步研究支持以下假设：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）的NaCl和水分泌过多。我们假设，（1）DKA导致刺激BBB转运NaCl和水，（2）阻断NaCl转运的药理学干预将减少DKA期间的水肿形成，（3）快速恢复脑灌注的药理学干预将导致与DKA相关的脑代谢异常更快地正常化。在目前的建议中，我们的目的是确定两种干预措施，布美他尼（一种特定的抑制剂，NaCl运输的血脑屏障），甘露醇（渗透剂，增强脑灌注）预防或改善CE的DKA和这些药物是否改善脑代谢异常与DKA。我们计划在DKA儿童和DKA动物模型中进行平行研究，以比较药物干预（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。在人体和动物研究中，我们将使用磁共振（MR）成像方法（质子和磷酸盐MR波谱、弥散加权成像和灌注加权成像）来研究这些干预措施。初步动物研究将提供关于预防或改善DKA儿童CE的最佳治疗方案的信息。这些初始动物数据将构成DKA儿童CE预防干预措施的随机临床试验的基础，这将是本研究的主要重点。

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.