Fluid Therapy and Cerebral Injury in Pediatric Diabetic Ketoacidosis

描述(申请人提供)：脑水肿是儿童糖尿病酮症酸中毒(DKA)最常见和最可怕的严重并发症。此外，在患有常见慢性病的脆弱儿科人群中，它是最重要的死亡原因。在儿童DKA发作中，大约1%会出现明显的症状性脑水肿，但最近的数据表明，轻度甚至明显无症状的脑水肿发生得更频繁，可能发生在大多数DKA儿童中。此外，最近的试验数据表明，即使表面上不复杂的DKA也可能导致轻微的脑损伤和长期的神经认知改变。液体疗法治疗DKA与脑损伤和脑水肿的风险之间的关系还不是很清楚，几十年来一直存在争议。一些研究人员认为，脑水肿可能是由于快速注射静脉输液导致血清渗透压迅速下降和渗透调节的细胞肿胀所致。然而，我们小组的最新数据表明，DKA可能与脑血流量的显著减少有关，DKA相关的脑水肿可能更类似于中风或其他缺氧/缺血性脑损伤引起的脑水肿，而不是渗透压介导的水肿。一些研究人员主张以较慢的速度输注静脉输液，以避免迅速的渗透变化。相反，如果脑水肿与脑低灌注有关，则更快地输液可能是有益的，从而更快地恢复正常的脑血流量。由于缺乏研究液体治疗方案与脑水肿风险之间关系的前瞻性、适当的对照研究，目前在美国各地使用的儿科DKA治疗方案存在很大差异。在拟议的项目中，我们旨在研究不同的DKA输液方案对几种神经结局的影响，包括在DKA治疗期间精神状态下降的风险(在以前的研究中与脑水肿相关)、风险显性、症状性脑水肿和长期神经认知功能。我们计划利用儿科急救应用研究网络(PECARN)的资源，利用析因设计对DKA治疗的四种液体方案(不同的速率和钠含量)进行一项大型随机对照试验。患有DKA的儿童将被随机分配到四种方案中的一种。DKA治疗期间的精神状态将每小时进行一次评估，并记录精神状态下降的频率、临床表现的频率、症状性脑水肿和其他DKA并发症的频率。儿童将在DKA事件发生三个月后返回进行进一步评估，以评估记忆功能和智商。输液速度和输液的钠含量对短期和长期神经损伤风险的影响将被确定。通过PECARN网络进行这项研究的独特机会将使我们能够招募必要的大样本(&gt；1500名患有DKA的儿童)，以使用严格的、前瞻性的标准化方法回答这一重要的临床问题。 公共卫生相关性：患有糖尿病的儿童可能发展为一种危及生命的疾病--糖尿病酮症酸中毒(DKA)。大多数由DKA引起的死亡与DKA治疗期间的脑肿胀(脑水肿)有关，最近的数据表明，即使在DKA中存活下来的儿童表面上没有并发症，也可能有轻微的脑损伤，这可能导致学习和记忆问题。DKA治疗是否导致或导致脑水肿尚不清楚，我们也不知道一种治疗方案是否比其他治疗方案更安全。在这项拟议的研究中，我们计划比较四种不同的DKA治疗方案，以确定哪种方案导致的脑损伤风险最低。

DESCRIPTION (provided by applicant): Cerebral edema is the most frequent and most feared serious complication of diabetic ketoacidosis (DKA) in children. Furthermore, it is the most important cause of death in this vulnerable pediatric population with a common chronic illness. Overt, symptomatic cerebral edema occurs in approximately 1% of pediatric DKA episodes, but recent data suggest that mild, or even apparently asymptomatic, cerebral edema occurs more frequently, likely in most children with DKA. Furthermore, recent pilot data suggest that even apparently uncomplicated DKA may result in subtle cerebral injury and long-term neurocognitive alterations. The relationship of fluid therapy for DKA and risk of cerebral injury and cerebral edema is not well understood and has been debated for decades. Some investigators have suggested that cerebral edema might be caused by rapid administration of intravenous fluids resulting in a rapid decline in serum osmolality and osmotically-mediated cell swelling. Recent data from our group, however, suggest that DKA may be associated with substantial reductions in cerebral blood flow and that DKA-related cerebral edema may be more similar to cerebral edema resulting from stroke or other hypoxic/ischemic cerebral injuries than to osmotically-mediated edema. Slower infusion of intravenous fluids has been advocated by some investigators, with the goal of avoiding rapid osmotic change. Conversely, more rapid infusion of fluids may be beneficial if cerebral edema is related to cerebral hypo-perfusion, resulting in more rapid restoration of normal cerebral blood flow. Because of the lack of prospective, appropriately controlled studies investigating the relationship between fluid treatment protocols and risk of cerebral edema, substantial variation exists in currently-used pediatric DKA treatment protocols across the United States. In the proposed project, we aim to study the effects of variations in fluid infusion protocols for DKA on several neurological outcomes including the risk of mental status declines during DKA treatment (which have been associated with cerebral edema in previous studies), the risk overt, symptomatic cerebral edema, and long- term neurocognitive function. We plan to utilize the resources of the Pediatric Emergency Care Applied Research Network (PECARN) to conduct a large, randomized controlled trial comparing four fluid protocols (differing in rate and sodium content) for DKA treatment using a factorial design. Children presenting with DKA will be randomly assigned to one of the four protocols. Mental status during DKA treatment will be assessed hourly and the frequency of declines in mental status, frequency of overt, symptomatic cerebral edema and frequency of other DKA complications will be recorded. Children will return for further evaluation three months after the DKA episode to assess memory function and IQ. The effects of both fluid infusion rate and sodium content of infused fluids on risks of both short term and long term neurological injury will be determined. The unique opportunity to conduct this study through the PECARN network will allow us to enroll the large sample size (>1500 children with DKA) necessary to answer this important clinical question using rigorous, prospective standardized methods. PUBLIC HEALTH RELEVANCE: Children with diabetes may develop a life-threatening condition, diabetic ketoacidosis (DKA). Most deaths caused by DKA are related to swelling of the brain (cerebral edema) during DKA treatment, and recent data indicates that even children who survive DKA apparently without complications may have subtle brain injuries which may result in learning and memory problems. Whether DKA treatment causes or contributes to cerebral edema is not known, nor do we know whether one treatment regimen is safer than others. In the proposed study, we plan to compare four different DKA treatment regimens to determine which regimen results in the least risk of brain injury.