Fluid Therapy and Cerebral Injury in Pediatric Diabetic Ketoacidosis

描述（由申请人提供）：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，它是这个患有常见慢性病的脆弱儿科人群的最重要死因。明显的症状性脑水肿发生在大约1%的儿科DKA发作中，但最近的数据表明，轻度，甚至明显无症状的脑水肿更频繁地发生，可能发生在大多数DKA儿童中。此外，最近的试点数据表明，即使明显不复杂的DKA也可能导致轻微的脑损伤和长期的神经认知改变。DKA的液体治疗与脑损伤和脑水肿风险之间的关系尚未得到充分理解，并且已经争论了几十年。一些研究者认为，脑水肿可能是由于静脉输液快速给药导致血清渗透压迅速下降和动脉介导的细胞肿胀所致。然而，我们小组最近的数据表明，DKA可能与脑血流量的大幅减少有关，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，而不是动脉介导的水肿。一些研究者提倡缓慢输注静脉液体，目的是避免快速渗透压变化。相反，如果脑水肿与脑灌注不足有关，则更快地输注液体可能是有益的，从而更快地恢复正常脑血流。由于缺乏前瞻性、适当对照的研究来调查液体治疗方案与脑水肿风险之间的关系，美国目前使用的儿科DKA治疗方案存在很大差异。在拟定项目中，我们旨在研究DKA输液方案的变化对几种神经学结局的影响，包括DKA治疗期间精神状态下降的风险（在既往研究中与脑水肿相关）、显性风险、症状性脑水肿和长期神经认知功能。我们计划利用儿科急诊应用研究网络（PECARN）的资源进行一项大型随机对照试验，使用析因设计比较DKA治疗的四种液体方案（速率和钠含量不同）。患有DKA的儿童将被随机分配到四种方案之一。将每小时评估DKA治疗期间的精神状态，并记录精神状态下降的频率、明显的症状性脑水肿的频率和其他DKA并发症的频率。儿童将在DKA发作后三个月返回进行进一步评估，以评估记忆功能和智商。将确定液体输注速率和输注液体的钠含量对短期和长期神经损伤风险的影响。通过PECARN网络进行这项研究的独特机会将使我们能够招募大样本量（>1500名DKA儿童），以便使用严格的前瞻性标准化方法回答这一重要的临床问题。

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.