Fluid Therapy and Cerebral Injury in Pediatric Diabetic Ketoacidosis

小儿糖尿病酮症酸中毒的液体治疗和脑损伤

• 批准号: 8051572
• 负责人: NICOLE S GLASER
• 金额: $ 61.09万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051572
• 关键词: Accident and Emergency department; Advocate; Affect; Agreement; Animal Model; Applied Research; Blood Vessels; Brain Edema; Brain Injuries; Cause of Death; Cells; Cerebral Edema; Cerebrovascular Circulation; Cerebrum; Child; Childhood; Chronic Disease; Chronically Ill; Clinical; Complication; Conduct Clinical Trials; Consensus; Controlled Study; Cytotoxic Cerebral Edema; Data; Development; Diabetes Mellitus; Diabetic Ketoacidosis; Edema; Emergency Care; Enrollment; Evaluation; Fluid Therapy; Frequencies; Fright; Functional disorder; Glasgow Coma Scale; Goals; Hospitals; Hyperemia; Hypoxia; IV Fluid; Infusion procedures; Injury; Insulin-Dependent Diabetes Mellitus; Intelligence quotient; Intracranial Hypertension; Intravenous; Ischemic-Hypoxic Encephalopathy; Learning; Life; Liquid substance; Mediating; Memory; Methods; Minor; Nervous System Trauma; Neurocognitive; Neurologic; Neurological outcome; Neurological status; Osmolalities; Outcome; Perfusion; Play; Population; Practice Management; Protocols documentation; Publishing; Randomized; Randomized Controlled Trials; Regimen; Rehydrations; Reperfusion Therapy; Research Personnel; Resources; Risk; Role; Safety; Sample Size; Serum; Severities; Short-Term Memory; Sodium; Stroke; Swelling; Testing; Tissues; Treatment Protocols; United States; Variant; Vasogenic Cerebral Edema; brain cell; brain tissue; cerebral hypoperfusion; cytotoxic; design; experience; improved; mental state; neuroimaging; patient population; prevent; prospective; public health relevance; randomized trial; restoration; trial comparing

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.

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，最近的试验数据表明，即使是明显不复杂的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救应用研究网络（PECARN）的资源，采用析因设计进行一项大型随机对照试验，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。 公共卫生相关性：糖尿病儿童可能会出现危及生命的疾病，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，即使是DKA明显没有并发症的儿童也可能有轻微的脑损伤，这可能导致学习和记忆问题。DKA治疗是否会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脑损伤的风险最小。

项目成果

Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis.

• DOI: 10.1056/nejmoa1716816
• 发表时间: 2018-06-14
• 期刊: The New England journal of medicine
• 作者: Kuppermann N;Ghetti S;Schunk JE;Stoner MJ;Rewers A;McManemy JK;Myers SR;Nigrovic LE;Garro A;Brown KM;Quayle KS;Trainor JL;Tzimenatos L;Bennett JE;DePiero AD;Kwok MY;Perry CS 3rd;Olsen CS;Casper TC;Dean JM;Glaser NS;PECARN DKA FLUID Study Group
• 通讯作者: PECARN DKA FLUID Study Group

Pediatric diabetic ketoacidosis, fluid therapy, and cerebral injury: the design of a factorial randomized controlled trial.

• DOI: 10.1111/pedi.12027
• 发表时间: 2013-09
• 期刊: Pediatric diabetes
• 影响因子: 3.4
• 作者: Glaser NS;Ghetti S;Casper TC;Dean JM;Kuppermann N;Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study Group
• 通讯作者: Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study Group