Hyperhydration to Improve Kidney Outcomes in Children with Shiga Toxin-Producing E. Coli Infection (HIKO STEC): A Multinational, Embedded, Cluster, Crossover, Randomized Trial

项目摘要 溶血性尿毒综合征（hemolytic uremic syndrome，HUS）是高危型滋贺毒素产生菌最严重的并发症 大肠杆菌（STEC）感染是获得性急性肾损伤的最常见原因， 健康儿童高达20%的儿童在感染STEC后发生HUS，其中60%需要 临时肾脏替代治疗（RRT）;另外50%发生严重的肾外并发症。 虽然急性溶血性尿毒综合征的死亡率很低（1-3%），但三十年来一直保持不变， 大约30%的HUS幸存者经历长期后遗症，主要是慢性肾病， 高血压和糖尿病。只有三个相对较小的随机试验， 一旦HUS建立，进展为HUS和/或减少肾损伤;没有一个显示出益处， 自1999年以来就没有进行过。 最近的队列研究表明，STEC感染者的早期血管内容量扩张（水化过度） 如果发生HUS，儿童可能具有肾保护作用。然而，在此之前， 过度水合取代了传统的“观望”（即，保守性液体管理）反应性护理 这些方法侧重于门诊护理，并最大限度地减少静脉输液，以避免液体 超负荷的儿童谁做开发HUS。在这里，我们将证实或反驳的假设，侵略性 在STEC感染的儿童中，早期给予容量扩张与更好的肾脏结局相关， 通过实现三个具体目标，比保守治疗减少不良事件：（1）确定 过度水化在降低主要肾脏不良事件发生率方面的有效性， 在STEC感染的患者中，持续30天（定义为死亡、RRT或30天时肾功能持续丧失） 儿童与保守性液体管理;（2）确定 在STEC感染者中，水化过度可减少HUS和危及生命的肾外并发症 儿童与保守的液体管理;（3）创建一个生物储存库，将与我们的 临床数据，以确定STEC感染儿童的预后生物标志物和治疗靶点。到 为了实现这些目标，我们将进行一项嵌入式、开放标签、随机分组交叉优效性研究 在26个急诊科试用。位于美国和加拿大的参与研究中心将 随机分配至方案实施顺序（过度水合或保守液体管理） 在NIAID R34资助的支持下开发的这项两间隔、两干预试验中。设计， 通过快速分子肠道诊断的促进，克服了研究这种具有挑战性的疾病的许多障碍， 并通过将干预嵌入到常规临床护理中来最大化潜在的治疗益处。如果我们 证实我们的假设，这个项目将提供有效的，实施准备的第一个因果证据 对感染高危STEC的儿童进行干预。

Project Summary The hemolytic uremic syndrome (HUS) is the most serious complication of high-risk Shiga toxin-producing Escherichia coli (STEC) infection and the most common cause of acquired acute kidney injury in otherwise healthy children. HUS develops in up to 20% of children following STEC infection, 60% of whom require temporary renal replacement therapy (RRT); an additional 50% develop serious extrarenal complications. Although mortality from acute HUS is low (1-3%), it has remained constant for three decades and approximately 30% of HUS survivors experience long-term sequelae, chiefly chronic kidney disease, hypertension, and diabetes. There have been only three relatively small, randomized trials to prevent progression to HUS and/or to reduce kidney injury once HUS is established; none have demonstrated benefits, and none have been performed since 1999. Recent cohort studies suggest that early intravascular volume expansion (hyperhydration) in STEC infected children could be nephroprotective if and when HUS occurs. However, more evidence is needed before hyperhydration supplants traditional ‘wait and see’ (i.e., conservative fluid management) reactive care approaches which focus on outpatient care and minimizing intravenous fluid administration to avoid fluid overload in children who do develop HUS. Here, we will confirm or refute the hypothesis that aggressive volume expansion, administered early in STEC infected children, is associated with better renal outcomes and fewer adverse events than conservative management by accomplishing three Specific Aims: (1) Determine the effectiveness of hyperhydration in decreasing the prevalence of Major Adverse Kidney Events by 30 days (defined as death, RRT, or sustained loss of kidney function at 30 days) in STEC-infected children versus conservative fluid management; (2) Determine the effectiveness and safety of hyperhydration in decreasing HUS and life-threatening, extrarenal complications in STEC-infected children versus conservative fluid management; (3) Create a biorepository that will be linked to our clinical data to identify prognostic biomarkers and therapeutic targets in STEC-infected children. To accomplish these Aims, we will conduct an embedded, open-label, cluster-randomized crossover superiority trial in 26 emergency departments. Participating sites, located in the United States and Canada, will be randomly allocated to the order of protocol implementation (hyperhydration or conservative fluid management) in this two-interval, two-intervention trial, developed with the support of an NIAID R34 grant. The design, facilitated by rapid molecular enteric diagnostics, overcomes many barriers to studying this challenging disease and maximizes the potential therapeutic benefits by embedding the intervention into routine clinical care. If we confirm our hypothesis, this project will provide the first causal evidence of an effective, implementation-ready intervention for children infected with high-risk STEC.