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

过度水化可改善产志贺毒素大肠杆菌感染儿童的肾脏预后 (HIKO STEC)：一项跨国、嵌入式、集群、交叉、随机试验

• 批准号: 10328703
• 负责人: Stephen Bradley Freedman
• 金额: $ 152.04万
• 依托单位: UNIVERSITY OF CALGARY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328703
• 关键词: 5 year old; Accident and Emergency department; Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Adverse event; Ambulatory Care; Anti-Inflammatory Agents; Antibiotics; Azotemia; Binding; Biological; Blood; Blood Vessels; Blood Volume; Canada; Caring; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Child Health; Chronic Kidney Failure; Clinical; Clinical Data; Cohort Studies; Complication; Consequentialism; Cross-Over Trials; Data; Dehydration; Diabetes Mellitus; Diagnosis; Diagnostic; Diarrhea; Disease; Enrollment; Enteral; Epidemiology; Escherichia coli EHEC; Escherichia coli Infections; Etiology; Event; Evidence based treatment; Extravasation; Feces; Fluid overload; Grant; Hematocrit procedure; Hemolytic Anemia; Hemolytic-Uremic Syndrome; Hypertension; IV Fluid; Infection; Injury to Kidney; Intervention; Intervention Trial; Kidney; Kidney Failure; Life; Link; Liquid substance; Mediating; Medical; Meta-Analysis; Metagenomics; Molecular; Morbidity - disease rate; Narcotics; National Institute of Allergy and Infectious Disease; Outcome; Patients; Phenotype; Prevalence; Prognostic Marker; Proteomics; Protocols documentation; Proxy; Randomized; Renal Replacement Therapy; Renal function; Research; Risk; Safety; Secondary to; Serious Adverse Event; Severities; Shiga Toxin; Site; Survivors; Technology; Testing; Therapeutic; Thrombocytopenia; Time; Treatment Protocols; United States; Urine; Work; adverse event monitoring; base; biobank; clinical care; clinical practice; combat; design; disability; effectiveness evaluation; experience; high risk; improved; improved outcome; insight; mortality; open label; outcome prediction; pathogen genomics; predictive marker; prevent; randomized trial; renal damage; targeted biomarker; therapeutic target; thrombotic; transcriptomics; vascular injury

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.

项目摘要 溶血性尿毒症综合征（HUS）是产生高风险志贺毒素的最严重并发症 大肠杆菌（STEC）感染和最常见的急性肾脏损伤原因 健康的孩子。 HUS在STEC感染后最多有20％的儿童发展，其中60％需要 临时肾脏替代疗法（RRT）；另外50％的人产生了严重的外部并发症。 尽管急性HUS的死亡率很低（1-3％），但它一直恒定了三十年，并且 大约30％ 高血压和糖尿病。只有三个相对较小的随机试验可以防止 建立HUS后，进展为HUS和/或减少肾脏损伤；没有人表现出好处， 自1999年以来，没有进行过。 最近的队列研究表明，在受感染的STEC中，早期血管内体积扩张（高水分） 如果发生HUS，儿童可能会受到肾脏保护。但是，需要更多证据 高水分取代传统的“等待和看到”（即保守的流体管理）反应性护理 专注于门诊护理并最大程度地减少静脉输液以避免液体的方法 发展HUS的孩子的超负荷。在这里，我们将确认或反驳积极的假设 在STEC感染的儿童早期进行管理的数量扩展与更好的肾脏结局有关 通过完成三个具体目标，比保守管理要少的不利事件：（1）确定 高氢化物在将主要不良肾脏事件的患病率降低30方面的有效性 在感染的天数（定义为死亡，RRT或肾功能的持续损失） 儿童与保守的流体管理； （2）确定的有效性和安全性 降低HUS和威胁生命的，感染性的肾外并发症的过度水合 儿童与保守的流体管理； （3）创建将链接到我们的生物座席 临床数据以识别受感染儿童的预后生物标志物和治疗靶标。到 完成这些目标，我们将进行嵌入的，开放标签的，群集随机的跨界优势 在26个紧急部门的审判。参加美国和加拿大的参与地点将是 随机分配给协议实施的顺序（高水分或保守的流体管理） 在这项两次间隔的两次干预试验中，在NIAID R34赠款的支持下开发了。设计， 快速分子肠诊断促进，克服了研究这种挑战疾病的许多障碍 并通过将干预措施嵌入常规临床护理中来最大化潜在的治疗益处。如果我们 确认我们的假设，该项目将提供有效实施的第一个因果证据 感染高危儿童的干预措施。