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)是高危志贺毒素产生的最严重的并发症 大肠埃希菌(STEC)感染和获得性急性肾损伤的最常见原因 健康的孩子。高达20%的儿童在感染STEC后发生HUS，其中60%的儿童需要 临时肾脏替代疗法(RRT)；另外50%会出现严重的肾外并发症。 尽管急性HUS的死亡率很低(1-3%)，但三十年来一直保持不变， 大约30%的HUS幸存者会经历长期的后遗症，主要是慢性肾脏疾病， 高血压和糖尿病。只有三个相对较小的随机试验可以预防 一旦HUS建立，进展到HUS和/或减少肾脏损伤；没有显示出益处， 自1999年以来，没有一次表演过。 最近的队列研究表明，STEC感染的早期血管内容量扩张(高水合) 如果和当HUS发生时，儿童可以保护肾脏。然而，在此之前还需要更多的证据 高水合作用取代了传统的“观望”(即保守的液体管理)反应性护理 侧重于门诊护理和尽量减少静脉输液以避免输液的方法 确实患有HU的儿童超负荷。在这里，我们将证实或驳斥攻击性的假设 在感染STEC的儿童中早期给予容量扩张与更好的肾脏结果和 通过实现三个具体目标比保守治疗减少不良事件：(1)确定 高水合作用将主要不良肾脏事件的发生率降低30% STEC感染的天数(定义为死亡、RRT或持续30天的肾功能丧失) 儿童与保守液体管理；(2)确定以下治疗的有效性和安全性 高水合作用降低STEC感染患者的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 确定STEC感染儿童预后生物标志物和治疗靶点的临床数据。至 为了实现这些目标，我们将进行嵌入式、开放标签、集群随机交叉优势 在26个急诊科试行。位于美国和加拿大的参与地点将是 按方案实施顺序随机分配(超水化或保守液体管理) 在这项由NIAID R34拨款支持下进行的两次间隔、两次干预试验中。这个设计， 在快速分子肠道诊断的帮助下，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，这个项目将提供第一个有效的因果证据，为实施做好准备 对感染高危STEC的儿童进行干预。