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: 10490868
• 负责人: Stephen Bradley Freedman
• 金额: $ 147.28万
• 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/10490868
• 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; long-term sequelae; 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.

项目概要 溶血性尿毒症综合征（HUS）是高危志贺毒素产生最严重的并发症 大肠杆菌 (STEC) 感染和其他情况下获得性急性肾损伤的最常见原因 健康儿童中，高达 20% 的儿童在感染 STEC 后会出现 HUS，其中 60% 需要进行治疗。 临时肾脏替代治疗 (RRT)；另外 50% 出现严重的肾外并发症。 尽管急性 HUS 的死亡率较低（1-3%），但三十年来一直保持稳定，并且 大约 30% 的 HUS 幸存者会出现长期后遗症，主要是慢性肾病、 只有三项相对较小的随机试验可以预防高血压和糖尿病。 进展为 HUS 和/或在 HUS 建立后减少肾损伤；没有一个已被证明有益处； 自 1999 年以来，再没有进行过此类活动。 最近的队列研究表明，STEC 感染者早期血管内容量扩张（过度水合） 如果发生 HUS，儿童可能具有肾保护作用，但在此之前还需要更多证据。 过度水合取代了传统的“观望”（即保守的液体管理）反应性护理 侧重于门诊护理并尽量减少静脉输液以避免输液的方法 在此，我们将证实或反驳攻击性假设。 STEC 感染儿童早期进行扩容治疗与更好的肾脏结局相关，并且 通过实现三个具体目标，比保守治疗更少的不良事件：(1) 确定 过度水合可有效将主要肾脏不良事件的发生率降低 30 STEC 感染者的天数（定义为死亡、RRT 或 30 天肾功能持续丧失） (2) 确定儿童与保守液体管理的有效性和安全性； 水合过多可减少 STEC 感染者的 HUS 和危及生命的肾外并发症 (3) 创建一个将链接到我们的生物存储库 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。 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 试验将在位于美国和加拿大的 26 个急诊科进行。 随机分配方案实施顺序（水合过多或保守液体管理） 在这项由 NIAID R34 拨款支持下开发的两个间隔、两次干预试验中， 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 并将干预措施纳入常规临床护理中，从而最大限度地提高潜在的治疗效果。 证实我们的假设，该项目将提供第一个有效的、可实施的因果证据 对感染高危 STEC 的儿童进行干预。