Hyperhydration in Children With Shiga Toxin-Producing E. Coli Infection

Not Applicable

Recruiting

• Conditions: Shiga Toxin-Producing Escherichia Coli (E. Coli) Infection; Hemolytic-Uremic Syndrome

• Registration Number: NCT05219110
• Lead Sponsor: University of Calgary

Brief Summary

The objective of this study is to determine if early high volume intravenous fluid administration (hyperhydration) may be effective in mitigating or preventing complications of shiga toxin-producing E. coli (STEC) infection in children and adolescents when compared with traditional approaches (conservative fluid management).

Detailed Description

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.

Study Timeline

• Study First Submitted: 2022-01-20
• Study First Submitted QC: 2022-01-20
• Study First Posted: 2022-02-01
• Study Start: 2022-09-29
• Status Verified: 2024-12
• Last Update Submitted: 2025-06-02
• Last Update Posted: 2025-06-05
• Primary Completion: 2026-08-31
• Study Completion: 2027-08-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1040

Inclusion Criteria

In order to be eligible to participate in this study (i.e., to be enrolled in the relevant institutional clinical care pathway), an individual must meet all of the following criteria:

1. Aged 9.0 months to <21 years at the time of informed consent.

2. Evidence of high-risk STEC infecting pathogen defined by any of the following:

   1. Bloody diarrhea within the preceding 7 days

      • Positive STEC culture OR
      • Positive antigen/polymerase chain reaction test for toxin/gene type not otherwise specified OR

   2. Bloody or Non-bloody diarrhea within the preceding 7 days

      •Presumptive diagnosis of HUS

      • (meeting all 3 HUS criteria - anemia, thrombocytopenia, and renal insufficiency) OR

   3. Non-bloody or no diarrhea

      • Positive STEC culture for high-risk strain (i.e., O103, O104, O111, O113, O121, O145 or O157) OR
      • Positive antigen/polymerase chain reaction test Stx2 toxin/gene

Exclusion Criteria

All individuals meeting any of the exclusion criteria at baseline will be excluded from study participation.

1. Presence of Advanced HUS defined by:

   1. Hematocrit <30% AND

   2. Platelet count <150 x 103/mm3 AND

   3. Creatinine > 2.0 mg/dL (177 µmol/L)

      • The presence of only 1 or 2 of these criteria will not result in patient exclusion, regardless of how close the 3rd criterion is to meeting the exclusion criteria.

2. Prior episode of HUS or diagnosis of atypical HUS.

3. Chronic disease limiting fluid volumes administered (e.g. impaired renal, liver, or cardiac function, chronic lung disease).

4. Evidence of anuria (i.e., no urine output for > 24 hours).

5. Hypoxemia requiring oxygen therapy

6. Hypertensive emergency

7. Greater than or equal to 10 days since onset of diarrhea or if no diarrhea then the onset of other symptoms.

8. Patients with known pregnancy

9. Patients or caregivers with language barriers impairing appropriate conduct of the study protocol.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Primary Outcome Measures

Name	Time	Method
Major Adverse Kidney Events by 30 days (MAKE30)	30 days	1. Death due to any cause censored at 30 days after enrollment OR; 2. Provision of RRT, any modality, within 30 days of trial enrollment OR; 3. Sustained loss of kidney function (100% increase of serum sCr from baseline at 30±7 days)

Secondary Outcome Measures

Name	Time	Method
Number of Participants who Develop HUS among those without it at randomization	30 days	1. Anemia (hematocrit level \<30%) AND; 2. Thrombocytopenia (platelet count \<150 X 103/mm3) AND; 3. Renal azotemia (serum creatinine concentration \>upper limit of reference range for age)
Number of Participants with Significant Extrarenal Complications (life-threatening):	30 days	a. Neurologic: i. Seizures requiring anticonvulsant therapy ii. Coma iii. Thrombotic or hemorrhagic stroke confirmed by neuroimaging b. Cardiac: i. Myocardial infarction ii. Myocarditis iii. Myocardial dysfunction iv. Arrhythmias requiring cardioversion or pharmacological anti-arrhythmic therapy c. Respiratory: i. Respiratory failure ii. Pleural effusions d. Gastrointestinal: i. Hyperglycemia requiring prolonged insulin therapy ii. Bowel obstruction/perforation requiring surgical repair iii. Intussusception requiring reduction iv. Acute cholecystitis v. Pancreatitis vi. Hepatitis/ liver failure vii. Ascites requiring paracentesis e. Infectious complications i. Bacteremia ii. Peritonitis

Trial Locations

Locations (26)

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Arkansas Children's Hospital; 🇺🇸 Little Rock, Arkansas, United States

University of California, San Diego; 🇺🇸 La Jolla, California, United States

University of California, Davis; 🇺🇸 Sacramento, California, United States

University of Colorado Denver; 🇺🇸 Denver, Colorado, United States

Children's Research Institute; 🇺🇸 Washington, District of Columbia, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

Indiana University Children's Hospital; 🇺🇸 Indianapolis, Indiana, United States

University of Kentucky; 🇺🇸 Lexington, Kentucky, United States

Norton Children's Hospital; 🇺🇸 Louisville, Kentucky, United States

Scroll for more (16 remaining)