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

Official title

Hyperhydration to Improve Kidney Outcomes in Children With Shiga Toxin-Producing E. Coli Infection: A Multinational Embedded Cluster Crossover Randomized Trial

Overview

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.

Interventions

• Other Infusion of 200% maintenance fluids as balanced crystalloid IV solution
  Infusion of 200% of maintenance fluids x 24 hours provided, ideally, as a balanced crystalloid (PlasmaLyteTM, Ringer's Lactate) IV solution. Electrolytes and dextrose may be administered as required and desired by the clinical care team; customized solutions are permitted if so desired. Intravenous fluid solutions containing \< 130 mEq/L sodium may increase risk for hyponatremia and may be less effective in achieving intravascular volume expansion and should be avoided.
• Other Oral fluids; infusion of up to 110% maintenance fluids as balanced crystalloid IV solution
  Administration of less than or equal to 110% of maintenance fluids as oral or balanced crystalloid IV solution.

Primary outcome measures

• Major Adverse Kidney Events by 30 days (MAKE30) [Time frame: 30 days]

Secondary outcome measures (2)

• Number of Participants with Significant Extrarenal Complications (life-threatening): [Time frame: 30 days]
• Number of Participants who Develop HUS among those without it at randomization [Time frame: 30 days]

Eligibility criteria

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:

• Aged 9.0 months to <21 years at the time of informed consent.
• Evidence of high-risk STEC infecting pathogen defined by any of the following:

• 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
• 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
• 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.

• Presence of Advanced HUS defined by:

• Hematocrit <30% AND
• Platelet count <150 x 103/mm3 AND
• 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.
• Prior episode of HUS or diagnosis of atypical HUS.
• Chronic disease limiting fluid volumes administered (e.g. impaired renal, liver, or cardiac function, chronic lung disease).
• Evidence of anuria (i.e., no urine output for > 24 hours).
• Hypoxemia requiring oxygen therapy
• Hypertensive emergency
• Greater than or equal to 10 days since onset of diarrhea or if no diarrhea then the onset of other symptoms.
• Patients with known pregnancy
• Patients or caregivers with language barriers impairing appropriate conduct of the study protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 22 centers

• University of Alabama at Birmingham — Birmingham
• Arkansas Children's Hospital — Little Rock
• University of California, San Diego — La Jolla
• University of California, Davis — Sacramento
• University of Colorado Denver — Denver
• Children's Research Institute — Washington D.C.
• Emory University — Atlanta
• Indiana University Children's Hospital — Indianapolis
• … and 14 more centers

Canada · 4 centers

• Alberta Children's Hospital — Calgary
• University of Alberta — Edmonton
• McMaster University — Hamilton
• The Hospital for Sick Children — Toronto

Publications

• Imdad A, Nelson JR, Tanner-Smith EE, Huang D, Gomez-Duarte OG. Interventions for preventing diarrhoea-associated haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2025 Apr 25;4(4):CD012997. doi: 10.1002/14651858.CD012997.pub3. PMID 40277027
• Freedman SB, Schnadower D, Estes M, Casper TC, Goldstein SL, Grisaru S, Pavia AT, Wilfond BS, Metheney M, Kimball K, Tarr PI; Hyperhydration to Improve Kidney Outcomes in children with Shiga Toxin-producing E. Coli infection (HIKO-STEC) Study Team. Hyperhydration to Improve Kidney Outcomes in Children with Shiga Toxin-Producing E. coli Infection: a multinational embedded cluster crossover randomiz PMID 37245030

Identifiers

NCT: NCT05219110 · DMID 21-0042 · R01AI165327

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗