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

NCT ID: NCT05219110

Last Updated: 2025-06-05

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

1040 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-09-29

Study Completion Date

2027-08-31

Brief Summary

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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

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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.

Conditions

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Shiga Toxin-Producing Escherichia Coli (E. Coli) Infection Hemolytic-Uremic Syndrome

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Cluster crossover
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Hyperhydration

In this study arm, all eligible children are admitted for the administration of intravenous fluids.

The following specifics will form the basis of the fluid management protocol:

1. Reversal of dehydration: Initial ED rehydration strategies should focus on rapidly reversing dehydration.
2. Infusion of 200% of maintenance fluids x 24 hours
3. If hematocrit reduction \< 20% from initial value, repeat step #2 \[infusion of 200% maintenance fluids x 24 hours\].
4. Oral fluids permitted ad lib.
5. Once the target hematocrit reduction is achieved (20% decrement in initial HCT) AND a 10% weight gain, adjust total IV fluid volume to maintain targeted weight gain: insensible plus output (i.e., urine plus stool).

Group Type EXPERIMENTAL

Infusion of 200% maintenance fluids as balanced crystalloid IV solution

Intervention Type OTHER

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.

Conservative Fluid Management

The conservative fluid management arm has been designed to align and integrate into existing local practice patterns. Implementation of this approach will allow institutions and their practitioners to choose their management of protocol eligible children. All children will undergo a protocolized baseline evaluation that includes reversal of dehydration (if present) and follow-up plan (see Pre-Pathway care). The fluid management decision in the ED (i.e., to treat dehydration) will be at the discretion of the clinical care team. In the absence of evidence of microangiopathy (i.e., normal urinalysis, LDH, hemoglobin and platelet counts, and creatinine concentrations), the decision to admit the child to hospital or discharge the child to home will be at the discretion of the clinical care team. If microangiopathy is present (i.e., abnormal urinalysis, LDH, hemoglobin or platelet counts, or creatinine concentrations) admission for monitoring will be required.

Group Type ACTIVE_COMPARATOR

Oral fluids; infusion of up to 110% maintenance fluids as balanced crystalloid IV solution

Intervention Type OTHER

Administration of less than or equal to 110% of maintenance fluids as oral or balanced crystalloid IV solution.

Interventions

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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.

Intervention Type 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.

Intervention Type OTHER

Eligibility Criteria

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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

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)

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.
Minimum Eligible Age

9 Months

Maximum Eligible Age

21 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role collaborator

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role collaborator

Washington University School of Medicine

OTHER

Sponsor Role collaborator

University of Utah

OTHER

Sponsor Role collaborator

Seattle Children's Hospital

OTHER

Sponsor Role collaborator

University of Colorado, Denver

OTHER

Sponsor Role collaborator

Emory University

OTHER

Sponsor Role collaborator

University of California, Davis

OTHER

Sponsor Role collaborator

Baylor College of Medicine

OTHER

Sponsor Role collaborator

Indiana University School of Medicine

OTHER

Sponsor Role collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role collaborator

Arkansas Children's Hospital Research Institute

OTHER

Sponsor Role collaborator

Children's National Research Institute

OTHER

Sponsor Role collaborator

Children's Hospitals and Clinics of Minnesota

OTHER

Sponsor Role collaborator

Medical University of South Carolina

OTHER

Sponsor Role collaborator

University of Louisville

OTHER

Sponsor Role collaborator

University of Oklahoma

OTHER

Sponsor Role collaborator

Oregon Health and Science University

OTHER

Sponsor Role collaborator

University of California, San Diego

OTHER

Sponsor Role collaborator

McMaster University

OTHER

Sponsor Role collaborator

The Hospital for Sick Children

OTHER

Sponsor Role collaborator

University of Alberta

OTHER

Sponsor Role collaborator

University of Kentucky

OTHER

Sponsor Role collaborator

Case Western Reserve University

OTHER

Sponsor Role collaborator

Nationwide Children's Hospital

OTHER

Sponsor Role collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role collaborator

University of Calgary

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Stephen Freedman, MDCM

Role: PRINCIPAL_INVESTIGATOR

University of Calgary

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status RECRUITING

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Site Status RECRUITING

University of California, San Diego

La Jolla, California, United States

Site Status RECRUITING

University of California, Davis

Sacramento, California, United States

Site Status RECRUITING

University of Colorado Denver

Denver, Colorado, United States

Site Status RECRUITING

Children's Research Institute

Washington D.C., District of Columbia, United States

Site Status RECRUITING

Emory University

Atlanta, Georgia, United States

Site Status RECRUITING

Indiana University Children's Hospital

Indianapolis, Indiana, United States

Site Status RECRUITING

University of Kentucky

Lexington, Kentucky, United States

Site Status RECRUITING

Norton Children's Hospital

Louisville, Kentucky, United States

Site Status RECRUITING

Children's Minnesota Hospital

Minneapolis, Minnesota, United States

Site Status RECRUITING

Washington University

St Louis, Missouri, United States

Site Status RECRUITING

Children's Hospital Medical Center

Cincinnati, Ohio, United States

Site Status RECRUITING

University Hospitals Rainbow Babies & Children's Hospital

Cleveland, Ohio, United States

Site Status RECRUITING

Nationwide Children's Hospital

Columbus, Ohio, United States

Site Status RECRUITING

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Site Status RECRUITING

Oregon Health & Science University

Portland, Oregon, United States

Site Status RECRUITING

Medical University of South Carolina

Charleston, South Carolina, United States

Site Status RECRUITING

Vanderbilt Children's Hospital

Nashville, Tennessee, United States

Site Status RECRUITING

Baylor College of Medicine

Houston, Texas, United States

Site Status RECRUITING

University of Utah

Salt Lake City, Utah, United States

Site Status RECRUITING

Seattle Children's Hospital

Seattle, Washington, United States

Site Status RECRUITING

Alberta Children's Hospital

Calgary, Alberta, Canada

Site Status RECRUITING

University of Alberta

Edmonton, Alberta, Canada

Site Status RECRUITING

McMaster University

Hamilton, Ontario, Canada

Site Status RECRUITING

The Hospital for Sick Children

Toronto, Ontario, Canada

Site Status RECRUITING

Countries

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United States Canada

Central Contacts

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Study Manager

Role: CONTACT

(801) 581-6410

References

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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.

Reference Type DERIVED
PMID: 40277027 (View on PubMed)

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 randomized trial (the HIKO STEC trial). Trials. 2023 May 27;24(1):359. doi: 10.1186/s13063-023-07379-w.

Reference Type DERIVED
PMID: 37245030 (View on PubMed)

Other Identifiers

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R01AI165327

Identifier Type: NIH

Identifier Source: secondary_id

View Link

DMID 21-0042

Identifier Type: -

Identifier Source: org_study_id

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