Hyperhydration in Children With Shiga Toxin-Producing E. Coli Infection (HIKO-STEC)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Hemolytic-Uremic Syndrome; Shiga Toxin-Producing Escherichia Coli (E. Coli) Infection
• Intervention / Treatment: Other: Infusion of 200% maintenance fluids as balanced crystalloid IV solution; Other: Oral fluids; infusion of up to 110% maintenance fluids as balanced crystalloid IV solution

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 Type: Interventional
• Enrollment (Estimated): 1040
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Study Manager; Phone Number: (801) 581-6410; Email: hikostec@hsc.utah.edu

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 1N4
      • Recruiting
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T5J 4P6
      • Recruiting
      • University of Alberta
  • Ontario
    • Hamilton, Ontario, Canada, L8S 4K1
      • Recruiting
      • McMaster University
    • Toronto, Ontario, Canada, M5G 1X8
      • Recruiting
      • The Hospital for Sick Children
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • University of Alabama at Birmingham
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Recruiting
      • Arkansas Children's Hospital
  • California
    • La Jolla, California, United States, 92093
      • Recruiting
      • University of California, San Diego
    • Sacramento, California, United States, 95817
      • Recruiting
      • University of California, Davis
  • Colorado
    • Denver, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Denver
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Recruiting
      • Children's Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 47401
      • Recruiting
      • Indiana University Children's Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40526
      • Recruiting
      • University Of Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • Norton Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Recruiting
      • Children's Minnesota Hospital
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Recruiting
      • Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • University Hospitals Rainbow Babies & Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health & Science University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 43205
      • Recruiting
      • Vanderbilt Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • University of Utah
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 months to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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: Reversal of dehydration: Initial ED rehydration strategies should focus on rapidly reversing dehydration.; Infusion of 200% of maintenance fluids x 24 hours; If hematocrit reduction < 20% from initial value, repeat step #2 [infusion of 200% maintenance fluids x 24 hours].; Oral fluids permitted ad lib.; 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).	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.
Active Comparator: 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.	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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Significant Extrarenal Complications (life-threatening):	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	30 days
Number of Participants who Develop HUS among those without it at randomization	Anemia (hematocrit level <30%) AND; Thrombocytopenia (platelet count <150 X 103/mm3) AND; Renal azotemia (serum creatinine concentration >upper limit of reference range for age)	30 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of Stay	Number of days as an inpatient; Number of days in an intensive care unit (a unit capable of providing mechanical ventilation); Hospital-Free Days: Measured as the number of calendar days alive and out of the hospital between randomization (day 0) and day 30. Patients who die prior to hospital discharge will be recorded as zero hospital-free days.; Score each hospital day# days with HUS with RRT# days with HUS without RRT# days in hospital - no HUS	30 days
Number of Participants who Receive Transfusion Therapy	Red Blood Cell; Platelets	30 days
Number of Participants who Receive Invasive Medical Procedures	Mechanical ventilation; Endotracheal intubation; Thoracentesis, thoracotomy, ARDS; Central venous catheter insertion; Dialysis catheter insertion; Therapeutic plasma exchange; Other operative room surgical interventions	30 days

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Medical University of South Carolina; University of Colorado, Denver; The Hospital for Sick Children; National Institute of Allergy and Infectious Diseases (NIAID); Baylor College of Medicine; Washington University School of Medicine; University of California, San Diego; University of Alabama at Birmingham; University of Oklahoma; Emory University; University of Alberta; University of California, Davis; Oregon Health and Science University; Seattle Children's Hospital; McMaster University; Vanderbilt University Medical Center; Nationwide Children's Hospital; Children's Hospital Medical Center, Cincinnati; University of Utah; Indiana University; Children's National Research Institute; University of Kentucky; Children's Hospitals and Clinics of Minnesota; Case Western Reserve University; University of Louisville; Arkansas Children's Hospital Research Institute
• Investigators: Principal Investigator: Stephen Freedman, MDCM, University of Calgary

Publications and helpful links

General 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2022
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2028

Study Registration Dates

• First Submitted: January 20, 2022
• First Submitted That Met QC Criteria: January 20, 2022
• First Posted (Actual): February 1, 2022

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Child; Emergency Department; Acute Kidney Injury; Renal Replacement Therapy; Ambulatory Care; Shiga-Toxigenic Escherichia coli; Hemolytic Uremic Syndrome
• Additional Relevant MeSH Terms: Urogenital Diseases; Cytopenia; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Hematologic Diseases; Renal Insufficiency; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Anemia, Hemolytic; Anemia; Blood Platelet Disorders; Thrombotic Microangiopathies; Enterobacteriaceae Infections; Thrombocytopenia; Uremia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Emergencies; Acute Kidney Injury; Infections; Escherichia coli Infections; Hemolytic-Uremic Syndrome; Therapeutics; Drug Therapy; Fluid Therapy
• Other Study ID Numbers: DMID 21-0042; R01AI165327 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No