Hemolytic-Uremic Syndrome, Shiga Toxin-Producing Escherichia Coli (E. Coli) Infection
Conditions
Keywords
Child, Hemolytic Uremic Syndrome, Shiga-Toxigenic Escherichia coli, Renal Replacement Therapy, Acute Kidney Injury, Ambulatory Care, Emergency Department
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.
Interventions
OTHERInfusion 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.
OTHEROral 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.
Sponsors
University of Calgary
National Institute of Allergy and Infectious Diseases (NIAID)
Children's Hospital Medical Center, Cincinnati
Washington University School of Medicine
University of Utah
Seattle Children's Hospital
University of Colorado, Denver
Emory University
University of California, Davis
Baylor College of Medicine
Indiana University
University of Alabama at Birmingham
Arkansas Children's Hospital Research Institute
Children's National Research Institute
Children's Hospitals and Clinics of Minnesota
Medical University of South Carolina
University of Louisville
University of Oklahoma
Oregon Health and Science University
University of California, San Diego
McMaster University
The Hospital for Sick Children
University of Alberta
University of Kentucky
Case Western Reserve University
Nationwide Children's Hospital
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Cluster crossover
Eligibility
Sex/Gender
ALL
Age
9 Months to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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) |
Countries
Canada, United States
Contacts
CONTACTStudy Manager
PRINCIPAL_INVESTIGATORStephen Freedman, MDCM
University of Calgary
Outcome results
None listed