Shock, Septic
Conditions
Keywords
Sepsis, Septic Shock, Fluid resuscitation, Saline, Balanced Fluid, Mortality, Crystalloid, PlasmaLyte, Lactated Ringer's, Kidney injury
Brief summary
The objectives of this multicenter pragmatic clinical trial are to compare the effectiveness and relative safety of balanced fluid resuscitation versus 0.9% "normal" saline in children with septic shock, including whether balanced fluid resuscitation can reduce progression of kidney injury.
Detailed description
Approximately 5,000 children die from septic shock each year in the United States (US); thousands more die worldwide. Most children admitted with sepsis receive initial resuscitation in an emergency department (ED), where septic shock remains one of the most critical of illnesses treated by ED clinicians. Sepsis is also the most expensive hospital condition in the US, and the most common cause of pediatric multiple organ dysfunction syndrome (MODS). While all crystalloid fluids help to reverse shock, the most effective and safest type of crystalloid fluid resuscitation is unknown. Crystalloid fluids can be categorized as non-buffered (most commonly 0.9% normal saline \[NS\]) or buffered/balanced fluids (BF). In the US, the most common BF is lactated Ringer's (LR), but other example include PlasmaLyte. NS and BF are inexpensive, stable at room temperature, and nearly universally available with identical storage volumes and dosing strategies. Notably, both are also of proven clinical benefit in septic shock and have extensive clinical experience for use in fluid resuscitation of critically ill patients. However, despite data suggesting that BF resuscitation may have superior efficacy and safety, NS remains the most commonly used fluid largely based on historical precedent. To definitively test the comparative effectiveness of NS and BF, a well-powered randomized controlled trial (RCT) is necessary. A large pragmatic randomized trial embedded within everyday clinical practice provides a cost-efficient and generalizable approach to inform clinicians about best comparative effectiveness of common therapies. Data from a prior single-center feasibility study demonstrated that a pragmatic randomized clinical trial of NS versus BF for children with septic shock presenting to an emergency department is feasible and can be successfully carried out by embedding simple study procedures within routine clinical practice. This multi-center study that will now test for differential clinical effects, as part of a definitive comparative effectiveness trial, of NS versus BF for crystalloid resuscitation of pediatric septic shock. This multicenter phase trial will include enrollment and study procedures across 30+ US and international sites to compare the effectiveness and relative safety of NS versus BF (LR and PlasmaLyte) for crystalloid resuscitation of children with septic shock. The primary endpoint is major adverse kidney events within 30 days along with other secondary clinical, safety, and kidney biomarker endpoints.
Interventions
DRUGLactated Ringer
LR is a sterile, nonpyrogenic "balanced" solution used for fluid and electrolyte replenishment via intravenous or intraosseous administration. Each 100 mL of LR contains 600 mg sodium chloride (NaCl), 310 mg of sodium lactate (C3H5NaO3), 30 mg of potassium chloride (KCl), and 20 mg of calcium chloride (CaCl2 · 2H20) with an approximate potential of hydrogen (pH) of 6.5 (6.0 to 7.5).
DRUGNormal Saline
Normal saline solution is an "unbalanced" crystalloid solution containing 154 mEq/L of sodium and 154 milliequivalent (mEq/L) of chloride.
DRUGPlasma-lyte
PL is a sterile, nonpyrogenic isotonic solution in a single dose container for intravenous administration. Each 100 mL contains 526 mg of Sodium Chloride, USP (NaCl); 502 mg of Sodium Gluconate (C6H11NaO7); 368 mg of Sodium Acetate Trihydrate, USP (C2H3NaO2•3H2O); 37 mg of Potassium Chloride, USP (KCl); and 30 mg of Magnesium Chloride, USP (MgCl2•6H2O). It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide. The pH is 7.4 (6.5 to 8.0).
Sponsors
Children's Hospital of Philadelphia
Boston Children's Hospital
Children's Healthcare of Atlanta
Children's Hospital Colorado
Children's Hospital Los Angeles
University of Pittsburgh
Children's Hospital and Health System Foundation, Wisconsin
Children's Medical Center Dallas
Children's National Research Institute
Children's Hospital Medical Center, Cincinnati
Hasbro Children's Hospital
Ann & Robert H Lurie Children's Hospital of Chicago
Nationwide Children's Hospital
Primary Children's Hospital
Seattle Children's Hospital
St. Louis Children's Hospital
Baylor College of Medicine
University of California, Davis
University of California, San Francisco
University of Michigan
Kidz First Hospital Middlemore
Gold Coast Hospital and Health Service
Queensland Children's Hospital
Westmead Children's Hospital
Sydney Children's Hospitals Network
Perth Children's Hospital
Starship Children's Hospital
Monash Children's Hospital
Women's and Children's Hospital, Australia
Royal Children's Hospital
Royal Darwin Hospital
Virginia Commonwealth University
Alberta Children's Hospital
British Columbia Children's Hospital
Centre Hospitalier Univeritaire Sainte Justine
Centre Hospitalier Universitaire de Quebec
Children's Hospital of Eastern Ontario
The Hospital for Sick Children
IWK Health Centre
Jim Pattison Children's Hospital
Kingston Health Sciences Centre
London Health Sciences Centre
McMaster Children's Hospital
Stollery Children's Hospital
The Children's Hospital of Winnipeg
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Pennsylvania Department of Health
Townsville University Hospital
Hospital nacional de niños Costa Rica
Morgan Stanley Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Multi-center, open-label, randomized pragmatic comparative effectiveness trial.
Eligibility
Sex/Gender
ALL
Age
2 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Males or females age \>2 months to \<18 years 2. Clinician concern for septic shock, operationalized as: 1. a "positive" ED sepsis alert confirmed by a physician OR 2. physician decision to treat for septic shock OR 3. a physician diagnosis of septic shock requiring parenteral antibiotics and fluid resuscitation 3. Administration of at least one IV/Intraosseous (IO) fluid bolus for resuscitation and additional fluid deemed likely to be necessary to treat poor perfusion, or clinician judgment that \>1 fluid bolus is highly likely to be required. Poor perfusion is defined as physician's judgement of hypotension or abnormal (either "flash" or "prolonged") capillary refill. 4. Receipt of ≤40 mL/kg IV/IO total crystalloid fluid prior to randomization 5. Parental/guardian permission (informed consent) if time permits; otherwise, Exception from informed consent (EFIC) criteria met
Exclusion criteria
1. Treating physician judges that patient's condition deems it unsafe to administer either NS or BF (since patients will be equally likely to receive NS or BF at time of study enrollment), including: 1. Clinical suspicion for impending brain herniation 2. Known hyperkalemia, defined as non-hemolyzed whole blood or plasma/serum potassium \> 6 mEq/L, based on data available at or before patient meets criteria for study enrollment 3. Known hypercalcemia, defined as plasma/serum total calcium \>12 mg/dL or whole blood ionized calcium \>1.35 mmol/L, based on data available at or before patient meets criteria for study enrollment 4. Known acute fulminant hepatic failure, defined as plasma/serum alanine aminotransferase (ALT) \>10,000 U/L or total bilirubin \>12.0 mg/dL, based on data available at or before patient meets criteria for study enrollment 5. Known history of severe hepatic impairment, defined as cirrhosis, "liver failure", or awaiting transplant 6. Known history of severe renal impairment, defined as peritoneal dialysis or hemodialysis 7. Known metabolic/mitochondrial disorder, inborn error of metabolism, or primary mineralocorticoid deficiency as reported by participant, legally authorized representative (LAR) or accompanying caregiver, or as listed in the medical record 8. Other concern for which the treating clinician deems it unsafe to administer either NS or LR 2. Known pregnancy determined by routine history disclosed by patient and/or accompanying acquaintance. 3. Known prisoner 4. Known allergy to a crystalloid fluid 5. Indication of declined consent to participate based on presence of an opt-out bracelet with appropriate messaging embossed into the bracelet, the presence of the patient's name on an opt-out list that will be kept up-to-date and checked prior to randomization, or verbal "opt-out" prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with Major Adverse Kidney Events within 30 days (MAKE30) | Between randomization and 30 days post enrollment, discharge or death, whichever comes first. | A composite of death, initiation of new inpatient renal replacement therapy (RRT), or persistent kidney dysfunction, at 30 days following study enrollment or hospital discharge, whichever comes first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with persistent kidney dysfunction | Censored at 30 days | Final creatinine greater than or equal to 200% of baseline and a minimum absolute increase of greater than or equal to 0.3 mg/dL |
| Proportion of participants with new inpatient renal replacement therapy | Censored at 30 days | Treatment with any renal replacement therapy that was not a continuation of pre-hospital chronic therapy |
| Hospital-free days alive between randomization and day 27 | With 27 days of randomization | Calendar days alive and out of the hospital between day of randomization and study day 27 |
| Proportion of participants with all-cause hospital mortality | Hospital discharge-censored at 90 days | Vital status at hospital discharge |
| Proportion of participants with all-cause mortality at 90 days | 90 days | Vital status from medical chart and/or data from National Death Index |
| Proportion of participants with hyperlactatemia | Within 4 calendar days of randomization | At least 1 venous or arterial blood lactate measurement \>4mmol/L |
| Proportion of participants with hyperkalemia | Within 4 calendar days of randomization | At least 1 venous or arterial blood potassium measurement \>6 milliequivalents/Liter (mEq/L) (without hemolysis) |
| Proportion of participants with hypercalcemia | Within 4 calendar days of randomization | At least 1 venous or arterial blood ionized calcium measurement of \>1.35 mEq/L or total calcium \>12 mEq/L |
| Proportion of participants with hypernatremia | Within 4 calendar days of randomization | At least 1 venous, arterial or capillary blood sodium measurement of \>155 mEq/L |
| Proportion of participants with hyponatremia | Within 4 calendar days of randomization | At least 1 venous, arterial or capillary blood sodium measurement of \<128 mEq/L |
| Proportion of participants with hyperchloremia | Within 4 calendar days of randomization | At least 1 venous, arterial or capillary blood chloride measurement of \>110 mEq/L |
| Proportion of participants with catheter thrombosis | Within 4 calendar days of randomization | Catheter thrombosis in participants given Ceftriaxone and BF? (not LR?) |
| Proportion of participants with brain herniation | Within 4 calendar days of randomization | Treatment with hyperosmolar therapy (as long as a clinical diagnosis of brain herniation is not disproven by radiographic studies) |
| Proportion of participants with thromboembolism | Within 7 calendar days of randomization | Therapy for thromboembolism |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORFran Balamuth, MD PhD MSCE
Attending Physician, Emergency Department
Outcome results
None listed