Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis

Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis

Sponsors

Lead Sponsor: Children's Hospital of Philadelphia

Collaborator: Boston Children's Hospital
Children's Healthcare of Atlanta
Children's Hospital Colorado
Children's Hospital Los Angeles
University of Pittsburgh
Morgan Stanley Children's Hospital
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
Alberta Children's Hospital
M.D. Anderson Cancer Center

Source Children's Hospital of Philadelphia
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.

Overall Status Recruiting
Start Date 2020-08-25
Completion Date 2025-06-30
Primary Completion Date 2025-05-31
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
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.
Secondary Outcome
Measure Time Frame
Proportion of participants with persistent kidney dysfunction Censored at 30 days
Proportion of participants with new inpatient renal replacement therapy Censored at 30 days
Hospital-free days alive between randomization and day 27 With 27 days of randomization
Proportion of participants with all-cause hospital mortality Hospital discharge-censored at 90 days
Proportion of participants with all-cause mortality at 90 days 90 days
Proportion of participants with hyperlactatemia Within 4 calendar days of randomization
Proportion of participants with hyperkalemia Within 4 calendar days of randomization
Proportion of participants with hypercalcemia Within 4 calendar days of randomization
Proportion of participants with hypernatremia Within 4 calendar days of randomization
Proportion of participants with hyponatremia Within 4 calendar days of randomization
Proportion of participants with hyperchloremia Within 4 calendar days of randomization
Proportion of participants with catheter thrombosis Within 4 calendar days of randomization
Proportion of participants with brain herniation Within 4 calendar days of randomization
Proportion of participants with thromboembolism Within 7 calendar days of randomization
Enrollment 8800
Condition
Intervention

Intervention Type: Drug

Intervention Name: Lactated Ringer

Description: 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).

Arm Group Label: Balanced fluids (BF)

Other Name: LR

Intervention Type: Drug

Intervention Name: Normal Saline

Description: Normal saline solution is an "unbalanced" crystalloid solution containing 154 mEq/L of sodium and 154 milliequivalent (mEq/L) of chloride.

Arm Group Label: 0.9% "Normal" Saline Fluid (NS)

Intervention Type: Drug

Intervention Name: Plasma-lyte

Description: 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).

Arm Group Label: Balanced fluids (BF)

Other Name: PL

Eligibility

Criteria:

Inclusion Criteria: 1. Males or females age >6 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/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, 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.

Gender:

All

Minimum Age:

6 Months

Maximum Age:

17 Years

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Fran Balamuth, MD PhD MSCE Principal Investigator Attending Physician, Emergency Department
Overall Contact

Last Name: Scott L Weiss, MD MSCE

Phone: 215-590-5505

Email: [email protected]

Location
Facility: Status: Contact: Contact Backup: The Children's Hospital of Philadelphia Fran Balamuth, MD PhD MSCE 215-590-7295 [email protected]
Location Countries

United States

Verification Date

2021-07-01

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Children's Hospital of Philadelphia

Investigator Full Name: Scott Weiss

Investigator Title: Principal Investigator

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Balanced fluids (BF)

Type: Experimental

Description: Balanced fluids (BF), including Lactated Ringer's and PlasmaLyte, will be administered to patients randomized to the experimental arm. BF will be used for all fluid boluses and maintenance fluids (supplemental electrolytes are allowed) from time immediately after randomization through 11:59 pm of the next calendar day. The determination of when to give fluid, how much fluid to give, how fast to give fluid, and what access to use to administer fluid will remain at the discretion of the treating team.

Label: 0.9% "Normal" Saline Fluid (NS)

Type: Active Comparator

Description: 0.9% "normal" saline (NS) fluid will be administered to patients randomized to the active comparator (control) arm. NS will be used for all fluid boluses and maintenance fluids (supplemental electrolytes are allowed) from time immediately after randomization through 11:59 pm of the next calendar day. The determination of when to give fluid, how much fluid to give, how fast to give fluid, and what access to use to administer fluid will remain at the discretion of the treating team.

Acronym PRoMPT BOLUS
Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Intervention Model Description: Multi-center, open-label, randomized pragmatic comparative effectiveness trial.

Primary Purpose: Treatment

Masking: None (Open Label)

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