Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis

Conditions
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Shock, Septic

Intervention / Treatment
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* Drug: Lactated Ringer
* Drug: Normal Saline
* Drug: Plasma-lyte


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females age >2 months to <18 years Clinician concern for septic shock, operationalized as: a positive ED sepsis alert confirmed by a physician OR physician decision to treat for septic shock OR a physician diagnosis of septic shock requiring parenteral antibiotics and fluid resuscitation 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. Receipt of ≤40 mL/kg IV/IO total crystalloid fluid prior to randomization Parental/guardian permission (informed consent) if time permits; otherwise, Exception from informed consent (EFIC) criteria met Exclusion Criteria: 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: Clinical suspicion for impending brain herniation 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 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 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 Known history of severe hepatic impairment, defined as cirrhosis, liver failure, or awaiting transplant Known history of severe renal impairment, defined as peritoneal dialysis or hemodialysis 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 Other concern for which the treating clinician deems it unsafe to administer either NS or LR Known pregnancy determined by routine history disclosed by patient and/or accompanying acquaintance. Known prisoner Known allergy to a crystalloid fluid 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.

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multi-center, open-label, randomized pragmatic comparative effectiveness trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Balanced fluids (BF)<br>Balanced fluids (BF), including Lactated Ringer's and Plasma-Lyte (PL), 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. | Drug: Lactated Ringer<br>* 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).<br>* Other names: LR;Drug: Plasma-lyte<br>* 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).<br>* Other names: PL;|
| Active Comparator: 0.9% Normal Saline Fluid (NS)<br>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. | Drug: Normal Saline<br>* Normal saline solution is an unbalanced crystalloid solution containing 154 mEq/L of sodium and 154 milliequivalent (mEq/L) of chloride.<br>* Other names: NS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with Major Adverse Kidney Events within 30 days (MAKE30) | 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. | Between randomization and 30 days post enrollment, discharge or death, whichever comes first. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with persistent kidney dysfunction | 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 | Censored at 30 days | 
| Proportion of participants with new inpatient renal replacement therapy | Treatment with any renal replacement therapy that was not a continuation of pre-hospital chronic therapy | Censored at 30 days | 
| Hospital-free days alive between randomization and day 27 | Calendar days alive and out of the hospital between day of randomization and study day 27 | With 27 days of randomization | 
| Proportion of participants with all-cause hospital mortality | Vital status at hospital discharge | Hospital discharge-censored at 90 days | 
| Proportion of participants with all-cause mortality at 90 days | Vital status from medical chart and/or data from National Death Index | 90 days | 
| Proportion of participants with hyperlactatemia | At least 1 venous or arterial blood lactate measurement >4mmol/L | Within 4 calendar days of randomization | 
| Proportion of participants with hyperkalemia | At least 1 venous or arterial blood potassium measurement >6 milliequivalents/Liter (mEq/L) (without hemolysis) | Within 4 calendar days of randomization | 
| Proportion of participants with hypercalcemia | At least 1 venous or arterial blood ionized calcium measurement of >1.35 mEq/L or total calcium >12 mEq/L | Within 4 calendar days of randomization | 
| Proportion of participants with hypernatremia | At least 1 venous, arterial or capillary blood sodium measurement of >155 mEq/L | Within 4 calendar days of randomization | 
| Proportion of participants with hyponatremia | At least 1 venous, arterial or capillary blood sodium measurement of <128 mEq/L | Within 4 calendar days of randomization | 
| Proportion of participants with hyperchloremia | At least 1 venous, arterial or capillary blood chloride measurement of >110 mEq/L | Within 4 calendar days of randomization | 
| Proportion of participants with catheter thrombosis | Catheter thrombosis in participants given Ceftriaxone and BF? (not LR?) | Within 4 calendar days of randomization | 
| Proportion of participants with brain herniation | Treatment with hyperosmolar therapy (as long as a clinical diagnosis of brain herniation is not disproven by radiographic studies) | Within 4 calendar days of randomization | 
| Proportion of participants with thromboembolism | Therapy for thromboembolism | Within 7 calendar days of randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Septic Shock, Fluid resuscitation, Saline, Balanced Fluid, Mortality, Crystalloid, PlasmaLyte, Lactated Ringer's, Kidney injury