Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis
Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis
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.
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.
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.