Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis (PRoMPT BOLUS)

Children's Hospital of Philadelphia (CHOP)

Status and phase: Active, not recruiting; Phase 3

Conditions: Septic; Shock

Treatments: Drug: Plasma-lyte; Drug: Normal Saline; Drug: Lactated Ringer

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT04102371

R01HD101528 (U.S. NIH Grant/Contract)

19-016484

Details and patient eligibility

About

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.

Full 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.

Enrollment: 8,800 estimated patients

Sex: All

Ages: 2 months to 17 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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8,800 participants in 2 patient groups

Balanced fluids (BF)

Experimental group

Description:

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.

Treatment:

Drug: Lactated Ringer

Drug: Plasma-lyte

0.9% "Normal" Saline Fluid (NS)

Active Comparator group

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.

Treatment:

Drug: Normal Saline