Clinical trial NCT04102371: Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis
Official title: Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Shock
Septic
Keywords: Sepsis
Septic Shock
Fluid resuscitation
Saline
Balanced Fluid
Mortality
Crystalloid
PlasmaLyte
Lactated Ringer's
Kidney injury
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: Boston Children's Hospital
name: Children's Healthcare of Atlanta
name: Children's Hospital Colorado
name: Children's Hospital Los Angeles
name: University of Pittsburgh
name: Morgan Stanley Children's Hospital
name: Children's Hospital and Health System Foundation, Wisconsin
name: Children's Medical Center Dallas
name: Children's National Research Institute
name: Children's Hospital Medical Center, Cincinnati
name: Hasbro Children's Hospital
name: Ann & Robert H Lurie Children's Hospital of Chicago
name: Nationwide Children's Hospital
name: Primary Children's Hospital
name: Seattle Children's Hospital
name: St. Louis Children's Hospital
name: Baylor College of Medicine
name: University of California, Davis
name: University of California, San Francisco
name: University of Michigan
name: Kidz First Hospital Middlemore
name: Gold Coast Hospital and Health Service
name: Queensland Children's Hospital
name: Westmead Children's Hospital
name: Sydney Children's Hospitals Network
name: Perth Children's Hospital
name: Starship Children's Hospital
name: Monash Children's Hospital
name: Women's and Children's Hospital, Australia
name: Royal Children's Hospital
name: Royal Darwin Hospital
name: M.D. Anderson Cancer Center
name: Virginia Commonwealth University
name: Alberta Children's Hospital
name: British Columbia Children's Hospital
name: Centre Hospitalier Univeritaire Sainte Justine
name: Centre Hospitalier Universitaire de Quebec
name: Children's Hospital of Eastern Ontario
name: The Hospital for Sick Children
name: IWK Health Centre
name: Jim Pattison Children's Hospital
name: Queen's University
name: London Health Sciences Centre
name: McMaster Children's Hospital
name: Stollery Children's Hospital
name: The Children's Hospital of Winnipeg
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Pennsylvania Department of Health
name: Townsville University Hospital
name: Kingston Health Sciences Centre
First posted: 2019-09-25
Enrollment: 8800
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-center, open-label, randomized pragmatic comparative effectiveness trial.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of participants with Major Adverse Kidney Events within 30 days (MAKE30)
timeFrame: Between randomization and 30 days post enrollment, discharge or death, whichever comes first.
Secondary outcomes:
measure: Proportion of participants with persistent kidney dysfunction
timeFrame: Censored at 30 days
measure: Proportion of participants with new inpatient renal replacement therapy
timeFrame: Censored at 30 days
measure: Hospital-free days alive between randomization and day 27
timeFrame: With 27 days of randomization
measure: Proportion of participants with all-cause hospital mortality
timeFrame: Hospital discharge-censored at 90 days
measure: Proportion of participants with all-cause mortality at 90 days
timeFrame: 90 days
measure: Proportion of participants with hyperlactatemia
timeFrame: Within 4 calendar days of randomization
measure: Proportion of participants with hyperkalemia
timeFrame: Within 4 calendar days of randomization
measure: Proportion of participants with hypercalcemia
timeFrame: Within 4 calendar days of randomization
measure: Proportion of participants with hypernatremia
timeFrame: Within 4 calendar days of randomization
measure: Proportion of participants with hyponatremia
timeFrame: Within 4 calendar days of randomization
measure: Proportion of participants with hyperchloremia
timeFrame: Within 4 calendar days of randomization
measure: Proportion of participants with catheter thrombosis
timeFrame: Within 4 calendar days of randomization
measure: Proportion of participants with brain herniation
timeFrame: Within 4 calendar days of randomization
measure: Proportion of participants with thromboembolism
timeFrame: Within 7 calendar days of randomization
Other outcomes:
measure: Kidney biomarkers measured from blood and urine samples
timeFrame: Day 2 and Day 27, prior to anticipated discharge or death, whichever comes first.
Locations:
city: Davis
country: United States
facility: UC Davis: University of California, Davis
state: California
city: Los Angeles
country: United States
facility: CHLA: Children's Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Denver
country: United States
facility: Children's Colorado: University of Colorado
state: Colorado
city: Emory
country: United States
facility: Children's Hospital of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: CS Mott Children's Hospital
state: Michigan
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New York
country: United States
facility: NYU Langone
state: New York
city: New York
country: United States
facility: Columbia: New York-Presbyterian Hospital
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Hasbro Children's Hospital
state: Rhode Island
city: Dallas
country: United States
facility: Dallas Children's: Children's Medical Center Dallas/UT southwestern
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Houston
country: United States
facility: Universtity of Texas MD Anderson
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's: University of Utah
state: Utah
city: Richmond
country: United States
facility: Children's Hospital of Richmond at VCU
state: Virginia
city: Columbia
country: United States
facility: Children's National Medical Center
state: Washington
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Milwaukee (MCW): Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Attending Physician, Emergency Department
name: Fran Balamuth, MD PhD MSCE
role: PRINCIPAL_INVESTIGATOR
References:
citation: Balamuth F, Kittick M, McBride P, Woodford AL, Vestal N, Casper TC, Metheney M, Smith K, Atkin NJ, Baren JM, Dean JM, Kuppermann N, Weiss SL. Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis: The PRoMPT BOLUS Randomized Controlled Trial Pilot Feasibility Study. Acad Emerg Med. 2019 Dec;26(12):1346-1356. doi: 10.1111/acem.13815. Epub 2019 Jul 18.
citation: Weiss SL, Balamuth F, Long E, Thompson GC, Hayes KL, Katcoff H, Cook M, Tsemberis E, Hickey CP, Williams A, Williamson-Urquhart S, Borland ML, Dalziel SR, Gelbart B, Freedman SB, Babl FE, Huang J, Kuppermann N; Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis (PRoMPT BOLUS) Investigators of the PECARN, PERC, and PREDICT Networks. PRagMatic Pediatric Trial of Balanced vs nOrmaL Saline FlUid in Sepsis: study protocol for the PRoMPT BOLUS randomized interventional trial. Trials. 2021 Nov 6;22(1):776. doi: 10.1186/s13063-021-05717-4.