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

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.

Study Overview

• Status: Recruiting
• Conditions: Shock; Septic
• Intervention / Treatment: Drug: Lactated Ringer; Drug: Plasma-lyte; Drug: Normal Saline

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.

• Study Type: Interventional
• Enrollment (Estimated): 8800
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Fran L Balamuth, MD PhD MSCE; Phone Number: 215-590-7295; Email: BalamuthF@chop.edu
• Study Contact Backup: Name: Weiss Scott, MD MSCE; Phone Number: 800-416-4441; Email: scott.weiss@nemours.org

Study Locations

• United States
  • California
    • Davis, California, United States, 95616
      • Recruiting
      • UC Davis: University of California, Davis
      • Contact: Cheryl Vance, MD; Email: cpvance@ucdavis.edu
      • Contact: Nathan Kupperman, MD; Email: nkuppermann@ucdavis.edu
    • Los Angeles, California, United States, 90027
      • Recruiting
      • CHLA: Children's Hospital Los Angeles
      • Contact: Ara Festekjian, MD; Email: afestekjian@chla.usc.edu
    • San Francisco, California, United States, 94143
      • Not yet recruiting
      • UCSF Benioff Children's Hospital
      • Contact: Karim Mansour, MD; Email: Karim.Mansour@ucsf.edu
  • Colorado
    • Denver, Colorado, United States, 80204
      • Recruiting
      • Children's Colorado: University of Colorado
      • Contact: Lilliam Ambroggio, PhD; Email: lilliam.ambroggio@cuanschutz.edu
  • Georgia
    • Emory, Georgia, United States, 30322
      • Recruiting
      • Children's Hospital of Atlanta
      • Contact: Claudia Morris, MD; Email: Claudia.r.morris@emory.edu
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Lurie Children's: Ann & Robert H. Lurie Children's Hospital of Chicago
      • Contact: Elizabeth Alpern, MD; Email: EAlpern@luriechildrens.org
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Matt Eisenberg, MD; Email: Matthew.Eisenberg@childrens.harvard.edu
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • CS Mott Children's Hospital
      • Contact: Alex Rogers, MD; Email: alexroge@umich.edu
      • Contact: Allison Cator, MD; Email: acator@med.umich.edu
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Recruiting
      • Washington University
      • Contact: Lindsay Clukies, MD; Email: lindsayedavidson@wustl.edu
  • New York
    • New York, New York, United States, 10016
      • Withdrawn
      • NYU Langone
    • New York, New York, United States, 10065-4870
      • Recruiting
      • Columbia: New York-Presbyterian Hospital
      • Contact: Maria Kwok, MD; Email: myk2102@cumc.columbia.edu
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Michelle Eckerle, MD; Email: Michelle.Eckerle@cchmc.org
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Julia Lloyd, MD; Email: Julia.Lloyd@nationwidechildrens.org
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • The Children's Hospital of Philadelphia
      • Contact: Fran Balamuth, MD PhD MSCE; Phone Number: 215-590-7295; Email: balamuthf@chop.edu
      • Contact: Scott Weiss, MD MSCE; Phone Number: 800-416-4441; Email: scott.weiss@nemours.org
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • Children's Hospital of Pittsburgh
      • Contact: Bob Hickey, MD; Email: robert.hickey@chp.edu
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Recruiting
      • Hasbro Children's Hospital
      • Contact: Susan Duffy, MD; Email: SDuffy@Lifespan.org
  • Texas
    • Dallas, Texas, United States, 75235
      • Recruiting
      • Dallas Children's: Children's Medical Center Dallas/UT southwestern
      • Contact: Mohamed Badawy, MD; Email: Mohamed.Badawy@UTSouthwestern.edu
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital
      • Contact: Julie McManemy, MD; Email: jkmcmane@texaschildrens.org
    • Houston, Texas, United States, 77030
      • Withdrawn
      • Universtity of Texas MD Anderson
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Recruiting
      • Primary Children's: University of Utah
      • Contact: Roni Lane, MD; Email: roni.lane@hsc.utah.edu
  • Virginia
    • Richmond, Virginia, United States, 23284
      • Not yet recruiting
      • Children's Hospital of Richmond at VCU
      • Contact: Nikki Miller Ferguson, MD; Email: nikki.millerferguson@vcuhealth.org
  • Washington
    • Columbia, Washington, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: Ioannis Koutroulis, MD; Email: IKOUTROULI@childrensnational.org
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: Neil Uspal, MD; Email: neil.uspal@seattlechildrens.org
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Milwaukee (MCW): Medical College of Wisconsin
      • Contact: Shannon Baumer-Mouradian, MD; Email: sbaumer@mcw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 0.9% "Normal" Saline Fluid (NS); 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; Normal saline solution is an "unbalanced" crystalloid solution containing 154 mEq/L of sodium and 154 milliequivalent (mEq/L) of chloride.; Other Names: 0.9% Saline; NS
Experimental: Balanced fluids (BF); 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; 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).; Other Names: LR; Drug: Plasma-lyte; 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).; Other Names: PL

What is the study measuring?

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 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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney biomarkers measured from blood and urine samples	Urine neutrophil gelatinase-associated lipocalin (NGAL), urine NGAL/Ucr ratio, Kidney injury molecule (KIM-1), KIM-1/ Ucr ratio, Liver-type fatty acid binding protein (L-FBP), L-FBP/ Ucr ratio, Interleukin (IL-18), IL-18/ Ucr ratio, and plasma cystatin C measured on study day 2 and on day 27 (or prior to anticipated discharge or death, whichever comes first).	Day 2 and Day 27, prior to anticipated discharge or death, whichever comes first.

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: M.D. Anderson Cancer Center; The Hospital for Sick Children; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Baylor College of Medicine; University of Pittsburgh; University of Michigan; Children's Hospital Colorado; Boston Children's Hospital; University of California, Davis; Seattle Children's Hospital; University of California, San Francisco; Ann & Robert H Lurie Children's Hospital of Chicago; Nationwide Children's Hospital; Children's Hospital Medical Center, Cincinnati; Queen's University; Virginia Commonwealth University; Children's National Research Institute; London Health Sciences Centre; Children's Hospital of Eastern Ontario; Children's Hospital and Health System Foundation, Wisconsin; Children's Healthcare of Atlanta; Children's Hospital Los Angeles; Morgan Stanley Children's Hospital; Children's Medical Center Dallas; Hasbro Children's Hospital; Primary Children's Hospital; St. Louis Children's Hospital; 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; British Columbia Children's Hospital; Centre Hospitalier Univeritaire Sainte Justine; Centre Hospitalier Universitaire de Quebec; IWK Health Centre; Jim Pattison Children's Hospital; McMaster Children's Hospital; Stollery Children's Hospital; The Children's Hospital of Winnipeg; Pennsylvania Department of Health; Townsville University Hospital; Kingston Health Sciences Centre (Kingston)
• Investigators: Principal Investigator: Fran Balamuth, MD PhD MSCE, Attending Physician, Emergency Department

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• PRoMPT BOLUS website

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2020
• Primary Completion (Estimated): May 31, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: September 23, 2019
• First Submitted That Met QC Criteria: September 23, 2019
• First Posted (Actual): September 25, 2019

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Lactated Ringer's; Septic Shock; Sepsis; Fluid resuscitation; Saline; Balanced Fluid; Mortality; Crystalloid; PlasmaLyte; Kidney injury
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Pharmaceutical Solutions; Ophthalmic Solutions; Plasma-lyte 148
• Other Study ID Numbers: 19-016484; R01HD101528 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Per NIH policy, the PRoMPT BOLUS investigators will provide a de-identified dataset and documentation necessary to utilize the study data (dictionary, calculated variables, and standard operating procedures) to the NIH no later than 3 years after the final 90-day assessment or 2 years after the primary paper has been published, whichever comes first. The investigators will submit this dataset to the National Institute of Child Health and Human Development (NICHD) data repository, Data and Specimen Hub (DASH). In addition, final datasets and statistical analyses will be archived.
• IPD Sharing Time Frame: No later than 3 years after the final 90-day assessment or 2 years after the primary paper has been published, whichever comes first.
• IPD Sharing Access Criteria: Anyone can access NICHD DASH, which is a public website with free access to the scientific research community. All users may browse and view information about studies and data archived in NICHD DASH. Users who are interested in submitting or requesting study data must register for a free account.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No