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

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ClinicalTrials.gov Identifier: NCT04102371
Recruitment Status : Recruiting
First Posted : September 25, 2019
Last Update Posted : September 16, 2020
Sponsor:
Collaborators:
Boston Children's Hospital
Children's Healthcare of Atlanta
Children's Hospital Colorado
Children's Hospital Los Angeles
University of Pittsburgh
Morgan Stanley Children's Hospital
Children's Hospital and Health System Foundation, Wisconsin
Children's Medical Center Dallas
Children's National Research Institute
Children's Hospital Medical Center, Cincinnati
Hasbro Children's Hospital
Ann & Robert H Lurie Children's Hospital of Chicago
Nationwide Children's Hospital
Primary Children's Hospital
Seattle Children's Hospital
St. Louis Children's Hospital
Baylor College of Medicine
University of California, Davis
University of California, San Francisco
University of Michigan
M.D. Anderson Cancer Center
University of Arkansas
Information provided by (Responsible Party):
Scott Weiss, Children's Hospital of Philadelphia

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.

Condition or disease Intervention/treatment Phase
Shock Septic Drug: Lactated Ringer Drug: Normal Saline Drug: Plasma-lyte Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 8800 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multi-center, open-label, randomized pragmatic comparative effectiveness trial.
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis
Actual Study Start Date : August 25, 2020
Estimated Primary Completion Date : May 31, 2025
Estimated Study Completion Date : June 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis

Arm Intervention/treatment
Experimental: Balanced fluids (BF)
Balanced fluids (BF), including Lactated Ringer's and PlasmaLyte, 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 Name: 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 Name: PL

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




Primary Outcome Measures :
  1. Proportion of participants with Major Adverse Kidney Events within 30 days (MAKE30) [ Time Frame: Between randomization and 30 days post enrollment, discharge or death, whichever comes first. ]
    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.


Secondary Outcome Measures :
  1. Proportion of participants with persistent kidney dysfunction [ Time Frame: Censored at 30 days ]
    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

  2. Proportion of participants with new inpatient renal replacement therapy [ Time Frame: Censored at 30 days ]
    Treatment with any renal replacement therapy that was not a continuation of pre-hospital chronic therapy

  3. Hospital-free days alive between randomization and day 27 [ Time Frame: With 27 days of randomization ]
    Calendar days alive and out of the hospital between day of randomization and study day 27

  4. Proportion of participants with all-cause hospital mortality [ Time Frame: Hospital discharge-censored at 90 days ]
    Vital status at hospital discharge

  5. Proportion of participants with all-cause mortality at 90 days [ Time Frame: 90 days ]
    Vital status from medical chart and/or data from National Death Index

  6. Proportion of participants with hyperlactatemia [ Time Frame: Within 4 calendar days of randomization ]
    At least 1 venous or arterial blood lactate measurement >4mmol/L

  7. Proportion of participants with hyperkalemia [ Time Frame: Within 4 calendar days of randomization ]
    At least 1 venous or arterial blood potassium measurement >6mEq/L (without hemolysis)

  8. Proportion of participants with hypercalcemia [ Time Frame: Within 4 calendar days of randomization ]
    At least 1 venous or arterial blood ionized calcium measurement of >1.35 mEq/L or total calcium >12 mEq/L

  9. Proportion of participants with hypernatremia [ Time Frame: Within 4 calendar days of randomization ]
    At least 1 venous, arterial or capillary blood sodium measurement of >155 mEq/L

  10. Proportion of participants with hyponatremia [ Time Frame: Within 4 calendar days of randomization ]
    At least 1 venous, arterial or capillary blood sodium measurement of <128 mEq/L

  11. Proportion of participants with hyperchloremia [ Time Frame: Within 4 calendar days of randomization ]
    At least 1 venous, arterial or capillary blood chloride measurement of >110 mEq/L

  12. Proportion of participants with catheter thrombosis [ Time Frame: Within 4 calendar days of randomization ]
    Catheter thrombosis in participants given Ceftriaxone and BF? (not LR?)

  13. Proportion of participants with brain herniation [ Time Frame: Within 4 calendar days of randomization ]
    Treatment with hyperosmolar therapy (as long as a clinical diagnosis of brain herniation is not disproven by radiographic studies)

  14. Proportion of participants with thromboembolism [ Time Frame: Within 7 calendar days of randomization ]
    Therapy for thromboembolism


Other Outcome Measures:
  1. Kidney biomarkers measured from blood and urine samples [ Time Frame: Day 2 and Day 27, prior to anticipated discharge or death, whichever comes first. ]
    Urine NGAL, urine NGAL/Ucr ratio, KIM-1, KIM-1/ Ucr ratio, L-FBP, L-FBP/ Ucr ratio, 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04102371


Contacts
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Contact: Scott L Weiss, MD MSCE 215-590-5505 WeissS@email.chop.edu
Contact: Fran Balamuth, MD PhD MSCE 215-590-7295 BalamuthF@email.chop.edu

Locations
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United States, Pennsylvania
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Fran Balamuth, MD PhD MSCE    215-590-7295    balamuthf@email.chop.edu   
Contact: Scott Weiss, MD MSCE    215-590-5505    weissS@email.chop.edu   
Sponsors and Collaborators
Children's Hospital of Philadelphia
Boston Children's Hospital
Children's Healthcare of Atlanta
Children's Hospital Colorado
Children's Hospital Los Angeles
University of Pittsburgh
Morgan Stanley Children's Hospital
Children's Hospital and Health System Foundation, Wisconsin
Children's Medical Center Dallas
Children's National Research Institute
Children's Hospital Medical Center, Cincinnati
Hasbro Children's Hospital
Ann & Robert H Lurie Children's Hospital of Chicago
Nationwide Children's Hospital
Primary Children's Hospital
Seattle Children's Hospital
St. Louis Children's Hospital
Baylor College of Medicine
University of California, Davis
University of California, San Francisco
University of Michigan
M.D. Anderson Cancer Center
University of Arkansas
Investigators
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Principal Investigator: Fran Balamuth, MD PhD MSCE Attending Physician, Emergency Department
Additional Information:
Publications:
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Responsible Party: Scott Weiss, Principal Investigator, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT04102371    
Other Study ID Numbers: 19-016484
First Posted: September 25, 2019    Key Record Dates
Last Update Posted: September 16, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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 NICHD data repository, Data and Specimen Hub (DASH). In addition, final datasets and statistical analyses will be archived.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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.
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Scott Weiss, Children's Hospital of Philadelphia:
Sepsis
Septic Shock
Fluid resuscitation
Saline
Balanced Fluid
Mortality
Crystalloid
PlasmaLyte
Lactated Ringer's
Kidney injury
Additional relevant MeSH terms:
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Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Plasma-lyte 148
Ophthalmic Solutions
Pharmaceutical Solutions