Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis

Shock Clinical Trial

— PRoMPT BOLUS  

Official title:

Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04102371
• Other study ID #: 19-016484
• Secondary ID: R01HD101528
• Status: Recruiting
• Phase: Phase 3
• Start date: August 25, 2020
• Est. completion date: June 30, 2025

Study information

• Verified date: March 2024
• Source: Children's Hospital of Philadelphia
• Contact: Fran L Balamuth, MD PhD MSCE
• Phone: 215-590-7295
• Email: BalamuthF[@]chop.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 8800
• Est. completion date: June 30, 2025
• Est. primary completion date: May 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Sepsis
• Septic
• Shock

Intervention

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).
• Normal Saline
Normal saline solution is an "unbalanced" crystalloid solution containing 154 mEq/L of sodium and 154 milliequivalent (mEq/L) of chloride.
• 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).

Locations

Country	Name	City	State
United States	CS Mott Children's Hospital	Ann Arbor	Michigan
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Lurie Children's: Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Children's National Medical Center	Columbia	Washington
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Dallas Children's: Children's Medical Center Dallas/UT southwestern	Dallas	Texas
United States	UC Davis: University of California, Davis	Davis	California
United States	Children's Colorado: University of Colorado	Denver	Colorado
United States	Children's Hospital of Atlanta	Emory	Georgia
United States	Texas Children's Hospital	Houston	Texas
United States	Universtity of Texas MD Anderson	Houston	Texas
United States	CHLA: Children's Hospital Los Angeles	Los Angeles	California
United States	Milwaukee (MCW): Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Columbia: New York-Presbyterian Hospital	New York	New York
United States	NYU Langone	New York	New York
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Hasbro Children's Hospital	Providence	Rhode Island
United States	Children's Hospital of Richmond at VCU	Richmond	Virginia
United States	Washington University	Saint Louis	Missouri
United States	Primary Children's: University of Utah	Salt Lake City	Utah
United States	UCSF Benioff Children's Hospital	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (51)

Lead Sponsor

Collaborator

Children's Hospital of Philadelphia

Alberta Children's Hospital, Ann & Robert H Lurie Children's Hospital of Chicago, Baylor College of Medicine, Boston Children's Hospital, British Columbia Children's Hospital, Centre Hospitalier Univeritaire Sainte Justine, Centre Hospitalier Universitaire de Quebec, Children's Healthcare of Atlanta, Children's Hospital and Health System Foundation, Wisconsin, Children's Hospital Colorado, Children's Hospital Los Angeles, Children's Hospital Medical Center, Cincinnati, Children's Hospital of Eastern Ontario, Children's Medical Center Dallas, Children's National Research Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Gold Coast Hospital and Health Service, Hasbro Children's Hospital, IWK Health Centre, Jim Pattison Children's Hospital, Kidz First Hospital Middlemore, Kingston Health Sciences Centre (Kingston), London Health Sciences Centre, M.D. Anderson Cancer Center, McMaster Children's Hospital, Monash Children's Hospital, Morgan Stanley Children's Hospital, Nationwide Children's Hospital, Pennsylvania Department of Health, Perth Children's Hospital, Primary Children's Hospital, Queen's University, Queensland Children's Hospital, Royal Children's Hospital, Royal Darwin Hospital, Seattle Children's Hospital, St. Louis Children's Hospital, Starship Children's Hospital, Stollery Children's Hospital, Sydney Children's Hospitals Network, The Children's Hospital of Winnipeg, The Hospital for Sick Children, Townsville University Hospital, University of California, Davis, University of California, San Francisco, University of Michigan, University of Pittsburgh, Virginia Commonwealth University, Westmead Children's Hospital, Women's and Children's Hospital, Australia

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.
Primary	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	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
Secondary	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
Secondary	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
Secondary	Proportion of participants with all-cause hospital mortality	Vital status at hospital discharge	Hospital discharge-censored at 90 days
Secondary	Proportion of participants with all-cause mortality at 90 days	Vital status from medical chart and/or data from National Death Index	90 days
Secondary	Proportion of participants with hyperlactatemia	At least 1 venous or arterial blood lactate measurement >4mmol/L	Within 4 calendar days of randomization
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Proportion of participants with catheter thrombosis	Catheter thrombosis in participants given Ceftriaxone and BF? (not LR?)	Within 4 calendar days of randomization
Secondary	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
Secondary	Proportion of participants with thromboembolism	Therapy for thromboembolism	Within 7 calendar days of randomization

External Links

•   PRoMPT BOLUS website