Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis: A Pilot Feasibility Study (PRoMPT BOLUS)

The objective of this pilot study is to assess overall feasibility prior to embarking on a larger randomized pragmatic trial comparing the clinical effectiveness of fluid resuscitation with NS versus LR for pediatric patients with suspected septic shock. Necessary feasibility assessments include ensuring appropriate compliance with study fluid in each of the two arms, effectiveness of study enrollment using a pragmatic study design embedded within routine clinical practice, and acceptability of using Exception from Informed Consent (EFIC).

Study Overview

• Status: Completed
• Conditions: Shock, Septic
• Intervention / Treatment: Drug: Lactated Ringer; Drug: Normal saline

Detailed Description

Approximately 5,000 children die from septic shock each year in the US and thousands more die worldwide. Despite widespread implementation of resuscitation protocols, contemporary studies still report 2-6% mortality for children with septic shock treated in the pediatric emergency department (ED). In the investigators' recent survey of the Pediatric Emergency Care Applied Research Network (PECARN), 45% of physicians had treated a child for septic shock in the ED who subsequently died in the hospital in the past two years.

Fluid resuscitation is the cornerstone of resuscitation for hypovolemia and shock, and intravenous fluids are among the most commonly used therapies worldwide. Yet, there remains uncertainty as to the most appropriate fluid type to restore effective blood volume and optimize organ perfusion. In the absence of a clear role for the early use colloids, administration of crystalloid fluids is generally preferred (except in cases of hemorrhage). For septic shock, in particular, crystalloid fluids have long been the standard resuscitative fluid. Crystalloid fluids can be categorized as non-buffered (most commonly 0.9% normal saline [NS]) or buffered/balanced (in the US, this is most commonly lactated Ringer's [LR]) solutions. NS and LR 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, while NS is currently used in 80-95% of cases of septic shock, an increasing body of data now suggest that LR resuscitation may have superior efficacy and safety. Buffered crystalloids, including LR, have demonstrated a 1-4% absolute mortality reduction and up to a 50% lower odds of dialysis compared to NS in observational and non-randomized interventional studies in adult sepsis. Nevertheless, because definitive conclusions have not been able to be drawn from existing observational and non-randomized studies, NS overwhelmingly remains the most commonly used fluid based on historical precedent while controversy remains.

To definitively test the comparative effectiveness of NS and LR, 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. Unlike explanatory RCTs, pragmatic trials need heterogeneity in patients, non-study therapies, and settings. To accomplish this, these trials must be large enough to detect small effects and simple enough to incorporate into routine clinical practice. The characteristics of LR and NS provide the ideal scenario for a large pragmatic trial.18 An ED-based trial is necessary to enroll patients at initiation of resuscitation. While any benefit is expected to be small, even a 1-2% absolute reduction in mortality that is in line with prior adult studies would be a clinically important difference by saving the lives of 50-100 children in the US (and many more worldwide) each year. This overall public health impact is commensurate with changing from NS to LR because such a practice change is a simple, cost-neutral shift from largely using NS to largely using LR.

However, before embarking on a large, pragmatic randomized trial that will determine the comparative effectiveness and safety of NS and LR, several concerns regarding feasibility of such a trial need to be addressed including a) ensuring adequate compliance with study fluid administration within each randomized arm using the proposed pragmatic study design, b) determining that a sufficient proportion of patients can be enrolled using the proposed pragmatic study design that will be embedded within routine clinical practice rather than use of a dedicated study team, and c) demonstrating that the study can feasibly be performed using EFIC when enrolling critically ill infants, children, and adolescents into this clinical trial. Demonstrating these feasibility criteria at a single site will strongly support success in a larger, multicenter study that will enroll several thousand patients across the 18 sites comprising Pediatric Emergency Care Applied Research Network (PECARN) to test morbidity and mortality outcomes.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

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

Description

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 at the physician-led "sepsis huddle" OR
   2. a physician diagnosis of suspected septic shock requiring parenteral antibiotics and fluid resuscitation as per the ED sepsis management pathway
3. administration of at least 20 mL/kg IV/ intraosseous (IO) fluid resuscitation
4. Receipt of ≤40 mL/kg IV/IO crystalloid fluid prior to randomization
5. Additional fluid deemed likely to be necessary to treat poor perfusion, defined as either hypotension or abnormal (either "flash" or >2 second) capillary refill (as determined by clinician's judgment)10
6. Parental/guardian permission (informed consent) if time permits; otherwise, EFIC criteria met

Exclusion Criteria:

1. Clinician judgement that patient's condition deems it unsafe to administer either NS or LR (since patients will be equally likely to receive NS or LR at time of study enrollment), including (but not limited to):

   1. Clinical suspicion for impending brain herniation based on data available at or before patient meets criteria for study enrollment
   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 diagnosis of cirrhosis, "liver failure", or active listing for liver transplant
   6. Known history of severe renal impairment, defined as current dependency on peritoneal dialysis or hemodialysis
   7. Known metabolic disorder, inborn error of metabolism, or primary mineralcorticoid deficiency (e.g., mitochondrial disorder, urea cycle disorder, amino acidemia, fatty acid oxidation disorder, glycogen storage disorder, congenital adrenal hypoplasia, Addison's disease) as reported by subject, LAR or accompanying caregiver, or as listed in the medical record
2. Known pregnancy determined by routine clinical history disclosed by patient and/or legally authorized representative (LAR) (or other accompanying acquaintance)
3. Known prisoner as determined by routine social history disclosed by patient and/or LAR (or other accompanying acquaintance)
4. Known allergy to either normal saline or lactated Ringer's as determined by routine allergy history disclosed by patient and/or LAR (or other accompanying acquaintance) or as indicated in the medical record
5. Indication of prior declined consent to participate based on presence of "PRoMPT BOLUS Opt-Out" bracelet

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lactated Ringer's fluid (LR); Lactated Ringer's (LR) fluid will be administered to patients randomized to the experimental arm. LR 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 calender 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
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 calender 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compliance With Study Fluid Administration in the Assigned Study Arm	Proportion of total crystalloids administered as saline in each arm during the intervention phase	up 48 hours after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Enrollment of Eligible Patients	Proportion of eligible patients treated in the pediatric ED who are enrolled, randomized, and treated with study fluid	up to 6 months
Acceptability of Enrollment Using "Exception From Informed Consent"	Proportion of eligible patients who meet criteria for EFIC who are enrolled, randomized, and treated with study fluid and do not withdraw prior to completion of the follow-up phase	up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Proportion of enrolled patients who do not survive	up to 90 days following randomization
Hospital-free Days	The number of calendar days alive and out of the hospital between randomization (day 0) and day 27 with death prior hospital discharge defined as "zero" hospital-free days	up to 28 days following randomization
New Inpatient Dialysis	Proportion treated with any replacement therapy that was not a continuation of pre-hospital chronic therapy	Up to 90 days following randomization
Hospital Length of Stay	Measured as the number of calendar days between ED arrival and ED or hospital discharge (whichever occurs later)	up to 90 days following randomization
Adverse Events	Hyperlactatemia, hyperkalemia, hypercalcemia, hypernatremia, hyponatremia, hyperchloremia, therapy for brain herniation	up to four days post-randomization
Adverse Events	Venous thromboembolism	up to seven days post-randomization

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: University of Pennsylvania; University of California, Davis; University of Utah
• Investigators: Principal Investigator: Fran Balamuth, MD PhD MSCE, Attending Physician, Emergency Department

Publications and helpful links

General Publications

• Weiss SL, Keele L, Balamuth F, Vendetti N, Ross R, Fitzgerald JC, Gerber JS. Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study. J Pediatr. 2017 Mar;182:304-310.e10. doi: 10.1016/j.jpeds.2016.11.075. Epub 2017 Jan 4.
• Emrath ET, Fortenberry JD, Travers C, McCracken CE, Hebbar KB. Resuscitation With Balanced Fluids Is Associated With Improved Survival in Pediatric Severe Sepsis. Crit Care Med. 2017 Jul;45(7):1177-1183. doi: 10.1097/CCM.0000000000002365.
• Semler MW, Rice TW. Saline Is Not the First Choice for Crystalloid Resuscitation Fluids. Crit Care Med. 2016 Aug;44(8):1541-4. doi: 10.1097/CCM.0000000000001941. No abstract available.
• Young P. Saline Is the Solution for Crystalloid Resuscitation. Crit Care Med. 2016 Aug;44(8):1538-40. doi: 10.1097/CCM.0000000000001844. No abstract available.

Helpful Links

• PRoMPT BOLUS website
• Children's Hospital of Philadelphia Pediatric Sepsis Program Website

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2018
• Primary Completion (Actual): August 31, 2018
• Study Completion (Actual): January 15, 2019

Study Registration Dates

• First Submitted: November 2, 2017
• First Submitted That Met QC Criteria: November 8, 2017
• First Posted (Actual): November 14, 2017

Study Record Updates

• Last Update Posted (Actual): August 5, 2019
• Last Update Submitted That Met QC Criteria: June 11, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Feasibility; Pediatric; Septic shock; Lactated Ringer's; Sepsis; Fluid resuscitation; Saline; Mortality; Crystalloid; Pragmatic trial
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Shock, Septic
• Other Study ID Numbers: 17-013936

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No