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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03340805
Recruitment Status : Completed
First Posted : November 14, 2017
Results First Posted : August 5, 2019
Last Update Posted : August 5, 2019
Sponsor:
Collaborators:
University of Utah
University of Pennsylvania
University of California, Davis
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Shock, Septic Drug: Lactated Ringer Drug: Normal saline Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Single-center, open-label, randomized pragmatic clinical trial
Masking: None (Open Label)
Masking Description: Study participants, care provider, investigator, and outcomes assessor will not be masked to intervention allocation.
Primary Purpose: Other
Official Title: Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis: A Pilot Feasibility Study
Actual Study Start Date : January 24, 2018
Actual Primary Completion Date : August 31, 2018
Actual Study Completion Date : January 15, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis Shock

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 Name: 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




Primary Outcome Measures :
  1. Compliance With Study Fluid Administration in the Assigned Study Arm [ Time Frame: up 48 hours after randomization ]
    Proportion of total crystalloids administered as saline in each arm during the intervention phase


Secondary Outcome Measures :
  1. Enrollment of Eligible Patients [ Time Frame: up to 6 months ]
    Proportion of eligible patients treated in the pediatric ED who are enrolled, randomized, and treated with study fluid

  2. Acceptability of Enrollment Using "Exception From Informed Consent" [ Time Frame: up to 6 months ]
    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


Other Outcome Measures:
  1. Mortality [ Time Frame: up to 90 days following randomization ]
    Proportion of enrolled patients who do not survive

  2. Hospital-free Days [ Time Frame: up to 28 days following randomization ]
    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

  3. New Inpatient Dialysis [ Time Frame: Up to 90 days following randomization ]
    Proportion treated with any replacement therapy that was not a continuation of pre-hospital chronic therapy

  4. Hospital Length of Stay [ Time Frame: up to 90 days following randomization ]
    Measured as the number of calendar days between ED arrival and ED or hospital discharge (whichever occurs later)

  5. Adverse Events [ Time Frame: up to four days post-randomization ]
    Hyperlactatemia, hyperkalemia, hypercalcemia, hypernatremia, hyponatremia, hyperchloremia, therapy for brain herniation

  6. Adverse Events [ Time Frame: up to seven days post-randomization ]
    Venous thromboembolism



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 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

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): NCT03340805


Locations
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United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Children's Hospital of Philadelphia
University of Utah
University of Pennsylvania
University of California, Davis
Investigators
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Principal Investigator: Fran Balamuth, MD PhD MSCE Attending Physician, Emergency Department
  Study Documents (Full-Text)

Documents provided by Children's Hospital of Philadelphia:
Additional Information:
Publications:
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Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT03340805    
Other Study ID Numbers: 17-013936
First Posted: November 14, 2017    Key Record Dates
Results First Posted: August 5, 2019
Last Update Posted: August 5, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Children's Hospital of Philadelphia:
Sepsis
Septic shock
Pediatric
Fluid resuscitation
Saline
Lactated Ringer's
Crystalloid
Mortality
Pragmatic trial
Feasibility
Additional relevant MeSH terms:
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Sepsis
Shock, Septic
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock