CompletedNCT03340805PRoMPT BOLUSUpdated Aug 5, 2019Results posted

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

A Phase 1 interventional study of Lactated Ringer and Normal saline in Shock, Septic, sponsored by Children's Hospital of Philadelphia. Completed at 1 site in United States. Open to participants aged 6 Months to 17 Years. Per ClinicalTrials.gov, last updated 2019-08-05.

Sponsored by Children's Hospital of Philadelphia · Phase 1, Interventional, and Other

Phase: Phase 1
Study type: Interventional
Enrollment: 50
Allocation: Randomized
Ages: 6 Months to 17 Years
Sex: All

Study 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).

Read the 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.

Conditions studied

Shock, Septic

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Keywords

Sepsis
Septic shock
Pediatric
Fluid resuscitation
Saline
Lactated Ringer's
Crystalloid
Mortality
Pragmatic trial
Feasibility

Who can participate

Ages eligible: 6 Months to 17 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Males or females age >6 months to \<18 years
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
administration of at least 20 mL/kg IV/ intraosseous (IO) fluid resuscitation
Receipt of ≤40 mL/kg IV/IO crystalloid fluid prior to randomization
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
Parental/guardian permission (informed consent) if time permits; otherwise, EFIC criteria met

Exclusion criteria

Exclusion Criteria:

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
Known pregnancy determined by routine clinical history disclosed by patient and/or legally authorized representative (LAR) (or other accompanying acquaintance)
Known prisoner as determined by routine social history disclosed by patient and/or LAR (or other accompanying acquaintance)
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
Indication of prior declined consent to participate based on presence of "PRoMPT BOLUS Opt-Out" bracelet

Study design

Phase: Phase 1
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 50 participants (actual)

Study arms

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
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

Interventions

DrugLactated 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).
Also known as: LR
DrugNormal saline
Normal saline solution is an "unbalanced" crystalloid solution containing 154 mEq/L of sodium and 154 milliequivalent (mEq/L) of chloride.
Also known as: 0.9% Saline, NS

What researchers measure

Primary outcomes

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

Secondary outcomes

Enrollment of Eligible Patients
Proportion of eligible patients treated in the pediatric ED who are enrolled, randomized, and treated with study fluid
Time frame: 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
Time frame: up to 6 months

Other outcomes

Mortality
Proportion of enrolled patients who do not survive
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: up to 90 days following randomization
Adverse Events
Hyperlactatemia, hyperkalemia, hypercalcemia, hypernatremia, hyponatremia, hyperchloremia, therapy for brain herniation
Time frame: up to four days post-randomization
Adverse Events
Venous thromboembolism
Time frame: up to seven days post-randomization

Results

Posted Aug 5, 2019

Participant flow

Participant flow — Overall Study
Milestone	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Started	24	26
Completed	24	26
Not completed	0	0

Outcome measures

PrimaryCompliance With Study Fluid Administration in the Assigned Study Arm

Proportion of total crystalloids administered as saline in each arm during the intervention phase

Time frame:: up 48 hours after randomization
Reported as:: Median · Proportion of total crystalloids adminis

Compliance With Study Fluid Administration in the Assigned Study Arm
Proportion of total crystalloids adminis	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Compliance With Study Fluid Administration in the Assigned Study Arm	0 (0 to 0)	100 (100 to 100)

SecondaryEnrollment of Eligible Patients

Proportion of eligible patients treated in the pediatric ED who are enrolled, randomized, and treated with study fluid

Time frame:: up to 6 months
Reported as:: Count of participants · Participants

Enrollment of Eligible Patients
Participants	All Eligible Patients
Enrollment of Eligible Patients	50

SecondaryAcceptability 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

Time frame:: up to 6 months
Reported as:: Count of participants · Participants

Acceptability of Enrollment Using "Exception From Informed Consent"
Participants	Subjects Enrolled Under Exception From Informed Consent
Acceptability of Enrollment Using "Exception From Informed Consent"	43

Other pre-specifiedMortality

Proportion of enrolled patients who do not survive

Time frame:: up to 90 days following randomization
Reported as:: Count of participants · Participants

Mortality
Participants	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Mortality	0	1

Other pre-specifiedHospital-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

Time frame:: up to 28 days following randomization
Reported as:: Median · days alive and free of hospitalization

Hospital-free Days
days alive and free of hospitalization	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Hospital-free Days	23 (20 to 25)	25 (20 to 26)

Other pre-specifiedNew Inpatient Dialysis

Proportion treated with any replacement therapy that was not a continuation of pre-hospital chronic therapy

Time frame:: Up to 90 days following randomization
Reported as:: Count of participants · Participants

New Inpatient Dialysis
Participants	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
New Inpatient Dialysis	0	0

Other pre-specifiedHospital Length of Stay

Measured as the number of calendar days between ED arrival and ED or hospital discharge (whichever occurs later)

Time frame:: up to 90 days following randomization
Reported as:: Median · days

Hospital Length of Stay
days	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Hospital Length of Stay	5 (3 to 8)	3 (2 to 9)

Other pre-specifiedAdverse Events

Hyperlactatemia, hyperkalemia, hypercalcemia, hypernatremia, hyponatremia, hyperchloremia, therapy for brain herniation

Time frame:: up to four days post-randomization
Reported as:: Number · adverse events

Adverse Events
adverse events	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Adverse Events	7	18

Other pre-specifiedAdverse Events

Venous thromboembolism

Time frame:: up to seven days post-randomization
Reported as:: Count of participants · Participants

Adverse Events
Participants	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Adverse Events	0	0

Adverse events

Collected over 7 days. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Lactated Ringer's Fluid (LR)	0/24 (0%)	4/24 (16.7%)	11/24 (45.8%)
0.9% "Normal" Saline Fluid (NS)	1/26 (3.8%)	2/26 (7.7%)	12/26 (46.2%)

Most frequent serious events

Most frequent serious events
Event	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Respiratory failureRespiratory, thoracic and mediastinal disorders	3/24	1/26
ShockCardiac disorders	2/24	2/26
Cerebral edemaNervous system disorders	1/24	0/26
DeathGeneral disorders	0/24	1/26

Most frequent other events

Showing 10 of 13

Most frequent other events
Event	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)
Respiratory failureRespiratory, thoracic and mediastinal disorders	7/24	6/26
HyperchloremiaMetabolism and nutrition disorders	3/24	7/26
RashSkin and subcutaneous tissue disorders	4/24	4/26
HyperlactatemiaMetabolism and nutrition disorders	2/24	4/26
HypercalcemiaMetabolism and nutrition disorders	0/24	4/26
HyperkalemiaMetabolism and nutrition disorders	2/24	2/26
SeizureNervous system disorders	1/24	2/26
Pressure injurySkin and subcutaneous tissue disorders	1/24	0/26
Acute kidney injuryRenal and urinary disorders	0/24	1/26
Liver dysfunctionHepatobiliary disorders	0/24	1/26

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)	Total
<=18 years	24	26	50
Between 18 and 65 years	0	0	0
>=65 years	0	0	0

Age, Continuous
Age, Continuous(years)	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)	Total
Median	3.8 (2.0 to 10.4)	9.7 (2.6 to 16.3)	5.8 (2.1 to 12.5)

Sex: Female, Male
Sex: Female, Male(Participants)	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)	Total
Female	11	12	23
Male	13	14	27

Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)	Total
Race/Ethnicity — Non-Hispanic White	11	11	22
Race/Ethnicity — Non-Hispanic Black	3	4	7
Race/Ethnicity — Hispanic	10	9	19
Race/Ethnicity — Asian	0	1	1
Race/Ethnicity — Unknown/Not Reported	0	1	1

Region of Enrollment
Region of Enrollment(participants)	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)	Total
United States	24	26	50

Comorbid Conditions
Comorbid Conditions(participants)	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)	Total
Cancer	4	5	9
Kidney disease	2	1	3
Neurologic dysfunction	7	5	12
Chronic ventilator dependence	6	5	11
Bone marrow or solid organ transplant	3	2	5
Sickle cell disease	0	2	2
Indwelling central venous catheter	6	4	10
Any comorbid condition	16	16	32

Site of Infection
Site of Infection(participants)	Lactated Ringer's Fluid (LR)	0.9% "Normal" Saline Fluid (NS)	Total
Bacteremia	2	4	6
Pneumonia/lung infection	5	5	10
Abdominal infection	1	0	1
Urinary Tract Infection	4	3	7
CNS infection	2	3	5
Skin/soft tissue infection	2	3	5
Other	6	6	12
Unknown	3	4	7
Alternative diagnosis other than infection	1	1	2

Study locations

1 site

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

References and documents

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. PubMed 28063688 ↗
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. PubMed 28437373 ↗
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. PubMed 27428117 ↗
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. PubMed 27153047 ↗

Study documents

Protocol and statistical analysis plan · Nov 6, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Registry details

Key details

Study ID: NCT03340805
Lead sponsor: Children's Hospital of Philadelphia
Collaborators: University of Utah, University of Pennsylvania, University of California, Davis
Responsible party: Sponsor
First posted: Nov 14, 2017
Start date: Jan 24, 2018
Primary completion: Aug 31, 2018
Completion: Jan 15, 2019
Results posted: Aug 5, 2019
Last update: Aug 5, 2019

Study contacts

Fran Balamuth, MD PhD MSCE

principal investigator · Attending Physician, Emergency Department

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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