Balanced Fluids for Pediatric Sepsis

(PRoMPT BOLUS Trial)

Not currently recruiting at 22 trial locations

Overseen By Weiss Scott, MD MSCE

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Hospital of Philadelphia

Disqualifiers: Brain herniation, Hyperkalemia, Hypercalcemia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different fluids to determine which is safer and more effective for treating septic shock in children. Researchers compare balanced fluids, such as Lactated Ringer's or Plasma-Lyte, with the standard saline solution to see if they better prevent kidney injury. The trial seeks children between 2 months and 18 years old diagnosed with septic shock who need fluid resuscitation. Participants will receive either the experimental fluids or normal saline, and doctors will closely monitor their progress. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It focuses on fluid resuscitation for septic shock in children.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both Lactated Ringer (LR) and Plasma-Lyte are generally safe for children. Studies have found that these balanced fluids do not result in worse outcomes than normal saline when treating children with sepsis. Some research even suggests that Plasma-Lyte might help address issues like acidosis, where the body's acid levels are imbalanced.

Hospitals have used balanced fluids for a long time, and most patients usually tolerate them well. Designed to resemble the body's natural fluids, they may reduce the risk of complications. However, each person may react differently, so healthcare professionals should monitor any treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using balanced fluids like Lactated Ringer's and Plasma-Lyte for pediatric sepsis because they offer a different approach to fluid resuscitation compared to the standard 0.9% "normal" saline. These balanced fluids are designed to more closely mimic the body's natural plasma composition, which may lead to better acid-base balance and less risk of developing complications like acidosis. This could potentially improve outcomes in children with sepsis by stabilizing their condition more effectively and with fewer side effects.

What evidence suggests that this trial's treatments could be effective for pediatric sepsis?

This trial will compare the use of balanced fluids, such as Lactated Ringer's and Plasma-Lyte, with normal saline in children with septic shock. Research has shown that balanced fluids do not always lead to better results compared to normal saline. Some studies found no major differences in outcomes like kidney health or overall recovery. While balanced fluids might help with issues like excess acidity in the body, normal saline remains a common treatment. Overall, the benefits of balanced fluids compared to normal saline in treating children with sepsis remain unclear. ^{1 2 6 7 8}

Who Is on the Research Team?

Fran Balamuth, MD PhD MSCE

Principal Investigator

Attending Physician, Emergency Department

Are You a Good Fit for This Trial?

This trial is for children aged over 2 months and under 18 years with a physician's diagnosis of septic shock needing antibiotics and fluid resuscitation. It excludes those with certain metabolic disorders, known pregnancy, prisoners, allergies to crystalloid fluids, severe liver or kidney issues, high potassium or calcium levels, or if the clinician deems it unsafe.

Inclusion Criteria

Parental/guardian permission (informed consent) if time permits; otherwise, Exception from informed consent (EFIC) criteria met

I've received IV fluids for resuscitation and may need more due to poor blood flow.

I have received 40 mL/kg or less of IV fluids before being selected for the study.

Exclusion Criteria

You are allergic to a type of fluid used during the study.

Known prisoner

I have severe liver problems, like cirrhosis or liver failure.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either balanced fluids (BF) or 0.9% normal saline (NS) for fluid resuscitation immediately after randomization through the next calendar day

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment, with primary endpoint being major adverse kidney events within 30 days

30 days

Extended Follow-up

Participants are monitored for additional outcomes such as all-cause mortality at 90 days

90 days

What Are the Treatments Tested in This Trial?

Interventions

• Lactated Ringer
• Normal Saline
• Plasma-lyte

Trial Overview The study compares balanced fluids like Lactated Ringer and Plasma-lyte against Normal Saline in treating pediatric septic shock. The goal is to see if balanced fluids can better prevent kidney injury progression compared to saline.

How Is the Trial Designed?

Group I: Balanced fluids (BF) Experimental Treatment 2 Interventions

Balanced fluids (BF), including Lactated Ringer's and Plasma-Lyte (PL), 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.

Group II: 0.9% "Normal" Saline Fluid (NS) Active Control 1 Intervention

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.

Lactated Ringer is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Lactated Ringer's for:

• fluid resuscitation after blood loss due to trauma or surgery
• sepsis
• acute pancreatitis
• burn injuries

Approved in United States as Lactated Ringer's for:

• fluid resuscitation after blood loss due to trauma or surgery
• sepsis
• acute pancreatitis
• burn injuries

Approved in Canada as Lactated Ringer's for:

• fluid resuscitation after blood loss due to trauma or surgery
• sepsis
• acute pancreatitis
• burn injuries

Approved in Japan as Lactated Ringer's for:

• fluid resuscitation after blood loss due to trauma or surgery
• sepsis
• acute pancreatitis
• burn injuries

Approved in China as Lactated Ringer's for:

• fluid resuscitation after blood loss due to trauma or surgery
• sepsis
• acute pancreatitis
• burn injuries

Approved in Switzerland as Lactated Ringer's for:

• fluid resuscitation after blood loss due to trauma or surgery
• sepsis
• acute pancreatitis
• burn injuries

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Queensland Children's Hospital

Collaborator

Queen's University

Collaborator

Kingston Health Sciences Centre

Collaborator

Trials

312

Recruited

112,000+

Townsville University Hospital

Collaborator

Trials

1

Recruited

8,800+

Queensland Children's Hospital

Collaborator

Trials

4

Recruited

9,700+

Royal Children's Hospital

Collaborator

Trials

38

Recruited

232,000+

The Children's Hospital of Winnipeg

Collaborator

Trials

5

Recruited

16,600+

Westmead Children's Hospital

Collaborator

Trials

1

Recruited

8,800+

Children's Hospital and Health System Foundation, Wisconsin

Collaborator

Trials

56

Recruited

93,300+

Published Research Related to This Trial

In a study of 12,529 pediatric patients with severe sepsis or septic shock, resuscitation with balanced fluids (lactated Ringer's solution) did not show improved outcomes compared to normal saline, with similar 30-day mortality rates (7.2% for LR vs. 7.9% for NS).

While there were no significant differences in mortality or acute kidney injury between the two groups, patients receiving lactated Ringer's had a longer hospital stay by an average of 2.4 days, suggesting that while LR is used, it may not provide additional benefits over normal saline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric Sepsis: A Matched Retrospective Cohort Study. Weiss, SL., Keele, L., Balamuth, F., et al.[2018]

In a study of 110 patients with severe burns, resuscitation with hypertonic lactate saline (HLS) resulted in significantly lower fluid requirements and fluid accumulation compared to traditional lactated Ringer's solution, especially in the first hour of treatment.

HLS also led to higher sodium loads and changes in plasma sodium and osmolality, indicating its effectiveness in managing fluid balance during the critical early phase of burn shock.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of hypertonic vs isotonic fluids during resuscitation of severely burned patients. Belba, MK., Petrela, EY., Belba, GP.[2018]

In a study of 2022 sepsis patients, there was no significant difference in 30-day mortality, hospital length of stay, or need for mechanical ventilation between those receiving Lactated Ringer's (LR) and those receiving Normal Saline (NS) as their primary resuscitation fluid.

Although patients receiving LR had a longer hospital stay and higher ICU admission rates initially, these differences were not statistically significant after adjusting for multiple factors, indicating that both fluids may be similarly effective in managing sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of normal saline and lactated ringers as resuscitation fluid in sepsis. Isha, S., Satashia, PH., Yarrarapu, SNS., et al.[2023]

In a study of 1,641 ICU patients with sepsis, using balanced crystalloids (like lactated Ringer's solution) instead of saline showed a significant reduction in 30-day in-hospital mortality when fluid choice was managed from the emergency department (ED) through to the ICU.

Specifically, during the ED and ICU period, the mortality rate was 24.9% for patients receiving balanced crystalloids compared to 30.6% for those receiving saline, indicating that early intervention with balanced crystalloids may improve outcomes for sepsis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Early Balanced Crystalloids Before ICU Admission on Sepsis Outcomes. Jackson, KE., Wang, L., Casey, JD., et al.[2022]

This study aims to compare the incidence of hyperchloremia in critically ill children receiving different intravenous fluids, specifically 0.9% sodium chloride versus balanced solutions like Plasma-Lyte 148 and Compound Sodium Lactate, with a target enrollment of 480 patients.

The primary outcome is to measure the increase in serum chloride levels within 48 hours, which will help determine if balanced solutions can reduce the risk of adverse outcomes associated with traditional saline therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

0.9% Sodium chloride solution versus Plasma-Lyte 148 versus compound sodium lacTate solution in children admitted to PICU-a randomized controlled trial (SPLYT-P): study protocol for an intravenous fluid therapy trial. Raman, S., Schibler, A., Marsney, RL., et al.[2021]

In a study of 120 septic patients in the emergency department, there was no significant difference in lactate clearance between those treated with lactated Ringer's solution (LRS) and normal saline solution (NSS) after 2 hours of resuscitation.

Both LRS and NSS resulted in similar changes in serum creatinine levels and 48-hour survival rates, indicating that neither solution was superior in these outcomes for septic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Normal Saline Solution or Lactated Ringer's Solution to Enhance Lactate Clearance in Septic Patients After Initial Resuscitation in the ED: A Retrospective Cohort Trial. Limapichat, T., Pattanapong, K.[2022]

The study successfully enrolled 85% of eligible pediatric patients with suspected septic shock, demonstrating the feasibility of conducting a pragmatic randomized trial comparing lactated Ringer's (LR) and normal saline (NS) for fluid resuscitation.

Patients receiving LR had a significantly lower proportion of their total fluid volume as NS (20%) compared to those in the NS group (99%), indicating effective adherence to the randomized fluid administration protocol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pragmatic Pediatric Trial of Balanced Versus Normal Saline Fluid in Sepsis: The PRoMPT BOLUS Randomized Controlled Trial Pilot Feasibility Study. Balamuth, F., Kittick, M., McBride, P., et al.[2020]

In a study involving healthy volunteers, the rapid infusion of 2 liters of isotonic sodium chloride and Ringer lactate solution resulted in minimal and statistically insignificant changes in serum electrolyte concentrations and acid-base status.

The infusion affected central venous pressure, which was linked to a delayed secretion of atrial natriuretic peptide, suggesting a physiological response to volume expansion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in serum electrolyte and atrial natriuretic peptide concentrations, acid-base and haemodynamic status after rapid infusion of isotonic saline and Ringer lactate solution in healthy volunteers. Kamp-Jensen, M., Olesen, KL., Bach, V., et al.[2019]

In a study comparing Ringer's lactate solution (RL) and PlasmaLyte (PL) for perioperative fluid therapy in children, PL showed superior acid-base balance and better serum electrolyte profiles, indicating it may be a more effective choice for this population.

Both fluids maintained stable hemodynamic parameters throughout the perioperative period, but children receiving RL experienced hyponatremia and increased blood lactate levels post-surgery, highlighting potential safety concerns with RL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comparative Study of Peri-Operative Fluid Therapy With Ringer Lactate and PlasmaLyte in Children Undergoing Intra-Abdominal Surgery: A Randomized Control Trial. Priyanka, A., Ganapathy, U., Choudhary, R., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5525152/

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric ... Balanced fluid resuscitation with LR was not associated with improved outcomes compared with NS in pediatric sepsis.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03043131

Comparative Analysis Between Ringer's Lactate vs Plasma ... ETHICAL JUSTIFICATION Recent studies have demonstrated that better outcomes in terms of acidosis with the use of Plasma Lyte-A (Acetate containing balanced ...

3. mcri.edu.au mcri.edu.au/research/projects/prompt-bolus

PRoMPT BOLUS Australia and New Zealand In paediatrics, 0.9 per cent saline is the preferred fluid used to treat sepsis, but balanced fluids are also commonly used, especially for children in ...

4. jpeds.com jpeds.com/article/S0022-3476(16)31383-X/abstract

Crystalloid Fluid Choice and Clinical Outcomes in Pediatric ... Balanced fluid resuscitation with LR was not associated with improved outcomes compared with NS in pediatric sepsis. Although the current practice of NS ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7302266/

Pragmatic Pediatric Trial of Balanced Versus Normal Saline ... A pragmatic study design proved feasible to study comparative effectiveness of LR versus NS fluid resuscitation for pediatric septic shock. Crystalloid fluid ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03043131

Comparative Analysis Between Ringer's Lactate vs Plasma ... ETHICAL JUSTIFICATION Recent studies have demonstrated that better outcomes in terms of acidosis with the use of Plasma Lyte-A (Acetate containing balanced ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04102371

Pragmatic Pediatric Trial of Balanced Versus Normal ... The objectives of this multicenter pragmatic clinical trial are to compare the effectiveness and relative safety of balanced fluid resuscitation versus 0.9% ...

8. nejm.org nejm.org/doi/full/10.1056/NEJMoa2416761

Lactated Ringer's Solution versus Normal Saline Data on outcomes were obtained from health administrative databases. The analyses were conducted at the hospital level, and the primary ...