# Finding Appropriate Subtypes in a Trial of Balanced versus nOrmaL Saline FlUid in Sepsis

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $667,907

## Abstract

PROJECT SUMMARY/ABSTRACT
Sepsis, defined as a dysregulated host response to infection, is responsible for 75,000 childhood
hospitalizations annually in the United States and 50% of inpatient pediatric deaths worldwide. Despite
multiple trials, there are no targeted therapies for adult or pediatric sepsis, and supportive care with timely
antibiotics and fluid resuscitation remains the mainstay of therapy. Fluid therapy is a cornerstone of sepsis
resuscitation, although the choice of fluid remains controversial. Recent trials in adults showed lower rates of
major adverse kidney events within 30 days (MAKE30) with balanced crystalloid, such as lactated Ringer’s
(LR), relative to normal saline (NS). MAKE30 is a composite endpoint incorporating persistent kidney
dysfunction, initiation of dialysis, or death. Balanced solutions like LR have a composition more similar to
normal human serum, whereas NS has been associated with worse kidney function, albeit via unclear
mechanisms. While much of pediatric sepsis management is extrapolated from adults, children have a distinct
epidemiology and outcome profile, making application of adult data problematic. Thus, to specifically assess
whether LR or NS resuscitation improves MAKE30 in children, the PRagMatic Pediatric Trial of Balanced
versus nOrmaL Saline FlUid in Sepsis (PRoMPT BOLUS) was undertaken, with planned enrollment of 8,800
children. However, heterogeneity has contributed to negative trials in sepsis, as therapies effective in some
patients are ineffective in others. To mitigate this heterogeneity, biomarkers have been proposed for both risk
stratification and identification of sub-phenotypes with shared pathophysiology. Our study, entitled Finding
Appropriate Subtypes in a Trial of Balanced versus nOrmaL Saline FlUid in Sepsis (FAST BOLUS), will assess
for heterogeneity of treatment effect of LR versus NS in the PRoMPT BOLUS trial. Leveraging our group’s
extensive experience with biomarker-defined risk stratification and sub-phenotyping, we will measure plasma
biomarkers in 800 children collected at randomization and assess the for differential effects of fluid assignment
on MAKE30 across risk strata using two separate biomarker-based mortality prediction models (Aim 1).
Additionally, we will test for differential effects of fluid assignment on MAKE30 after stratifying subjects
according to one of two biomarker-defined inflammatory sub-phenotypes (Aim 2). Lastly, we will leverage this
biobank to investigate potential mechanisms between fluid choice and MAKE30 by measuring markers of
endothelial cell (angiopoietin-2) and endothelial glycocalyx (syndecan-1) damage (Aim 3). These Aims will
assess the utility of established biomarker-based strategies for prognostic (Aim 1) and predictive enrichment
(Aim 2) strategies by leveraging an ongoing pediatric sepsis trial, which is a necessary analysis of randomized
trials conducted in heterogeneous critical illness syndromes. Successful completion of the Aim...

## Key facts

- **NIH application ID:** 10892884
- **Project number:** 5R01GM145698-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Nadir Yehya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $667,907
- **Award type:** 5
- **Project period:** 2022-09-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892884

## Citation

> US National Institutes of Health, RePORTER application 10892884, Finding Appropriate Subtypes in a Trial of Balanced versus nOrmaL Saline FlUid in Sepsis (5R01GM145698-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10892884. Licensed CC0.

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