# Mechanisms of improved organ function following sepsis treatment with vitamin c, thiamine and hydrocortisone (triple therapy)

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $247,500

## Abstract

Sepsis remains a devastating disease exacting substantial mortality\morbidity and consuming significant health
care resources. Hydrocortisone, Ascorbic acid and Thiamine (HAT) therapy has been hypothesized to reduce
cell and organ injury through synergistic actions. A small clinical HAT trial improved survival in septic patients
and sparked interest into examining mechanism(S). Pre-clinical models have limitations and flawed murine
models have not produced effective clinical therapies. These deficiencies include use of endotoxin injections,
failure to provide routine, effective sepsis treatments (antibiotics and fluids) and very high mortality rates.
However, appropriate sepsis models do respond to proven sepsis treatments and have predicted failed
interventions. The premise for the current proposal derives from the hypothesis that the three HAT components
synergize to reduce cell and organ injury, especially in the kidney. The current R21 proposal addresses the
unresolved issues of defining how HAT therapy is effective through two specific aims. The first aim will
measure in vivo reductions in oxidative stress (OS) and improvements in phagocytic cell function. Non-invasive
physiologic measurements of heart rate (HR) obtained six hours after the onset of sepsis accurately predict
mortality in the cecal ligation and puncture (CLP) model. Outbred mice, both males and females, will be
stratified into predicted to live or die based on HR and then randomized to receive HAT or vehicle, an
experimental approach with both innovation and significance. The design is innovative since it directs the
therapy towards the animals where it may be beneficial, rather than employing the typical one-size-fits-all
approach. The plan is significant, since clinical trials could adopt the same approach of stratifying patients. We
will measure multiple OS parameters in several different organs to determine if HAT reduces OS in septic
mice. Such studies are not really feasible in patients since actual tissue samples are required, and sampling of
vital organs such as the kidney would be difficult to do in a septic patient. OS will be quantified in these initial
studies as a marker of efficacy, but the premise for the proposal is that all three HAT components synergize to
reduce cell injury and not merely reduce OS. Phagocytic cell function has been postulated to be decreased by
OS in sepsis and these cells will be studied with innovative techniques in aim 1. Alternative treatments with
double therapy combinations will be tested, as well as different doses and times of treatment after the onset of
sepsis. Since renal injury is the most frequently observed dysfunctional organ in sepsis, the second specific
aim examines the mechanism(s) of how HAT reduces this injury. Sophisticated in vivo techniques will localize
hypoxia-stressed individual cells, and mitochondrial function will quantified to determine if HAT improves this
cellular powerhouse. Successful completion of the pr...

## Key facts

- **NIH application ID:** 9978302
- **Project number:** 1R21AI147168-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Daniel G. Remick
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $247,500
- **Award type:** 1
- **Project period:** 2020-02-06 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978302

## Citation

> US National Institutes of Health, RePORTER application 9978302, Mechanisms of improved organ function following sepsis treatment with vitamin c, thiamine and hydrocortisone (triple therapy) (1R21AI147168-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978302. Licensed CC0.

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