# Early Diagnosis and Novel Treatment of Sepsis

> **NIH VA I01** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2020 · —

## Abstract

Sepsis is a common and devastating syndrome induced by infection and results from an
uncontrolled inflammatory response. As highlighted in the updated consensus definition for
sepsis published this year (JAMA 23; 315:801), the initial inflammatory response to infection is
beneficial; but this protective response can become dysregulated and harmful. The theoretical
tipping-point at which inflammation transitions from defending to destroying homeostasis is not
predictable, but it identifies the point at which the risks for sepsis-related organ failure and
mortality increase significantly. Consequently, improving sepsis survival requires understanding
the neuro-immune interactions that define this transition, developing indices to identify this point,
and testing novel therapeutics to tip the system back towards a beneficial response. The
proposed project addresses each of these important knowledge gaps. Our general hypothesis is
that a destructive loop exists such that peripheral inflammation evokes brainstem inflammation
during sepsis, which is permissive for immune dysregulation and organ dysfunction; ultimately
leading to further peripheral inflammation. In support of this hypothesis, we discovered that
brainstem inflammation develops progressively in cardiorespiratory control nuclei in a rodent
model of sepsis; leading to decreased efficacy of sensory feedback, reduced heart rate and
ventilatory pattern variabilities, and uncoupling of autonomic and respiratory rhythms. Inhibiting
brainstem cytokine expression reversed many of these changes. Furthermore, our preliminary
results from a clinical trial involving patients with vasopressor-dependent septic shock identified
that cardiac beat-to-beat dynamics predicted 28-day mortality with higher accuracy than
standard clinical severity of illness scores. These findings underlie our specific hypotheses: 1)
brainstem inflammation itself causes the loss of regulation of autonomic homeostasis and
propagates the disordered inflammatory response during sepsis; and 2) cardiorespiratory
uncoupling and the appearance of unstable patterns define a tipping point to a dysregulated
host immune response that precedes and promotes the development of organ failure. We will
test these hypotheses in an animal model of E. coli sepsis. We also propose a pre-clinical, pilot
study of vagal nerve stimulation (VNS), applied as the inflammatory response tips from
beneficial to harmful, as a novel `electroceutical' therapy to modulate the neuro-inflammatory
response. Our planned experiments will establish a novel pathway for sepsis progression and
identify markers to guide the use of VNS to oppose disease progression and improve outcomes
in sepsis.

## Key facts

- **NIH application ID:** 9898317
- **Project number:** 5I01BX004197-03
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** Frank Joseph Jacono
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898317

## Citation

> US National Institutes of Health, RePORTER application 9898317, Early Diagnosis and Novel Treatment of Sepsis (5I01BX004197-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898317. Licensed CC0.

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