# The role of ketone metabolism in sequelae resulting from volatile anesthetic exposure.

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2022 · $372,000

## Abstract

Project Summary/Abstract
Our overarching goal is to define the molecular mechanisms underpinning the actions of VA
compounds. Our overall objective in the studies proposed here, which represent the next step in pursuing this
goal, is to define the impact and mechanisms of volatile anesthetics on tissue-specific and circulating
metabolism in conditions where volatile anesthetics carry known risks of morbidity and in states of metabolic
ketosis.
Volatile anesthetics are invaluable tools in modern medicine. Despite their prevalent use, the precise molecular
mechanisms of volatile anesthetic (VA) activity remain largely unclear. Where data are available, a complex
picture emerges. Experimental evidence has revealed multiple direct targets mediating both the
anesthetic/sedative and non-anesthesia related effects of these agents, including neuro-receptors, ion
channels, and mitochondrial electron transport chain complex I (ETC CI). Among known molecular targets of
VA’s, the relative contributions of each to the functional effects of VAs is poorly understood. VAs are generally
regarded as devoid of long term sequelae, but specific populations of patients are at risk for intrinsic
detrimental effects of VAs. For example, both extremes of age are sensitive to CNS damage following
anesthetic exposure. Additionally, patients with primary mitochondrial disorders are hypersensitive to VAs; the
literature harbors multiple reports of children with mitochondrial disease who have died after a routine
anesthetic. Unexplained extreme responses to VAs are rare, but also remain a source of concern in clinical
practice. Understanding the mechanisms underlying negative responses to anesthesia may lead to improved
patient screening, monitoring, and care. At-risk populations may benefit most from this knowledge, but, given
that all VAs have off target effects that may impact patient outcomes, understanding their mechanisms may
lead to safer practices throughout the field.
The goal of this proposal is to define impact and mechanisms of volatile anesthetics on tissue-specific and
circulating metabolism in conditions where volatile anesthetics carry known risks of morbidity, and the potential
therapeutic benefit of intervening in altered metabolism. We hypothesize that altered metabolism mediates
multiple sequelae of VA exposure in sensitive populations, including both toxicity and neurocognitive deficits in
sensitive settings. Defining the role of VA exposure on metabolism will provide new insights into these complex
drugs.

## Key facts

- **NIH application ID:** 10425335
- **Project number:** 5R01GM133865-04
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Simon C Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,000
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425335

## Citation

> US National Institutes of Health, RePORTER application 10425335, The role of ketone metabolism in sequelae resulting from volatile anesthetic exposure. (5R01GM133865-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10425335. Licensed CC0.

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