# Personalized Anesthetic Pharmacology Across the Lifespan

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $579,588

## Abstract

Abstract.
Decisions concerning anesthetic dosing typically rely on population-based measures of drug potency.
However, similar anesthetic doses have markedly different effects on distinct individuals. While some patients
recover from anesthesia uneventfully, in others, recovery is complicated by postoperative delirium and
cognitive dysfunction. Such complications are disproportionally prevalent in the elderly. It is presently unclear
why some elderly patients exhibit these debilitating and costly complications. To answer this question,
individual-based rather than population-based measures of drug effects must be developed. We create such
measures for anesthetics in mice. Preliminary data indicate that standard population-based measures of
anesthetic potency, such as half-maximal effective concentration (EC50), are insufficient to explain anesthetic
responses in each individual. This is because at a fixed anesthetic concentration, the level of consciousness in
each individual fluctuates. While fluctuations in the state of arousal occur spontaneously, there is an inertial
tendency in each animal to resist state transitions. Hence, the response in each individual depends not just
upon the anesthetic concentration, but also upon the individual’s previous state of arousal. Standard drug
potency measures fail to account for this history-dependence. Thus, to adequately quantify individual-based
responses to anesthetics, we develop two independent measures: personalized drug sensitivity and resistance
to state transitions. We hypothesize that resistance to state transitions contributes to delayed restoration of
cognitive function after anesthesia. We investigate age-dependence of resistance to state transitions in a first
of a kind longitudinal study (Aim 1). To investigate a neurobiological basis of resistance to state transitions, we
selectively decrease resistance to state transitions using chemogenetic activation of orexinergic neurons that
are critically involved in stabilization of sleep and wakefulness (Aim 2). To determine whether resistance to
state transitions is causally linked to restoration of cognition, we use a behavioral test of sustained attention
(SA) performed immediately upon recovery after anesthesia. Our published results indicate that SA is
dramatically disrupted after recovery from anesthesia in human volunteers. We determine if increased
resistance to state transitions is associated with greater impairment on SA performance after emergence in
mice. We attempt to restore normal SA performance by modulating resistance to state transitions using
chemogenetic activation of orexinergic neurons (Aim 3). In summary, we develop a qualitatively novel measure
of personalized, rather than population-based anesthetic responses: resistance to state transitions. We
determine the neurobiological underpinnings of resistance to state transitions, and investigate its relationship to
subsequent cognitive recovery. Thus, we offer a critical first s...

## Key facts

- **NIH application ID:** 10339719
- **Project number:** 1R01GM144377-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Max Kelz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $579,588
- **Award type:** 1
- **Project period:** 2021-09-21 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339719

## Citation

> US National Institutes of Health, RePORTER application 10339719, Personalized Anesthetic Pharmacology Across the Lifespan (1R01GM144377-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10339719. Licensed CC0.

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