Revisiting MAC as a static measure of anaesthesia: evidence for dynamic responses under isoflurane in male mice

Aden Mandel; Jackson Soohoo; Chloe Deitelzweig; Isha Patkar; Dennis Han; Madona Farag; Andrew McKinstry-Wu

doi:10.1016/j.bja.2026.02.045

Revisiting MAC as a static measure of anaesthesia: evidence for dynamic responses under isoflurane in male mice

Br J Anaesth. 2026 Apr 29:S0007-0912(26)00181-9. doi: 10.1016/j.bja.2026.02.045. Online ahead of print.

Authors

Aden Mandel¹, Jackson Soohoo¹, Chloe Deitelzweig¹, Isha Patkar¹, Dennis Han², Madona Farag³, Andrew McKinstry-Wu⁴

Affiliations

¹ School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
² School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴ Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Center for the Neuroscience of Unconsciousness and Reanimation Research Alliance, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Chronobiology and Sleep Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address: Andrew.McKinstry@pennmedicine.upenn.edu.

PMID: 42062153
DOI: 10.1016/j.bja.2026.02.045

Abstract

Background: The presence of a righting reflex is known to vary over time in an individual at the population half-maximal effective anaesthetic concentration (EC₅₀). However, it is unclear whether similar variability occurs for other anaesthetic endpoints at comparable anaesthetic concentrations. We sought to test whether individual responses to a pedal pinch, a strong aversive stimulus, vary over time in individuals at the population EC₅₀ for stimulus response and to explore the dynamics of individual responses.

Methods: Male mice were exposed to fixed concentrations of isoflurane, and aversive pedal stimulation was repeatedly assessed to determine a population EC₅₀. In a second cohort of male mice, either righting reflex or pedal pinch was repeatedly assessed at empirically determined population EC₅₀ values for those stimuli (0.6 vol% and 0.95 vol%, respectively) over multiple anaesthetic exposures. Stochasticity of responses was determined by evaluating if response dwell times correspond to exponential distributions. The presence of resistance to state transitions (RST) in responses was tested by simulation of response data using a process lacking any RST, comparing real data with the simulated data.

Results: Like a righting reflex, at a population EC₅₀ for response to an aversive stimulus, individual mice switch between responsive and unresponsive states. These responses are stochastic and display resistance to state transitions. Neither individual sensitivity nor RST for righting reflex at population EC₅₀ (0.6 vol% isoflurane) was predictive of sensitivity or RST for aversive stimulus response at its population EC₅₀ (0.95 vol% isoflurane).

Conclusions: Similar to the righting reflex, responses to an aversive stimulus change stochastically in individuals at population EC₅₀ but differ from the dynamics seen with a righting reflex such that sensitivity and resistance to state transition are dependent on the test and vary independently between test modalities within an individual.

Keywords: MAC; anaesthetic sensitivity; behavioural dynamics; behavioural state transition; isoflurane; righting reflex.