Abstract

Routine general anesthesia is considered to be safe in healthy individuals. However, pre-clinical studies in mice, rats, and monkeys have repeatedly demonstrated that exposure to anesthetic agents during early post-natal periods can lead to acute neurotoxicity. More concerning, later-life defects in cognition, assessed by behavioral assays for learning and memory, have been reported. Although the potential for anesthetics to damage the neonatal brain is well-documented, the clinical significance of the pre-clinical models in which damage is induced remains quite unclear. Here, we systematically evaluate critical physiological parameters in post-natal day 7 neonatal mice exposed to 1.5% isoflurane for 2–4 hours, the most common anesthesia induced neurotoxicity paradigm in this animal model. We find that 2 or more hours of anesthesia exposure results in dramatic respiratory and metabolic changes that may limit interpretation of this paradigm to the clinical situation. Our data indicate that neonatal mouse models of AIN are not necessarily appropriate representations of human exposures.

Highlights

  • IntroductionWidely used and generally safe in healthy individuals, neurotoxicity related to anesthetic exposure has been reported in multiple animal models and retrospective clinical studies (reviewed in [1,2,3,4])

  • General anesthesia has been a key feature of modern medicine for over 150 years

  • We report striking physiological and metabolic aberrations caused by common anesthesia paradigms in neonatal mice and discuss the implications of these findings as they apply to the pre-clinical anesthesia induced neurotoxicity (AIN) literature

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Summary

Introduction

Widely used and generally safe in healthy individuals, neurotoxicity related to anesthetic exposure has been reported in multiple animal models and retrospective clinical studies (reviewed in [1,2,3,4]). These studies have linked anesthetic exposure during early post-natal periods to acute anesthesia induced neurotoxicity (AIN) and later-life defects in performance in behavioral assays for learning and memory. 3% isoflurane: 2 hr/day for 3 days [37] P6

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