Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits

TLDR

Exposure of the developing brain to NMDA‑blocking or GABA A‑enhancing anesthetics during synaptogenesis can trigger widespread apoptotic neurodegeneration, and these properties are common to all general anesthetics routinely used in pediatric and obstetric practice. The study asks whether the routine combination of such agents during pediatric anesthesia poses a significant risk of inducing apoptotic neurodegeneration in the developing human brain. In 7‑day‑old rats, a 6‑hour surgical‑plane combination of midazolam, nitrous oxide, and isoflurane produced widespread apoptotic neurodegeneration, impaired hippocampal synaptic function, and lasting memory/learning deficits.

Abstract

Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABA A receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABA A receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.