Are Anaesthetics Toxic to the Brain?

From British Journal of Anaesthesia

A.E. Hudson; H.C. Hemmings Jr

Posted: 07/20/2011; Br J Anaesth. 2011;107(1):30-37. © 2011

Abstract and Introduction

Abstract

It has been assumed that anaesthetics have minimal or no persistent effects after emergence from anaesthesia. However, general anaesthetics act on multiple ion channels, receptors, and cell signalling systems in the central nervous system to produce anaesthesia, so it should come as no surprise that they also have non-anaesthetic actions that range from beneficial to detrimental.
Accumulating evidence is forcing the anaesthesia community to question the safety of general anaesthesia at the extremes of age.
Preclinical data suggest that inhaled anaesthetics can have profound and long-lasting effects during key neurodevelopmental periods in neonatal animals by increasing neuronal cell death (apoptosis) and reducing neurogenesis.
Clinical data remain conflicting on the significance of these laboratory data to the paediatric population.
At the opposite extreme in age, elderly patients are recognized to be at an increased risk of postoperative cognitive dysfunction (POCD) with a well-recognized decline in cognitive function after surgery.
The underlying mechanisms and the contribution of anaesthesia in particular to POCD remain unclear. Laboratory models suggest anaesthetic interactions with neurodegenerative mechanisms, such as those linked to the onset and progression of Alzheimer's disease, but their clinical relevance remains inconclusive. Prospective randomized clinical trials are underway to address the clinical significance of these findings, but there are major challenges in designing, executing, and interpreting such trials.
It is unlikely that definitive clinical studies absolving general anaesthetics of neurotoxicity will become available in the near future, requiring clinicians to use careful judgement when using these profound neurodepressants in vulnerable patients.

Introduction

General anaesthesia is a complex pharmacological response produced by a chemically heterogeneous class of drugs involving mechanisms that remain incompletely understood.
Current concepts define anaesthesia by its core features of amnesia, unconsciousness, and immobility (in the order of decreasing potency), each mediated by pharmacological effects on specific neuronal networks in different regions of the central nervous system. The molecular targets of these region- and dose-specific actions on neuronal network function have not been defined for most anaesthetics, although likely candidates have been identified and characterized.
This diversity of potential targets increases the probability of both positive and negative non-anaesthetic effects

While the actions of the i.v. anaesthetics can often be ascribed primarily to one or a few targets, the potent inhaled anaesthetics (ethers and alkanes) appear to be particularly promiscuous, interacting with many functionally important targets, both in the nervous system and in other organs.
As an example of the former, the anaesthetic effects of propofol and etomidate are mediated primarily though the potentiation of GABA_A receptors as demonstrated in the resistance to immobility of a knock-in mouse harbouring a mutant receptor engineered to be insensitive to these drugs.
Analogous experiments have not been as conclusive for the inhaled anaesthetics, which are more than 100-fold less potent than i.v. anaesthetics and consequently are less selective in their target interactions.
Nevertheless, i.v. and inhaled anaesthetics share overlapping effects on many targets including GABA_A and NMDA receptors. Actions on these two targets implicated in the desirable effects of anaesthetics, and other effects on unrelated targets, have come under renewed scrutiny for their potential roles in mediating potentially long-lasting detrimental effects on the developing and mature brain.
A defining feature of general anaesthetics is their ability to reversibly induce a coma-like state, but recent findings of changes in gene and protein expression persisting beyond emergence from anaesthesia provide a molecular basis for more durable effects.
This brief review highlights some of the critical laboratory findings that have called attention to the neurotoxic effects of anaesthetics, and efforts to establish the clinical significance of potential effects of anaesthetics on neurodevelopmental outcome.

Conclusions

Accumulating evidence from animal studies justifies recent concerns regarding the neurotoxic potential of anaesthetic drugs, particularly at the extremes of age.
In the young brain, neurodevelopmental factors predispose to anaesthetic excitotoxicity and effects on neurogenesis and synaptogenesis that can impair neurocognitive performance after early anaesthetic exposure. In the old brain, progressive neurodegenerative disease pathways can be exacerbated by anaesthetics in laboratory studies.
The clinical impact of these preclinical findings has not been established owing to difficulties in designing definitive studies and the significant delay between exposure and testing. Clearly further investigations, both experimental and epidemiological, are warranted to establish the clinical relevance and possible neuroprotective strategies for these untoward effects.
Alternatives to surgery and general anaesthesia are usually not available and pain itself can cause long-term neurodevelopmental deficits.
As current data do not support significant changes in practice other than avoiding purely elective procedures, anaesthesiologists should strive to minimize unnecessary exposure to general anaesthetic agents and other factors that might potentiate toxicity in susceptible patients.