Every year, millions of patients receive general anaesthesia for surgery or diagnostic procedures, and there is a growing concern that anaesthetic drugs might exert long-term effects on the CNS, especially at the extremes of age.
There is currently mixed epidemiological evidence in humans for an association between early-life anaesthesia exposure and an increased risk of subsequent sustained neurobehavioural deficits. Postoperative cognitive dysfunction in elderly individuals is of multifactorial origin, and there is no evidence for a direct causal link between anaesthesia exposure and Alzheimer disease in humans.
In both neonatal and ageing animals, exposure to general anaesthetics can induce lasting behavioural and cognitive deficits. These effects are dose, exposure length and sex dependent.
In the neonatal brain of experimental animals, administration of general anaesthetics induces impaired growth factor signalling and mitochondrial dysfunction, which in turn result in apoptosis, impaired neurogenesis or altered synaptogenesis. How these events are related to altered cognitive function remains unclear.
In the mature brain of rodents, general anaesthetics can induce dose- and exposure length-dependent amyloid-β aggregation and tau hyperphosphorylation, as well as neuroinflammation.
There are important gaps related to the translational relevance of currently available experimental models in anaesthesia-neurotoxicity research. Among them, determining how concurrent surgical and other perioperative stimuli modify the effect of general anaesthetics on the brain is of primary importance.
General anaesthesia is usually considered to safely induce a reversible brain state allowing the performance of surgery under optimal conditions. An increasing number of clinical and experimental observations, however, suggest that anaesthetic drugs, especially when they are administered at the extremes of age, can trigger long-term morphological and functional alterations in the brain. Here, we review available mechanistic data linking general-anaesthesia exposure to impaired cognitive performance in both young and mature nervous systems. We also provide a critical appraisal of the translational value of animal models and highlight the important challenges that need to be addressed to strengthen the link between laboratory work and clinical investigations in the field of anaesthesia-neurotoxicity research.
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The authors thank M. de Roo for helpful discussions during the preparation of this manuscript.
The authors declare no competing financial interests.
A syndrome characterized by an acute disturbance of consciousness that usually occurs in association with impairment in attention and cognitive functions.
A member of the benzodiazepine family of sedative drugs, which act as positive allosteric modulators of type A GABA receptors.
- Anaesthetic equipotency
The comparative dose or concentration of anaesthetic drugs that provides equal ability or strength to induce general anaesthesia.
- Volatile anaesthetic
A chemical compound that can be volatilized to vapour, which, when inhaled, can induce general anaesthesia.
- Brain growth spurt
This term refers to the rapid growth of the developing brain that takes place between the last trimester of pregnancy and the first few years of life in humans and during the first postnatal month in rodents.
- Mitochondrial fission–fusion balance
Dynamic fluctuations in the architecture of mitochondria that aim to allow cells to adapt to environmental demands; impairment of these dynamics can result in reduced oxidative phosphorylation, cell death and thereby disease.
- Amyloid precursor protein
(APP). A transmembrane protein that is thought to have a central role in the pathogenesis of Alzheimer disease.
A peptide of varying length (between 36 and 43 amino acids) that is generated by the proteolytic cleavage of β-amyloid precursor protein and that constitutes the main component of the amyloid plaques that are found in the brains of patients with Alzheimer disease.
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Vutskits, L., Xie, Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci 17, 705–717 (2016). https://doi.org/10.1038/nrn.2016.128
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