Journal Article

Lasting impact of general anaesthesia on the brain: mechanisms and relevance

Vutskits, Laszlo, Xie, Zhongcong

2016

Overview

Key Points 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. Some epidemiological studies suggest associations between general anaesthesia and long-term cognitive dysfunction in children and the elderly, although these remain to be proven. Here, Vutskits and Xie review the evidence for general anaesthetic-induced cognitive impairment in young and old rodents and non-human primates, and the potential underlying mechanisms. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/2 / 13/21 / 14/19 / 14/28 / 631/378/1689/1283 / 631/378/1934 / 631/378/2591 / 692/700/565/545 / 82/1 / 96/100 / Age Factors / Anesthesia, General - adverse effects / Anesthesia, General - trends / Anesthetics - administration & dosage / Anesthetics - adverse effects / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological Techniques / Biomedicine / Brain - drug effects / Brain - pathology / Brain - physiology / Brain research / Cell Death - drug effects / Cognition Disorders - chemically induced / Cognition Disorders - diagnosis / Cognition Disorders - psychology / Cognitive disorders / Complications and side effects / General anesthesia / Humans / Neurobiology / Neurosciences / Postoperative Complications - chemically induced / Postoperative Complications - diagnosis / Postoperative Complications - psychology / Public health / review-article / Risk factors / Rodents / Surgery / Time Factors