Colorado Anesthesia Services Group

Data on Long-Term Cognitive Effects of General Anesthesia

Modern anesthesia has opened the door for increasingly complex surgical and diagnostic procedures, significantly advancing the field of medicine. For many years, it was believed general anesthetics (GAs) had reversible effects on the central nervous system, which would return to its baseline state after anesthetic exposure stopped. However, recent research proposes that general anesthesia may have long-term effects in the central nervous system, in the form of cellular signaling changes, functional, and even morphological differences, with potential implications for cognitive health.1 

Worsening cognitive health is a key feature of dementia and many other degenerative diseases, causing increasing impairment to normal function. Some types of dementia, including Alzheimer’s disease (AD) are characterized by accumulations of proteins in the brain.2 Studies conducted in animals suggested a link between exposure to certain volatile anesthetics and protein misfolding and aggregation following the pathological patterns of AD and related dementias. Tg2576 transgenic mice have the human APP-Swedish mutation, which produce increasing amounts of β-amyloid plaques, leading to cognitive decline. A 2008 study used these mice as a model for AD and found mice exposed to halothane, but not isoflurane, had greater amyloidopathy than control mice.3 The researchers proposed that halothane, as a GA, exerts such effect through a reduction in solubility of the β-amyloid monomer, which has been shown to enhance oligomerization and cytotoxicity of β-amyloid in vitro.3 However, data in humans is necessary.

A clinical review from the University of Toronto investigated the long-term cognitive effects of general anesthesia on human patients in a 2011 systematic review and meta-analysis. Of the 15 studies that were controlled for age and gender, there was no significant association between exposure to general anesthesia and subsequent development of AD.4 Unfortunately, the study was limited by its retrospective nature and the diversity of studies included.

In 2014, a case-controlled study found a mild increased risk of Alzheimer’s Disease and other forms of dementia for patients exposed to general anesthesia. This risk increased linearly with repeated exposure to anesthetic agents. Further, the risk is amplified by presence of patient comorbidities, such as diabetes mellitus, hypertension, stroke, or atherosclerosis.5

A multicenter, randomized, open-label, phase 4 trial used data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial, assessing 97 children with cystic fibrosis to determine the impact of early GA exposure. Children who underwent bronchoalveolar lavage (BAL) therapy were exposed to higher levels of general anesthesia than their age-matched counterparts, who received standardized CF care. Researchers collected data on executive function, IQ, and brain imaging to examine whether these metrics differed based on exposure to general anesthesia. The study found no significant differences.6

Although patients may experience acute cognitive effects after surgery and general anesthesia, many of the observed behavioral and physiological changes can be attributed to the stress of surgical trauma and recovery, rather than any aspects of general anesthesia.4 Large-scale observational studies report 25% of patients undergoing non-cardiac surgery develop some sort of post-operative cognitive dysfunction (POCD) in the week following surgery. However, studies also report no significant difference between the association of either general anesthesia or regional anesthesia and POCD development.7

Based on current information, there is only a slight trend supporting an association between general anesthesia and long-term cognitive effects. The decision of what type of anesthesia to be used should be made after careful consideration of the surgical procedure at hand and patient-specific factors. Further long-term RCTs using biomarkers or imaging techniques would be necessary to clarify the relationship between general anesthesia and long-term cognitive decline.


References

  1. Wu, Lingzhi, et al. “Lasting Effects of General Anesthetics on the Brain in the Young and Elderly: ‘Mixed Picture’ of Neurotoxicity, Neuroprotection and Cognitive Impairment.” Journal of Anesthesia, vol. 33, no. 2, Apr. 2019, pp. 321–35. https://doi.org/10.1007/s00540-019-02623-7 
  2. Querfurth, Henry W., and Frank M. LaFerla. “Alzheimer’s Disease.” New England Journal of Medicine, vol. 362, no. 4, Jan. 2010, pp. 329–44. https://doi.org/10.1056/NEJMra0909142 
  3. Bianchi, Shannon L., et al. “Brain and Behavior Changes in 12-Month-Old Tg2576 and Nontransgenic Mice Exposed to Anesthetics.” Neurobiology of Aging, vol. 29, no. 7, July 2008, pp. 1002–10. https://doi.org/10.1016/j.neurobiolaging.2007.02.009 
  4. Seitz, Dallas P., et al. “Exposure to General Anesthesia and Risk of Alzheimer’s Disease: A Systematic Review and Meta-Analysis.” BMC Geriatrics, vol. 11, no. 1, Dec. 2011, p. 83. https://doi.org/10.1186/1471-2318-11-83
  5. Chen, Chia-Wen, et al. “Increased Risk of Dementia in People with Previous Exposure to General Anesthesia: A Nationwide Population-Based Case–Control Study.” Alzheimer’s & Dementia, vol. 10, no. 2, Mar. 2014, pp. 196–204. ScienceDirect, https://doi.org/10.1016/j.jalz.2013.05.1766
  6. Wainwright, Claire Elizabeth, et al. “Long-Term Outcomes of Early Exposure to Repeated General Anaesthesia in Children with Cystic Fibrosis (CF-GAIN): A Multicentre, Open-Label, Randomised Controlled Phase 4 Trial.” The Lancet Respiratory Medicine, June 2024. https://doi.org/10.1016/S2213-2600(24)00170-X
  7. Rasmussen, L. S., et al. “Does Anaesthesia Cause Postoperative Cognitive Dysfunction? A Randomised Study of Regional Versus General Anaesthesia in 438 Elderly Patients.” Acta Anaesthesiologica Scandinavica, vol. 47, no. 3, Mar. 2003, pp. 260–66.  https://doi.org/10.1034/j.1399-6576.2003.00057.x