Anesthesia and Long-Term Cognitive Decline: Is There a Link?

For many of the estimated 234 million individuals who undergo surgery each year worldwide, general anesthesia is a necessity.¹ However, findings from animal studies indicate that these anesthetics may be neurotoxic and could result in long-term central nervous system alterations and cognitive dysfunction, particularly in very young or elderly patients.^2,3

Mechanisms and Findings

“Anesthetics and other perioperative factors may cause cognitive dysfunction by inducing apoptosis, neuroinflammation, [amyloid] beta accumulation, tau phosphorylation, mitochondrial dysfunction, energy deficits, and synaptic dysfunction,” Zhongcong Xie, MD, PhD, the Henry Knowles Beecher Professor of Anesthesia at Harvard Medical School, and the director of the Geriatric Anesthesia Research Unit at Massachusetts General Hospital, told Neurology Advisor.

In children, the pharmacologic impact on experience-driven physiologic activity patterns of the developing brain can have enduring effects on brain function. In older individuals, alterations in neuronal cell properties and cell-cell interactions can lead to “impairments in the capacity of neuronal networks to adapt to or recover from transient changes in neuronal homeostasis,” which “may then result in a pronounced vulnerability of neuronal networks to pharmacologic challenges such as general anaesthesia,” as explained in a recent paper published in Nature Reviews Neuroscience coauthored by Dr Xie.²

In addition to observations from animal research, links between anesthesia and subsequent neurobehavioral deficits have been supported by results of human epidemiologic studies, although such findings have been inconclusive overall.² For example, several cohort studies found educational, developmental, and behavioral impairments in children who had received anesthesia before the age of 3 or 4, whereas other cohort studies and clinical trials showed no differences between previously exposed and unexposed children on similar outcomes.^4-8

Anesthesia or Age Related?

Older adults are especially vulnerable to postoperative delirium (POD) and postoperative cognitive dysfunction (POCD). “POD is an acute, transient, and fluctuating decline in cognitive functioning in the early postoperative period, whereas POCD is a chronic impairment with more subtle deterioration in memory, attention, and speed of information processing following anaesthesia and surgery,” as described in the Nature paper.² Diagnostic criteria for POCD have not been established, and diagnosis can be challenging because of the subtlety of the cognitive changes associated with the condition. A multicenter trial of patients over age 60 who underwent noncardiac surgery detected POCD in 10% of patients 3 months after surgery, and it was determined that 1% of patients may have POCD that persists for years.⁹

Findings from a population-based case-control study published in 2017 in Anesthesia and Analgesia suggest that such long-term impairments may actually reflect patients’ natural trajectory of cognitive decline.¹⁰ The investigators noted that much of the research in this area has used dementia as the primary outcome and proposed that mild cognitive impairment (MCI) may “represent a more sensitive outcome to detect an association between anesthesia and long-term cognitive dysfunction, because diagnosis of MCI often precedes the diagnosis of dementia.” In their sample of 387 patients (57% male; mean age, 81 ± 5 years at time of enrollment), no association was demonstrated between prevalent MCI and general anesthesia exposure after age 40 (based on medical records). This is in line with observations from the group’s previous research and that of other investigators.

It may be that the relationship between anesthesia and long-term cognitive impairment is only temporal. Transient postsurgical cognitive decline is more likely to occur in patients who already have lower levels of cognitive reserve, and recovery from this state may take months. “By that time, the patient’s cognitive status ‘recovers’ to a lower level, which is on trajectory of their ongoing cognitive decline,” but family members and other observers may interpret this new, lower cognitive state as related to the anesthesia, coauthor Juraj Sprung, MD, PhD, a professor of anesthesiology at Mayo Clinic, told Neurology Advisor. However, he and colleagues believe that “anesthesia-induced postoperative cognitive decline only unmasks individuals who are already in cognitive decline.”

Next Steps

Dr Sprung noted the importance of this topic for the elderly surgical population particularly, and says that more research is needed before the proposed association can be confirmed or excluded definitively. His group also recently found postsurgical delirium to be a potential marker for future dementia. “The main takeaways [are] that development of transient POCD or POD can be an indicator of preexisting low cognitive reserve and that these patients may already be on trajectory toward more profound decline in cognitive status,” he said. “And when it occurs — months after surgery — it is attributed falsely to the anesthesia exposure.”

He stated that further research should investigate links between transient POCD or POD and dementia, and if confirmed, then “these individuals need to be closely monitored, and they should receive counseling and even measures designed to slow the progression of this devastating disease.”

Dr Xie said additional studies should explore why POCD develops in some patients and not in others, and whether some anesthetics are less neurotoxic than others and, if so, why. Researchers should also continue to examine “whether anesthesia and other perioperative factors have neurotoxicity, and if so, what the underlying mechanisms” and interventions may be.

References

1. Fodale V, Tripodi VF, Penna O, et al. An update on anesthetics and impact on the brain. Expert Opin Drug Saf. 2017;16(9):997-1008.
2. Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci. 2016;17(11):705-717.
3. Mandal PK, Saharan S, Penna O, Fodale V. Anesthesia issues in central nervous system disorders. Curr Aging Sci. 2016;9(2):116-143.
4. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796-804.
5. DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21(4):286-291.
6. Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12:246-253.
7. Davidson AJ, Disma N, de Graaff JC, et al. Neurodevelopmental outcome at 2 years of age after general and awake‑regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016;387(10015):239-250.
8. Sun LS, Li G, Miller TL, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA. 2016;315(21):2312-2320.
9. Abildstrom H, Rasmussen LS, Rentowl P, et al. Cognitive dysfunction 1-–2 years after non‑cardiac surgery in the elderly. Acta Anaesthesiol Scand. 2000;44(10):1246-1251.
10. Sprung J, Roberts RO, Knopman DS, et al. Mild cognitive impairment and exposure to general anesthesia for surgeries and procedures: a population-based case-control study. Anesth Analg. 2017;124:1277-1290.