Anesthesia and Cognitive Decline: No Link?

Liam Davenport

January 26, 2016

There is no significant link between exposure to general anesthesia and the development of mild cognitive impairment (MCI) in individuals aged 40 years and older, a large, comprehensive, population-based study shows.

The potential link between exposure to surgical anesthesia, MCI, and dementia has been a matter of recent debate, with previous research contradicting the current findings.

This new study also found no link between exposure to anesthesia and MCI when assessed as a dichotomous variable or when analyzed in terms of the number of exposures or the total cumulative duration of exposure.

"It is reassuring for the majority of older folks who might need surgery that they can be relatively reassured based on the state of the literature right now that just the experience of having anesthesia and surgery itself is probably not going to be associated with long-term cognitive decline," senior author David O. Warner, MD, professor of anesthesiology, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

Subgroup analyses, however, hinted that there may be an increased risk for MCI following anesthesia exposure in older patients and in those undergoing vascular surgery, which will need to be investigated in further studies.

The results were published online January 20 in Mayo Clinic Proceedings.

Dementia Risk

As previously reported by Medscape Medical News, in 2014, a study that included almost 25,000 Chinese patients aged 50 years and older who underwent anesthesia for surgery and more than 110,000 control participants suggested that the risk for dementia was nearly doubled within 3 to 7 years after the procedure.

A number of other studies published in recent years, including a retrospective analysis of 877 case-control sets, have indicated, however, that there is no association between anesthesia and the risk for dementia.

In the current study, investigators examined data from the Mayo Clinic Study of Aging and the Rochester Epidemiology Project, which included residents of Olmsted County, Minnesota, aged 70 to 89 years, who underwent cognitive assessment every 15 months. Surgical and anesthetic records after age 40 years were obtained for each participant.

The study included a total of 1731 individuals (mean age, 79 years). Of these, 536 (31.0%) developed MCI over a median follow-up period of 4.8 years.

Proportional hazards regression analysis that took into account known risk factors for MCI indicated that anesthesia exposure, assessed as a dichotomous variable, was not associated with MCI (adjusted hazard ratio [aHR], 1.07; P = .61).

Moreover, there was no link between the number of anesthesia exposures and MCI (aHR vs no exposure, 1.05 for one exposure, 1.12 for two to three exposures, and 1.02 for at least four exposures; P = .73). Total cumulative anesthesia exposure was also not linked to MCI (aHR, 1.00 per 60-min increase in exposure; P = .83).

The current findings are valuable in part because of the richness of the source material. Dr Warner said that because the Olmsted County records are highly comprehensive, it is possible to ascertain what patients experienced in terms of medical care and diagnoses.

Furthermore, the Mayo Clinic Study of Aging, which is based on the Olmsted County dataset, takes all that retrospective information and prospectively assesses the patients' cognitive function.

"When you put those two together, we have a very complete record of all the medical care and then also a very complete assessment of their cognitive status over time. So it was a nice tool for us to be able to use," he said.

Caveats in Interpretation

Although Dr Warner believes the findings are reassuring for patients and physicians alike, he emphasized that there are some caveats to interpreting the data.

"We always have notes of caution when you look at these kinds of studies. The caution usually goes the other way, though. You see the associations, and you're always left wondering: 'Well, maybe that's something meaningful, or maybe it's just a random association.'

"When we see something like this, when we don't see an association, it does make us feel reasonably confident that it doesn't look like there's any clinically significant associations going on.

"Although, again, studies like this are purely observational, and it certainly could be that there's a particular subset of patients, a particular subset of procedures that could be associated with problems that we weren't able to detect with the size of study that we have," he added.

A subanalysis suggested that some factors were associated with an increased risk for MCI following exposure to general anesthesia. For example, use of anesthesia after age 60 years was associated with incidence MCI (aHR, 1.25; P = .04).

Anesthesia exposure within 20 years of an MCI diagnosis and exposure within 10 years of diagnosis were both associated with an increased risk for incident MCI (HR, 1.33 and 1.23, respectively; P = .006 and P = .02).

Undergoing nonbypass cardiac or vascular surgery after age 60 years or within 20, 10, and 5 years of an MCI diagnosis was also associated with an increased risk for incident MCI (HR, 1.55, 1.61, 1.78, and 2.15, respectively; P = .002, P = .005, P = .009, and P = .001).

Clearer Picture

Commenting on the findings of Medscape Medical News, Roderic G. Eckenhoff, MD, Austin Lamont Professor of Anesthesia, Department of Anesthesia and Critical Care, University of Pennsylvania, in Philadelphia, said that a number of recent studies of the effect of surgery and anesthesia on incident dementia and cognitive decline have allowed a clearer picture to emerge.

Although the current findings are "comforting," they reinforce the notion that a signal begins to emerge once the study populations are enriched for various risk factors associated with MCI and dementia, he said.

"It's not a huge signal, which again is comforting, but it is a significant effect. The bottom-line message is that if you enrich your population for a vulnerability that the patient brings to surgery with them, then the inflammatory stress and everything imposed by surgery does accelerate what's going on.

"You can argue ― reasonably, I guess ― that these are just comorbidities that, of course, are going to get worse anyway, but there does appear to be an incremental effect of having surgery and anesthesia in these vulnerable subgroups," said Dr Eckenhoff.

Dr Warner agreed that this is "possible," although he argued that the population-based nature of the current study should have taken into account that sort of phenomenon.

"Let's take vascular surgery. There's now increasing evidence that, in some ways, Alzheimer's and MCI may have a fairly important vascular component to the pathophysiology of the disease, so that patients with vascular disease may be at greater risk to develop these kinds of problems.

"If you say that one of the things that puts you at risk for having vascular surgery is vascular disease, then you might expect that maybe having vascular surgery is a marker for patients who have vascular disease who then would go on to develop these problems.

"It doesn't necessarily mean that the anesthesia or the surgical experience itself was responsible for the cognitive decline, it's just that those types of patients are at greater risk," he said.

"The real answer is that we just don't know.... It's a limitation of this kind of study design that you just can't make these kinds of definitive conclusions, but I wouldn't exclude it either," Dr Werner added.

Further Research Needed

Consequently, Dr Eckenhoff believes that more research is needed on the link between exposure to general anesthesia, surgery, and MCI.

"Carrying this forward, the imperative for anesthesiology and surgery is to begin to test for these vulnerabilities prior to anesthesia and surgery, so that we can inform patients and their families of the potential risk. That's number one. And then, number two, of course, is to figure out how to mitigate that risk, and right now we don't know how to do that," he said.

"What's the mechanism for this incremental effect? We think we know. It probably lies in the domain of neuroinflammation, but we don't really know yet, and we certainly don't know how to mitigate it appropriately at this point," Dr Eckenhoff added.

He noted that large, retrospective analyses of, for example, the Medicare database and good prospective studies are required.

"Prospective studies, of course, are going to be very difficult to do because they're expensive, they're going to take a long time, and they're never going to be big enough to definitively answer the question."

Nevertheless, he added that "we need all these different kinds of studies, and I think the real progress is going to be in the realm of biomarkers. If we can really understand biomarkers, how they reflect disease and disease progression, we can then focus on using those with our interventions, like anesthesia and surgery, and on mitigating strategies."

The study was supported by National Institutes of Health grants; by the Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program; and by Mayo Clinic Center for Translational Sciences Activities grant UL1 TR000135 from the National Center for Advancing Translational Sciences. The Rochester Epidemiology Project is funded by National Institute on Aging grant R01-AG034676. A number of coauthors have reported various ties to industry, which are listed in the original article.

Mayo Clin Proc. Published online January 20, 2016. Full text

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