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June 1, 2013 Volume 77, Number 6
Anesthesia and Surgery in the Elderly: 15 Years of Progress on Postoperative Central Nervous System Dysfunction Christopher J. Jankowski, M.D. Committee on Geriatric Anesthesia

Deborah J. Culley, M.D. Committee on Geriatric Anesthesia



“A journey of a thousand miles must begin with a single step.”
– Chinese Proverb


Surgery before the advent of anesthetics was harrowing. In 1843, Professor George Wilson underwent an ankle disarticulation. Four years later, he described his experience:

“The horror of great darkness, and the sense of desertion by God and man, bordering close on despair, which swept through my mind and overwhelmed my heart, I can never forget, however gladly I would do so … I still recall with unwelcome vividness the spreading out of the instruments: the twisting of the tourniquet: the first incision: the fingering of the sawed bone: the sponge pressed on the flap: the tying of the blood-vessels: the stitching of the skin: the bloody dismembered limb lying on the floor.”1

Professor Wilson’s experience – three years before the first public demonstration of anesthesia – drives home the significance of anesthesia from an individual patient’s perspective. Given the important role of anesthesia in modern medical practice, it is ironic that, until recently, there was a paucity of research about its impact on the brain, the target organ of the drugs we administer every day.

This year marks the 15th anniversary of the publication of the original report from the International Study of Postoperative Cognitive Dysfunction (ISPOCD) group describing the risk factors for postoperative cognitive dysfunction (POCD) in elderly surgical patients.2 The paper was groundbreaking in several respects: it marked the first systematic study of the medium-term cognitive sequelae of anesthesia and surgery in non-cardiac surgical patients, established a definition of POCD that accounted for preoperative cognitive status and took into account cognitive changes over time of non-operative controls. More importantly, it established age as the primary risk factor for POCD. Though postoperative cognitive changes have been reported since 1955,3 the ISPOCD group’s work (published 152 years after the first public demonstration of anesthesia) marks the beginning of serious inquiry into the effects of anesthesia and surgery on the elderly brain. Since the number of elderly patients presenting for surgery and anesthesia continues to increase, an interest in this area could not be timelier. Improved understanding of the risks, mechanisms and potential ways to prevent or mitigate postoperative cognitive changes has important public health implications since postoperative cognitive changes occur in up to 50 percent of older surgical patients and are associated with increased mortality, morbidity and costs, and decreased functional status.4

Before reviewing progress over the last decade and a half, however, some definitions are in order, since there tends to be confusion over the various forms of postoperative central nervous system dysfunction (PCNSD). PCNSD is divided into two broad categories: delirium and POCD. In addition to differences in symptoms (see above), delirium and POCD have varying time courses. Acutely altered levels of consciousness, cognition and attention deficiencies, and perceptual disturbances characterize delirium. Its onset occurs over the course of hours to days and fluctuates over time. By definition, it cannot be accounted for by a preexisting or evolving dementia. Delirium may be categorized as hyperactive, hypoactive or mixed.

Unlike delirium, POCD is a research construct without a universally agreed-upon definition. Broadly, it consists of cognitive changes after surgery. Many studies of POCD involve tests of a variety of cognitive functions and use statistical methods to arrive at the research classification of POCD. For example, a patient may have POCD if postoperative testing demonstrates minor declines in a number of cognitive domains or a significant decline in just one. Unlike patients with delirium, those with POCD tend to be alert and oriented. A more detailed discussion of PCNSD can be found in an excellent review by Silverstein and Deiner.4

What have we learned about these entities over the past 15 years? Plenty. First, the risk factors for PCNSD have been defined. For POD they include age, neurocognitive reserve, type of operation, visual and hearing impairment, dehydration and metabolic derangements. Risk factors for POCD outside the immediate perioperative period include age and major surgery. POD does not appear to be a risk factor for subsequent POCD.5 Further, as suggested above, there appears to be growing consensus that POD and POCD are distinct entities.

Extensive laboratory work has been done to investigate possible contributions of anesthetics to PCNSD. In aged rodents, clinically relevant concentrations of volatile anesthetics cause persistent impairment of learning and the ability to perform previously learned tasks.6,7 They also induce structural brain changes similar to those seen in degenerative neurologic disease.8 In cell culture models, volatile anesthetics cause increases in the production, oligomerization and cytotoxicity of beta-amyloid, a protein associated with Alzheimer’s disease.9 They also induce capsase activation leading to programmed cell death in a manner similar to Alzheimer’s disease.10

These laboratory findings led to investigations into whether anesthesia and surgery increase the risk of dementia. It is reassuring that the limited literature has not found an association.11,12 However, there is a need for long-term prospective studies in this area.

Despite a tremendous increase in our understanding of PCNSD, a number of important questions remain. First, there is a need for a consensus definition of POCD. Ideally, it should correlate with patient and caregiver reports of postoperative changes in cognition. We also need to identify the mechanisms by which POCD develops and whether genetics play a role. Both are important for the development of targeted strategies to prevent and treat PCNSD. Although a recent article suggests that the apolipoprotein ε4 allele, a marker for increased risk for Alzheimer’s disease, is associated with a greater degree of cognitive decline after surgery and general anesthesia using a volatile anesthetic when compared to propofol,13 this is an area in need of further investigation.

Interestingly, we have no data on the CNS effects of anesthesia and surgery on patients with preexisting mild cognitive impairment, nor whether they alter the trajectory of cognitive aging or the pathology-related cognitive decline, as all published studies of POCD have excluded patients with cognitive deficits. Since the number of patients with preexisting cognitive impairment presenting for surgery will undoubtedly increase, an understanding of this issue is imperative. Fortunately, an ongoing multicenter prospective study is addressing this question.14

Similarly, while in vitro and in vivo models suggest that exposure to clinically relevant concentrations of volatile anesthetics have long-term effects on CNS function and induce neuronal changes associated with Alzheimer’s disease, it is not known whether exposure to anesthesia without surgery causes cognitive decline in humans since the choice of regional versus general anesthesia does not appear to influence the incidence of POCD.15 This is a key question for anesthesiologists as the results may lead to alterations in anesthetic management of elders. However, if anesthetics are not involved it would suggest that further investigations should include an evaluation of whether minimizing the degree of surgical insult or mitigating the physiological response to surgery are beneficial.

While the thousand-mile journey of fully comprehending how anesthesia and surgery affect the elderly brain is far from complete, our specialty has travelled far in the 15 years since the first step was taken. Members of SAGA, the ASA Committee on Geriatric Anesthesia, other groups such as the American Delirium Society, and the research community at large are committed to improving understanding of PCNSD and the care of elderly surgical patients.



Christopher J. Jankowski, M.D. is Assistant Professor of Anesthesiology, and Consultant in Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Deborah J. Culley, M.D. is Assistant Professor of Anesthesiology, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School, Boston.


References:
1.  Robertson HR. Without benefit of anesthesia: George Wilson’s amputation and Fanny Burney’s mastectomy. Ann R Coll Physicians Surg Can. 1989;22:28-28.
2. Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. Lancet. 1998;351(9106):857-861.
3. Bedford PD. Adverse cerebral effects of anaesthesia on old people. Lancet. 1955; 269(6884):259-263.
4.  Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction. Br J Anaesth. 2009;103(suppl 1):i41-i46.
5. Jankowski CJ, Trenerry MR, Cook DJ, et al. Cognitive and functional predictors and sequelae of postoperative delirium in elderly patients undergoing elective joint arthroplasty. Anesth Analg. 2011;112(5):1186-1193.
6. Culley DJ, Baxter M, Yukhananov R, Crosby G. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth Analg. 2003;96(4):1004–1009.
7.  Culley DJ, Baxter MG, Yukhananov R, Crosby G. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats. Anesthesiology. 2004;100(2):309–314.
8. Bianchi SL, Tran T, Liu C, et al. Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics. Neurobiol Aging. 2008;29(7):1002–1010.
9. Eckenhoff RG, Johansson JS, Wei H, et al. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology. 2004;101(3):703–709.
10. Xie Z, Dong Y, Maeda U, et al. The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci. 2007;27(6):1247-1254.

For a complete list of references, please refer to the back of the online version of the ASA NEWSLETTER at asahq.org or email communications@asahq.org