Advancement of health care and continuous improvement of perioperative medicine which result in reduction of surgical mortality and morbidity have led to an exponential increase in the safety of surgery. The number of elderly patients undergoing surgical procedures is progressively increasing, and postoperative cognitive decline in these patients has emerged as a major health concern. Postoperative cognitive dysfunction (POCD) refers to cognitive problems that involve memory, learning, and the ability to concentrate after surgery. In 1982, Savageau first described cognitive dysfunction, which had a strong association with surgery and anesthesia exposure.¹ Particularly among the elderly, a number of cases with short-term or long-term POCD have been globally reported.¹

The incidence of POCD has been found to be higher after cardiac surgery than noncardiac surgery, and the risk increases with age.² However, it is of interest to note that the off-pump coronary artery bypass graft has not significantly reduced the occurrence of POCD in comparison with the on-pump coronary artery bypass graft. The clinical research report by Dr Karen Ritchie and her team (who paid close attention to study design and statistical and analytic procedures) on the long-term effects of anesthesia on cognitive functioning after orthopedic surgery in a large number of elderly patients stresses that POCD is not confined only to cardiac surgery, according to their observation.³ Neurocognitive dysfunction occurs frequently in patients undergoing noncardiac surgery, indicating that some elements of surgery and/or anesthesia might contribute to this condition.

POCD is now receiving greater attention because it could be associated with major health and social issues, such as higher morbidity of mental illness, increased expenditure on hospitalization, increased domestic economy, and reduced quality of life. Because many elderly patients undergo inhalational anesthesia with volatile agents, a mechanistic association between anesthesia, POCD, and neurodegenerative disorders is possible. Increasing evidence indicates that inhalational anesthetic agents may cause or increase the risk of developing POCD. A more rigorous approach is needed to codify the frequency and extent of early and delayed POCD against the data on the anesthetic agents used in the medical field.

Surgery is associated with stress response, such as increased secretion of cortisol and catecholamines. Persistently high levels of stress may inhibit memory and interfere with hippocampal function. Surgery also activates specific homeostatic responses, thus triggering immune mechanisms and the inflammatory cascade through the release of various inflammatory mediators. Fluctuations in hormone levels after surgical trauma may affect neurotransmitter synthesis, thereby disturbing cognitive function. Neuroinflammation has been shown to play a role in the pathogenesis of neurodegenerative disorders and can cause cognitive impairment in humans and in animals. Wu et al found that clinically relevant isoflurane anesthesia increased the production of tumor necrosis factor-α, interleukin-β, and interleukin-6 in the mice neurons.⁴ This finding suggested that inflammation plays a pivotal role in the development of POCD. The neuroinflammatory response to surgery appears to be a significant contributor to the pathogenesis of POCD.⁵

In the operating room, anesthesia and surgery affect the patient concomitantly. Surgical trauma and its consequential damages most likely play a greater role than anesthesia in the development of POCD. The pathophysiology of POCD is poorly understood, and multicomponent interventions that target well-documented risk factors would be helpful. It is important to assess the risk factors predisposing patients to POCD preoperatively and to modulate preexisting disorders of patients before major surgery is performed. In examining the role of anesthesia and surgery in generating POCD, it is extremely difficult to discriminate whose effects between anesthesia and surgery or its associate inflammation should be responsible.

Although anesthesia is an indispensable component of surgery and is generally considered to be safe and effective, in some situations there is growing concern about its potential neurotoxicity.⁶ Inhalational anesthetic agents have been the most widely administered drugs in general anesthesia. According to our understanding, general anesthesia affects brain function at all levels, including neuronal membranes, receptors, ion channels, neurotransmitters, cerebral blood flow, and metabolism. Short-term impairment of cognitive and psychomotor performance is common after general anesthesia and is typically attributed to incomplete drug clearance. At the organismic level, they affect not only consciousness but also hemodynamics, thermal balance, ventilatory control, and possibly immune function. Thus, it is not unreasonable to expect that these drugs may have deleterious effects on brain function. Increasing evidence indicates that inhalational anesthetic agents may cause or increase the risk of developing POCD, especially in the elderly population. The most common agents currently used in inhalational anesthesia are volatile anesthetic agents (isoflurane, desflurane and sevoflurane),7, 8, 9 all of which are highly lipid soluble and of low affinity; hence, they can rapidly access the brain in high concentrations.

Interactions of anesthetic agents and different targets have been studied at the molecular, cellular, and structural anatomic levels. Animal models have suggested that inhalational anesthetic agents may precipitate a decline in cognitive function.¹⁰ Studies on nonhuman primates have raised valid questions about the safety and implications of anesthesia in the developing or green brain. Merle Paule demonstrated that the effect of anesthesia on brain development and the negative impact it can have on brain functioning.¹¹ Dr. Gong and his team members stated in their article that inhaled anesthetic induced hyperphosphorylation of tau protein is also a significant observation in animal model studies.¹² As highlighted by Dr. Tripati and colleague, from a neurologic diagnostic point of view, clinical awareness of the emerging metabolic, nutritional, endocrinal, toxic, autoimmune, cerebrovascular, genetic, infectious, and hemorheologic factors need to be kept in mind in the differential diagnosis of dementia, and be added to the already established causes of dementia, which require consideration in the presence of POCD.

There remains a great discrepancy between clinical studies investigating the prevalence of POCD and inhalational anesthetic agents because an association between them has not been shown. The possibility that general anesthesia contributes to cognitive deterioration has not been tested directly, partly because clinical studies have not controlled the anesthetic agents used and cannot differentiate the effects between illness, hospitalization, surgery, and anesthesia. Another methodologic problem was the lack of a control group in which the individuals studied did not undergo surgery. This is an important limitation and a common weakness of the studies of this area. Without a control group it is impossible to compensate for the practice effect and estimate the variation related to the specific neuropsychologic tests. Moreover, one of the difficulties of human research in this area is that anesthesia is seldom administered as a sole treatment procedure but is almost invariably administered to facilitate surgery. Additional studies to improve the understanding of the influence of perioperative management on POCD, especially in terms of anesthesia, appear to be necessary. The development of more effective prevention strategies remains an important goal.

In the December issue 2011 of Acta Anaesthesiologica Taiwanica, Ma raises the important issue in his article “Does inhalational anesthetics cause cognitive dysfunction?”, in which inhalational anesthesia and its role on the development of postoperative cognitive dysfunction have been reviewed. A reliable link between the animal and human data emerges. For instance, numerous animal studies have suggested that inhalational anesthetics may alter cognitive function via amyloid β accumulation, modified neurotransmission, synaptic changes, and dysregulated calcium homeostasis. Other factors such as neuroinflammation and proinflammatory cytokines may also play a role. However, the relationship among anesthesia, surgery, and POCD or other dementias in humans remains inconclusive. Determining the association between inhalational anesthesia and cognitive decline is essential to optimize postoperative outcomes in surgical patients and reduce the incidence of POCD in the future. As research continues to define the roles of various inflammatory mediators involved in the pathophysiology of POCD, more specific anti-inflammatory therapies will be available in this field. It is hoped that this review will encourage further incentives, especially triggering research in elucidating which anesthetic agents may be more suitable and safer as far as cognitive dysfunction is concerned.