Current Perspectives on Postoperative Cognitive Dysfunction in the Ageing Population

10%-54


Introduction
Postoperative cognitive dysfunction (POCD) is a prolonged impairment in cognitive function that lasts weeks to months following surgery (1).First documented in the late 1800s, it is still a poorly understood problem in the medical community (2).POCD is especially prevalent in the elderly (3,4).As such, the fragility of cognition in the elderly is already carefully monitored to prevent the manifestation of delirium or the progression to dementia, both of which increase morbidity and are main contributors to major financial burden on our healthcare system (5)(6)(7).POCD has been associated with increased mortality, and it can develop as a result of delirium (8).It is therefore crucial to examine any factors that may contribute to the cognitive decline in preoperative patients.With a rapidly increasing need for surgical procedures and an increase in the number of elderly patients undergoing elective surgical procedures that necessitate the use of anaesthetic medications, the medical community is responsible for exploring the risk factors, strategies for prevention and treatment of POCD.

Epidemiology
The POCD incidence is estimated at 10%-54%.POCD occurs several weeks postoperatively and affects primarily the elderly (9).The ISPOCD1 study found an incidence of 25.8% one week and 9.9% three months postsurgery in patients >60 years who underwent major non-cardiac surgery (10).As the number of surgical procedures in the elderly population increases, so does the need to identify the POCD risk factors (11).
Preoperatively, some established POCD risk factors are similar to those of mild cognitive impairment (MCI), and they include diabetes, poor glycaemic control and low cognitive reserve (12)(13)(14).Other MCI risk factors such as obesity, sleep fragmentation and APOE4 homozygosity have shown to have weaker risk associations with POCD (15)(16)(17).In addition, preoperative history of cognitive or functional impairment, major coronary bypass surgery, pulmonary disease, alcohol abuse, electrolyte abnormalities, psychoactive medication or preoperative delirium (POD) have all been shown to increase the POCD risk (18)(19)(20).Chief among these is an increased risk due to pre-existing MCI, which has a prevalence of 38%-56% in elderly patients.Intraoperatively, cerebral desaturation, a prolonged exposure and depth of anaesthesia have been associated with an increased POCD risk (21).Finally, postoperative patients are at higher risk of developing POCD if they experience POD, infection, respiratory complications, poorly controlled pain or low haematocrit.
The effect of the type of surgery has been debated in POCD.Some factors that implicate the type of surgery are the length of procedure, postoperative complications, stress response or hospitalisation length of stay (22).Previous studies have described a higher incidence of POCD in major cardiac surgeries, such as coronary artery bypass graft, even reporting an incidence of 30%-80% a few weeks post cardiac surgery and 10-%60% three to six months post non-cardiac surgery in the elderly (23).However, recently Evered et al. (24) denied the importance of the surgery type in POCD.Most literature emphasises the need for specific epidemiological research on POCD, and for that reason, a precise definition is required.

Clinical Presentation
The primary issue facing POCD is finalising a distinct definition.Until this task is complete, clinical identification of POCD will vary between medical professionals.Some general guidelines suggest considering POCD as form of mild cognitive impairment and looking for similar clinical signs to help with diagnosis.Using this concept, POCD can be considered a persistent cognitive dysfunction that gradually develops postoperatively after a period of at least 1 week (25).The ISPOCD1 study identifies POCD as the presence of postoperative deficits in at least one area of mental state, including concentration, attention, memory, executive function, visuospatial ability and psychomotor speed.To achieve a reliable diagnosis, appropriate pre-and postoperative cognitive testing must be performed.Several tests are available to assess the cognitive function and impairment such as the mini mental state exam, Montreal cognitive assessment, Cognistat exam and Postoperative Quality Recovery Scale, as well as several computerised examinations (26).At this point, clinical evidence that suggests a new cognitive decline in postoperative patients from a pre-established baseline can qualify as POCD at the treating physician's discretion.

Pathophysiology
Although the pathophysiology behind the development of POCD has been debated, causative mechanisms are thought to be the following: the mode of anaesthesia application, anaesthetic choice, hypoperfusion, hyperventilation and neuroinflammation (27).Multiple studies have proposed a possible correlation between the mode of anaesthesia and the subsequent likelihood of developing POCD (Table 1).Specifically, long-term outcomes in patients receiving general anaesthesia or regional anaesthesia have been compared.The study by Mason et al. (28) is based on the hypothesis that general anaesthesia affects gene transcription, receptor efficacy, synaptic vesicle cycling, intracellular calcium homeostasis and anticholinergic effects.However, results did not statistically prove that regional anaesthesia is less likely to cause POCD.Another study involving 483 elderly patients found that POCD was less likely in patients who received regional anaesthesia than in those who received general anaesthesia 1 week postoperatively but that it did not vary significantly 3 months following general or regional anaesthesia (29).While limiting the depth of anaesthesia has been shown to reduce the risk of POD, no such research has been successful with POCD.
Additional research has attempted to correlate the incidence of Alzheimer's disease and specific modes of anaesthesia.Inhaled anaesthetics have been demonstrated to increase the formation of B-amyloid plaques and neurofibrillary tangles in animal models and in vitro studies.Such pathologies are typically present in Alzheimer's disease (30,31).However, a subsequent meta-analysis showed no correlation between previous exposure to inhaled anaesthetics and the development of Alzheimer's disease.
The incidence of POCD is not correlated with the use or avoidance of sedating agents such as propofol when a patient is receiving anaesthesia (Table 2).With this in mind, the use of dexmedetomidine instead of a propofol supplementary for a peripheral nerve block is significantly associated with a reduced incidence of POCD (32).Interestingly, patients who received dexmedetomidine in place of Propofol were found to have a significantly lower postoperative creatinine and a significantly higher postoperative GFR (33).Dexmedetomidine also yielded a significantly lower number of cases of postoperative hyperactive delirium and postoperative agitation.
Another hypothesis addressing the development of POCD involves intraoperative cerebrovascular autoregulation and hypoperfusion.In patients receiving general anaesthesia, the mean arterial pressure may stray outside the range in which cerebrovascular autoregulation can be maintained (Table 3).A study that involved patients undergoing surgery with a cardiopulmonary bypass found that the duration of the longest cerebrovascular autoregulation impairment was significantly associated with the occurrence of POCD (34).Currently, there is no consensus on an optimal mean arterial pressure during cardiopulmonary bypass.Using near-infrared spec-  troscopy to monitor cerebral oxygen saturation and the mean arterial pressure as a surrogate for cerebral blood flow, clinicians can monitor cerebral autoregulation in real time during surgery.Research has found a relationship between the mean arterial pressure falling below the lower limit of cerebral autoregulation and an increased incidence of major morbidity and operative mortality.Thus, the blood pressure management during cardiopulmonary bypass using physiologic endpoints to monitor cerebral autoregulation may optimise organ perfusion and improve postoperative outcomes (35).
Cognitive dysfunction has been linked to hyperoxia caused by hyperventilation following surgical procedures involving cardiopulmonary bypass.High oxygen content has been shown to be toxic to many organ systems, including cardiovascular, nervous, respiratory and gastrointestinal.High levels of oxygen increase free-radical formation and oxidative stress.Such stress is particularly damaging to the brain, as neurons have a higher rate of oxygen consumption and lower antioxidant defences (36).In a randomised controlled trial, patients were divided into one group receiving supplemental oxygen at a FiO 2 of 0.35 (normoxic) and another group receiving a FiO 2 of 1.0 (hyperoxic).It is currently suggested that monitoring and maintaining normal levels of oxygen intraoperatively, and avoiding a hyperoxic state, will reduce the incidence and presentation of POCD (37).The role of hypertension and risk of POCD is also being investigated, as one study found that hypertension is not associated with the POCD development, while also admitting that many confounding variables have not been adjusted for (38).
Anaesthesia during surgery is thought to produce a neuroinflammatory state that leads to POCD.The role of inflammation leading to neuronal dysfunction has been assessed.Systemic inflammation from bacterial LPS produces both working memory deficits and acute brain injury by acting on hippocampal neurons, causing hyperexcitation and permanent loss of membrane potential (39).Specifically, preoperative elevations in Il-6 and Il-8 were associated with poorer cognitive function postoperatively (40).POCD patients also had an increased plasma TNF-a and a decreased IGF-1 when compared to healthy patients (41).Neuroinflammation and oxidative stress secondary to anaesthesia are also thought to be caused by interrupted plasticity of neurons and  GA: general anaesthesia; RA: regional anaesthesia; CPB: cardiopulmonary bypass interference in glutamate signalling (Table 4).The need for neuroprotective agents is therefore justified.Although more research needs to be conducted before definitive results can be concluded, lidocaine, ketamine, Cox II inhibitors, minocycline, and dexmedetomidine currently show the most neuroprotective potential (42,43).The use of remifentanil instead of fentanyl is correlated with lower levels of inflammation (specifically IL-6) on postoperative Day 7, but no correlation was found between the remifentanil use and a decreased incidence of POCD (44).

Differentiating postoperative delirium from postoperative cognitive dysfunction
Differentiating POCD from POD is an important step to guide future clinical research (Table 5).POD is a subset of delirium and is defined in DSM-5 as a disturbance in attention and awareness, an acute change from baseline, and a disturbance in cognition that cannot be explained by an existing cognitive or otherwise attributable disorder.Millions are spent annually to alleviate the burden of POD, and current studies focus on addressing the risk of stratification, geriatric consultation, multidisciplinary programmes, optimising depth of anaesthesia, opioid-sparing pain management and polypharmacy avoidance (45).POCD also poses a significant burden on healthcare worldwide, but statistical analysis is thus far most limited by the inability of many POCD patients to adhere to study guidelines (46).
Although POCD currently has no agreed-upon diagnostic criteria, it broadly includes a prolonged impairment in cogni- tive function after surgery with deficits in memory, intellectual ability and executive function.While POD may develop between 24 and 72 hours following surgery, POCD may occur anywhere between 1 week to 1 month afterwards.Inadequate sample sizes renders many POCD clinical studies statistically insignificant, indicating the need for a structured consensus on a POCD definition (47).Research also indicates that many patients with POD may go on to develop POCD (48).

Prevention and improving outcomes
Outlining parameters to clinically assess POCD is required first to identify factors and guide the prevention of its development.This includes the incorporation of pre-and postoperative neuropsychological tests for POCD diagnosis into presurgical routine (49).Rasmussen et al. (23) point out that special considerations must be made when using neuropsychological exams.The tests must possess a high sensitivity for POCD and a clear definition of what constitutes as postoperative change.O'Brien et al. (1) state that change within one standard deviation from baseline may be a good starting point for identifying POCD.Finally, we should remember the preoperative setting is one of efficiency, and thus preoperative cognitive testing should not delay the process to the point that physicians will not use them regularly.
Knowing patient baselines can prove important for not only diagnosis of POCD, but also prevention.Several preoperative measures can be taken to prevent POCD and hopefully improve patient outcomes.For example, O'Brien et al. (1) has identified that cognitive training in preoperative patients reduces POCD incidence.They also point out that patients should be carefully assessed for factors such as polypharmacy that may predispose them to delirium.Also, assessing the patient for weakness or frailty may alert the healthcare team to extra precautions to be taken.These kinds of interventions are especially important in patients with known risk factors for POCD as discussed above.Finally, Lu et al. (50) found that pretreatment with parecoxib sodium combined with dexmedetomidine followed by a continuous low dose infusion causes a decrease in the incidence of POCD in patients undergoing arthroscopy by over 10%.This combined therapy is theorised to improve the sleep quality as, well as provide the central nervous system protective, anti-inflammatory and improved analgesic effects.This intervention should be considered especially in high-risk patients, moving forward.
Intraoperatively, other aspects to consider to reduce the incidence are the extent and duration of anaesthesia.Two interventional approaches address this: minimise the length of exposure accompanied by careful monitoring while exposed.

Conclusion
With the rapid increase of the elderly population undergoing elective surgical procedures, understanding their vulnerabilities to POCD, and the morbidity and mortality it can cause, only increases in importance.POCD is a well-documented phenomenon that places patients in a daunting situation.The first step is undoubtedly settling upon a finite definition of POCD, independent of CI and POD.Despite that they share many of the same risk factors, establishing a POCD definition will allow for homogeneity among studies and create a clear path for POCD research.Current research presents several theories as to the pathogenesis of POCD, most prominent among them being increased inflammation, hypoperfusion and anaesthetic use during surgery.Prior to this, physicians can take precautions with patients to prevent POCD, such as pre-and postoperative cognitive testing, careful monitoring during anaesthesia, blood pressure control and early treatment of postoperative complications as they arise.The research and understanding of POCD could significantly change the perioperative, and especially the postoperative, experience for elderly patients from a time of fearful tension to the one of safety and heathy recovery.
Urits et al.Postoperative Cognitive Dysfunction

Table 1 . Comparing the outcomes of general to regional anaesthesia
GA: general anaesthesia; RA: regional anaesthesia; AD: Alzheimer's disease

Table 5 . Comparing postoperative delirium to postoperative cognitive dysfunction POD POCD
: postoperative delirium; POCD: postoperative cognitive dysfunction; CAM-ICU: Confusion Assessment Method for the ICU; MMSE: Mini Mental Status Exam; t-MoCA: Telephone Montreal Cognitive Assessment complications, such as delirium and infection, may decrease the POCD risk.Special attention should be paid to polypharmacy and pain relief in elderly postoperative patients, which can be difficult in and of itself, in case this triggers the progression to POCD or delirium. POD