Abstract

Elderly patients are more vulnerable to cognitive dysfunction in the postoperative period. Patients who are apparently well in cognitive functions in the preoperative period after undergoing anesthesia in noncardiac surgery will develop symptoms of cognitive dysfunction. Postoperative cognitive dysfunction (POCD) doesn’t continue for a long duration and usually undergoes self-resolution. Proper definitions and congruous tests for diagnosis are absent. Rigorous preoperative assessment of cognitive function and distinguishing risk factors are indispensable for recognizing the range of POCD and its association with surgery and anesthesia. Recent studies haven’t revealed any anesthesia technique or drug which can significantly reduce the incidence of POCD. Therefore, giving accurate information to patients can be challenging.

Keywords

cognitive disorders, delirium, amnesia, dementia, postoperative cognitive complications

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Introuction

Postoperative cognitive dysfunction (POCD) was described as early as in 1955 as “adverse cerebral effects of anesthesia on old people”. ¹ POCD is a clinical condition where patients experience a deterioration in cognitive function in the form of diminished memory, reduced attention span, and difficulty in decision-making, after surgery and anesthesia.

There are various forms of cognitive dysfunction which can occur in the postoperative period even among apparently well patients with no previous history of cognitive impairment. One of the most common and earliest forms of cognitive dysfunction is delirium which presents as an acute state of confusion associated with disturbance in attention and decreased awareness towards the environment. Severe symptoms of delirium require treatment as recommended by The National Institute for Health and Care Excellence guidelines.²

POCD is a relatively common complication of surgery, particularly in older patients or those undergoing more invasive procedures. The exact cause of POCD is not fully understood, but it is believed to be related to a combination of factors, including anesthesia & surgery-related inflammation, age-related factors, and underlying health conditions.

The majority of the research regarding POCD manifestations has been focused on cardiac surgery. Other conditions commonly associated with cognitive impairment include HIV/AIDS and Alzheimer’s disease. Regardless of the exact incidence, POCD can have significant impacts on patients’ quality of life and recovery from surgery. Patients with POCD may experience difficulties with daily activities, such as work or household tasks, and may require additional support and care. There is currently no definitive treatment for POCD, but some interventions may help to mitigate its effects. These include cognitive rehabilitation, physical exercise, and social engagement. Additionally, efforts to minimize the risk of POCD, such as careful monitoring of anesthesia and inflammation may be beneficial.

This review article aims to present the existing perception of POCD in non-cardiac surgery to proselytize integrative dialogue.

Definitions

Delirium is defined as a state of acute confusion presenting symptoms that may or may not be associated with organic illness.³ The Diagnostic and Statistical Manual of Mental Disorders V acknowledges delirium and dementia as separate well-defined diseases and incorporated under major neurocognitive disorder; and subclassified on its aetiology.⁴

Postoperative delirium presents with an acute onset state of confusion and disorientation which varies throughout the day with periods of alternating hyperactivity, hypoactivity or mixed type usually associated with sleepiness in the day and agitation in the night,^5,6 presenting most commonly within first 3 days after surgery.

Emergence delirium is differentiated from postoperative delirium on the basis of onset. Emergence delirium occurs immediately after anesthesia during the transition to awakening and is marked by agitation and hyperactivity.^7,8 POCD and postoperative delirium increases the duration of hospital stay, associated costs and mortality.^9,10

The major manifestation is significant cognitive decline as compared to a previous level, leading to interference with independence in daily activities. POCD can be diagnosed using a number of neuropsychological tests. (Table 1)

Incidence and Risk Factors

POCD is a well-known complication after non-cardiac surgeries especially in the patients undergoing major surgeries and the geriatric age group. Incidence in non-cardiac surgery depends on the type of surgery, patient population, and other factors.

The etiology of POCD in non-cardiac surgery is not fully understood and is considered to be an interplay of multiple factors such as anesthesia, surgery-related inflammation and underlying health conditions. Some potential causes or contributing factors of POCD are mentioned. (Table 2)

POCD and postoperative delirium, and in particular hypoactive delirium, are often missed. There are large variations in incidence depending on multiple patient factors. Previous studies reported the incidence to range from 25% to 60% in clinical settings with geriatric age groups and even up to 73% post-cardiac surgery.¹¹

Efforts to minimize the risk of POCD in non-cardiac surgery include careful monitoring of anesthesia and inflammation, as well as proactive management of underlying health conditions. Additionally, interventions such as cognitive rehabilitation, physical exercise, and social engagement may help to mitigate the effects of POCD in affected patients.

In non-cardiac surgery patients, a systematic review reported an incidence of 11.7% over a period of 3 months.¹² Hip fractures with multiple underlying co-morbidities and age ≥ 65 with some degree of pre-existing cognitive impairment are at enhanced risk and incidence has been estimated to be 22%.^9,13 Persistence of cognitive dysfunction for ≥ 6–12 months could be termed as long-term cognitive dysfunction. Long-term cognitive dysfunction as well as the risk of developing dementia is more in elderly patients receiving general anesthesia (GA).^14-16 Previous studies have reported that delirium could be linked to long-term cognitive dysfunction or dementia.^17,18

It has been noted in a number of previous studies that risk factors include elderly age, lower level of education, utilization of sedatives, previous history of depression & stroke, evidence of postoperative infection & pulmonary complications, lacunae on brain imaging and longer intraoperative duration of bispectral index (BIS) readings < 40.^12,19,20

Krenk et al.²¹ observed that POCD can arise at any age, but manifestations are more severe and long-lasting in patients with age > 60 years. POCD is more prevalent in patients with coronary atherosclerosis or pre-existing dementia.^22,23 It was observed in a study that incidence of POCD was highest in patients > 60 years and lowest in the age group 18–39 years. It was further noted that POCD was associated with increased mortality.²⁴

It has been noted that a history of excessive alcohol intake was associated with an increased risk of POCD. ²⁵ Genetic factors as well as low educational level are risk factors for the development of POCD.²⁶

Pathophysiology

The exact pathophysiology of POCD is not well understood, and multiple mechanisms have been proposed. (Table 3)

Research has concentrated on the interaction between anesthetic agents and the pathology of Alzheimer’s disease. The pathological effects of tau proteins and extracellular amyloid plaques of Ab40 and Ab42 peptides result in increased neuronal death and loss of synapses, mostly of cholinergic neurones in the basal forebrain.²⁷ These cholinergic neurons are vital in the formation and regulation of consciousness, learning and memory. Amyloid plaques in this region of the forebrain result in declining memory, reasoning, judgment and orientation.²⁷

Animal models have demonstrated that isoflurane sevoflurane and desflurane promote neuronal death when associated with Alzheimer’s disease. One such study revealed that both normal mice and Transgenic Alzheimer’s disease mice when exposed to sevoflurane resulted in increased caspase-3 activation (apoptosis marker) in brain.²⁸

Kline et al.²³ studied whether surgery influences the course of dementia in Alzheimer’s disease. They found out in MRI scans 5–9 months post-surgery were associated with reduced volume of gray matter, atrophic changes in hippocampus, and increased size of ventricles. POCD was more pronounced in patients already having mild cognitive dysfunction prior to surgery.²³

In cardiac surgeries, it has been reported that decreased cerebral oxygenation due to cerebral hypoperfusion or hypoxia is associated with POCD. Therefore, during cardiac surgery target mean arterial pressure is 80–90 mm Hg.²⁹

Hypotension, hypoxia, and altered cerebral perfusion have been suggested as underlying mechanisms for POCD. The ISPOCD cohort study however didn’t find any association between either hypotension or hypoxia and POCD.

Terrando et al.³⁰ suggested that surgery in mice leads to activation of TNF-α, NF-κB, and inflammatory cytokines which increases the permeability of the blood–brain barrier and promotes migration of macrophages towards the hippocampus leading to memory impairment. This impairment can be prevented if the release of pro-inflammatory cytokines is blocked by the activation of anti-inflammatory cholinergic cascades.

Biomarkers in POCD

• S100B Protein: It is associated with Alzheimer’s disease, autoimmune diseases, multiple sclerosis, schizophrenia, and cerebrovascular diseases.³¹ Higher concentrations are associated with the release of cytokines, apoptosis, neuroinflammation, and neurodegeneration.³² It has been reported that levels of S100B were significantly higher in patients who developed POCD undergoing total hip arthroplasty, transurethral resection of the prostate, and robot-assisted laparoscopic radical prostatectomy.^33-35

• Interleukin-6 [IL-6]: In a normal scenario, low levels of IL-6 are present in the central nervous system. It has been found in animal models that a high concentration of IL-6 could inhibit neuronal synapses and hippocampal neurons in the dentate gyrus.³⁶ Palta et al.³⁷ reported that high plasma levels of IL-6 are associated with a higher incidence of cognitive dysfunction.

• Interleukin-1β [IL-1β]: IL-1β is a potent proinflammatory cytokine with abundant receptors in the hippocampal region.³⁸ Animal studies have shown that increased levels of IL-1β were associated with cognitive impairment.³⁹

• Interleukin-17 [IL-17]: IL-17 levels are increased in T cell-mediated inflammatory response and are closely related to the regulation of autoimmunity.⁴⁰ It could induce the secretion of IL-1β, IL-6, and TNF-α, thereby aggravating inflammatory response.⁴¹ It is involved in the pathophysiology of multiple sclerosis, Alzheimer’s disease, and cerebral hemorrhage, by damaging the blood-brain barrier and promoting neuroinflammation.^42-44 It has been observed that Anti-IL-17 treatment improved cognitive dysfunction due to neuroinflammation caused by surgical trauma.⁴⁵

• Tumor Necrosis Factor-α [TNF-α]: TNF-α is a protein which causes an increase in the production of pro-inflammatory cytokines, such as IL-1, IL-6, and IL-8. TNF-α causes the downregulation of GABA receptors thereby decreasing inhibitory neurotransmission, which in turn causes an imbalance between excitatory and inhibitory neurotransmission, and glutamate toxicity.⁴⁶ It has been demonstrated in animal models that high levels of TNF-α are present in isoflurane anesthesia and associated with increased incidence of POCD.⁴⁷ Many studies have reported that high TNF-α levels were associated with a higher incidence of POCD in patients undergoing head and neck cancer surgery and unilateral hip replacement.^48,49

• Cyclooxygenase-2 and Prostaglandin E: Cyclooxygenases are heme-containing isoenzymes (COX-1 and COX-2) that catalyze the conversion of arachidonic acid to prostaglandin. COX-2 is present in the postsynaptic dendrites, cortical neurons, and spinal neurons. Induction of COX-2 induction is associated with neuroinflammation and neurodegeneration.⁵⁰ COX-2 results in increased production of PGE2 as a result of synaptic activation, which causes glutamate release.⁵¹ The increase in glutamate causes a decrease in the number of small albumin-positive GABA cells and ultimately results in an imbalance between excitatory and inhibitory neurotransmission.⁵²

Effects of Anesthesia

POCD is a common complication following surgery, particularly in older adults. It is characterized by a decline in cognitive function that occurs after surgery and can last for weeks or even months. The choice of anesthesia, inhalational anesthesia, or total intravenous anesthesia (TIVA) has been investigated as a potential risk factor for POCD.

The effect of inhalational agents on POCD has been extensively studied. Inhalational anesthetics, such as desflurane, sevoflurane, and isoflurane, are commonly used to induce and maintain anesthesia during surgery.

Some studies have suggested that inhalational anesthesia may be associated with a higher incidence of POCD compared to TIVA, while others have found no significant difference between the two types of anesthesia. Overall, the relationship between inhalational anesthesia and POCD is complex and not fully understood. Other factors, such as patient age, surgical procedure, and duration of anesthesia, may also play a role in the development of POCD. Further research is needed to fully understand the relationship between inhalational anesthesia and POCD, and to identify effective strategies for prevention and management of this complication.

The use of TIVA could be beneficial in POCD. It has been documented that propofol has positive effects on inhibiting inflammation by reducing levels of cytokines in plasma, in contrast to inhalational agents which promote inflammation in animal models.^53,54

The results of these studies have been mixed, with some showing a higher incidence of POCD following inhalational anesthesia, while others have found no significant difference between the two types of anesthesia. Despite the mixed results, some experts suggest that TIVA may be a safer choice of anesthesia in patients at higher risk of POCD, such as elderly patients and those undergoing complex or prolonged surgery. However, further research is needed to fully understand the relationship between anesthesia type and POCD, and to identify effective strategies for prevention and management of this complication.

Many studies have been undertaken to compare the risk of POCD in GA vs. regional and neuraxial anesthesia techniques. A meta-analysis evaluated the incidence of POCD in GA vs. non-GA techniques which included spinal, epidural, regional, and the combination of GA plus neuraxial or regional anesthesia. It showed a non-significant increase of POCD incidence in GA as compared to non-GA techniques.⁵⁵ Furthermore, an RCT conducted by Silbert et al.⁵⁶ evaluated the incidence of POCD in patients undergoing extracorporeal shock wave lithotripsy. It was concluded that the type of anesthesia did not impact rates of POCD up to 3 months postoperatively. It was reported in the practice guidelines for perioperative brain health that based on current data, the evidence is insufficient to point out the benefit of regional anesthesia over GA regarding POCD.⁵⁷ It has been observed that the use of TIVA can potentially decrease the incidence of POCD in patients undergoing thoracic surgery.^58,59 Furthermore, TIVA has more neuroprotective effects when compared to sevoflurane in patients undergoing abdominal surgery and cancer surgery.^60,61 However, many studies have reported that the use of propofol may be associated with worsened cognitive function sevoflurane.^62-64 There are studies which haven’t demonstrated any differences in the incidence of POCD between propofol and sevoflurane.^65,66

Depth of anethesia is an independent risk factor in the development of POCD. A meta-analysis compared reduced vs. increased depth of anesthesia monitored by BIS using either propofol or isoflurane for maintenance of anesthesia. It was found that there was no significant impact of depth of anesthesia on the development of POCD.⁶⁷ The meta-analysis however included only 3 RCTs and didn’t likely represent the patient population at risk for POCD. Hou et al.⁶⁸ studied the risk of POCD with varying depths of anesthesia in patients undergoing total knee replacement. Anesthesia in all patients was maintained using sevoflurane and propofol infusion. It was concluded that patients with BIS 40–50 had a higher incidence of POCD as compared to patients with BIS 55–65 in the immediate postoperative period. However, no significant difference was observed in postoperative days 3–7. BIS or entropy used for monitoring the depth of anesthesia don’t correlate with age or pre-existing cognitive dysfunction and therefore not reliable for assessing the risk of POCD in the patient population.^69,70 Many studies identify a correlation between cerebral autoregulation and POCD, hypothermia and perioperative glycemic status as potential risk factors for POCD.^71-73

The meta-analysis by Kim et al.⁷⁴ used data from the Korean National Health Insurance Service. This was a large prospective cohort study which assessed the incidence of dementia in patients undergoing GA. It was concluded that GA was associated with the increased risk of developing dementia as compared to non-GA groups. It was also noted that the risk of dementia was higher with the use of desflurane and isoflurane, but lower with sevoflurane. The study design however would not be able to differentiate between the effects of anesthesia exposure from that of surgical stress and other factors such as perioperative hypothermia, use of narcotics and other medications.

The 5th International Perioperative Neurotoxicity Working groups recommendations are as follows⁵⁷:

• Individuals over the age of 65 should be informed of the risk of postoperative delirium and perioperative neurocognitive disorder prior to their procedure.

• Baseline cognitive function should be assessed preoperatively using a brief screening tool.

• Current literature is insufficient to define a specific anesthetic regimen to decrease the risk of perioperative neurocognitive disorder; however, cautious use or avoidance of medications such as first-generation antihistamines, centrally acting anticholinergics, benzodiazepines, and meperidine was recommended. Avoid relative hypotension, maintenance of normothermia, use age-adjusted minimal alveolar concentration of volatile anesthetic agents, and use EEG-based depth of anesthesia monitoring to titrate anesthetic delivery.

• Additional research is required to determine the feasibility, efficacy, and cost- effectiveness of postoperative follow-up to assess cognitive outcomes.

Role of Dexmedetomidine

The exact mechanism of action of dexmedetomidine regarding POCD isn’t clearly understood, but it can be attributed to a reduction in dose requirements of opioids and anesthetic drugs, systemic stress-response modulation, promotion of natural sleep cycle, and direct neuroprotection.^75,76 Su et al.⁷⁶ have reported that low-dose dexmedetomidine in the postoperative period is associated with a decrease in the incidence of delirium among the geriatric population. A meta-analysis found that dexmedetomidine may result in a decreased incidence of cognitive dysfunction and improvement in mini-mental state exam (MMSE) scores.⁷⁷ Deiner et al.⁷⁸ didn’t observe any significant difference in the incidence of postoperative delirium and POCD in patients receiving dexmedetomidine infusion during intraoperative and postoperative periods. Yu et al.⁷⁹ in a meta-analysis concluded that dexmedetomidine reduces the risk of POCD in older patients undergoing major surgeries under GA.

Limitations

Studying the relationship between POCD and anesthesia presents several challenges and limitations. Human researches must adhere to strict ethical guidelines, which can sometimes limit the scope and methodology of the studies. Gathering a large enough sample size can be difficult due to the specialized nature of the population. However, a small sample size can limit the statistical power of the study. Anesthesia is often administered alongside various other medications and numerous interventions are being done during surgery. It, therefore, becomes challenging to isolate the specific effects of anesthesia on cognitive function. Also, there are a variety of anesthetic agents, with different characteristics and potential effects on cognition. Hence, studying the correlation between POCD and anesthesia further becomes complicated.

Understanding the long-term effects of anesthesia on cognitive function requires longitudinal studies that track patients over extended periods. However, such studies can be resource-intensive and may face challenges with participant retention. Assessing cognitive function accurately and consistently across different individuals and settings is a difficult task. The choice of assessment tools and methods can impact the results and comparability of studies. There may exist a publication bias, as studies that find significant correlations between anesthesia and POCD may be more likely to be published than those with null results.

Various confounding factors that are correlated with both anesthesia and POCD can lead to misleading conclusions about the relationship between them. Several confounding factors that need to be considered are age, pre-existing cognitive dysfunction, comorbidities, type and duration of surgery, choice of anesthetic agent and technique, trauma caused due to surgery, and other medications given alongside anesthetic agents.

The type and duration of surgery can affect the stress response, inflammation, and overall physiological impact on the body, which may influence cognitive function independent of anesthesia. Postoperative complications such as infection, hypoxia, and hypotension can also affect postoperative cognitive function. Psychological factors such as anxiety, depression, and stress can impact cognitive function in the perioperative period. Environmental factors such as noise, lighting, and quality of care in the perioperative environment can affect cognitive function.

Addressing these limitations requires careful study design, rigorous methodology, collaboration across disciplines, and ongoing research efforts to better understand the complex relationship between anesthesia and POCD.

Conclusion

In summary, POCD is a recognized complication of non-cardiac surgery that can have significant impacts on patients’ cognitive function and quality of life after surgery. Efforts to minimize the risk of POCD and support affected patients are important considerations in perioperative care for all types of surgeries. It remains doubtful whether anesthesia itself or surgical or patient factors might be responsible for POCD. There is conflict among studies regarding anesthesia exposure and the risk of developing POCD. The studies which assessed the risk profile of various anesthetic techniques are heterogeneous, and therefore no strong evidence is present in favor of any technique.

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References