The Vulnerable Brain and General Anaesthesia: Is This a Wakeup Call?

By 2050, the global population of people aged 60 and above is predicted to double to 2.1 billion. Increasing lifespan carries a complexity of health conditions naturally developing through age, including chronic respiratory diseases, musculoskeletal disorders, diabetes and dementia [1].  

Indeed, as the population ages, the need for surgical intervention increases too – of England’s population aged 75 and above, one in five will undergo surgical intervention by 2030 [2]. Yet, without anaesthesia, what surgery would be possible? 

“He that sleeps feels not the toothache,” says Shakespeare [3]. He inferred that by creating a state of unconsciousness, pain would alleviate. Here, he simply demonstrates the concept of anaesthesia long before its modern founding in 1846 and its pivotal role in the transformation of surgery.  

The word “anaesthesia” originates from Greece, the birthplace of medicine, meaning without (an-) sensation (-aesthesis). The aim of anaesthesia, specifically general, is to achieve a triad of states: unconsciousness, muscle relaxation and analgesia.  

It would be impossible to carry out many surgical procedures without this as it allows patient comfort and the absence of pain [4].  

Whilst anaesthesia has allowed for the evolution of surgery, concerns now extend beyond surviving surgery and GA and now involve recovery and the risk of developing post operative complications such as post-operative delirium (POD) and post-operative cognitive dysfunction (POCD), especially in those with cognitive vulnerabilities and an aged brain. Risk factors of reduced cognitive reserve may include age, underlying vascular disease, presence of neurological disorders or impairment, genetic pre-disposition to neurological disorder, surgical trauma and anaesthesia [5].

POD is an acute, common presentation which can arise from 10 minutes post GA, up to seven days, or up until discharge. It is characterised by fluctuating and typically reversible disruption of usual mental state, including hyperactivity and agitation as well as hypoactivity and reduced responsiveness [6].  

The development of POD is associated with longer hospital stays, reduced independence, and an increased likelihood of dementia or mild cognitive impairment diagnosis and requirement of a long-term care facility [7]. 

POCD is described as a decline from baseline cognitive function occurring after surgery and anaesthesia, predominantly affecting the elderly. It may precipitate from 7 days post procedure, and can last for weeks, months and its prevalence has also been noted in 1% of elderly patients after one year. POCD results in social dysfunction, inability to complete activities of daily living, and increases the risk of mortality one-year post-surgery [8]. 

Whilst POD and POCD are distinct from each other, both embody the post-surgical and anaesthetic complications affecting patients with reduced cognitive reserve.  The aim of this article is to explore and critically analyse the theories behind the relationship between general anaesthesia and the development of POCD as well as the potential to reduce the risk of this occurring.  

The pathophysiological mechanisms underlying the development of POD and POCD are multifactorial and may overlap. They can be outlined as: disruption to the blood brain barrier and neuroinflammation, neurotransmitter alterations, amyloid-β plaque aggregation and tau protein hyperphosphorylation, and physiological stress.

Mechanisms 

Blood brain barrier disruption and neuroinflammation

The blood brain barrier (BBB) is a protective layer in blood vessels, separating systemic circulation and brain tissue. It acts as a semipermeable filter to prevent toxins from the blood entering the brain and removing neurotoxins. The BBB is composed of specialised endothelial cells connected by tight junctions. The neural cells pericytes and astrocytes also support the BBB, displayed in figure 1 [9]. 

Figure 1. Components of the blood brain barrier in a healthy individual. Endothelial cells, tight junctions, pericytes and astrocytes preserve integrity of the BBB and regulate the molecular exchange between systemic circulation and the brain [9]. Made using Canva. 

In the ageing brain, the BBB becomes disrupted due to a number of factors causing an accumulation of damage to cells such as oxidative stress, epigenetic modifications and genomic instability as well as the dysregulation of cellular signalling. This results in a leaky BBB allowing the entry of pro-inflammatory and neurotoxic molecules into brain tissue [9].  Anaesthesia further threatens the BBB via a number of mechanisms affecting endothelial cells and tight junctions which, in turn, facilitates the infiltration of systemic inflammatory mediators, generated by surgery, into the CNS [10].  

The extent of the postoperative systemic inflammatory response is related to the severity of surgical trauma. A healthy individual with an intact BBB and the ability to control levels of inflammation may withstand this. However, in elderly patients, even minor surgeries can induce neuroinflammation due to the fragility of the aged BBB [9], especially during GA. 

Furthermore, anaesthetic agents can induce inflammation of the central nervous system (CNS) by activating pro-inflammatory cells, called microglia, and inducing the release of pro-inflammatory cytokines IL-1, IL-6 and TNF-alpha. The creation of a chronically inflamed environment in the CNS and subsequent neuronal malfunction may contribute to lasting cognitive impairment [10]. 

In a study with aged rats, the commonly used inhaled anaesthetic, sevoflurane, led to activation of pro-inflammatory neural cells as well as the release of inflammatory cytokines.  This was clarified in a human study where the incidence of POCD in elderly patients increased after sevoflurane use in comparison to placebo [11]. 

Therefore, general anaesthesia may be detrimental to further breakdown of the BBB and occurrence of neuroinflammation in an aged, cognitively fragile brain. This may result in increased risk of POCD.  

Neurotransmitter dysregulation

The occurrence of neuroinflammation plays a huge role in the dysregulation of neurotransmitters in the brain which is considered a second mechanism for developing POCD in cognitively vulnerable patients, particularly levels of acetyl choline (ACh). 

ACh is a neurotransmitter, part of the cholinergic system, involved in regulating many aspects of cognitive functioning such as memory, arousal, attention and learning [12].  As the brain ages, levels of ACh are found to deplete, as well as in neurological conditions such as Alzheimer’s disease [13], making these patients vulnerable to GA where the use of  ACh receptor antagonist drugs suppress ACh release in order to achieve a state of unconsciousness as well as amnesia and muscle relaxation [14].  

The anaesthetic agents, desflurane, isoflurane and sevoflurane, bind to both types of cholinergic neuron receptors (nicotinic and muscarinic) as well as barbiturate and opiate drugs, specifically morphine and fentanyl [15].  

Whilst healthy individuals return to a baseline level of ACh post anaesthetic, levels are compromised in cognitively vulnerable patients, making it a contributory factor in the cognitive decline seen in these patients as well as post operative delirium [14]. 

Other neurotransmitters such as dopamine, serotonin, GABA and glutamate are, too, found to be dysregulated during GA due to anaesthetic agents, and may also play a role in the development of post-operative cognitive dysfunction and delirium.

Amyloid-β aggregation and tau hyperphosphorylation

In individuals with pre-existing neurological conditions specifically Alzheimer’s disease (AD), Aβ plaques and abnormal tau protein are a recognised part of pathology. Therefore, after surgery and general anaesthesia, further ab plaque aggregation may worsen cognitive functioning in AD patients. 

Normally, amyloid exists as amyloid precursor protein (APP). APP can be converted into a soluble form or amyloid-β which requires clearance. In healthy individuals, levels of Aβ are controlled. However, failure to remove Aβ results in the formation of Aβ plaques. Thus, injury and death of neurons activate an inflammatory response and the hyperphosphorylation of tau.  

Tau protein is required in neurons in the brain to conserve their structure allowing transmission of nerve impulses. In neurodegenerative diseases, like AD, tau becomes impaired. When damaged, tau proteins disconnect from neurons and form neurofibrillary tangles within the cell. 

The combination of Aβ aggregation and tau hyperphosphorylation results in neuroinflammation and neuronal cell death, reflected in symptoms of dementia such as cognitive impairment due to interrupted neurotransmission [16]. The use of certain GA is known to precipitate the formation of Aβ plaques and the hyperphosphorylation of tau.  Increased aggregation of Aβ was observed in transgenic mice with AD after the administration of inhaled halogenic anaesthesia [17]. Therefore, this suggests that patients with underlying Alzheimer’s disease or reduced cognitive reserve are at risk of exacerbating their condition with anaesthesia, promoting the development of postoperative cognitive dysfunction. 

Physiological stressors

Physiological stressors during anaesthesia are thought to be associated with an increased risk of developing POCD, including hypoxia, hypothermia, hypotension and cerebral hypoperfusion in vulnerable brains.  

Hypoxia is defined by an insufficient supply of oxygen reaching cells. This may occur during surgery and anaesthesia where decreased levels of regional cerebral oxygen saturation (displaying oxygen supply and demand) are correlated to the occurrence of POCD [18].  Studies have shown that a longer duration of desaturation is associated with the risk of cognitive decline, but the level of desaturation is insignificant [19]. 

However, evidence is inconsistent suggesting that low cerebral saturation is a possible contributor but is not a proven direct cause of POCD.  

In addition, vulnerable patients with an already compromised cerebral perfusion due to  underlying vascular disease and pre-existing cognitive impairment may be more susceptible  to the development of POCD. Reduced intraoperative blood pressure may result in ischaemia  in the brain tissue, potentially worsening neuroinflammation and causing injury.  However, in a study on 1218 elderly patients where 266 had developed POCD one week  post-surgery, hypoxia and hypotension were not found to be significant risk factors in their  cognitive decline [20].  

Hypothermia may also occur during GA due to a redistribution of heat and lack of thermoregulation. This may be accidental (inadequate patient warming) or controlled depending on the type of surgery. A study was performed on rats during anaesthetic comparing their brains after hypothermic and normothermic conditions. In hypothermic conditions, it was found that memory, and spatial learning and working memory were affected displaying an association with POCD [21]. Yet, this study did not specifically explore the vulnerable brain and is also limited by the use of animal models. Further research in humans with reduced cognitive reserve is therefore required.  

Consequently, post-operative recovery has been outlined by the concept of ‘Enhanced Recovery After Surgery’ (ERAS) which encompasses pre-operative, peri-operative, and post-operative protocols which may be applied to POCD [22].  

Reducing the risk in clinical practice

Pre-operative

• Gathering a thorough history is a part of every clinician’s duty. It becomes a critical responsibility when performing pre-operative assessment for individuals undergoing surgery under anaesthesia. It is here where the identification of high-risk patients with reduced cognitive reserve should occur. Pre-existing neurological conditions, previous delirium or cognitive decline, functional status and frailty should be recognised [23]. Baseline cognition may be established using the Mini Mental State Examination (MMSE). The MMSE consists of multiple domains, including short term memory, attention and calculation and immediate recall. It is a highly specific and lowly sensitive test when identifying mild cognitive impairment, but it can be completed swiftly, taking approximately 5-15 minutes.  

The Montreal Cognitive Assessment (MoCA) is another tool which considers more domains and is highly specific and sensitive in detecting mild cognitive impairment.  Both of these tools may be used for detecting POCD after general anaesthesia. Several studies have found that whilst the MMSE is extensively used, the MoCA provides more sensitivity in recognising cognitive deterioration [24]. Therefore, using MoCA may be used clinically, pre and post operatively, as an early identifier of POCD. 

• In order to expand cognitive reserve prior to surgery, existing co-morbidities and modifiable risk factors should be treated including malnutrition, smoking, nutritional deficiencies (such as vitamin D), and diabetes and hypertension. Managing these with correction of deficiencies as well as adjusting medications may reduce the risk of developing POCD. Through patient education and support, clinicians may also promote exercise and smoking cessation [25].  

• Informed decision-making and consent are vital components of pre-operative assessment. POD and POCD risks should be discussed and consented for in patients who are cognitively vulnerable. Making a patient aware of risks and explaining this in a way which is understandable is of utmost importance to emphasise the long-lasting effects POCD may have – loss of independence, persistent decline in cognition and increased risk of mortality. It is also important to weigh up the benefits of the surgery with the risk of POCD which may be subjective to each individual. Family input as part of shared-decision making should also be encouraged with the patient at the centre, as The Kings Fund states, “no decision about me without me” [23]. 

Peri-operative

• Where appropriate, it is reasonable to undergo surgery with local or regional anaesthetic. However, if this is not possible there are a number of ways thought to reduce the risk of POCD occurring in association with general anaesthetic. Using drugs considered high risk such as anti-cholinergic agents as well as opiates and benzodiazepines should be avoided where possible [26]. 

• Dexmedetomidine, an alpha2-adrenoreceptor agonist drug, is used for sedation and analgesia. It has been proven to be a potential option in the general anaesthesia of cognitively vulnerable patients due to its role in inhibiting the release of pro inflammatory mediators and reducing neuroinflammation, therefore contributing to the prevention of POCD. In one study, compared with a placebo, dexmedetomidine significantly reduced the incidence of POCD [27].  

However, a contradicting study found dexmedetomidine did reduce agitation in  recovery from anaesthesia compared to sevoflurane but did not reduce the incidence  of POD [28].  

• Recovering patients from GA by electrically stimulating areas of the brain which release dopamine (a neurotransmitter in the CNS) may also be an option for reducing POCD and POD. Dopamine’s role in arousal and consciousness may help to wake patients quickly rather than unnecessary prolonged anaesthesia. As the same areas are also responsible for cognition, they may be targeted in the prevention or treatment of POD and POCD [29]. This was successfully displayed in a study using rats; however, this has not yet been translated into human trials. Although, a similar technique, Deep Brain Stimulation, is used to stimulate dopaminergic activity in other areas of the brain for Parkinson’s disease [30], making it a plausible study for humans.  

• Electroencephalography (EEG) which measures brain activity may be used during GA to observe the depth of consciousness in real-time and allow for more controlled titration of anaesthesia. This may avoid overusing anaesthesia and thus, limit physiological stressors such as haemodynamic changes and cerebral hypoperfusion which may contribute to post-operative cognitive decline. This was supported by a systematic review and meta-analysis, including 4,000 elderly people, where there was a reduction of POCD incidences by 22% when monitoring anaesthetic depth with EEG [31]. 

• Managing physiological stressors in other ways too may reduce the risk of cognitive impairment post-operatively. As discussed, hypothermia, haemodynamic instability, hypoxia and cerebral hypoperfusion may play a role in POD acutely and POCD long term in patients with an already reduced cognitive reserve. Monitoring these factors by ensuring sufficient oxygenation, maintaining blood pressure and cerebral perfusion, and regulating body temperature with patient warming may contribute to reducing the risk of POCD. A relationship between hypothermia and cognitive dysfunction has been identified post-operatively. The subjects included in the study began with a ‘normal’ MMSE score which changed post anaesthesia. This was a small study with just 105 patients and focused mainly on acute cognitive impairment. It also did not find significant relations between other physiological stressors and POCD.  Although, more research could be performed on this area due to the link between vascular diseases and ischaemia and the development of neurodegenerative disorders which could be translated in hypoxia and cerebral hypoperfusion, and POCD [24].  

Post-operative

• Effective post-operative pain management is fundamental in reducing cognitive decline. The use of opiates and benzodiazepines may increase risk of sedation, delirium and POCD in elderly patients. Therefore, it is advised to avoid these high-risk analgesics. Instead, non-opioids are promoted such as paracetamol and non-steroid anti-inflammatory drugs (NSAIDs). A study has also suggested the use of the analgesic esketamine, which is derived from ketamine, as it is thought to have neuroprotective properties in cognitively vulnerable patients and reduce inflammation [32]. Local anaesthetic may also be used to relieve pain in wound sites.  

• Encouraging early mobilisation post-operatively improves circulation and reduces  inflammation, in addition to promoting cognitive recovery, especially important in  elderly patients. Maintaining a quiet environment with minimal change (for example,  moving wards and lack of continuity of staff) also plays a role in reducing risk of  POCD in those with reduced cognitive reserve. The company of family also  contributes [22].  

• Readjusting the circadian rhythm post-operatively may reduce cognitive decline in the  vulnerable brain. Anaesthetic agents are found to disturb the sleep-wake cycle by  increasing sleep fragmentation due to neuroinflammation. This is thought to occur when levels of cortisol, the arousal hormone, and melatonin, the sleep hormone, are  disrupted. Therefore, promoting sleep quality by ensuring a consistent day-night  routine, exposing patients to sunlight and providing a quiet environment where  possible may regulate secretion of these hormones and reduce the probability of  POCD and POD. Yet, studies suggest that these are not the only contributors. There  are many other proposed modulators contributing to a disrupted circadian rhythm  which should also be explored to understand a full picture of the sleep cycle’s role in  POCD [33]. 

Throughout the vulnerable patient’s journey, a multi-disciplinary approach must be taken involving clinicians and healthcare professionals from a number of specialties. This may include the surgeon, anaesthetist, and geriatrician as well as therapies and psychosocial care.  Providing specialised input and taking a holistic approach avoids fragmented care and provides optimal patient outcomes [22].  

Conclusion 

In conclusion, surgical intervention and general anaesthesia are fundamental aspects of  medicine and are becoming more necessary as the population ages. Therefore, understanding  the consequences is important in the cognitively vulnerable.  

Currently, evidence has not established a causal link between general anaesthesia and post operative cognitive dysfunction, but several peri-operative stimuli may contribute to its  development which must be further researched in human subjects. 

Anaesthesia comes with risks. It is how those risks are managed and reduced that will enable  clinicians to protect the vulnerable brain in order to optimise positive patient outcomes. 

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