Drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium

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Summary

Given the progressive and constant increase of average life expectancy, an increasing number of elderly patients undergo surgery. After surgery, elderly patients often exhibit a transient reversible state of cerebral cognitive alterations. Among these cognitive dysfunctions, a state of delirium may develop. Delirium is an aetiologically non-specific syndrome characterised by concurrent disturbances of consciousness and attention, perception, thinking, memory, psychomotor behaviour and the sleep–wake cycle. Delirium appears to occur in 10–26% of general medical patients over 65, and is frequently associated with a significant increase in morbidity and mortality. During hospitalization, mortality rates have been estimated to be 10–26% of patients who developed post-operative delirium, and 22–76% during the following months. Over the last few decades, post-operative delirium has been associated with several pre-operative predictor factors, as well as age (50 years and older), alcohol abuse, poor cognitive and functional status, electrolyses or glucose abnormalities, and type of surgery. The uncertain pathogenesis of post-operative cognitive dysfunctions and delirium has not permitted a causal approach to developing an effective treatment.

General anesthesia affects brain function at all levels, including neuronal membranes, receptors, ion channels, neurotransmitters, cerebral blood flow and metabolism. The functional equivalents of these impairments involve mood, memory, and motor function behavioural changes. These dysfunctions are much more evident in the occurrence of stress-regulating transmission and in the alteration of intra-cellular signal transduction systems. In addition, more essential cellular processes, that play an important role in neurotransmitter synthesis and release, such as intra-neuronal signal transduction and second messenger system, may be altered.

Keeping in mind the functions of the central muscarinic cholinergic system and its multiple interactions with drugs of anesthesia, it seems possible to hypothesize that the inhibition of muscarinic cholinergic receptors could have a pivotal role in the pathogenesis not only of post-operative delirium but also the more complex phenomena of post-operative cognitive dysfunction.

Introduction

Given the progressive and constant increase of average life expectancy, an increasing number of elderly patients will be undergoing anesthesia [1]. Because of the physiologic changes associated with aging, geriatric patients are at an increased risk for drug-induced post-operative complications [2]. After surgery, elderly patients often exhibit a transient reversible state of cerebral alterations in attention and cognition. Studies indicate that anesthesia and surgery are associated with post-operative cognitive impairment in 10–14% of elderly patients [3].

Among these cognitive dysfunctions, after surgical treatment a state of delirium may develop over a short period of time. Delirium is an aetiologically non-specific syndrome characterised by concurrent disturbances of consciousness and attention, perception, thinking, memory, psychomotor behaviour and the sleep–wake cycle [4]. The uncertain pathogenesis of post-operative delirium (POD) has not permitted a homogeneous approach to developing an effective treatment.

The proportion and real incidence of POD are not precisely known because of methodological difficulties and limitations. Delirium appears to occur in 10–26% of general medical patients over 65 [5], [6]. Marcantonio et al. [7] associated this phenomenon with some pre-operative predictor factors, including age (50 years and older), alcohol abuse, poor cognitive and functional status, electrolyses or glucose abnormalities, and type of surgery. Data obtained by the authors allowed us to divide patients into three groups, with substantially different risk outcomes for post-operative delirium: (low risk group: 2%; middle risk group: 8–13%; high risk group: 50%) indicating the real usefulness of a preventive approach for elderly surgical patients [7]. Lynch et al. [8], studying the incidence of post-operative delirium, the role of pre-operative risk factors and post-operative pain resolution, came to the conclusion that the incidence of post-operative delirium is different for patients with a higher pain score at rest, in movement and maximal pain. Bekker and Weeks [9] demonstrated that delirium incidence undergoes a significant modification when related to different types of surgery: 3–47% of patients who underwent major cardiac surgery develop delirium; after major general surgery the incidence is approximately 10%; with regard to elderly patients, the incidence of post-operative delirium after major orthopaedic surgery varies from 24% to 50%. These data support the evidence of a non-specific, multiple factor aetiology, suggesting a pre-operative prevention approach on studied risk factors [7], [8], [9]. Therefore, a specific and causal approach to POD would appear to be very difficult.

Risks associated with cerebral impairments after surgery could be minimized through the identification of anatomical and functional factors which have a significant predictive value. From the most recent studies, it is possible to apply a distinction among pre-, intra- and post-operative risk factors (Table 1) [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. Understanding the true significance of each risk factor in POD allows the anaesthesiologist to identify different risk categories for surgical patients at risk of developing delirium during the post-operative period, and to take necessary measures to prevent delirium.

Delirium is frequently associated with a significant increase in morbidity and mortality. During hospitalization, mortality rates have been estimated to be 13% of patients who developed POD [20]; 72.4% of patients with post-operative delirium died within 5 years, compared with 34.7% of those who remained lucid post-operatively [21]. Other important aspects concerning the management of elderly surgical patients include the high probability of prolonged hospital stay, increased complications, increased costs, and long-term disability [21].

Section snippets

Clinical manifestations

There are several difficulties in the diagnosis of delirium, particularly with regard to the time course of development of the delirium, and to the prior existence of dementia or other psychiatric illness. Key features of delirium are [22]:

  • 1.

    Disturbance of consciousness, especially attention and level of arousal (i.e., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention.

  • 2.

    Alterations in cognition (e.g., memory deficit, disorientation, language

The previous hypotheses

In the last few years, many aspects of clinical interest have been seen to be closely related to the physiopathology of POD. Despite the fact that the aetiology of delirium remains unclear, specific relationships with the patient’s general condition have been shown. The general and specific conditions, which over the last few decades have been proposed as having a causal role in the development of post-operative delirium are reported in Table 2.

The neurotransmitter pathogenetic hypothesis

There has been much speculation about the causes

The interaction of drugs administered during anaesthesia with muscarinic receptors

The suppression of cholinergic cells is, at least in part, one of the mechanisms of anaesthesia. Post-operative effects of inhalation anaesthetics on the central nervous system may produce a number of varied changes in mental status after surgery such as headache, emergence excitement and delirium [67]. The effects of anaesthetics are described in relation to age-related and physiological changes [68], [69]. Changes in CNS neural activity are associated with alteration in transmitter release

Conclusions

Brain acetylcholine release and cognitive performance are strictly related. Cholinergic neurons innervate many areas of the brain, and the disruption of acetylcholine neurotransmission at the muscarinic receptors in these areas produces dysfunction in a wide variety of mental, emotional and physiological activities [82]. It is necessary to keep the fluctuation of ACh levels in mind according to age-related cerebral changes and anaesthetic/drug interference [83]. In old rats, cortical and

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    ☆Possible conflicts of interest: support was provided solely from departmental sources.

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