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Neurological sequelae
BaillieÁre's Clinical Anaesthesiology Vol. 13, No. 3, pp. 451±463, 1999
16 Neurological sequelae Paul Sharpe
MB, ChB, FRCA
Lecturer and Honorary Specialist Registrar University Department of Anaesthesia, Leicester Royal In®rmary, Leicester LE1 5WW, United Kingdom
Christopher Hanning
MD, FRCA
Consultant Anaesthetist and Honorary Senior Lecturer Department of Anaesthesia, Leicester General Hospital, Leicester LE5 4PW, United Kingdom
Cognitive dysfunction, dementia and stroke may all follow apparently uncomplicated anaesthesia and surgery. The incidence, pathophysiology, prevention and treatment of each condition are reviewed. Key words: age; anaesthesia; cognitive function; delirium; hypoxaemia; operation; stroke; surgery.
Patients are at risk of neurological injury from all forms of surgery and anaesthesia including local and regional analgesia. This chapter will discuss the complications associated with surgery under general anaesthesia alone, referring only to regional techniques to illustrate key points. It is tempting to attribute all of these injuries to the anaesthetic, not least as most of the drugs given as part of the anaesthetic have a direct eect on the brain. However, the physical trespass of surgery causes disturbances in a number of physiological systems which may impact on the central nervous system and may thus cause or contribute to injury. Surgery and anaesthesia are never given alone but always together and thus separating the contributions of each element may be very dicult. We have therefore chosen to use the term `operation' to denote the procedure that includes both activities. Adverse neurological events following operation can be separated into three broad groups: cognitive impairment, delirium and stroke. Each of these categories will be considered in turn, patterns of incidence, the associated morbidity and mortality being emphasized and risk factors and the role of the anaesthetist in prevention of these complications being identi®ed. COGNITIVE DYSFUNCTION De®nition Cognition refers to the mental processes of perception, memory and information processing by which the individual acquires knowledge, solves problems and plans for the future.1 This process may become disturbed following an operation. 1521±6896/99/030451+13 $12.00/00
c 1999 Harcourt Publishers Ltd. *
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Incidence Early reports of prolonged post-operative cognitive dysfunction (POCD) were mostly anecdotal. Simpson et al, in a study of the outcome of surgery in 741 elderly patients, reported one patient who had prolonged cognitive problems2 while Knill et al noted that 25% of elderly patients with early post-operative delirium had persistent problems 6 weeks later.3 POCD has long been known to follow cardiac surgery and is regarded as a consequence of cardiopulmonary bypass occurring in 24±33% of patients.4,5 The International Study of Postoperative Cognitive Dysfunction (ISPOCD1)6 was the ®rst major study to try to con®rm the presence of POCD and to examine its possible causation and consequences. In 1200 patients, the study showed that 26% of elderly patients, aged over 60 years, following major surgery had cognitive dysfunction 1 week after surgery, and 10% continued to have dysfunction 3 months after surgery. Further follow-up of a proportion of these patients showed that cognitive dysfunction was present in 10% of them 1±2 years later, suggesting that the changes may be permanent (Abildstrom, 1999, personal communication). The ISPOCD1 study showed that age was the major risk factor for the development of POCD but there are few data on its incidence in younger patients. In a study of day case patients with a mean age of 34 years having general anaesthesia, a signi®cant number of these patients reported a perceived residual impairment of their cognitive function 3 days after general anaesthesia.7 However, there was no formal testing of cognitive function and the question remains open. Presentation and consequences A lack of concentration and problems with memory are the most commonly reported manifestations of POCD.6 These symptoms are often self-reported by patients, expressed as diculty with everyday activities such as completing the crossword or memory lapses. Family members may also notice the diculties and both parties may attribute the changes to advancing age rather than the recent operation. The consequences of POCD are unclear also. The ISPOCD1 study showed a signi®cantly reduced Activities of Daily Living score for patients with POCD compared with those who did not, suggesting that POCD did have deleterious eects on daily life.6 Pathophysiology Hypoxaemia and hypotension occur commonly during and after an operation and are apparently self-evident potential causes of POCD. This appeared to be supported by the work of Houx and Jolles, investigating the decline of cognitive function with age. They described a number of `biological life events' (BLEs), which may have occurred many years previously, associated with early cognitive decline.8 BLEs included `one or more operations' as well as minor head injuries and self-poisoning. Subjects who had not suered any BLEs had little decline in cognitive function with advancing age in contrast with those who had not. Several similar studies, as well as anecdotal reports, prompted the ISPOCD1 study. Studies of post-operative oxygenation and sleep showed that rapid eye movement (REM) and, to a lesser extent, slow-wave sleep were suppressed on the ®rst postoperative night and rebound on subsequent nights and are associated with, often severe, hypoxaemia. This potential association with POCD was investigated in the ISPOCD1 study. As noted above, the presence of POCD was con®rmed but no
Neurological sequelae 453
association was found with post-operative hypoxaemia or hypotension. Early postoperative cognitive dysfunction was shown to be related to a number of factors: age, duration of anaesthesia, limited education, repeat anaesthesia, infection and respiratory complications. Late cognitive dysfunction was only related to age.6 The ISPOCD1 study does not exclude the possibility that hypoxaemia or hypotension may not be causative factors in POCD in a few patients but they are clearly not the most important. The search has thus begun for alternative causes to POCD. Elevated glucocorticoid levels have been known, for some years, to cause cognitive impairment.9 Recent work on the hypothalamic±pituitary±adrenal (HPA) axis has suggested a mechanism for relating prolonged stress to cognitive dysfunction. Surgery produces increased activity of the HPA axis and thus increased glucocorticoid activity, which may be prolonged in the elderly as a result of impaired of regulatory feedback. The latter factor may explain the susceptibility of the elderly to POCD. The cyotokines, intercellular protein mediators, may also be mediators in a link between the stress response and POCD. Interleukin-1 (IL-1) and tumour necrosis factor are involved in the initiation of the classical stress response. IL-6 also has a profound positive in¯uence on the `stress' cascade; IL-6 production increases with age and may therefore explain the increased susceptibility of elderly patients to postoperative cognitive dysfunction.10 A genetic predisposition to the development of POCD also bears consideration. The APOE genetic system has three major allelic variants: E2, E3 and E4. The E4 allele has been shown to be linked with Alzheimer's disease11, and to be predictive of a poor cognitive outcome after head injury.12 It is therefore possible that the E4 allele may be a predictor of POCD. The drugs used in anaesthesia may be considered as potential causes of POCD. Previous studies have generally shown very little dierence between general and regional anaesthesia for cognitive dysfunction.13,14 However, the studies were generally small and used relatively insensitive tests of cognitive function and larger studies are in progress. Bene®ts from a regional technique would be explicable either by a reduction in stress response or by avoidance of the drugs used as part of a general anaesthetic technique. Many of these agents have cholinergic eects. The cholinergic system is known to be important for cognition, hyoscine being used as a model for delirium15 and anti-cholinesterases may be of value in the management of Alzheimer's disease.16 At present there is no evidence to suggest that anaesthetic drugs have any prolonged eect on cholinergic or other transmitter function but as a potential mechanism for POCD they merit investigation.
Management As no causative mechanism has been found, no prevention or treatment can be advocated although patients with early POCD may be encouraged to expect improvement with time. POCD is a complication that has been reliably shown to occur in 7±14% of elderly patients undergoing major surgery, depending on age.6 Consideration should be given to the possibility of this complication when obtaining informed consent for anaesthesia and surgery. However, at present, it is impossible to predict which patients will develop POCD and, as those patients with later POCD at 3 months±2 years after operation are not necessarily those who had POCD at one week, the natural history of the condition is not clear.
454 P. Sharpe and C. Hanning
A second European Community supported collaborative program of studies, ISPOCD2, has started to try to answer some of the questions posed above. The results are expected in early 2001. DELIRIUM De®nition Delirium is de®ned as an organic brain syndrome which develops acutely, has a ¯uctuating clinical course and is characterized by disturbances of attention, memory, orientation, perception, psychomotor behaviour and sleep.17 Delirium which develops in the ®rst 24 hours after surgery is termed emergence delirium. If delirium follows a lucid period of more than 24 hours then it is termed interval delirium. Both of the above forms can be further subdivided by their clinical appearance. The classically delirious, agitated patient is categorised as `hyperalert±hyperactive' and the more withdrawn patient is described as suering from `hypoalert±hypoactive' delirium.18 Delirium is not an insigni®cant clinical problem, mortality is increased ®ve-fold, hospitalization is prolonged and considerable cost is incurred. Its early diagnosis and management should be regarded as a clinical priority. Incidence The incidence of peri-operative delirium varies markedly in the literature, predominantly because of a lack of uniformity in diagnostic terms and because of a lack of awareness among medical and nursing sta looking after the patients. Rentowl (1999, personal communication) surveyed the understanding of postoperative delirium in teaching hospital junior medical and nursing sta. Awareness of hyperalert±hyperactive delirium and its association with alcohol withdrawal were well recognized by both groups; however, both doctors and nurses were far less aware of signs and symptoms of hypoalert±hypoactive delirium. The signi®cance of medication, depression, epilepsy and previous operations was appreciated by less than 50% of respondents, and less than 25% were aware of the ¯uctuating nature of delirium. Despite the lack of awareness of certain contributing factors, the incidence tended to be overestimated by a factor of 4. The awareness of the potential link between hypoxia and peri-operative delirium was again poorly understood. Clinicians that prescribed oxygen did so for a maximum of 48 hours, believing that the peak incidence of hypoxia occurred on the ®rst post-operative night. Knill et al showed that hypoxaemia was worst on the second to the fourth post-operative night19, the very time when the prescribed oxygen was being withdrawn. In the general surgical population, up to 14% of patients may develop post-operative delirium18 and in those requiring intensive care admission or organ transplantation this ®gure can be as high as 40%. Patients sustaining a hip fracture have probably the greatest incidence of post-operative delirium for any single procedure with just under 50% developing the problem.18 Pathophysiology This is not fully understood. Clearly delirium arises as a result of a central nervous system insult and the clinical progress of delirium would also point to the insult being reversible as most patients return to normal within a few days.
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Current theory is that delirium is caused by reversible disruption in cerebral oxidative metabolism and neurotransmission. It is suggested that the ®nal common pathway in the production of delirium is impaired cholinergic neurotransmission; however, other central neurotransmitters such as serotonin and norepinephrine are also important in regulating the state of arousal and may therefore contribute to a delirious state.20 Presentation The ®rst signs of delirium developing in peri-operative patients may be mild confusion (Table 1), progressing to a reduced ability to sustain attention and concentration on surroundings. Memory is impaired and patients may have altered perception of events around them. Speech may become incoherent and confused. Up to 70% of delirious patients may develop delusions which are usually persecutory in nature and 10% will become aggressive. Psychomotor activity may be increased or decreased and the symptoms vary quite markedly throughout the course of the day, often being worse at night. The variation in symptoms with time inevitably results in a disrupted sleep pattern which will further potentiate the problem.18 The agitated, hyperactive delirium is usually readily diagnosed but the withdrawn hypoactive state is easily missed, the patient's quietness while plucking at the bed clothes being taken to indicate well-being. Table 1. `Signs for diagnosis of delirium'.18 Reduced clarity of awareness Decreased attention span Perceptual disturbances Incoherent speech Disturbed sleep±wake cycle Altered psychomotor activity Memory impairment Disorientation Develops over hours to days Fluctuating course over the day Evidence of underlying speci®c organic cause
Risk factors Advancing age and poor medical condition are signi®cant risk factors for peri-operative delirium. Over the age of 75 years, patients have a three-fold increase in their risk of developing delirium. Multiple comorbid conditions increase the likelihood of delirium, again predisposing the elderly as many have one or more pre-existing illnesses.18 Neurological Structural. Dementia, cerebrovascular disease and Parkinson disease all predispose to delirium in the peri-operative setting. This is thought to represent true structural alterations in neuronal circuitry rather than eects of concurrent pharmacological therapy.21
456 P. Sharpe and C. Hanning
Traumatic. Disruption in oxygen delivery and blood ¯ow following trauma may lead to delirium. Trauma to the brain may be direct, in the form of concussion or contusion, subdural haemorrhage, or as a consequence of distant trauma, for example, with fat embolus from long-bone fracture. Psychological. Depression is associated with an increased risk of post-operative delirium and the same may be true for anxiety.22 Both the anti-depressant drugs, which have anti-cholinergic properties, and the small subcortical lesions found commonly in elderly depressed patients have been suggested as causes.23,24 Cardiorespiratory Any imbalance in oxygen delivery to the brain tissues may have a deleterious eect in the peri-operative period. Hypotension, hypoxaemia, hypovolaemia, hypocapnia, heart failure, myocardial infarction, pulmonary embolus and cardiac bypass are all capable alone, or in combination, of causing sucient decrease in cerebral oxygen delivery to precipitate delirium. The combination of hypoxaemia and infection accompanying post-operative pneumonia is important as up to 20% of elderly patients may develop this complication. Delirium is often the earliest clinical manifestation of chest infection as many do not develop pyrexia and cough in the early stages.25 Metabolic Electrolytes. Severe hypo- and hypernatraemia will cause delirium. In the peri-operative setting electrolyte imbalance may occur for several reasons. Part of the physiological response to surgery is an increased release of anti-diuretic hormone leading to ¯uid retention. Peri-operative ¯uid administration may also play a part in the development of electrolyte imbalance, for example large quantities of sodium-depleted ¯uids, such as 5% dextrose, or absorption of irrigation ¯uid through open venous sinuses during transurethral prostatectomy. Inadequate ¯uid replacement leads to dehydration and subsequent hypernatraemia with a risk of developing delirium when serum sodium concentrations exceed 150 mmol/l.26 Nutrition. Thiamine de®ciency may be a common cause of delirium and is often overlooked as the classical picture of Wernicke±Korsako psychosis may only be seen in alcoholic patients.27 Hypo- and hyperglycaemia, hypoalbuminaemia, hypercalcaemia, hypophosphataemia and acid±base disturbance have all been suggested as causative factors.18 Pharmacological The administration of drugs new to the patient or the withdrawal of concurrent drugs may equally cause delirium. In the latter group, alcohol, benzodiazepines and barbiturates are the most likely. Centrally acting anti-cholinergics and opioid drugs are in common use in anaesthetic practice and are both ranked highly in the list of drugs responsible for peri-operative delirium (Table 2). The elderly are at most risk, presumably as a result of altered pharmacokinetics and pharmacodynamics, leading to delayed clearance and exaggerated clinical eects from these drugs.
Neurological sequelae 457 Table 2. Pharmacological agents and delirium.18 Drugs with central anti-cholinergic activity Belladonna alkaloids Tricyclic anti-depressants Neuroleptics Anti-parkinsonian agents Anti-arrythmics Benzodiazepines Opioids Ketamine Halogenated anaesthetics Cardiovascular agents Digoxin b-Blockers Diuretics Calcium-channel blockers Anti-convulsants Anti-in¯ammatory agents Corticosteroids Non-steroidal agents Cyclosporin OKT3 Gastrointestinal agents H2 blockers Metoclopramide Antibiotics Penicillin Cipro¯oxacin Gentamicin Cephalosporins Oral hypoglycaemics
Management of peri-operative delirium Prevention and detection Prevention of delirium requires an awareness of the condition, identi®cation of the patient at risk and avoidance of precipitating factors. A careful history, with particular attention being paid to medication and alcohol consumption, is vital. Pre-operative optimization of the patient's medical condition by correction of dehydration, infection, metabolic disturbances and hypoxaemia should improve outcome.
Management of post-operative delirium . Identify the patient at risk . Avoid precipitating factors . Use psychology before drugs . Give sedatives with caution
458 P. Sharpe and C. Hanning
Intraoperatively, the usual principles for a safe anaesthetic should be followed. Short-acting drugs without active metabolites are to be preferred. Locoregional analgesia allows the patient to remain conscious and in contact with their surroundings and may be preferable to general anaesthesia. Centrally acting anti-cholinergics such as hyoscine and atropine should be avoided. Continuous regional analgesia for post-operative pain relief may be less likely to precipitate delirium than parenteral opioid techniques although this bene®t may be lost if spinal opioids are used for prolonged periods. Post-operative oxygen therapy is likely to be helpful and may also have therapeutic bene®t.28 Identi®cation of patients who might bene®t is dicult as is enforcing compliance with treatment. Oxygen masks are often noisy and may inhibit communication, which is important for all patients, particularly the elderly. Nasal cannulae may be better tolerated. Nursing sta and other carers have an important role in the prevention of delirium. Patients bene®t from orientation prompts, such as time of day, place etc. They also bene®t from continuity of care and regular communication, especially in the presence of their family. Several tests and scoring systems have been described to screen susceptible patients for delirium.29 One of the simplest is the `mini-mental state'30 (Table 3). This is quick to perform, patients tend to co-operate well and although there are only 11 questions it concentrates solely on the cognitive markers of mental function and has proved to correlate well with more extensive tests. It may therefore be possible to use this as a tool to monitor cognitive dysfunction in the ward setting. Table 3. The `mini-mental state' examination.30 Score
Maximum score
( ) ( )
5 5
( )
3
Attention and calculation Serial 7s. 1 point for each correct. Count backwards from 100. Stop after ®ve subtractions. Alternatively spell `world' backwards
( )
5
Recall Ask for the three objects named in Registration. Give one point for each correct.
( )
3
( )
9
( )
30
Orientation What is the (year) (season) (date) (day) (month)? Where are we? (state) (county) (town) (hospital) ( ¯oor) Registration Name three objects: 1 second to say each. Then ask the patient all three after you have said them. Give 1 point for each correct answer. Then repeat them until he or she learns all three. Count trials and record.
Language Name a pencil, and watch. (2 points) Repeat the following: `No ifs, ands or buts' (1 point) Follow a three-stage command: `Take a paper in your right hand, fold it in half and put it on the ¯oor' (3 points) Read and obey the following: `CLOSE YOUR EYES' (1 point) Write a sentence. (1 point) Copy a design. (1 point) Total score
Neurological sequelae 459
Treatment Psychological support of the patient should be a mainstay of treatment with elucidation and correction of any underlying cause. Every eort should be made to orient the patient in time and place, to maintain a day±night cycle, which will reinforce sleep patterns, and to encourage the presence of family members to decrease feelings of fear and anxiety. The history should be re-examined for evidence of alcohol abuse, benzodiazepine withdrawal or other pre-existing factors. Careful examination of the patient may reveal a focus of infection, dehydration, electrolyte disturbance or urinary retention as the underlying cause. The drug chart should be scrutinized for known precipitants or recent changes in therapy. Urea and electrolytes, serum glucose, full blood count, liver function tests, arterial blood gases, cultures of blood, sputum and urine, electrocardiogram and chest x-ray should be performed as baseline tests on all delirious patients.18 Sedation is often necessary during the initial presentation of delirium, especially when patients become aggressive, but should not be regarded as the sole management. The use of appropriate pharmacological agents will allow further investigation and treatment of the underlying cause. Neuroleptic drugs are the agents of choice31 in treating the agitated patient. Thioridazine is one of the most commonly used drugs but carries a high incidence of anti-cholinergic side-eects. Current clinical practice supports the use of haloperidol via the oral, intramuscular or intravenous routes. The route chosen should re¯ect the degree of agitation and therefore the urgency of treatment. Once initial control has been established, further doses should be given according to clinical response. Some authorities recommend small regular doses for short periods of time rather than p.r.n. doses but this should only be given where close supervision is possible. If the delirium is thought to be secondary to benzodiazepine withdrawal then treatment with short-acting benzodiazepines such as temazepam may be appropriate. It must be remembered that these are sedative drugs and therefore there is a real risk of worsening hypoxaemia. Alcohol withdrawal can be treated with short-acting benzodiazepines or chlormethiazole. The oral route for the latter drug is to be preferred as water overload may occur inadvertently if large volumes of the intravenous preparation are administered. STROKE De®nition Stroke is de®ned as a rapidly developing episode of focal and, at times, global loss of cerebral function, with symptoms lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin. Symptoms lasting less than 24 hours are termed transient ischaemic attacks.32 Those strokes which occur during anaesthesia or in the ®rst 30 post-operative days, are considered as peri-operative strokes.32 Pathophysiology Stroke is due to either infarction or haemorrhage. Of all strokes, 85% are secondary to infarction, the remainder to cerebral haemorrhage.33 Non-traumatic cerebral haemorrhage is almost entirely due to leakage from malformations of the arterial supply, particularly aneurysmal dilatations within the cerebral circulation, for example berry aneurysms around the circle of Willis.34
460 P. Sharpe and C. Hanning
Incidence and implications The annual incidence of stroke in the United Kingdom is of the order of 0.1±0.2% and is the third most common cause of death following heart disease and cancer.35 The mortality following an acute stroke is of the order of 15±30%; of the survivors only 45% will be leading an independent life at 1 year post-stroke.32 As the incidence of stroke increases with age, and the proportion of elderly patients rises, it is clear that an increasing number of patients at greater risk of sustaining a peri-operative stroke will attend for surgery, including those that have already survived a stroke. The incidence of peri-operative stroke in the current literature varies from 0.08% to 2.9% for general surgical patients32,36 and may be as high as 5% in those presenting for head and neck surgery.32 A mortality of 46% for peri-operative stroke has been reported. With the possible exception of carotid artery surgery, the vast majority of peri-operative strokes occur in the post-operative period on average on the seventh post-operative day, range 2±10 days. The incidence of stroke in patients with a previous stroke is at least 2.1% with a mortality of 60%.32 Table 4. Risk factors for stroke.32 Age Previous cerebrovascular disease Hypertension Cardiac arrythmias Hypercoagulability Type of surgery Comorbidity Carotid bruits
Identi®cation and management of the `at-risk' patient (Table 4) Age The incidence of stroke in patients under 80 years is less than 0.5% in contrast to those over the age of 80 years where the risk is over 3%.32 Previous cerebrovascular disease Patients having already sustained a stroke have a 10-fold increase in their risk of developing a further stroke.37 Hypertension This, in conjunction with atherosclerosis, is probably the most signi®cant risk factor for the development of stroke in the general population. Larsen and colleagues showed a four-fold increase in stroke rate among hypertensive patients.38 Cardiac arrhythmias Patients in atrial ®brillation are at risk of embolus formation resulting in ischaemic stroke formation.39
Neurological sequelae 461
Carotid bruits This remains an area of controversy and the predictive value of a pre-operative carotid bruit, symptomatic or otherwise, is not known. Studies that are available have been on relatively small numbers and have not followed the patients throughout the full risk period for development of a peri-operative stroke.32 Type of surgery Patients undergoing head and neck surgery are at a 4.8% risk of developing a perioperative stroke. There are several reasons for this increased risk: the patients are often older, the common presence of comorbidity, the increased incidence of peripheral vascular disease which in its own right can cause an eight-fold increase in stroke risk and positioning of the head leading to vascular spasm, occlusion and embolism.36 Snoring and obstructive sleep apnoea A history of snoring was the most signi®cant risk factor for stroke in a recent survey, independently of associated factors such as hypertension.40 The cortical arousal which occurs with each episode of airway obstruction during sleep causes a surge in blood pressure. In severe cases of obstructive sleep apnoea, episodic hypertension may occur 50±80 times per hour of sleep.41 Sleep apnoea typically worsens in the post-operative period and it is tempting to postulate that it may be a risk factor for peri-operative stroke. Comorbidity Both peripheral vascular disease and chronic obstructive airways disease are signi®cant factors in increasing risk of a peri-operative stroke.36 As for delirium, identi®cation of at-risk patients and avoidance of precipitating factors are the mainstay of management. Hypertension should be controlled in the pre-operative period as this reduces the general incidence of stroke. The control of atrial ®brillation is bene®cial also, preferably by cardioversion. Long-term anticoagulation should be converted to heparin which is discontinued 6 hours before surgery and re-instituted 24 hours after. Patients with signi®cant arrythmias that are not taking anti-coagulants should be commenced on the same heparinization regime. The European Carotid Surgery Trial42 and the North American Symptomatic Carotid Endarterectomy Trial43 both suggest the bene®t of carotid surgery for symptomatic patients with 470% stenosis to reduce their risk of stroke. Such patients identi®ed in the pre-operative setting may bene®t from assessment by a vascular surgeon. Combined procedures, or vascular correction prior to the scheduled operation, may improve the overall outcome for the patient. The timing of any operation following a previous stroke does not appear to in¯uence the risk of developing a further peri-operative stroke37; however, it would be prudent to defer surgery for 4±6 weeks if possible to allow the ischaemic penumbra around the stroke to heal. There are no prospective trials showing that control of intra-operative blood pressure aects the incidence of peri-operative stroke. Despite this lack of evidence, it is advisable to maintain the patient's blood pressure within his or her normal range as autoregulation may be lost in ischaemic tissue. Carbon dioxide tension should be kept
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in the normal range also as changes in vessel calibre may lead to steal or inverse steal phenomena around the territories of diseased vessels. The post-operative period presents the greatest risk to the patient in terms of developing a peri-operative stroke. Con¯icting evidence36,37 exists for the role of hypotension causing stroke in the post-operative period. Common sense suggests that the blood pressure should be kept in the normal range. Prevention of dehydration and hypercoagulability and the institution of heparin in `at-risk' patients are all suggested as bene®cial but the prospective evidence to support these assertions is lacking. Potential advances in stroke care Neuroprotection for stroke patients has shown varying degrees of success in clinical trials. Selfotel, aptiganel, enlimomab, clomethiazole, tirilazad and piracetam have all been used in recent trials, but none was shown to be bene®cial. Lubeluzole is a sodium-channel blocker, which is thought to reduce the amount of glutamate produced by ischaemic neurones and thus excitotoxicity at the post-synaptic membrane. It may also decrease the amount of intracellular damage by inhibiting post-synaptic nitric oxide synthetase activity. Recent trials have shown functional improvement in stroke patients but have not shown any clear improvements in mortality.44 Magnesium sulphate and a glycine antagonist (GV150526) are currently under investigation in large international trials.44 REFERENCES 1. Atkinson RL, Atkinson RC, Smith EE et al. Hilgard's Introduction to Psychology, 12th edn. New York: Harcourt Brace, 1996. 2. Simpson BR, Williams M, Scott JF & Crampton Smith A. The eects of anaesthesia and elective surgery on old people. Lancet 1961; ii: 887±893. 3. Knill RL, Novick TY & Skinner MI. Idiopathic post-operative delirium is associated with longterm cognitive impairment. Canadian Journal of Anesthesia 1991; 38: A54. 4. Shaw PJ, Bates D, Cartlidge NEF et al. Neurologic and neuropsychological morbidity following major surgery: comparison of coronary artery bypass and peripheral vascular surgery. Stroke 1987; 18: 700±707. 5. Segatore M, Dutkiewicz M & Adams D. The delerious cardiac surgical patient: theoretical aspects and principles of management. Journal of Cardiovascular Nursing 1998; 12: 32±48. * 6. Moller JT, Cluitmans P, Rasmussen LS et al. Long term post-operative cognitive dysfunction in the elderly: ISPOCD 1 study. Lancet 1998; 351: 857±861. 7. Tzabar Y, Asbury AJ & Millar K. Cognitive failures after general anaesthesia for day-case surgery. British Journal of Anaesthesia 1996; 76: 194±197. 8. Houx PJ & Jolles J. Age-related decline of psychomotor speed: eects of age, brain health, sex and education. Perceptual and Motor Skills 1993; 76: 195±211. * 9. O'Brien JT. The `glucocorticoid cascade' hypothesis in man ± prolonged stress may cause permanent brain damage. British Journal of Psychiatry 1997; 170: 199±210. 10. Maier SF & Watkins LR. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychological Revue 1998; 105: 83±107. 11. Saunders AM, Strittmatter WJ, Schmechel D et al. Association of apolipoprotein E allele E4 with lateonset familial and sporadic Alzheimer's disease. Neurology 1993; 43: 1467±1472. 12. Mayeux R, Ottoman R, Maestre G et al. Synergistic eects of traumatic head injury and apolipoproteinE4 in patients with Alzheimer's disease. Neurology 1995; 45: 555±557. 13. Williams-Russo P, Sharrock NE, Mattis S et al. Cognitive eects after epidural vs general anaesthesia in older adults: a randomised trial. Journal of the American Medical Association 1995; 274: 44±50. 14. Hole A, Terjesen T & Breivik H. Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anesthesiologica Scandinavica 1980; 24: 279±287. 15. Ebert U & Kirch W. Scopolamine model of dementia: electroencephalogram ®ndings and cognitive performance. European Journal of Clinical Investigation 1998; 28: 944±949.
Neurological sequelae 463 16. Levy ML, Cummings JL & KahnRose R. Neuropsychiatric symptoms and cholinergic therapy for Alzheimer's disease. Gerontology 1999; 45: S1.15±S1.22. 17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised. Washington, DC: American Psychiatric Association, 1994. *18. O'Keefe ST & Chonchubhair AN. Post-operative delirium in the elderly. British Journal of Anaesthesia 1994; 73: 673±687. 19. Knill RL, Moote CA, Skinner MI & Rose EA. Anaesthesia with abdominal surgery leads to intense REM sleep during the ®rst post-operative week. Anesthesiology 1990; 73: 52±61. 20. Lindesay J, Macdonald A & Starke I. Delirium in the Elderly. Oxford: Oxford University Press, 1990. 21. Gustafson Y, Berggren D, Brannstrom B et al. Acute confusional states in elderly patients treated for femoral neck fractures. Journal of the American Geriatric Society 1988; 36: 525±530. 22. Morse RM & Litin EM. Post-operative delirium: a study of etiologic factors. American Journal of Psychiatry 1969; 126: 388±395. 23. Berggren D, Gustafson Y, Eriksson B et al. Post-operative confusion after anaesthesia in elderly patients with femoral neck fractures. Anesthesia and Analgesia 1987; 66: 497±504. 24. Figiel GS, Krishnan KRR, Breitner JC & Nemero CB. Radiologic correlates of antidepressant-induced delirium: the possible signi®cance of basal-ganglia lesions. Journal of Neuropsychology 1989; 1: 188±190. 25. Mesulam MM & Geschwind N. Disordered mental states in the post-operative period. Urologic Clinics of North America 1976; 3: 199±215. 26. Marcantonia ER, Goldman L, Mangione CM et al. A clinical prediction rule for delirium after elective non-cardiac surgery. Journal of the American Medical Association 1994; 271: 134±139. 27. Harper CG, Giles M & Finley-Jones R. Clinical signs in the Wernicke-Korsako complex: a retrospective analysis of 131 cases diagnosed at necropsy. Journal of Neurology, Neurosurgery and Psychiatry 1986; 49: 341±345. 28. Aakerland LP & Rosenberg J. Post-operative delirium: abolition with supplemental oxygen. British Journal of Anaesthesia 1994; 72: 286±290. 29. Innouye SK, Viscoli CM, Horwitz RI et al. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Annals of Internal Medicine 1993; 119: 474±481. 30. Folstein MF, Folstein SE & McHugh PR. `Mini-mental state'. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research 1975; 12: 189±198. *31. Anonymous. Drugs causing confusion and drugs to treat confusion. Prescribers Journal 1998; 38: 242±249. *32. Kam PCA & Calcroft RM. Peri-operative stroke in general surgical patients. Anaesthesia 1997; 52: 879±883. 33. McGee JO'D, Isaacson PG & Wright NA. Oxford Textbook of Pathology. Oxford: Oxford University Press, 1992. 34. Parums DV. Essential clinical pathology. London: Blackwell Scienti®c, 1996. 35. Hinton RC. Thrombosis and cerebrovascular disease. Medical Clinics of North America 1998; 82: 523±544. *36. Limburg M, Wijdicks EF & Li H. Ischaemic stroke after surgical procedure: clinical features, neuroimaging, and risk factors. Neurology 1998; 50: 895±901. 37. Landercasper J, Mertz BJ & Cogbill TH. Perioperative stroke risk in 173 consecutive patients with a past history of stroke. Archives of Surgery 1990; 125: 986±989. 38. Larsen SF, Zaric D & Boysen G. Post-operative cerebrovascular accidents in general surgery. Acta Anesthesiologica Scandinavica 1988; 32: 698±701. 39. Kaarisalo MM, Imonen-Raiha P, Marttila RJ et al. Atrial ®brillation in older stroke patients: association with recurrence and mortality after ®rst ischaemic stroke. Journal of the American Geriatric Society 1997; 45: 1297±1301. 40. Anonymous. Snoring-stroke link elucidated. Lancet 1998; 351: 117. *41. Silverberg DS, Oksenberg A & Iaina A. Sleep-related breathing disorders as a major cause of essential hypertension: fact or ®ction. Current Opinion in Nephrology and Hypertension 1998; 7: 353±357. 42. European Carotid Surgery Trialists Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70±90%) or mild (1±29%) carotid stenosis. Lancet 1991; 337: 1235±1243. 43. North American Symptomatic Carotid Endarterectomy Trial Group. Bene®cial eects of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. New England Journal of Medicine 1991; 325: 445±453. *44. Lees KR. Does neuroprotection improve stroke outcome? Lancet 1998; 351: 1447±1448.
16 Neurological sequelae Paul Sharpe
MB, ChB, FRCA
Lecturer and Honorary Specialist Registrar University Department of Anaesthesia, Leicester Royal In®rmary, Leicester LE1 5WW, United Kingdom
Christopher Hanning
MD, FRCA
Consultant Anaesthetist and Honorary Senior Lecturer Department of Anaesthesia, Leicester General Hospital, Leicester LE5 4PW, United Kingdom
Cognitive dysfunction, dementia and stroke may all follow apparently uncomplicated anaesthesia and surgery. The incidence, pathophysiology, prevention and treatment of each condition are reviewed. Key words: age; anaesthesia; cognitive function; delirium; hypoxaemia; operation; stroke; surgery.
Patients are at risk of neurological injury from all forms of surgery and anaesthesia including local and regional analgesia. This chapter will discuss the complications associated with surgery under general anaesthesia alone, referring only to regional techniques to illustrate key points. It is tempting to attribute all of these injuries to the anaesthetic, not least as most of the drugs given as part of the anaesthetic have a direct eect on the brain. However, the physical trespass of surgery causes disturbances in a number of physiological systems which may impact on the central nervous system and may thus cause or contribute to injury. Surgery and anaesthesia are never given alone but always together and thus separating the contributions of each element may be very dicult. We have therefore chosen to use the term `operation' to denote the procedure that includes both activities. Adverse neurological events following operation can be separated into three broad groups: cognitive impairment, delirium and stroke. Each of these categories will be considered in turn, patterns of incidence, the associated morbidity and mortality being emphasized and risk factors and the role of the anaesthetist in prevention of these complications being identi®ed. COGNITIVE DYSFUNCTION De®nition Cognition refers to the mental processes of perception, memory and information processing by which the individual acquires knowledge, solves problems and plans for the future.1 This process may become disturbed following an operation. 1521±6896/99/030451+13 $12.00/00
c 1999 Harcourt Publishers Ltd. *
452 P. Sharpe and C. Hanning
Incidence Early reports of prolonged post-operative cognitive dysfunction (POCD) were mostly anecdotal. Simpson et al, in a study of the outcome of surgery in 741 elderly patients, reported one patient who had prolonged cognitive problems2 while Knill et al noted that 25% of elderly patients with early post-operative delirium had persistent problems 6 weeks later.3 POCD has long been known to follow cardiac surgery and is regarded as a consequence of cardiopulmonary bypass occurring in 24±33% of patients.4,5 The International Study of Postoperative Cognitive Dysfunction (ISPOCD1)6 was the ®rst major study to try to con®rm the presence of POCD and to examine its possible causation and consequences. In 1200 patients, the study showed that 26% of elderly patients, aged over 60 years, following major surgery had cognitive dysfunction 1 week after surgery, and 10% continued to have dysfunction 3 months after surgery. Further follow-up of a proportion of these patients showed that cognitive dysfunction was present in 10% of them 1±2 years later, suggesting that the changes may be permanent (Abildstrom, 1999, personal communication). The ISPOCD1 study showed that age was the major risk factor for the development of POCD but there are few data on its incidence in younger patients. In a study of day case patients with a mean age of 34 years having general anaesthesia, a signi®cant number of these patients reported a perceived residual impairment of their cognitive function 3 days after general anaesthesia.7 However, there was no formal testing of cognitive function and the question remains open. Presentation and consequences A lack of concentration and problems with memory are the most commonly reported manifestations of POCD.6 These symptoms are often self-reported by patients, expressed as diculty with everyday activities such as completing the crossword or memory lapses. Family members may also notice the diculties and both parties may attribute the changes to advancing age rather than the recent operation. The consequences of POCD are unclear also. The ISPOCD1 study showed a signi®cantly reduced Activities of Daily Living score for patients with POCD compared with those who did not, suggesting that POCD did have deleterious eects on daily life.6 Pathophysiology Hypoxaemia and hypotension occur commonly during and after an operation and are apparently self-evident potential causes of POCD. This appeared to be supported by the work of Houx and Jolles, investigating the decline of cognitive function with age. They described a number of `biological life events' (BLEs), which may have occurred many years previously, associated with early cognitive decline.8 BLEs included `one or more operations' as well as minor head injuries and self-poisoning. Subjects who had not suered any BLEs had little decline in cognitive function with advancing age in contrast with those who had not. Several similar studies, as well as anecdotal reports, prompted the ISPOCD1 study. Studies of post-operative oxygenation and sleep showed that rapid eye movement (REM) and, to a lesser extent, slow-wave sleep were suppressed on the ®rst postoperative night and rebound on subsequent nights and are associated with, often severe, hypoxaemia. This potential association with POCD was investigated in the ISPOCD1 study. As noted above, the presence of POCD was con®rmed but no
Neurological sequelae 453
association was found with post-operative hypoxaemia or hypotension. Early postoperative cognitive dysfunction was shown to be related to a number of factors: age, duration of anaesthesia, limited education, repeat anaesthesia, infection and respiratory complications. Late cognitive dysfunction was only related to age.6 The ISPOCD1 study does not exclude the possibility that hypoxaemia or hypotension may not be causative factors in POCD in a few patients but they are clearly not the most important. The search has thus begun for alternative causes to POCD. Elevated glucocorticoid levels have been known, for some years, to cause cognitive impairment.9 Recent work on the hypothalamic±pituitary±adrenal (HPA) axis has suggested a mechanism for relating prolonged stress to cognitive dysfunction. Surgery produces increased activity of the HPA axis and thus increased glucocorticoid activity, which may be prolonged in the elderly as a result of impaired of regulatory feedback. The latter factor may explain the susceptibility of the elderly to POCD. The cyotokines, intercellular protein mediators, may also be mediators in a link between the stress response and POCD. Interleukin-1 (IL-1) and tumour necrosis factor are involved in the initiation of the classical stress response. IL-6 also has a profound positive in¯uence on the `stress' cascade; IL-6 production increases with age and may therefore explain the increased susceptibility of elderly patients to postoperative cognitive dysfunction.10 A genetic predisposition to the development of POCD also bears consideration. The APOE genetic system has three major allelic variants: E2, E3 and E4. The E4 allele has been shown to be linked with Alzheimer's disease11, and to be predictive of a poor cognitive outcome after head injury.12 It is therefore possible that the E4 allele may be a predictor of POCD. The drugs used in anaesthesia may be considered as potential causes of POCD. Previous studies have generally shown very little dierence between general and regional anaesthesia for cognitive dysfunction.13,14 However, the studies were generally small and used relatively insensitive tests of cognitive function and larger studies are in progress. Bene®ts from a regional technique would be explicable either by a reduction in stress response or by avoidance of the drugs used as part of a general anaesthetic technique. Many of these agents have cholinergic eects. The cholinergic system is known to be important for cognition, hyoscine being used as a model for delirium15 and anti-cholinesterases may be of value in the management of Alzheimer's disease.16 At present there is no evidence to suggest that anaesthetic drugs have any prolonged eect on cholinergic or other transmitter function but as a potential mechanism for POCD they merit investigation.
Management As no causative mechanism has been found, no prevention or treatment can be advocated although patients with early POCD may be encouraged to expect improvement with time. POCD is a complication that has been reliably shown to occur in 7±14% of elderly patients undergoing major surgery, depending on age.6 Consideration should be given to the possibility of this complication when obtaining informed consent for anaesthesia and surgery. However, at present, it is impossible to predict which patients will develop POCD and, as those patients with later POCD at 3 months±2 years after operation are not necessarily those who had POCD at one week, the natural history of the condition is not clear.
454 P. Sharpe and C. Hanning
A second European Community supported collaborative program of studies, ISPOCD2, has started to try to answer some of the questions posed above. The results are expected in early 2001. DELIRIUM De®nition Delirium is de®ned as an organic brain syndrome which develops acutely, has a ¯uctuating clinical course and is characterized by disturbances of attention, memory, orientation, perception, psychomotor behaviour and sleep.17 Delirium which develops in the ®rst 24 hours after surgery is termed emergence delirium. If delirium follows a lucid period of more than 24 hours then it is termed interval delirium. Both of the above forms can be further subdivided by their clinical appearance. The classically delirious, agitated patient is categorised as `hyperalert±hyperactive' and the more withdrawn patient is described as suering from `hypoalert±hypoactive' delirium.18 Delirium is not an insigni®cant clinical problem, mortality is increased ®ve-fold, hospitalization is prolonged and considerable cost is incurred. Its early diagnosis and management should be regarded as a clinical priority. Incidence The incidence of peri-operative delirium varies markedly in the literature, predominantly because of a lack of uniformity in diagnostic terms and because of a lack of awareness among medical and nursing sta looking after the patients. Rentowl (1999, personal communication) surveyed the understanding of postoperative delirium in teaching hospital junior medical and nursing sta. Awareness of hyperalert±hyperactive delirium and its association with alcohol withdrawal were well recognized by both groups; however, both doctors and nurses were far less aware of signs and symptoms of hypoalert±hypoactive delirium. The signi®cance of medication, depression, epilepsy and previous operations was appreciated by less than 50% of respondents, and less than 25% were aware of the ¯uctuating nature of delirium. Despite the lack of awareness of certain contributing factors, the incidence tended to be overestimated by a factor of 4. The awareness of the potential link between hypoxia and peri-operative delirium was again poorly understood. Clinicians that prescribed oxygen did so for a maximum of 48 hours, believing that the peak incidence of hypoxia occurred on the ®rst post-operative night. Knill et al showed that hypoxaemia was worst on the second to the fourth post-operative night19, the very time when the prescribed oxygen was being withdrawn. In the general surgical population, up to 14% of patients may develop post-operative delirium18 and in those requiring intensive care admission or organ transplantation this ®gure can be as high as 40%. Patients sustaining a hip fracture have probably the greatest incidence of post-operative delirium for any single procedure with just under 50% developing the problem.18 Pathophysiology This is not fully understood. Clearly delirium arises as a result of a central nervous system insult and the clinical progress of delirium would also point to the insult being reversible as most patients return to normal within a few days.
Neurological sequelae 455
Current theory is that delirium is caused by reversible disruption in cerebral oxidative metabolism and neurotransmission. It is suggested that the ®nal common pathway in the production of delirium is impaired cholinergic neurotransmission; however, other central neurotransmitters such as serotonin and norepinephrine are also important in regulating the state of arousal and may therefore contribute to a delirious state.20 Presentation The ®rst signs of delirium developing in peri-operative patients may be mild confusion (Table 1), progressing to a reduced ability to sustain attention and concentration on surroundings. Memory is impaired and patients may have altered perception of events around them. Speech may become incoherent and confused. Up to 70% of delirious patients may develop delusions which are usually persecutory in nature and 10% will become aggressive. Psychomotor activity may be increased or decreased and the symptoms vary quite markedly throughout the course of the day, often being worse at night. The variation in symptoms with time inevitably results in a disrupted sleep pattern which will further potentiate the problem.18 The agitated, hyperactive delirium is usually readily diagnosed but the withdrawn hypoactive state is easily missed, the patient's quietness while plucking at the bed clothes being taken to indicate well-being. Table 1. `Signs for diagnosis of delirium'.18 Reduced clarity of awareness Decreased attention span Perceptual disturbances Incoherent speech Disturbed sleep±wake cycle Altered psychomotor activity Memory impairment Disorientation Develops over hours to days Fluctuating course over the day Evidence of underlying speci®c organic cause
Risk factors Advancing age and poor medical condition are signi®cant risk factors for peri-operative delirium. Over the age of 75 years, patients have a three-fold increase in their risk of developing delirium. Multiple comorbid conditions increase the likelihood of delirium, again predisposing the elderly as many have one or more pre-existing illnesses.18 Neurological Structural. Dementia, cerebrovascular disease and Parkinson disease all predispose to delirium in the peri-operative setting. This is thought to represent true structural alterations in neuronal circuitry rather than eects of concurrent pharmacological therapy.21
456 P. Sharpe and C. Hanning
Traumatic. Disruption in oxygen delivery and blood ¯ow following trauma may lead to delirium. Trauma to the brain may be direct, in the form of concussion or contusion, subdural haemorrhage, or as a consequence of distant trauma, for example, with fat embolus from long-bone fracture. Psychological. Depression is associated with an increased risk of post-operative delirium and the same may be true for anxiety.22 Both the anti-depressant drugs, which have anti-cholinergic properties, and the small subcortical lesions found commonly in elderly depressed patients have been suggested as causes.23,24 Cardiorespiratory Any imbalance in oxygen delivery to the brain tissues may have a deleterious eect in the peri-operative period. Hypotension, hypoxaemia, hypovolaemia, hypocapnia, heart failure, myocardial infarction, pulmonary embolus and cardiac bypass are all capable alone, or in combination, of causing sucient decrease in cerebral oxygen delivery to precipitate delirium. The combination of hypoxaemia and infection accompanying post-operative pneumonia is important as up to 20% of elderly patients may develop this complication. Delirium is often the earliest clinical manifestation of chest infection as many do not develop pyrexia and cough in the early stages.25 Metabolic Electrolytes. Severe hypo- and hypernatraemia will cause delirium. In the peri-operative setting electrolyte imbalance may occur for several reasons. Part of the physiological response to surgery is an increased release of anti-diuretic hormone leading to ¯uid retention. Peri-operative ¯uid administration may also play a part in the development of electrolyte imbalance, for example large quantities of sodium-depleted ¯uids, such as 5% dextrose, or absorption of irrigation ¯uid through open venous sinuses during transurethral prostatectomy. Inadequate ¯uid replacement leads to dehydration and subsequent hypernatraemia with a risk of developing delirium when serum sodium concentrations exceed 150 mmol/l.26 Nutrition. Thiamine de®ciency may be a common cause of delirium and is often overlooked as the classical picture of Wernicke±Korsako psychosis may only be seen in alcoholic patients.27 Hypo- and hyperglycaemia, hypoalbuminaemia, hypercalcaemia, hypophosphataemia and acid±base disturbance have all been suggested as causative factors.18 Pharmacological The administration of drugs new to the patient or the withdrawal of concurrent drugs may equally cause delirium. In the latter group, alcohol, benzodiazepines and barbiturates are the most likely. Centrally acting anti-cholinergics and opioid drugs are in common use in anaesthetic practice and are both ranked highly in the list of drugs responsible for peri-operative delirium (Table 2). The elderly are at most risk, presumably as a result of altered pharmacokinetics and pharmacodynamics, leading to delayed clearance and exaggerated clinical eects from these drugs.
Neurological sequelae 457 Table 2. Pharmacological agents and delirium.18 Drugs with central anti-cholinergic activity Belladonna alkaloids Tricyclic anti-depressants Neuroleptics Anti-parkinsonian agents Anti-arrythmics Benzodiazepines Opioids Ketamine Halogenated anaesthetics Cardiovascular agents Digoxin b-Blockers Diuretics Calcium-channel blockers Anti-convulsants Anti-in¯ammatory agents Corticosteroids Non-steroidal agents Cyclosporin OKT3 Gastrointestinal agents H2 blockers Metoclopramide Antibiotics Penicillin Cipro¯oxacin Gentamicin Cephalosporins Oral hypoglycaemics
Management of peri-operative delirium Prevention and detection Prevention of delirium requires an awareness of the condition, identi®cation of the patient at risk and avoidance of precipitating factors. A careful history, with particular attention being paid to medication and alcohol consumption, is vital. Pre-operative optimization of the patient's medical condition by correction of dehydration, infection, metabolic disturbances and hypoxaemia should improve outcome.
Management of post-operative delirium . Identify the patient at risk . Avoid precipitating factors . Use psychology before drugs . Give sedatives with caution
458 P. Sharpe and C. Hanning
Intraoperatively, the usual principles for a safe anaesthetic should be followed. Short-acting drugs without active metabolites are to be preferred. Locoregional analgesia allows the patient to remain conscious and in contact with their surroundings and may be preferable to general anaesthesia. Centrally acting anti-cholinergics such as hyoscine and atropine should be avoided. Continuous regional analgesia for post-operative pain relief may be less likely to precipitate delirium than parenteral opioid techniques although this bene®t may be lost if spinal opioids are used for prolonged periods. Post-operative oxygen therapy is likely to be helpful and may also have therapeutic bene®t.28 Identi®cation of patients who might bene®t is dicult as is enforcing compliance with treatment. Oxygen masks are often noisy and may inhibit communication, which is important for all patients, particularly the elderly. Nasal cannulae may be better tolerated. Nursing sta and other carers have an important role in the prevention of delirium. Patients bene®t from orientation prompts, such as time of day, place etc. They also bene®t from continuity of care and regular communication, especially in the presence of their family. Several tests and scoring systems have been described to screen susceptible patients for delirium.29 One of the simplest is the `mini-mental state'30 (Table 3). This is quick to perform, patients tend to co-operate well and although there are only 11 questions it concentrates solely on the cognitive markers of mental function and has proved to correlate well with more extensive tests. It may therefore be possible to use this as a tool to monitor cognitive dysfunction in the ward setting. Table 3. The `mini-mental state' examination.30 Score
Maximum score
( ) ( )
5 5
( )
3
Attention and calculation Serial 7s. 1 point for each correct. Count backwards from 100. Stop after ®ve subtractions. Alternatively spell `world' backwards
( )
5
Recall Ask for the three objects named in Registration. Give one point for each correct.
( )
3
( )
9
( )
30
Orientation What is the (year) (season) (date) (day) (month)? Where are we? (state) (county) (town) (hospital) ( ¯oor) Registration Name three objects: 1 second to say each. Then ask the patient all three after you have said them. Give 1 point for each correct answer. Then repeat them until he or she learns all three. Count trials and record.
Language Name a pencil, and watch. (2 points) Repeat the following: `No ifs, ands or buts' (1 point) Follow a three-stage command: `Take a paper in your right hand, fold it in half and put it on the ¯oor' (3 points) Read and obey the following: `CLOSE YOUR EYES' (1 point) Write a sentence. (1 point) Copy a design. (1 point) Total score
Neurological sequelae 459
Treatment Psychological support of the patient should be a mainstay of treatment with elucidation and correction of any underlying cause. Every eort should be made to orient the patient in time and place, to maintain a day±night cycle, which will reinforce sleep patterns, and to encourage the presence of family members to decrease feelings of fear and anxiety. The history should be re-examined for evidence of alcohol abuse, benzodiazepine withdrawal or other pre-existing factors. Careful examination of the patient may reveal a focus of infection, dehydration, electrolyte disturbance or urinary retention as the underlying cause. The drug chart should be scrutinized for known precipitants or recent changes in therapy. Urea and electrolytes, serum glucose, full blood count, liver function tests, arterial blood gases, cultures of blood, sputum and urine, electrocardiogram and chest x-ray should be performed as baseline tests on all delirious patients.18 Sedation is often necessary during the initial presentation of delirium, especially when patients become aggressive, but should not be regarded as the sole management. The use of appropriate pharmacological agents will allow further investigation and treatment of the underlying cause. Neuroleptic drugs are the agents of choice31 in treating the agitated patient. Thioridazine is one of the most commonly used drugs but carries a high incidence of anti-cholinergic side-eects. Current clinical practice supports the use of haloperidol via the oral, intramuscular or intravenous routes. The route chosen should re¯ect the degree of agitation and therefore the urgency of treatment. Once initial control has been established, further doses should be given according to clinical response. Some authorities recommend small regular doses for short periods of time rather than p.r.n. doses but this should only be given where close supervision is possible. If the delirium is thought to be secondary to benzodiazepine withdrawal then treatment with short-acting benzodiazepines such as temazepam may be appropriate. It must be remembered that these are sedative drugs and therefore there is a real risk of worsening hypoxaemia. Alcohol withdrawal can be treated with short-acting benzodiazepines or chlormethiazole. The oral route for the latter drug is to be preferred as water overload may occur inadvertently if large volumes of the intravenous preparation are administered. STROKE De®nition Stroke is de®ned as a rapidly developing episode of focal and, at times, global loss of cerebral function, with symptoms lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin. Symptoms lasting less than 24 hours are termed transient ischaemic attacks.32 Those strokes which occur during anaesthesia or in the ®rst 30 post-operative days, are considered as peri-operative strokes.32 Pathophysiology Stroke is due to either infarction or haemorrhage. Of all strokes, 85% are secondary to infarction, the remainder to cerebral haemorrhage.33 Non-traumatic cerebral haemorrhage is almost entirely due to leakage from malformations of the arterial supply, particularly aneurysmal dilatations within the cerebral circulation, for example berry aneurysms around the circle of Willis.34
460 P. Sharpe and C. Hanning
Incidence and implications The annual incidence of stroke in the United Kingdom is of the order of 0.1±0.2% and is the third most common cause of death following heart disease and cancer.35 The mortality following an acute stroke is of the order of 15±30%; of the survivors only 45% will be leading an independent life at 1 year post-stroke.32 As the incidence of stroke increases with age, and the proportion of elderly patients rises, it is clear that an increasing number of patients at greater risk of sustaining a peri-operative stroke will attend for surgery, including those that have already survived a stroke. The incidence of peri-operative stroke in the current literature varies from 0.08% to 2.9% for general surgical patients32,36 and may be as high as 5% in those presenting for head and neck surgery.32 A mortality of 46% for peri-operative stroke has been reported. With the possible exception of carotid artery surgery, the vast majority of peri-operative strokes occur in the post-operative period on average on the seventh post-operative day, range 2±10 days. The incidence of stroke in patients with a previous stroke is at least 2.1% with a mortality of 60%.32 Table 4. Risk factors for stroke.32 Age Previous cerebrovascular disease Hypertension Cardiac arrythmias Hypercoagulability Type of surgery Comorbidity Carotid bruits
Identi®cation and management of the `at-risk' patient (Table 4) Age The incidence of stroke in patients under 80 years is less than 0.5% in contrast to those over the age of 80 years where the risk is over 3%.32 Previous cerebrovascular disease Patients having already sustained a stroke have a 10-fold increase in their risk of developing a further stroke.37 Hypertension This, in conjunction with atherosclerosis, is probably the most signi®cant risk factor for the development of stroke in the general population. Larsen and colleagues showed a four-fold increase in stroke rate among hypertensive patients.38 Cardiac arrhythmias Patients in atrial ®brillation are at risk of embolus formation resulting in ischaemic stroke formation.39
Neurological sequelae 461
Carotid bruits This remains an area of controversy and the predictive value of a pre-operative carotid bruit, symptomatic or otherwise, is not known. Studies that are available have been on relatively small numbers and have not followed the patients throughout the full risk period for development of a peri-operative stroke.32 Type of surgery Patients undergoing head and neck surgery are at a 4.8% risk of developing a perioperative stroke. There are several reasons for this increased risk: the patients are often older, the common presence of comorbidity, the increased incidence of peripheral vascular disease which in its own right can cause an eight-fold increase in stroke risk and positioning of the head leading to vascular spasm, occlusion and embolism.36 Snoring and obstructive sleep apnoea A history of snoring was the most signi®cant risk factor for stroke in a recent survey, independently of associated factors such as hypertension.40 The cortical arousal which occurs with each episode of airway obstruction during sleep causes a surge in blood pressure. In severe cases of obstructive sleep apnoea, episodic hypertension may occur 50±80 times per hour of sleep.41 Sleep apnoea typically worsens in the post-operative period and it is tempting to postulate that it may be a risk factor for peri-operative stroke. Comorbidity Both peripheral vascular disease and chronic obstructive airways disease are signi®cant factors in increasing risk of a peri-operative stroke.36 As for delirium, identi®cation of at-risk patients and avoidance of precipitating factors are the mainstay of management. Hypertension should be controlled in the pre-operative period as this reduces the general incidence of stroke. The control of atrial ®brillation is bene®cial also, preferably by cardioversion. Long-term anticoagulation should be converted to heparin which is discontinued 6 hours before surgery and re-instituted 24 hours after. Patients with signi®cant arrythmias that are not taking anti-coagulants should be commenced on the same heparinization regime. The European Carotid Surgery Trial42 and the North American Symptomatic Carotid Endarterectomy Trial43 both suggest the bene®t of carotid surgery for symptomatic patients with 470% stenosis to reduce their risk of stroke. Such patients identi®ed in the pre-operative setting may bene®t from assessment by a vascular surgeon. Combined procedures, or vascular correction prior to the scheduled operation, may improve the overall outcome for the patient. The timing of any operation following a previous stroke does not appear to in¯uence the risk of developing a further peri-operative stroke37; however, it would be prudent to defer surgery for 4±6 weeks if possible to allow the ischaemic penumbra around the stroke to heal. There are no prospective trials showing that control of intra-operative blood pressure aects the incidence of peri-operative stroke. Despite this lack of evidence, it is advisable to maintain the patient's blood pressure within his or her normal range as autoregulation may be lost in ischaemic tissue. Carbon dioxide tension should be kept
462 P. Sharpe and C. Hanning
in the normal range also as changes in vessel calibre may lead to steal or inverse steal phenomena around the territories of diseased vessels. The post-operative period presents the greatest risk to the patient in terms of developing a peri-operative stroke. Con¯icting evidence36,37 exists for the role of hypotension causing stroke in the post-operative period. Common sense suggests that the blood pressure should be kept in the normal range. Prevention of dehydration and hypercoagulability and the institution of heparin in `at-risk' patients are all suggested as bene®cial but the prospective evidence to support these assertions is lacking. Potential advances in stroke care Neuroprotection for stroke patients has shown varying degrees of success in clinical trials. Selfotel, aptiganel, enlimomab, clomethiazole, tirilazad and piracetam have all been used in recent trials, but none was shown to be bene®cial. Lubeluzole is a sodium-channel blocker, which is thought to reduce the amount of glutamate produced by ischaemic neurones and thus excitotoxicity at the post-synaptic membrane. It may also decrease the amount of intracellular damage by inhibiting post-synaptic nitric oxide synthetase activity. Recent trials have shown functional improvement in stroke patients but have not shown any clear improvements in mortality.44 Magnesium sulphate and a glycine antagonist (GV150526) are currently under investigation in large international trials.44 REFERENCES 1. Atkinson RL, Atkinson RC, Smith EE et al. Hilgard's Introduction to Psychology, 12th edn. New York: Harcourt Brace, 1996. 2. Simpson BR, Williams M, Scott JF & Crampton Smith A. The eects of anaesthesia and elective surgery on old people. Lancet 1961; ii: 887±893. 3. Knill RL, Novick TY & Skinner MI. Idiopathic post-operative delirium is associated with longterm cognitive impairment. Canadian Journal of Anesthesia 1991; 38: A54. 4. Shaw PJ, Bates D, Cartlidge NEF et al. Neurologic and neuropsychological morbidity following major surgery: comparison of coronary artery bypass and peripheral vascular surgery. Stroke 1987; 18: 700±707. 5. Segatore M, Dutkiewicz M & Adams D. The delerious cardiac surgical patient: theoretical aspects and principles of management. Journal of Cardiovascular Nursing 1998; 12: 32±48. * 6. Moller JT, Cluitmans P, Rasmussen LS et al. Long term post-operative cognitive dysfunction in the elderly: ISPOCD 1 study. Lancet 1998; 351: 857±861. 7. Tzabar Y, Asbury AJ & Millar K. Cognitive failures after general anaesthesia for day-case surgery. British Journal of Anaesthesia 1996; 76: 194±197. 8. Houx PJ & Jolles J. Age-related decline of psychomotor speed: eects of age, brain health, sex and education. Perceptual and Motor Skills 1993; 76: 195±211. * 9. O'Brien JT. The `glucocorticoid cascade' hypothesis in man ± prolonged stress may cause permanent brain damage. British Journal of Psychiatry 1997; 170: 199±210. 10. Maier SF & Watkins LR. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychological Revue 1998; 105: 83±107. 11. Saunders AM, Strittmatter WJ, Schmechel D et al. Association of apolipoprotein E allele E4 with lateonset familial and sporadic Alzheimer's disease. Neurology 1993; 43: 1467±1472. 12. Mayeux R, Ottoman R, Maestre G et al. Synergistic eects of traumatic head injury and apolipoproteinE4 in patients with Alzheimer's disease. Neurology 1995; 45: 555±557. 13. Williams-Russo P, Sharrock NE, Mattis S et al. Cognitive eects after epidural vs general anaesthesia in older adults: a randomised trial. Journal of the American Medical Association 1995; 274: 44±50. 14. Hole A, Terjesen T & Breivik H. Epidural versus general anaesthesia for total hip arthroplasty in elderly patients. Acta Anesthesiologica Scandinavica 1980; 24: 279±287. 15. Ebert U & Kirch W. Scopolamine model of dementia: electroencephalogram ®ndings and cognitive performance. European Journal of Clinical Investigation 1998; 28: 944±949.
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