Parikh, Smita S. MD; Chung, Frances FRCPC
The age-old saying "Granny has never been the same since her operation" does have an element of truth in it. In 1955, Bedford  reported on 120 elderly patients who developed postoperative dementia. Acute postoperative psychosis was recognized as early as the 16th century and first documented in 1819. Over the past century, as understanding of the condition evolved, it acquired many synonyms such as acute confusional state, acute brain syndrome, mental dysfunction, and many others . Postoperative delirium is a well defined entity today. The high incidence of postoperative delirium in the elderly (i.e., 65 yr or older), ranging from 10%-60% [3-6], has rekindled interest in this disorder. Recent studies have been conducted in ophthalmic [7-9], orthopedic [4,5], and cardiac surgical populations [10-15]. Some of these studies have revealed the preventive potential of a geriatric anesthesiologic program , the correlation of postoperative delirium with perioperative hypoxemia [16-18], and the predictive value of intraoperative quantitative electroencephalographic monitoring  in the occurrence of delirium. Moreover, efforts have been made to devise newer tests [19-23] for an early diagnosis of delirium.
The transient mental dysfunction has an important impact on the patient's health and therefore on health care costs. This condition can result in increased morbidity, delayed functional recovery, and prolonged hospital stay. The adverse effects of postoperative delirium on health and health care costs make early diagnosis and prompt treatment imperative. Since anesthesiologists have an important role in the perioperative management of elderly patients undergoing surgery, it is imperative for them to have a good understanding of postoperative delirium. There has been no definitive analysis of postoperative delirium in the elderly with emphasis on anesthesia care; therefore we undertook to present such an analysis.
Diagnosis and Clinical Features
The distinguishing features of this transient global disorder are impaired cognition, fluctuating levels of consciousness, altered psychomotor activity, and a disturbed sleep-wake cycle . It is usually seen on the first or second postoperative day and symptoms are often worse at night. The condition can be silent and go unnoticed, or it may be misdiagnosed as depression . Recovery is common . In 20%-30%, delirium is followed by death.
The main disorders are cognitive function, thinking, perception, and memory . Disturbed perception results in illusions or hallucinations. These are often visual or both visual and auditory. The hallucinations tend to be vivid and frightening. Patients in delirium have disorganized and incoherent thinking and delusions may be present. Short-term memory is impaired. Patients are usually disoriented in regard to time. In more severe delirium, patients are disoriented to place and person. Attention disturbance is always present with the patient easily distracted. Patients are drowsy during the day whereas at night, awake and agitated.
The defining criteria of postoperative delirium are described in the Diagnostic and Statistical Manual of Mental Disorders (DSM (R) III) manual and are shown in Table 1 . Bedside tests devised to diagnose this condition include the commonly used Mini Mental State Exam (MMS; Table 2) , and other tests, such as The Saskatoon Delirium Checklist , Geriatric Mental State Exam , Clifton Assessment Procedures for the Elderly [21,22], and Confusion Assessment Method . These tests assess speech, consciousness, perception, orientation, coherence, memory, and motor activity. The MMS is easy to conduct, reliable, and can be used for serial testing in fluctuating conditions. Because it is simple, it has a high compliance rate among elderly subjects . However, MMS may be less useful for detecting mild or transient impairment in the early phases of drug toxicity and early dementias . The Saskatoon Delirium Checklist is more useful for detecting these subtle changes .
The reported incidence of postoperative delirium varies widely. Incidence in patients in the general surgery group for all age groups ranges from 5% to 10% and, for the elderly, from 10% to 15% ; for those in the orthopedic surgery group, from 28% to 61.3% [4-6]; and for those in the cataract surgery group, from 1% to 3% . Knill et al.  found a 12% incidence of idiopathic postoperative delirium in 239 patients. In another study of 61 patients, 70 yr and older, they found idiopathic postoperative delirium lasting up to 6 days in 12 days. Noticeable dysfunction persisted for 6 wk in 5% of the elderly patients . A 25%-50% incidence of acute delirium in elderly patients hospitalized for medical problems has been reported [33-35]. Differences in diagnostic criteria, populations under study, and methods of surveillance used probably account for the wide range of figures. Further studies are needed to determine the risk and the long-term outcome of delirium in the different elderly age groups, the young-old and the old-old.
Various hypotheses have been proposed to explain the pathogenesis of postoperative delirium . One suggests that when the oxidative metabolism of the brain decreases, the levels of neurotransmitters within the brain, such as acetylcholine, decline and cause mental dysfunction [36,37]. Studies have shown that cerebral acetylcholine synthesis is sensitive to hypoxia [38,39]. Moreover, an association between postoperative confusion and anticholinergic drug activity has also been observed .
The second hypothesis suggests that an increase of serum cortisol from the stress of surgery or anesthesia may be responsible for postoperative confusion [4,40]. Reduced availability of tryptophan after cardiopulmonary bypass has also been incriminated in the pathogenesis of postcardiotomy psychosis .
Etiology is divided into preoperative, intraoperative, and postoperative factors. These are listed in Table 3.
Aging. A decrease in cerebral neuronal density, blood flow, metabolism , and levels of neurotransmitters  decreases anesthetic requirement . These biologic changes may also account for the increased predisposition of the elderly to postoperative delirium. There can be a difference between a person's chronologic and biologic age . Biologic age, which is determined by the number of diseases a person has had, seems to be the prime determinant of how the person withstands the stress of anesthesia [5,46,47]. Although it is not feasible at this stage to quantify a patient's biologic age, it should prove a better predictor of postoperative dysfunction than chronologic age.
Pathologic States in the Brain. Cerebrovascular disease increases a person's vulnerability to hypoxia, which in turn results in reduced acetylcholine synthesis, thus predisposing a person to confusion . In patients with organic brain disease or baseline deficits in perception, perioperative stress can induce illusions, hallucinations, and paranoia, thereby setting the stage for delirium . In the postoperative period, a patient deprived of antiseizure medication can also develop seizure delirium , which may last for several days .
Polypharmacy and Drug Interactions. The elderly consume the most drugs of all age groups and are more sensitive to adverse drug reactions . Drugs that are likely to affect cognitive function are listed in Table 4 . Hurwitz  observed that the incidence of adverse drug interactions in patients aged 70-79 yr was three times that in patients aged 40-45 yr (7%). Antihypertensives, antiparkinsonism drugs, psychotropics, and cardiac drugs pose the highest risk of adverse drug reactions . Regular use of long-acting benzodiazepines can result in dementia in the elderly, which itself predisposes them to development of postoperative delirium. Chung et al.  have also reported the possible interaction of tricyclic antidepressants and general anesthesia as a cause of postoperative delirium.
Alcohol and Sedative-Hypnotic Withdrawal. Surveys of the hospitalized elderly show that the prevalence of alcohol abuse is approximately 18%  and that 10%-15% of the elderly are regular users of hypnotic drugs . Delirium caused by withdrawal of alcohol or hypnotics may ensue 12-48 h after surgery. Delirium tremens from alcohol withdrawal is dramatic and readily identifiable. However, in an alcoholic with thiamine deficiency, administration of intravenous (IV) glucose can precipitate a possibly fatal delirious state of Wernicke-Korsakoff psychosis . This state could go undiagnosed because the associated neurologic signs may be difficult to detect in a delirious patient, especially in the postoperative setting. Chronic subdural hematoma may also cause delirium in an alcoholic.
Endocrine and Metabolic Problems. Intravascular volume depletion has been associated with poor mental function. Although advanced age itself increases the risk of dehydration only slightly, it has been suggested that when a patient's mental score on diagnostic tests is low, the patient should be carefully examined for signs of dehydration . Moreover, the use of diuretics in the elderly can often cause hyponatremia, hypokalemia, hypomagnesemia, and metabolic alkalosis . When this fluid and electrolyte imbalance is exacerbated perioperatively, it can produce confusion. Endocrinopathies like diabetic ketoacidosis or nonketotic hyperglycemic diabetes , hyper- or hypothyroidism [59,60], and hepatic, renal, or pulmonary insufficiency have been shown to predispose a patient to delirium .
Depression, Dementia, and Anxiety. Gustafson et al.  observed an 88% incidence of acute confusional state after surgery in patients with preoperative depression. Patients with depression are known to have a deficiency of serotonergic and noradrenergic transmitter systems that may predispose them to delirium . Some studies  have found increased cortisol levels in depressed patients, a finding that has been hypothesized as a possible cause of delirium.
Dementia may be caused by a deficiency in the cholinergic system and in somatostatin [63,64], both of which are essential for normal cognitive functioning, attention, and sleep-wake cycle. A demented patient is, therefore, more vulnerable to delirium. Hypoxia and anticholinergic drugs pose a special threat to these patients.
Psychologic factors, such as anxiety, also play an important role in the incidence of delirium. Some [65-68] strongly believe that adequate psychologic preparation of the patient before surgery is essential and that patients who exhibit normal amounts of preoperative anxiety are least likely to have delirium. It is possible that emergency surgery allows the patient no time for mental preparation and results in subsequent fright-neurosis . However, other reports  suggest that when the patients' dominant mechanism for coping is denial and their anxiety levels are low, postoperative delirium is less likely to occur.
Gender. In a metaanalytic review of 18 studies, Cryns et al.  observed that gender may be predictive of the kind of mental impairment likely to occur after surgery. Women manifest a greater predilection for delirium, and men for cognitive decompensation.
Type of Surgery. In elderly patients undergoing cardiac surgery, hypoperfusion and microemboli of air or blood cells resulting in brain ischemia are two major factors implicated in the development of postoperative confusion [10-13]. Hypoperfusion rather than embolization may play a more significant role in this confusion [14,15]. Metabolic demand, ventilation-perfusion mismatch, embolism, vasospasm, or free-radical-induced cerebral microcirculatory impairment may each benefit from increased flow, either through the affected vessels or vital collaterals. Thus neuropsychologic dysfunction after cardiopulmonary bypass could be minimized by maintenance of adequate cerebral perfusion. Hypothermia during cardiopulmonary bypass may offer some cerebroprotection .
Among elderly patients undergoing orthopedic surgery, the highest incidence (44%-61%) of postoperative confusion has been observed in patients treated for femoral neck fractures [4,5]. Preexisting mental depression, use of anticholinergic drugs, and age were significant predictors for the occurrence of postoperative confusion. Patients who developed delirium required a hospital stay approximately four times longer than those who remained lucid . Williams-Russo  found that the incidence of postoperative delirium was 41% in patients undergoing bilateral knee replacement compared with 14% in those undergoing unilateral knee replacement. Fat embolism was probably an important contributing factor in the postoperative confusional states in orthopedic patients with fractures or surgery involving reaming of bone marrow [72,73].
Elderly patients undergoing cataract surgery are especially vulnerable because of severe bilateral loss of vision and regular use of anticholinergic drugs or drops . Preexisting dementia in this age group compounds the problem . When Chung et al.  evaluated the mental recovery of patients after cataract surgery with neuroleptanalgesia, they observed that the baseline scores of cognitive function were significant predictors of postoperative cognitive dysfunction. As the acuity of vision deteriorated, psychiatric symptoms increased; with restoration of vision through cataract surgery, the symptoms normalized .
Anesthetic Drugs. Various studies [16,19,74] have shown the relation of anticholinergics to postoperative delirium. Acetylcholine acts as a key transmitter in the pathways concerned with arousal and awareness . Cholinergic deficiency in the elderly makes them susceptible to even low doses of anticholinergic drugs. Similarly, drugs that are not anticholinergic, but that block the muscarinic sites, such as phenothiazines, antihistaminics, and some hypnotics, are also implicated in the cause of postoperative psychosis . Glycopyrrolate, a quaternary compound, does not cross the blood-brain barrier and does not cause the central nervous system effects that atropine or scopolamine does . Glycopyrrolate is the drug of choice in the elderly when an anticholinergic is needed.
As for general anesthetics, barbiturate premedication is implicated in the development of postoperative delirium [26,52]. The elimination half-life of benzodiazepines is increased in the elderly. Benzodiazepines also produce greater effects on the central nervous system in the elderly than in all other age groups [78-81]. Habitual users of benzodiazepines may have preexisting cognitive impairment  that makes them more vulnerable to developing delirium under the stress of anesthesia or surgery. Rogers et al.  studied 46 orthopedic patients to determine the risk factors associated with postoperative delirium. Treatment with flurazepam, propranolol, or scopolamine conferred a relative risk for delirium of 11.7 . In addition, postoperative delirium could also be a manifestation of benzodiazepine withdrawal [52,82].
Several studies [16,29,83] have found no difference in the effects of general, epidural, or spinal anesthesia on postoperative confusion. Similarly, no differences in the long-term cognitive or psychosocial sequelae have been found with the use of general or regional anesthesia . A common cause of delirium is iatrogenic, drug-induced delirium. In the first 48-72 h after surgery, the effects of residual anesthetics have been considered probably causes of impaired cognitive function [85-87]. The choice of anesthetic drugs may affect postoperative cognition. Therefore it is important to use newer anesthetics with shorter elimination half-lives.
Hypoxia. Perioperative disturbances of oxygenation and ventilation, underlying pulmonary disease, and anemia can contribute to perioperative hypoxia . In patients not monitored with pulse oximetry, hypoxemia is common . Oxygen saturation less than 85% may occur for many hours postoperatively at night . Nocturnal desaturation was particularly severe in obese patients after major operations .
Patients undergoing major surgery have decreased mental function on the third day. There was a significant correlation between mental function on the third day after operation and mean SaO2 on the second postoperative night after major surgery . However, the sample size of this study was small and the measurement of mental function was crude. Moller et al.  studied 736 surgical patients, half of whom had been monitored with pulse oximetry during anesthesia and in the postanesthesia care unit. Of the 736 patients, 7.3% suffered a decline of 17% in their postoperative psychologic tests. Three months later, 40% of these patients still had a lower test score than preoperatively. Six weeks postoperatively, 7% of the patients who had been monitored, and treated if hypoxemic, complained of new forgetfulness, while 11% of patients not monitored, and presumably after hypoxemia, voiced the same complaints (P < 0.06). Nielson et al.  studied 64 elderly patients 3 mo after undergoing arthroplasties. No cognitive changes were detected . Therefore, there is no conclusive evidence of association of hypoxia and cognitive dysfunction.
The consequences of hypoxemia on cerebral function in the elderly have not been studied. Hornbein et al.  found that normal volunteers exposed to profound hypoxemia (SaO2 50%-60%) for several days had shown some mild cognitive deficits. Although the use of supplemental oxygen for postoperative hypoxemia has been recommended , there are no well controlled studies to indicate that oxygen therapy was beneficial and improves outcome. An editorial in Lancet recommended to characterize the exact risk factors, to identify the deleterious effects of hypoxemia on heart, brain, and other organs, and to clarify the influence of hypoxemia on outcome after surgery . Then oxygen can be prescribed in a cost-effective manner.
Hypocarbia. Artificially controlled ventilation can cause hypocarbia. Katzman  and Wollman et al.  observed a 43% decrease in cerebral blood flow at PaCO2 of 19 mm Hg. Every millimeter decrease in PaCO2 decreases the cerebral blood flow by 2%. Such a decrease may prove crucial in the aged.
Sepsis. Postoperative delirium may often be the only manifestation of an underlying septic process such as pneumonia, or may even herald the onset of myocardial infarction. Similarly, inadequate analgesia subjects the patient to undue stress and can precipitate a full-blown confusional state in a marginally compensated patient.
Prevention can be applied at preoperative, intraoperative, and postoperative levels. The principles of prevention are mentioned in Table 5.
Preoperative evaluation gives important clues to the preoperative etiologic factors which increase the chance of perioperative delirium Table 3. A thorough assessment of the patient's physical and mental status and medications is very important. Preexisting sensory or perceptual deficits compound a patient's chances of developing confusional states. Any evidence of cognitive impairment should be carefully noted.
The incidence of delirium is significantly lowered when a geriatric-anesthesiologic intervention program is implemented. This intervention program consists of pre- and postoperative geriatric assessment, early surgery, thrombosis prophylaxis, oxygen therapy, prevention and treatment of perioperative decrease in blood pressure, and vigorous treatment of any postoperative complications . The outcome of the intervention of 103 patients was compared with a historical control of 111 patients. The incidence of delirium was lower, 47.6% in the intervention study versus 61.3% (P < 0.05) in the control study. The incidence of postoperative decubitus ulcers, severe falls, and urinary retention was also lower. The mean duration of hospital stay was lower in the intervention group--11.6 days versus 17.4 days in the control group (P < 0.001). Although the design of this study has a methodologic flaw in using a historical control rather than randomization, there is some evidence that the intervention program reduced the incidence, severity, and duration of delirium with a shortened hospital stay .
However, a recent study showed that the beneficial effects of systemic detection and intervention in cases of delirium in elderly inpatients were few . Medical elderly patients with delirium were randomized to the intervention group or the control group. The treatment group received a geriatric consultation and followup by a liaison nurse. Those in the control group received regular medical care. Further studies in this area are necessary to determine the benefits of the intervention program.
The mainstay of intraoperative preventive measures is maintaining good oxygenation, normal blood pressure, correct drug dosage, and normal electrolyte levels. The anesthesia regimen should be as simple as possible. The elderly are sensitive to even small doses of drugs. Moreover, altered metabolism or kidney function may result in prolonged action of the drugs. Hence it is essential that anesthetic doses for the elderly be carefully titrated. Drug cocktails should be avoided. Atropine, scopolamine, and flurazepam should be used only if necessary, and the dose should be as low as possible.
Quantitative monitoring of electroencephalographic waves has been used to detect abnormalities during hypotensive episodes during cardiopulmonary bypass. These abnormalities in electroencephalographic waves can predict the occurrence of delirium in the postoperative period, but the role of quantitative electroencephalography monitoring in routine anesthetic practice has yet to be defined .
Ambulatory surgery may have a role to play in preventing delirium by maintaining a familiar home environment postoperatively. Therefore, more ambulatory surgery for the elderly should be encouraged. The postanesthetic care environment should be conducive to the patient's feeling of well being. Adjusting the light and dark cycles to ensure adequate sleep is very helpful, since sleep deprivation may be an important factor in the genesis of postoperative delirium [97,98]. Patients often find intensive care units rather frightening. The various gadgets, each with a different sound, unceasing activity, and constant illumination can cause sensory overload. Delirium developed in this setting often is best treated by transfer of the patient to a regular floor, as soon as medically possible.
Adequate analgesia, especially in patients who cannot communicate easily because of endotracheal tubes or tracheostomy, is crucial. Untreated pain or under treatment of pain can easily tip the balance toward delirium in borderline patients .
The importance of nursing care cannot be over-stressed. Since they are the main contact with the patient, nurses should be well versed in detecting the earliest signs of delirium. When delirium sets in, the patient and the family need to have constant reassurance from their health care givers.
Drugs associated with the risk of precipitating or worsening delirium should be used with discretion. These include central nervous depressants, H2-antagonists, anticholinergics, digitalis, phenytoin, lignocaine, and aminophylline.
Management of Postoperative Confusion
Once postoperative confusion has been diagnosed, the patient should be managed with extra vigilance. Although recovery is common, delirium can result in unwarranted complications. Hospitalization may be prolonged; altered cognition may lead to falls and fractures; lines may be pulled out; bandages or wounds may be torn open; prolonged immobilization may lead to decubitus ulcers, pneumonia, or venous thrombosis. Moreover, these patients may have delayed functional recovery and hence may be a burden on relatives and friends.
The first consideration in the management of delirium is to find and treat any underlying organic cause of the confusion. In the elderly, delirium may in fact be the only signal of the onset of conditions such as pneumonia, sepsis, or myocardial infarct . An organic cause must be ruled out first with a thorough history, physical examination, laboratory tests, or other diagnostic procedures. If the patient is taking any risk-associated drugs, their doses may be reduced or stopped temporarily.
When confusion is evident, treatment must be instituted promptly. Haloperidol, the drug of choice, does not produce significant hypotension or autonomic effects. It does not aggravate diabetes, hepatic disease, or renal disease. It is compatible with anticholinergic drugs. It does not cause oversedation and, because it is odorless and tasteless, it is palatable . Doses of 0.25-2 mg oral haloperidol 1-2 h before bedtime is the preferred treatment. The daily amount may be given as a single dose at bedtime or it may be divided and given two or three times a day. When patients are severely agitated, more rapid control of symptoms can be achieved with intramuscular (IM) haloperidol. A small dose, 0.5 mg IM, is given every hour until symptoms are adequately controlled. IV administration may be preferred to the IM route in the presence of circulatory compromise because the absorption of IM drugs may be erratic . Also, the pain of IM injection may add to the patient's confusion and the assessment of enzymes, such as lactate dehydrogenase and creatine kinase, may be complicated . Haloperidol also has an advantage of causing less hypotension than chlorpramazine .
Droperidol has also been used in rapid tranquilization. Resnick and Burton  have observed that droperidol is less anticholinergic and hypotensive and more sedating than other antipsychotic drugs used for rapid tranquilization. Although chlorpromazine is extremely effective, it is a potent alpha-adrenergic antagonist and can lead to a severe drop in blood pressure. It is not the drug of choice in a critically ill patient who may be dependent on his or her peripheral resistance.
Diazepam can be used alone or in combination with other antipsychotic drugs. It is especially useful in the treatment of delirium tremens. Thiamine is the key drug for the management of Korsakoff's psychosis .
Neither muscle relaxants nor physical restraints are particularly effective in the treatment of postoperative confusion. Muscle relaxants are not very practical since their use requires intubation and mechanical ventilation. Physical restraints may aggravate the confusion of an already confused patient because they create the impression of being tied down. Use of restraints should therefore be minimal, and whenever they are used, the reasons for their use should be explained frequently to the patient.
Finally, if delirium progresses to coma, standard treatment for control of airway, breathing, and circulation should be instituted. After recovery from an acute episode, a psychiatric or psychosocial referral may aid early functional rehabilitation. Similarly, nursing assistance at home will help with early discharge from the hospital. Physiotherapy and occupational therapy are also important adjuncts in the management of postoperative delirium.
Postoperative delirium is common in the elderly in the postoperative period. It can result in increased morbidity, delayed functional recovery, and prolonged hospital stay. In surgical patients, factors such as age, alcohol abuse, low baseline cognition, severe metabolic derangement, hypoxia, hypotension, and type of surgery appear to contribute to postoperative delirium. Anesthetics, notably anticholinergic drugs and benzodiazepines, increase the risk for delirium. Despite the above recommendations, postoperative delirium in the elderly is poorly understood. Clearly, further studies are needed to determine the risk and long-term outcome of delirium in the elderly population. Research is also needed to define the effects of hypoxemia on cerebral function and whether oxygen therapy has any benefits. The geriatric-anesthesiologic intervention program of pre- and postoperative geriatric assessment, early surgery, thrombosis prophylaxis, oxygen therapy, prevention and treatment of perioperative decrease in blood pressure, and vigorous treatment of any postoperative complications showed some promise, but further definitive studies are needed.
The authors would like to thank Ms. C. Drane for her secretarial assistance in the preparation of this paper.
1. Bedford PD. Adverse cerebral effects of anaesthesia on old people. Lancet 1955;2:257-63.
2. Lipowski ZJ. Delirium in the elderly patient. N Engl J Med 1989;320:578-82.
3. Seymour G. Acute and chronic confusional states in the elderly surgical patient. In: Medical assessment of the elderly surgical patient. Kent, England: Croom Helm, 1986:229-39.
4. Gustafson Y, Brannstrom B, Berggren D, et al. A geriatric-anesthesiologic program to reduce acute confusional states in elderly patients treated for femoral neck fractures. J Am Geriatr Soc 1991;39:655-62.
5. Williams-Russo P, Urquhart BL, Sharrock NE, Charlson ME. Postoperative delirium: predictors and prognosis in elderly orthopedic patients. J Am Geriatr Soc 1992;40:759-67.
6. Rogers MP, Liang MH, Daltroy LH, et al. Delirium after elective orthopedic surgery: Risk factors and natural history. Int J Psychiatry Med 1989;19:109-21.
7. Chung F, Lavelle PA, McDonald S, et al. Cognitive impairment after neurolept analgesia in cataract surgery. Anesth Analg 1989;68:614-8.
8. Carpenter WT Jr. Precipitous mental deterioration following cycloplegia with 0.2% cyclopentolate HCl. Arch Ophthalmol 1967;78:445-7.
9. Fagerstrom R. Correlation between psychic and somatic symptoms and vision in aged patients before and after a cataract operation. Psychol Rep 1991;69:707-21.
10. Blauth CI, Arnold JV, Schulenberg WE, et al. Cerebral microembolism during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1988;95:668-76.
11. Nevin M, Adams S, Colchester ACF, Pepper JR. Evidence for involvement of hypocapnia and hypoperfusion in etiology of neurological deficit after cardiopulmonary bypass. Lancet 1987;2:1493-5.
12. Taylor KM. Brain damage during open heart surgery. Thorax 1982;37:873-6.
13. Malone M, Prior P, Scholtz CL. Brain damage after cardiopulmonary bypass: correlations between neurophysiological and neuropathological findings. J Neurol Neurosurg Psychiatry 1981;44:924-31.
14. Edmonds HL Jr, Griffiths LK, Van der Laken J, et al. Quantitative electroencephalographic monitoring during myocardial revascularisation predicts postoperative disorientation and improves outcome. J Thorac Cardiovasc Surg 1992;103:555-63.
15. John ER, Prichep LS, Chabot RJ, et al. Monitoring brain function during cardiovascular surgery: hypoperfusion vs microembolism as the major cause of neurological damage during cardiopulmonary bypass. In: Refsum H, Sulg IA, Rasmussen K, eds. Heart and brain, brain and heart. Berlin: Springer-Verlag, 1989:405-21.
16. Berggren D, Gastafson Y, Eriksson B, et al. Postoperative confusion after anesthesia in elderly patients with femoral neck fractures. Anesth Analg 1987;66:497-504.
17. Krasheninnikoff M, Ellitsgaard N, Rude C, Moller JT. Hypoxemia after osteosynthesis of hip fractures. Int Orthop 1993;17:27-9.
18. Rosenberg J, Kehlet H. Postoperative mental confusion--association with postoperative hypoxemia. Surgery 1993;114:76-81.
19. Miller PS, Richardson JS, Jyu CA, et al. Association of low serum anticholinergic levels and cognitive impairment in elderly presurgical patients. Am J Psychiatry 1988;145:342-5.
20. Duckworth GS. The reliability of G.E.M.S. Proceedings of the Ontario Psychogeriatric Association, September 1976:54-9.
21. Pattie AH. A survey version of the Clifton Assessment Procedures for the Elderly (CAPE). Br J Clin Psychol 1981;20:173-8.
22. McPherson FM, Gamsu CV, Kiemle G, et al. The concurrent validity of the survey version of the Clifton Assessment Procedures for the Elderly (CAPE). Br J Clin Psychol 1985;24:83-91.
23. Inouye SK, VanDyck CH, Alessi CA, et al. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990;113:941-8.
24. Sullivan EM, Wanish CK, Kurlowicz LH. Elder care, nursing assessment, management of delirium in the elderly. AORN J 1991;53:820-8.
25. Tune LE. Postoperative delirium. Int Psychogeriatr 1991;3:325-32.
26. Lipowski ZJ. Delirium (acute confusional states). JAMA 1987;258:1789-92.
27. Diagnostic and statistical manual of mental disorders. 3rd rev. ed. Washington, DC: American Psychiatric Association, 1987:100-4.
28. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatry Res 1975;12:189-98.
29. Chung FF, Chung A, Meier RH, Lautenschlaeger E. Comparison of perioperative mental function after general anaesthesia and spinal anesthesia with intravenous sedation. Can J Anaesth 1989;36:382-7.
30. Linn L, Kahn RL, Coles R, et al. Patterns of behaviour disturbance following cataract operation. Am J Psychiatry 1953;110:281-9.
31. Knill RL, Rose EA, Berko SL. Idiopathic postoperative delirium in the elderly. Can J Anaesth 1989;36:S90-1.
32. Knill RL, Novick TY, Skinner MI. Idiopathic postoperative delirium is associated with long-term cognitive impairment. Can J Anaesth 1991;38:A54.
33. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA 1990;263:1097-101.
34. Eckenhoff JE, Kneale DH, Dripps RD. The incidence and etiology of postanesthetic excitement. Anesthesiology 1961;22:667-73.
35. Rockwood K. Acute confusion in elderly medical patients. J Am Geriatr Soc 1989;37:150-4.
36. Blass JP, Gibson GE. Carbohydrates and acetylcholine synthesis: implications for cognitive disorders. In: Davis KL, Berger PA, eds. Brain acetylcholine and neuropsychiatric disease. New York: Plenum, 1979:215-36.
37. Blass JP, Plum F. Metabolic encephalopathies in older adults. In: Katzman R, Terry R, eds. The neurology of aging. Philadelphia: FA Davis, 1983:189-220.
38. Gibson GE, Peterson C, Sansone J. Neurotransmitter and carbohydrate metabolism during aging and mild hypoxia. Neurobiol Aging 1981;2:165-72.
39. Hirsch JA, Gibson GE. Selective alteration of neurotransmitter release by low oxygen in vitro. Neurochem Res 1984;9:1039-49.
40. McIntosh TK, Bush HL, Yeston NS, et al. Beta endorphin, cortisol and postoperative delirium: a preliminary report. Psychoneuroendocrinology 1985;10:303-13.
41. Vander Mast RC, Fekkes D, Moleman P, Pepplinkhuizen L. Is postoperative delirium related to reduced plasma tryptophan? Lancet 1991;338:851-2.
42. Lassen NA, Ingvar DH, Skinhoj E. Brain function and blood flow. Sci Am 1978;239:62-71.
43. McGeer E, McGeer PL. Neurotransmitter metabolism in the aging brain. In: Terry RD, Gershon S, eds. Neurobiology of aging. New York: Raven Press, 1976;389-403.
44. Muravchick S. Immediate and long term nervous system effects of anesthesia in elderly patients. Clin Anesthesiol 1986;4:1035-45.
45. Ludwig FC, Smoke ME. The measurement of biological age. Exp Aging Res 1980;6:497-522.
46. Smith C, Carter M, Sebel P, Yate P. Mental function after general anesthesia for transurethral procedures. Br J Anaesth 1991;67:262-8.
47. Carter M. Effects of anesthesia on mental performance in the elderly. Nurs Times 1989;85:40-2.
48. Seibert CP. Recognition, management and prevention of neuropsychological dysfunction after operation. Int Anesthesiol Clin 1986;24:39-99.
49. Mesulam MM, Geschwind N. Disordered mental states in the postoperative period. Urol Clin North Am 1976;3:199-215.
50. Larson EB, Kukull WA, Buchner D, Reifler BV. Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med 1987;107:169-73.
51. Hurwitz N. Predisposing factors in adverse reactions to drugs. Br Med J 1969;1:536-9.
52. Lipowski ZJ. Intoxication with medical drugs. In: Delirium: acute confusional states. New York: Oxford University Press, 1990:229-76.
53. Chung F, Meier R, Lautenschlager E, et al. General or spinal anesthesia: which is better in the elderly? Anesthesiology 1987;67:422-7.
54. Scott RB, Mitchell MC. Aging, alcohol and the liver. J Am Geriatr Soc 1988;36:255-65.
55. Morgan K, Dallosso H, Ebrahim S, et al. Prevalence, frequency and duration of hypnotic drug use among the elderly living at home. Br Med J 1988;296:601-2.
56. Seymour DG, Henschke PJ, Cape RDT, Campbell J. Acute confusional states and dementia in the elderly: the role of dehydration/volume depletion, physical illness and age. Age Ageing 1980;9:137-46.
57. Hyams DE. The elderly patient. A special case for diuretic therapy. Drugs 1986;31:138-53.
58. Gambert SR, Benson D, Grosenick DJ, et al. Psychiatric manifestations of common endocrine disorders in the elderly. Psychiatr Med 1984;1:407-27.
59. Morrow LB. How thyroid disease presents in the elderly. Geriatrics 1978;33:42-5.
60. Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly. JAMA 1987;258:209-13.
61. Lipov EG. Emergence delirium in the PACU. Crit Care Nurs Clin North Am 1991;3:145-9.
62. Blazer DG II. Psychobiology. In: Depression in late life. St. Louis: CV Mosby, 1982:49-66.
63. Katzman R. Alzheimer's disease. N Engl J Med 1986;314:964-73.
64. Cummings JL, Benson DF. The role of the nucleus basalis of Meynert in dementia: Review and reconsideration. Alzheimer Dis Assoc Discord 1987;1:128-55.
65. Olympio MA. Postanesthetic delirium: historical perspectives. J Clin Anesth 1991;3:60-3.
66. Schnaper N. Postanesthetic (postoperative) emotional responses. Anesthesiology 1961;22:674-81.
67. Bowman A. Relationship of anxiety to development of postoperative delirium. J Gerontol Nurs 1992;18:24-30.
68. Layne OL, Yudofsky SC. Postoperative psychosis in cardiotomy patients. N Engl J Med 1971;284:518-20.
69. Deutsch H. Some psychoanalytic observations in surgery. Psychosom Med 1942;4:105-15.
70. Morse RM, Litin E. Postoperative delirium: a study of etiologic factors. Am J Psychiatry 1969;126:388-95.
71. Cryns AG, Gorey KM, Goldstein MZ. Effects of surgery on the mental status of older persons. A meta-analytic review. J Geriatr Psychiatry Neurol 1990;3:184-91.
72. Eddy AC, Rice CL, Carrico CJ. Fat embolism syndrome. Monitoring and management. J Crit Illness 1987;2:24-37.
73. Jacobson DM, Terrence CF, Reinmuth OM. The neurologic manifestations of fat embolism. Neurology 1986;36:847-51.
74. Tune LE, Holland A, Folstein MF, et al. Association of postoperative delirium with raised serum levels of anticholinergic drugs. Lancet 1981;2:651-3.
75. Longo VG. Behavioural and electroencephalographic effects of atropine and related compounds. Pharmacol Rev 1966;18:965-96.
76. Greenblatt DJ, Shader RI. Drug therapy. Anticholinergics. N Engl J Med 1973;288:1215-9.
77. Smith DS, Orkin FK, Gardner SM, Zakeosian G. Prolonged sedation in the elderly after intraoperative atropine administration. Anesthesiology 1979;51:348-9.
78. Thompson TL II, Moran MG, Neis AS. Psychotropic drug use in the elderly. N Engl J Med 1983;308:134-8.
79. Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975;55:347-59.
80. Castleden CM, George CF, Marcer D, Hallett C. Increased sensitivity to nitrazepam in old age. Br Med J 1977;1:10-2.
81. Greenblatt DJ, Allen MD, Shader RI. Toxicity of high dose flurazepam in the elderly. Clin Pharmacol Ther 1977;21:355-61.
82. Madi S, Langonnet F. Postoperative agitation: a new cause [in French, English abstract]. Cah Anesthesiol 1988;36:509-12.
83. Crul BJP, Hulstijn W, Burger IC. Influence of the type of anesthesia on postoperative subjective physical well-being and mental function in elderly patients. Acta Anaesthesiol Scand 1992;36:615-20.
84. Neilson WR, Gelb AW, Casey JE, et al. Long term cognitive and social sequelae of general versus regional anesthesia during arthroplasty in the elderly. Anesthesiology 1990;73:1103-9.
85. Manner R, Kanto J, Salonen M. Use of simple tests to determine the residual effects of the analgesic component of balanced anesthesia. Br J Anaesth 1987;59:978-82.
86. Bruce DL, Bach MJ. Effects of trace anesthetic gases on behavioural performance of volunteers. Br J Anaesth 1976;48:871-6.
87. Herbert M, Healy TEJ, Bourke JB, et al. Profile of recovery after general anesthesia. Br Med J 1983;286:1539-42.
88. Wollman H, Alexander SC, Cohen PJ, et al. Cerebral circulation during general anesthesia and hyperventilation in man: thiopental induction to nitrous oxide and d-tubocurarine. Anesthesiology 1965;26:329-34.
89. Moller JT, Jensen PF, Johannessen NW, et al. Hypoxaemia is reduced by pulse oximetry monitoring in the operating room and in the recovery room. Br J Anaesth 1992;68:146-50.
90. Postoperative hypoxaemia [editorial]. Lancet 1992;340:580-1.
91. Grundy B, Hardcastle BSE, Crampton C, et al. Postoperative nocturnal hypoxia: correlations with patient characteristics and treatment factors. Anesthesiology 1992;77:A1058.
92. Moller JT, Svennild I, Johannessen NW. Association between intraoperative pulse oximetry monitoring and postoperative cognitive function. Br J Anaesth 1993;71:340-7.
93. Hornbein TF, Townes BD, Schoene RB, et al. The cost to the central nervous system of climbing to extremely high altitudes. N Engl J Med 1989;321:1714-9.
94. Hanning CD. Prolonged postoperative oxygen therapy. Br J Anaesth 1992;69:115-6.
95. Wollman H, Smith TC, Stephan GW, et al. Effects of extremes of respiratory and metabolic alkalosis on cerebral blood flow in man. J Appl Physiol 1968;24:60-5.
96. Cole MG, Primeau FJ, Bailey RF, et al. Systemic intervention for elderly inpatients with delirium; a randomized trial. Can Med Assoc J 1994;151:965-70.
97. Johns W, Large AA, Masterton JP, et al. Sleep and delirium after open heart surgery. Br J Surg 1974;61:377-81.
98. Sveinsson I. Postoperative psychosis after heart surgery. J Thorac Cardiovasc Surg 1975;70:717-26.
99. Marks RM, Sachar EJ. Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med 1973;78:173-81.
100. Hodkinson HM. Common symptoms of disease in the elderly. 2nd ed. Oxford: Blackwell, 1976;24-5.
101. Steinhart MJ. The use of haloperidol in geriatric patients with organic mental disorder. Curr Ther Res 1983;33:132-43.
102. Moulaert P. Treatment of acute non-specific delirium with i.v. haloperidol in surgical intensive care patients. Acta Anesthesiol Belg 1989;40:183-6.
103. Ellison JM, Jacobs D. Emergency psychopharmacology: a review and update. Ann Emerg Med 1986;15:962-8.
104. Resnick M, Burton BT. Droperidol vs haloperidol in the initial management of acutely agitated patients. J Clin Psychiatry 1984;45:298-9.