Anesthesia for the elderly: selected topics Wilton C. Levine, Vipin Mehta and Giora Landesberg

Purpose of review With the graying of the Western population, there is a continuous increase in the proportion of elderly patients undergoing surgical procedures. Geriatric anesthesia is emerging from a ‘subspecialty’ to the mainstream of today’s anesthesia and perioperative care. Much has been written on anesthesia for the elderly, but this review will concentrate on selected topics related to elderly care that represent current unresolved and pertinent issues for the care of the elderly surgical patient. Recent findings Postoperative cognitive dysfunction, cardiac diastolic dysfunction and prophylactic perioperative β-blockade in the process of major noncardiac surgery are three main topics that have recently attracted great interest in clinical practice and research, and have therefore been chosen as the selected topics for this current review. Summary Although age is a clear risk factor for postoperative cognitive dysfunction, the association of general anesthesia with cognitive dysfunction is less clear, as is the effect of anesthesia per se or surgery on long-term cognitive dysfunction. Cardiac diastolic dysfunction is a relatively new and evolving concept in anesthesia and perioperative medicine, yet clearly diastolic dysfunction even with a normal ejection fraction may have a significant effect on the perioperative outcome and management of elderly patients. Small, but powerful studies have shown significant outcome benefit with prophylactic perioperative β-blockade in high-risk patients undergoing major noncardiac surgery. Data from other studies, however, are still conflicting and the final verdict awaits larger scale outcome studies. Keywords cognitive dysfunction, diastolic dysfunction, prophylactic β-blockade Curr Opin Anaesthesiol 19:320–324. # 2006 Lippincott Williams & Wilkins. Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA Correspondence to Giora Landesberg MD, DSc, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA 02114-2696, USA. E-mail: [email protected] Current Opinion in Anaesthesiology 2006, 19:320–324

Abbreviations CAD ISPOCD LV POCD PPBB

coronary artery disease International Study of Postoperative Cognitive Dysfunction left ventricle postoperative cognitive dysfunction prophylactic perioperative β-blockade

# 2006 Lippincott Williams & Wilkins 0952-7907

Introduction Age has profound effects on each and every organ in our body. While we tend to believe that time refines our personalities, just like it works on wine, the simplest, down-to-earth physiological definition of aging is that of gradual deterioration of our body’s ability to cope with extreme or uncommon physiological conditions. When this natural process of aging is combined with age-related diseases, such as coronary artery disease, chronic pulmonary disease and so on, the physiological limitations are further enhanced and compounded. Surgery and its accompanying perioperative pathophysiological processes definitely fall into the category of everybody’s uncommon and sometimes extreme physiological stresses. The basic role of anesthesia and perioperative medicine is then to ‘walk’ the patient through these stressful situations while maintaining their relatively normal physiological modus operandi, keeping in mind each patient’s limiting boundaries and margins of safety. A lot has been written on the effects of anesthesia and surgery on the elderly patient. This review will concentrate on three selected topics that currently pose important perioperative clinical dilemmas.

Postoperative cognitive dysfunction Postoperative cognitive dysfunction (POCD) is most frequently characterized by an impairment of memory and concentration and can be detected by neuropsychologic testing. Until the 1980s, most literature that dealt with POCD was limited to cognitive dysfunction after cardiac surgery using cardiopulmonary bypass. In 1993, Moller et al. [1] published their first randomized study testing whether pulse oximetry monitoring in patients undergoing elective noncardiac non-neurosurgical procedures affected POCD. Cognitive function evaluated on postoperative day 7 using the Wechsler memory scale and continuous reaction time test, and by a questionnaire 6 weeks after surgery, found no differences with or without pulse oximetry monitoring.

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In 1998, the same group [2] evaluated 1218 patients aged 60 years or greater undergoing noncardiac surgery [International Study of Postoperative Cognitive Dysfunction 1 (ISPOCD1)]. POCD was found in 25.8% 1 week postoperatively and in 9.9% 3 months postoperatively, compared with 3.4% and 2.8%, respectively, of the controls. Risk factors for early POCD were age, duration of anesthesia, lower education, a second operation, postoperative infection and respiratory complications. Only age, however, correlated with late POCD. Hypoxemia and hypotension measured thoroughly up to the third postoperative night were not associated with POCD at any time. When a subset of these patients was re-evaluated 1–2 years later [3], 10.4% showed cognitive dysfunction, similar to the incidence in the control group (10.6%), implying no long-term difference. The predictors of late POCD were age, early POCD and infection within the first three postoperative months. POCD could be explained by serum levels of benzodiazepines on the seventh postoperative day [4], and no correlation was found between POCD and the serum concentration of two markers of brain damage – S-100 beta protein and neuron-specific enolase – measured 24, 48 and 72 h postoperatively [5,6]. The ISPOCD investigators continued with their studies (ISPOCD2) and showed [7] no significant difference in POCD between general and regional anesthesia (14.3% compared with 13.9%, respectively) on the seventh day or 3 months after surgery. This result corroborated findings of a systematic review of trials published during the period 1966 to 2003 [8], the majority of which (23 of 24) showed no difference between neuraxial and general anesthesia in the incidence of POCD, collapsing the theory of a possible causal relationship between general anesthesia and intermediate or long-term POCD. POCD was also not found [9] to correlate with apolipoprotein E genotype, an important marker of recovery after neuronal damage. The epsilon-4 allele of the apolipoprotein E gene has been implicated as a risk factor for Alzheimer disease, poor outcome after cerebral injury, and accelerated cognitive decline with aging. Elderly patients undergoing minor operations have, however, a lower incidence of POCD – 6.8% at 7 days to 3 months – and the predictors of an increased risk of POCD with minor surgery are age greater than 70 years and inpatient rather than outpatient surgery [10]. There are a number of other smaller studies [11] on POCD following noncardiac surgery, although the ISPOCD studies remain the largest and best controlled studies conducted to date. In one other study [12], 112 patients were randomized to undergo major abdominal surgery with or without cerebral oxygen saturation

monitoring. Elderly patients allocated to the intervention group (the monitor being visible and cerebral oxygen saturation being maintained at greater than 75% of preinduction values) had less cerebral desaturation. There was, however, no difference between the groups in mini-mental status examination 7 days after surgery, although in patients with cerebral oxygen desaturation there was an association between the severity of cerebral desaturation (an area under the oxygen saturation curve of less than 75%) and the results of the mini-mental status examination. Another interesting study [13] measured intraoperative high-intensity transient signals on transcranial Doppler ultrasonography in patients during total knee arthroplasty and correlated them to postoperative complications and cognitive function. Previous studies have shown that tourniquet deflation during total knee arthroplasty is associated with findings of echogenic material in the heart from presumed embolic origin, which may reach the systemic circulation through an unrecognized intracardiac right-to-left shunt (patent foramen ovale) or transpulmonary passage and lead to multiple subcortical infarcts [14,15]. Cognitive dysfunction was found in 41% of patients at 1 week, and in 18% at 3 months, yet with no significant correlation to highintensity transient signals on transcranial Doppler scanning. A correlation was, however, found between postoperative complications, particularly infectious complications, and POCD. In conclusion, age is a risk factor for long-term POCD. Higher age per se is, however, also associated with a higher incidence of dementia. Other factors such as low educational level and a history of cognitive dysfunction before surgery, emphasize the need for large studies with adequate control and randomization. Cognitive dysfunction at 1 week after surgery predicts late POCD, although the majority of patients showing cognitive dysfunction after 1 week recover within a few months. Major surgery increases the risk of POCD, but general anesthesia alone does not. Future research is needed to better assess other factors, such as baseline disability, pain, depression and the metabolic and psychological response to the surgical trauma, on the cognitive function of elderly patients.

Cardiac diastolic dysfunction Clinically overt heart failure afflicts approximately 5 million Americans with an annual incidence of approximately 500 000 new cases, and results in about 300 000 deaths annually. The incidence and prevalence of heart failure increase dramatically with age, and the segment of the population and number of persons with heart failure older than 65 years are expanding rapidly [16].

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Diastolic dysfunction and diastolic heart failure are relatively new concepts (the term diastolic heart failure first being introduced by Kessler in 1988) and are currently well distinguished from systolic dysfunction and failure. In systolic dysfunction, cardiac myofibrils lack the ability to shorten against the load of aortic pressure. In contrast, diastolic dysfunction refers to the inability of the myofibrils to rapidly or completely return to their resting length during diastole; thus the ventricle cannot accept blood at too low a pressure, and ventricular filling is slowed or incomplete unless atrial pressure rises to augment left ventricle (LV) filling. Diastolic dysfunction is detected by specific echocardiography measurements [isovolumic relaxation time, early diastole (peak E wave) and atrial contraction (peak A wave) flow ratios and mitral annular diastolic motion] or by direct measurement of LV pressure deceleration (–dP/dt). In contrast to systolic heart failure, which is characterized by eccentric remodeling represented by increased LV diastolic volume, decreased systolic performance and decreased contractility, diastolic heart failure is characterized by concentric remodeling, normal LV diastolic volume yet slow and delayed active relaxation and increased passive stiffness. Half of all patients with heart failure have a normal ejection fraction [17], that is, pure diastolic dysfunction, which is as predictive of death as systolic heart failure [18]. Pure diastolic heart failure is characterized by clinical evidence of heart failure, a normal LV ejection fraction and laboratory findings of diastolic dysfunction [19]. Patients with diastolic heart failure are older and more likely to be female than patients with systolic heart failure. Approximately 45% of patients with diastolic heart failure have echocardiographic features of left ventricular hypertrophy, and 45% have coronary artery disease (CAD). Other causes of diastolic heart failure are diabetes mellitus, metabolic syndrome and aortic or mitral valvular disease. Little has been written so far on diastolic dysfunction and anesthesia, although it is most likely very common among subsets of patients undergoing noncardiac surgery. For instance, about 50% of patients undergoing aortic aneurysm repair exhibit signs of diastolic dysfunction [20]. Diastolic dysfunction may significantly affect perioperative hemodynamics, response to fluid shifts, anesthetic drugs and other perioperative medications. Patients with diastolic dysfunction are sensitive to hypovolemia and require higher filling pressures to generate an adequate cardiac output. Myocardial ischemia may worsen diastolic dysfunction and lead to heart failure even with an apparently normal ejection fraction. Conversely, diastolic dysfunction may precipitate and aggravate subendocardial myocardial ischemia by requiring higher than normal left ventricular end-

diastolic pressures to contract and therefore chronic high LV subendocardial wall stress. Nair et al. [21] demonstrated that anemia was strongly associated with diastolic dysfunction in patients with CAD. The prevalence of diastolic dysfunction ranged from 8% in patients with a normal hemoglobin level to 13% in those with moderate anemia (hemoglobin level of 11–13 g/dl) and 24% in patients with severe anemia (hemoglobin less than 11 g/dl). Filipovic et al. [22] showed that volatile anesthetics improved diastolic parameters as measured by echocardiography, with a shorter isovolumic relaxation time and a higher early diastolic peak velocity of the lateral mitral annulus, whereas propofol had the opposite effect. Schmidt et al. [23] reported improved cardiac function owing to better diastolic characteristics of the LV caused by high thoracic epidural anesthesia in patients with CAD undergoing coronary artery bypass surgery. Similarly, intravenous milrinone infusion has been shown [24] to ameliorate failure related to diastolic dysfunction in patients with a preserved LV ejection fraction. In summary, diastolic function plays an important role in the cardiovascular dynamics of the elderly patient. Although its diagnosis requires more elaborate echocardiographic examination than systolic dysfunction, diastolic dysfunction even with a normal or supranormal ejection fraction may have a significant effect on the perioperative outcome and management of elderly patients.

Prophylactic perioperative β-blockade

Prophylactic perioperative β-blockade (PPBB) is strongly recommended for high-risk patients undergoing noncardiac surgery, many of whom are elderly. This recommendation is based predominantly on two relatively small prospective randomized studied. First, Mangano et al. [25] showed a survival benefit starting at 6 months and lasting up to 2 years after surgery from the relatively short-term (1-week) perioperative use of atenolol in patients with known CAD or at risk for CAD undergoing major noncardiac surgery. Second, Poldermans et al. showed both a short-term (30-day) [26] and a long-term (2-year) [27] survival benefit with the intensive use of bisoprolol starting 30 days before, and continuing until 30 days after, surgery in selected highrisk patients undergoing major vascular surgery. In addition, less powerful studies [28–30] also suggest reduced morbidity with perioperative β-blockade and added to the evidence in support of PPBB. These studies have been the impetus to suggest PPBB as the standard of care for at-risk patients undergoing major surgery [31]. Although many clinicians strongly believe in the benefit of perioperative β-blockade, London et al. [32] have

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demonstrated a wide range of opinions regarding the efficacy, safety and administration of these drugs. Clinicians are more likely to utilize β-blockers in patients with known CAD rather than patients with risk factors for CAD. Although clinicians are likely to use perioperative β-blockade for patients undergoing vascular surgery, they are significantly less likely to utilize the drug for patients undergoing nonvascular surgery [32]. It is important to shrink this disparity as our population ages and older, sicker patients undergo noncardiac and nonvascular surgery such as orthopedic surgery for elective procedures or in the setting of trauma. Recently, however, a growing number of researchers have questioned the utility of broad-spectrum use of PPBB, challenging the strength of the evidence for its benefit. The statistical strength of the available data has been questioned [33], realizing that the total number of patients studied so far by randomized controlled trial has been relatively small (866 patients), and, in particular, the number of events, that is, myocardial infarctions and cardiac deaths, has been small (18 and 15, respectively). Most of these events were contributed by the study of Poldermans et al. [26], and when this study was excluded from the meta-analysis there was no significant benefit to PPBB in terms of either mortality or nonfatal myocardial infarction. In another publication [34], these researchers warned clinicians to view with skepticism randomized controlled trials such as the study of Poldermans et al. that were stopped early for benefit showing ‘implausibly large treatment effects, particularly when the number of events is small’. The issue of PPBB has become even more complicated with the recent publication by Lindenauer et al. [35] that showed a paradoxical increase in perioperative mortality (up to 43%) in low-risk patients (revised cardiac risk index = 0 or 1) receiving perioperative β-blockade and a survival benefit (of up to 43%) only in high-risk patients (revised cardiac risk indexing ≥ 3). The results of the latter enormous retrospective study, which included close to 782 929 patients after noncardiac surgery in 329 US hospitals, must, however, also be viewed with caution because of some serious limitations inherent to its design and methodology. For example, the study lacked data about which patients were on chronic preoperative β-blockade as opposed to newly initiated PPBB. Also, information regarding the date of surgery was not available, leading the authors to assume [36] that only β-blockade given on the first day of hospitalization was for prophylaxis, whereas β-blockade given after the second day of hospitalization was for the treatment of ischemia or complications, the patient therefore being included in the control group.

As more patients are being treated chronically with β-blockade, the effect of chronic preoperative β-blockade on postoperative outcome is of particular interest, but it has not yet been fully investigated by randomized controlled trials. In fact, recent studies have found a lack of benefit [37] or an even worse postoperative outcome from chronic preoperative β-blockade [38]. A meta-analysis by Giles et al. [38] found that patients on chronic preoperative β-blockade were more likely to suffer a perioperative myocardial infarction while undergoing noncardiac surgery. The authors attributed this finding to possible upregulation of the patients’ β-adrenergic receptors, leading to an acute withdrawal of β-blockers in the perioperative period. Another recent study [39] retrospectively analysed a cohort of 37 151 patients aged 65 years or more undergoing elective noncardiac surgery in 252 hospitals across Canada, who were without symptomatic CAD and who were on either chronic atenolol or chronic metoprolol therapy. The authors found 45% more postoperative myocardial infarctions and deaths in the metoprolol compared with the atenolol group within the first 30 days after surgery. This can again be attributed to the higher risk of acute withdrawal of β-blockade when doses of the drugs are missed in the postoperative period or when large fluid shifts and blood loss occur in major operations. As metoprolol is a shorter-acting drug, the risk of such acute withdrawal is presumably greater than with a longer-acting drug such as atenolol. As our population ages, more patients are receiving β-blockers for the treatment of two main clinical conditions: chronic ischemic heart disease and chronic heart failure. Chronic β-blockers have recently been shown to ameliorate symptoms and improve outcome in both diastolic and systolic heart failure. In the perioperative setting, β-blockers are not contraindicated in patients with diastolic heart failure and should be continued in patients with systolic heart failure, yet caution is warranted with the acute administration of β-blockers in situations of decompensating systolic heart failure. From the available data, it seems that longer-acting β-blockers confer greater benefit and safety to patients than short-acting β-blockers. Patients receiving β-blockade acutely in the perioperative period probably have greater benefit than those treated chronically. Still, given the risk of acute withdrawal, it would be unwise to discontinue β-blockade in patients with CAD or CAD risk factors preoperatively; rather, an increase in the dosage of their β-blockade perioperatively is probably prudent. Better powered trials, such as the PeriOperative ISchemic Evaluation study [33], with an enrollment of 10 000 patients and an anticipated end date in 2007, are

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critical to evaluate and understand this question. Until we have the complete necessary data, we will continue using best practices based on the available data.

Conclusion Anesthesia for the elderly with its specific challenges will continue to generate intriguing questions and dilemmas regarding the mechanisms of postoperative neurological and cardiac complications in geriatric patients and the methods to prevent them. In the present review we have examined the recent developments in three such specific issues and appraised the current state of the art these fields.

References .

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 351–353). 1

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