Cardiovascular aging and anesthetic implications

Cardiovascular aging and anesthetic implications

REVIEW ARTICLE Martin J. London, MD Section Editor Cardiovascular Aging and Anesthetic Implications G. Alec Rooke, MD, PhD T HE MEDICAL CARE of an ...

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REVIEW ARTICLE Martin J. London, MD Section Editor

Cardiovascular Aging and Anesthetic Implications G. Alec Rooke, MD, PhD

T

HE MEDICAL CARE of an aging population represents an almost overwhelming challenge to the US medical system. Currently, 12.4% of the population is over 65; by 2020, the value is expected to climb to 16.5%. When coupled with the expected 15% increase in the US population, this figure should represent 54 million people, a greater than 50% increase from the 35 million in 2000 (Bureau of the Census, www.census. gov).1 Older patients have invasive procedures at almost 4 times the frequency of people under 65 (CDC National Center for Health Statistics, www.cdc.gov/nchs/data/ad/ad319.pdf and www.cdc.gov/nchs/data/ad/ad300.pdf).2 They also suffer complications more frequently and require longer hospitalization on average.1 In 1999, patients over 65 accounted for 48% of all inpatient hospital days (CDC National Center for Health Statistics, www.cdc.gov/nchs/data/ad/ad319.pdf and www.cdc. gov/nchs/data/ad/ad300.pdf). Without question, great strides have been made at reducing medical costs in the past decade. The shift to outpatient surgery or at least morning admission and more extensive use of laparoscopic surgery are obvious examples. With health care dollars becoming increasingly tight, it is in the public’s best interest to use those dollars as effectively as possible and to continue to find ways to reduce the incidence of perioperative complications. Perioperative morbidity and mortality are functions of the disease that leads to the surgery, the patient’s comorbid disease, the severity of the surgery, and the reduction in physiologic reserve that accompanies aging. Of age and comorbid disease, which is more important? In univariate analysis, age is a strong correlate of risk, with each decade of age increasing risk by a factor of approximately 1.75.2 Studies that involve multivariate analysis occasionally fail to include age, but in most studies age remains an independent risk factor. The Veterans Affairs, in their National Surgical Quality Improvement Program and their Continuous Improvement in Cardiac Surgery Program, have identified a number of risk factors that are used to calculate expected mortality. For noncardiac surgery, 30-day mortality is

From the University of Washington and the Veterans Affairs Puget Sound Health Care System, Seattle, Washington. Supported by the Department of Veterans Affairs. Address reprint requests to G. Alec Rooke, MD, PhD, S-112-ANES VAPSHCS, 1660 South Columbian Way, Seattle, WA 98108. E-mail: [email protected] © 2003 Elsevier Inc. All rights reserved. 1053-0770/03/1704-0000$30.00/0 doi:10.1016/S1053-0770(03)00161-7 Key words: aging, anesthesia, cardiovascular system 512

expected to increase by a factor of 1.35 per decade of age.3 For cardiac surgery, the value is higher at 1.55 per decade. Nevertheless, there is some evidence that age is not so much an independent risk factor as it is a factor that interacts with comorbid disease to increase risk. Support for such a contention comes mainly from an older study that examined 268 major complications (including death) in 198,103 surgical procedures.1 In the study, comorbid disease influenced risk more than age influenced risk (Fig 1). More importantly, the effect of age appeared to involve an interaction with comorbid disease. At any level of chronic disease, the risk of complications was approximately 4 times greater for patients older than 75 than for adults under 35. So a working hypothesis is that healthy elderly have only a smaller increase in perioperative risk than their younger counterparts, whereas ill patients are at much higher risk if they are also elderly. Unfortunately, most of the patients presenting for thoracic, cardiac, or vascular surgery fall into this latter group. It would be nice to say that knowledge of how aging affects the cardiovascular system permits clinicians to deliver a smoother anesthetic and to reduce cardiopulmonary complications. There is no evidence to support such a contention even though it is logical to think that knowledge of the physiology of aging can help the anesthesiologist avoid management pitfalls and detect problems more rapidly before he/she progresses to a more serious situation. Certainly, the cardiovascular complications that are most feared are myocardial ischemia or infarction, congestive heart failure, stroke, arrhythmias that compromise cardiac function, and ultimately death in association with any of these complications. Perioperative hemodynamic instability is another consequence of aging and disease, but the impact of hemodynamic instability on outcome is less clear. The magnitude and duration of hemodynamic aberration necessary to lead to complications are undefined and probably patient specific. Perhaps, for that reason, there is a desire to maintain hemodynamic variables as constant as possible. This review will therefore attempt to impart an understanding of cardiovascular aging and how those changes may contribute to hemodynamic instability, myocardial ischemia, heart failure, arrhythmias, and stroke. Suggestions for anesthetic management may be given, but it must be acknowledged that the suggestions often represent the author’s opinions, however rooted in physiology they may be. Unfortunately, very little hard data exist on the appropriate hemodynamic management of elderly patients. The hope is that knowledge will improve the practitioner’s ability to analyze complicated clinical situations and determine a rational plan of action.

Journal of Cardiothoracic and Vascular Anesthesia, Vol 17, No 4 (August), 2003: pp 512-523

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vascular system that do not appear to be affected by the aging process. Vasoconstriction does not appear to become impaired by aging and neither does the strength of the muscular contraction of the heart. Although the speed of the contraction declines with age, the ability to generate pressure inside the ventricular chamber does not diminish, at least in healthy, elderly hearts. Connective Tissue Stiffening

Fig 1. The effect of age and comorbid disease on perioperative major complications is shown. In any age bracket, risk increases with additional comorbid disease. The effect of age is best determined by comparing points of equal comorbid disease. When patients with no chronic disease are isolated, the effect of age on risk is small. In contrast, when patients with, for example, 2 chronic diseases are examined, the influence of age on risk is very pronounced. (Reprinted with permission from Tiret et al.1)

PHYSIOLOGY OF CARDIOVASCULAR AGING

Overview Of the many changes to the cardiovascular system, 2 in particular appear to have far-reaching consequences. These changes comprise stiffening of the connective tissue and a decrease in the response to ␤-receptor stimulation. In brief, connective tissue stiffening causes the arteries, veins, and myocardium to become less compliant. Arterial stiffening leads to systolic hypertension, impaired impedance matching between the ejecting heart and the aorta, and myocardial hypertrophy. Myocardial stiffening, in combination with the delayed relaxation of myocardial hypertrophy, leave the ventricles increasingly dependent on an adequate atrial filling pressure and also predisposed to diastolic heart failure. Venous stiffening impairs the ability of the veins to buffer the effect of changes in blood volume or blood distribution on central blood volume and filling pressures. The diminished response to ␤-receptor stimulation reduces the heart rate and contractile response to hypotension, exercise, and exogenous catecholamine administration. Furthermore, the limited ability to increase contractility enhances the heart’s dependence on the Frank-Starling (lengthtension) relationship. Between the heart’s dependency on adequate ventricular filling, the increased difficulty of filling the ventricle (because of myocardial stiffening and diastolic dysfunction), and the decreased ability of the venous system to maintain central blood volume, cardiac performance becomes sensitive to the patient’s volume status (Table 1). Other changes to the cardiovascular system alter the response to atropine, impair the conduction system, and affect the autonomic nervous system including an increase in sympathetic nervous system activity at rest and in response to stimuli. Equally important, however, are the components of the cardio-

Connective tissue elastance depends primarily on the properties of its constituent collagen and elastin. Both are long-lived proteins, but elastin production essentially ceases by age 25 and collagen turnover becomes an even slower process with age. As such, both proteins accumulate damage over time, mostly from free radical production and from glycosylation.4 Free radicals are generated by ionizing radiation and as a byproduct of oxidative metabolism. Glycosylation is a chemical reaction between sugars and amines that does not require an enzyme to facilitate the reaction. Much like the situation with free radicals, glycosylation produces reactive intermediates that can attack other organic molecules and continue such propagation until stable, pigmented compounds are formed such as furans and pyrroles. One of the benefits of controlling sugar levels in diabetes is to slow down the damage caused by glycosylation. Elastin is considerably more flexible than collagen. So when damaged elastin is replaced by collagen, the tissue becomes stiffer. Damaged collagen may be replaced as well, but turnover takes time so the damage accumulates with such changes as ring cleavage and increased crosslinking between collagen molecules that lead to stiffened collagen. These changes affect the arteries, veins, and the myocardium. Arterial stiffening has at least 2 detrimental effects on blood pressure. Given that during ejection much of the stroke volume is stored in the thoracic aorta, a stiffened aorta must build to a higher pressure during systole.5,6 This is one mechanism for the high incidence of systolic hypertension in even healthy elderly adults. The second detrimental effect is more complicated. As the pressure wave travels down the arterial tree, the wave reflects off the vessel walls and branch points. These reflected waves return to the thoracic aorta and alter the pressure in the aortic root. In young adults, pressure wave velocity is slow enough to prevent the reflected waves from returning to the aortic root until after ejection is completed. The buildup in pressure therefore occurs in early diastole (the bump in pressure just after the dicrotic notch) and does not affect ejection. In contrast, elderly arteries are stiff and the pressure wave velocity is increased accordingly. Now the reflected waves return to the aortic root at the end of systole (Fig 2).7 This situation creates a poor (impedance) match between the declining strength of the myocardial contraction and the increasing pressure in the aortic root. The consequent strain on the myocardium at the end of ejection thus serves as a stimulus for myocyte hypertrophy. Hypertrophy of individual muscle cells is further exaggerated as myocytes die and are not generally replaced.8 Accompanying hypertrophy is an increase in the duration of the contraction.9 Calcium transport slows, thereby making the rate of pressure development more gradual, especially during isovolemic contraction. The decline in the speed of contraction represents a decrease in contractility only if contractility is

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Table 1. Cardiovascular Aging and Anesthetic Implications Aging-Induced Cardiovascular Change

Loss of sinoatrial node cells; conduction system fibrosis Stiff arteries

Myocardial hypertrophy; connective tissue stiffening Decreased beta-receptor responsiveness

Stiff veins

Increased sympathetic nervous system activity at rest and in response to stimuli

Physiologic Consequence

Anesthetic and Perioperative Implication

1st

Severe bradycardia when coupled with potent opioids

Systolic hypertension Impedance mismatching at endejection leading to myocardial hypertrophy and impaired diastolic relaxation Increased ventricular stiffness Ventricular filling dependent on a well-maintained atrial pressure

Labile blood pressure Diastolic dysfunction, sensitivity to volume status

degree block, occasional sick sinus syndrome

Limited increases in heart rate and contractility in response to endogenous and exogenous catecholamines Impaired baroreflex control of blood pressure Decreased buffering of changes in body blood volume impairs ability to maintain constant atrial pressure

Basal vascular resistance more dependent on basal sympathetic nervous system

Failure to maintain filling causes an exaggerated decline in cardiac performance; excessive volume more easily increases filling pressures to congestive failure levels Increased dependency on Frank-Starling mechanism to maintain cardiac performance.

Labile blood pressure, more hypotension Changes in blood volume or body distribution of blood cause exaggerated changes in cardiac filling Hypovolemia more easily impairs cardiac performance whereas hypervolemia more easily leads to symptoms of congestive heart failure Hypotension from anesthetic blunting of sympathetic tone Increased blood pressure lability from changes in sympathetic tone in response to the surgical stimulus

Modified with permission from Rooke GA: Anesthesia for elderly patients, in Hazzard WR, Blass JP, Halter JB, et al (eds): Principles of Geriatric Medicine and Gerontology, 5th ed., New York, NY, McGraw-Hill, 2003 (in press).

defined as dP/dT, the rate of change in pressure. The ultimate strength of the contraction does not appear to be impaired. More importantly, the calcium uptake by the sarcoplasmic reticulum also slows as a result of hypertrophy. The failure to

Fig 2. The effect of arterial stiffening with age is shown by this comparison of a thoracic aorta pressure waveform from an elderly subject (solid line) versus a young subject (dashed line). The increase in pressure during ejection in the elderly subject is because of decreased compliance of the thoracic aorta and the more rapid return of the reflected pressure wave. The pressure wave travels more rapidly in stiff vessels, so when the wave reflects off the walls and branch points of the arteries, the wave returns to the heart in late systole instead of early diastole as occurs in young adults. An increase in pressure during late systole causes myocardial hypertrophy as the heart attempts to maintain or even increase its force of contraction at a time when the heart’s force would normally be decreasing. (Reprinted with permission from Nichols et al.7)

remove calcium rapidly from the cytoplasm slows the process of muscle relaxation. The consequence of this prolongation becomes manifest in early diastole. Normally, the ventricular muscle is compressed on itself by the end of contraction. If the muscle relaxes promptly, then by the time the atrioventricular valve opens and ventricular filling begins, the ventricle can expand like a compressed spring and literally suck blood into it from the atrium. It is this mechanism that is responsible for the rapid ventricular filling in early diastole (tall “E” wave on a Doppler echocardiogram). In elderly hearts in which relaxation is delayed, the ventricle cannot spring open in early diastole because the muscle is still partially contracted. Early filling is impaired and must be compensated for later on in diastole. On an echocardiogram, this change is visible as “E” to “A” reversal, unless the atrial pressure increases to force blood into the ventricle more rapidly than a more normal atrial pressure would (pseudonormalization). Stiffening of the connective tissue in the ventricles associated with aging further worsens the situation. Late diastolic filling depends on the atrial pressure and the atrial kick, but when the ventricle becomes stiffer, the atrial pressures must, and do, increase to maintain end-diastolic volume (Fig 3).10 The net effect of these changes is to make the heart prone to diastolic dysfunction. Although other factors undoubtedly play

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body negative pressure are applied. In this circumstance, old and young subjects show a similar decrease in central blood volume. However, now the older subjects also show a greater decrease in cardiac output than their younger counterparts. These results suggest that venous stiffening, in general, permits less shifting of blood distribution in old versus young subjects for a given change in venous pressure. They also suggest that similar changes in cardiac filling have more profound effects on cardiac performance in elderly hearts. Therefore, under circumstances in which similar changes in central blood volume occur, the cardiac response to the change in preload will be exaggerated in older subjects. It appears, then, that venous stiffening may make elderly patients more resistant to some stresses such as assumption of upright posture but more susceptible to stresses that alter preload, such as blood loss during surgery. Changes in Response to ␤-Receptor Stimulation Fig 3. The effect of ventricular stiffening with age can be shown by a shift upward in the passive pressure-volume curve. As the ventricles stiffen, the same end-diastolic volume can only be achieved with a higher atrial pressure. Furthermore, the poor early diastolic filling that characterizes older hearts requires an increase in late diastolic filling, putting more dependence on the atrial kick and atrial pressure to complete ventricular filling. (Reprinted with permission from Rooke GA, Robinson BJ: Cardiovascular and autonomic nervous system aging, in Fleisher LA, Prough DS (eds): Problems in Anesthesia, Management of the Elderly Surgical Patient (vol 9). Philadelphia, PA, Lippincott-Raven, 1997, pp 482-497.)

a role, this phenomenon likely contributes to the increasing incidence in the elderly of heart failure not caused by systolic dysfunction. Approximately half of all patients with heart failure who are older than 75 have systolic function that is considered normal enough (ejection fraction above 40%) to be unable to account for the failure. Veins also appear to stiffen with age.11 The veins contain upward of 80% of the blood volume and constitute a reservoir that serves to maintain a fairly stable preload to the heart. Such buffering of blood input into the central circulation (heart and lungs) is most effective when changes in total body blood volume or shifts in the distribution of a constant blood volume result in minimal changes to venous pressures and therefore minimal changes in flow to the central circulation. Consequently, venous stiffening impairs the ability to keep cardiac preload constant when stressed by changes in blood volume or shifts in blood distribution such as can occur with changes in sympathetic nervous system activity. The evidence that venous stiffening occurs with age and impairs the ability to maintain a constant preload is indirect but supportive. When supine, leg elevation increases central venous pressure and central blood volume, whereas application of lower body negative pressure or the assumption of a more upright position should decrease those 2 variables. When subjected to these maneuvers, the changes in central venous pressure are virtually identical in young and old subjects. However, the changes in central blood volume were smaller (increase or decrease) in the older subjects, and the subsequent changes in cardiac output, when measured, are also smaller in the older subjects.12-14 The only exception to this picture is when very modest degrees of lower

The response to ␤-receptor stimulation is reduced in the elderly (Fig 4).15 As such, the cardiovascular system of an elderly person has been likened to that of a young adult on ␤-blockade. The number of ␤-receptors on the heart do not appear to decline with age, but the coupling of the receptor to the intracellular transmitter linked to adenylate cyclase activity appears to diminish with age.16 There is also some evidence that the density of ␤-receptors on the heart decreases modestly with age and the percentage of high-affinity receptors decreases.17,18 The consequences of the receptor changes may be minimal, however, because elderly and young subjects show the same sensitivity to the relatively pure ␤-1 agonist dobutamine, if the response to dobutamine for each subject is expressed as a percentage of the maximum effect.19 The use of isoproterenol, such as shown in Figure 4, may exaggerate the difference between young and old subjects because the ␤-2 stimulation will lower blood pressure more in the young adults, thereby activating the baroreflex-induced increase in heart rate in the young subjects more than in the elderly. Regardless of

Fig 4. Elderly subjects show much smaller increases in heart rate after intravenous boluses of isoproterenol than observed in young adults. (Reprinted with permission from Lakatta.15)

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the mechanism, the end result is a diminished chronotropic and inotropic response by the heart to ␤-receptor stimulation. This change affects the cardiovascular response to exogenous administration of catecholamines and to any stress including exercise and the baroreflex. At rest, older subjects have a higher blood pressure (especially systolic), similar heart rates, and ejection fractions but lower left ventricular end-diastolic volumes, stroke volumes, and cardiac outputs than young adults. More recent studies suggest that the degree to which cardiac output at rest declines with age may be far more trivial than originally thought, especially after correction for changes in body habitus.20 During exertion, heart rate, stroke volume, and ejection fraction increase, despite the increase in blood pressure. Body oxygen consumption increases because of increased cardiac output and oxygen delivery, and because of an increase in the body’s arteriovenous oxygen difference caused by the high extraction of oxygen by exercising muscle. With aging, the most prominent change is the lower heart rate at any level of exertion because exercise is accompanied by a graded increase in sympathetic nervous system activity and the heart has a decreased chronotropic response to the sympathetic stimulation. The estimation of maximal heart rate (220-age) also serves to define the proportionately lesser increase in heart rate at all levels of exercise. The limited chronotropic response in aging limits cardiac output and body oxygen delivery. At any age, stroke volume is increased during exercise, but the mechanism is different with age. In young adults, end-diastolic volume decreases with exertion, but stroke volume remains increased over resting values because of a progressive increase in the ejection fraction. Older adults show a very modest increase in ejection fraction with exertion, but end-diastolic volume increases to keep stroke volume higher than at rest.21 Maximal body oxygen consumption is further limited in the elderly by an inability to increase the arteriovenous oxygen difference to the same extent observed in young subjects, both because of decreased muscle mass and an apparent decline in muscle oxidative capacity.22 Exercise training improves maximal oxygen consumption by increasing left ventricular end-diastolic volume and stroke volume at rest and at all levels of exercise and by increasing oxygen extraction.23 Although both sexes improve by both mechanisms, elderly men improve mostly by the increases in volume, whereas elderly women rely more on increased oxygen extraction.24 In short, about the only compensatory mechanism for limitations in chronotropy, inotropy, and oxygen extraction that is available to older adults is the ability to increase end-diastolic volume to improve cardiac performance. Even though the increase in end-diastolic volume provides incomplete compensation, it does highlight the importance of preload and the length-tension relationship to the aging heart. The baroreflex system also suffers from the diminished cardiac response to beta-receptor stimulation. When the baroreflex is defined as the change in heart rate for a given change in pressure, the baroreflex becomes weaker with age (Fig 5).25 However, the baroreflex encompasses many components, and the evidence for an effect of aging elsewhere is less convincing. Recording sympathetic nerve activity in skeletal muscle reveals a higher level of basal activity in older subjects, and the change

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in activity for a given change in blood pressure is as great or greater than in young adults.26 When the peripheral response to the change in sympathetic nerve activity is estimated by measuring changes in forearm vascular resistance, the change in resistance in older adults is at least as much as that observed in young adults. Thus, it appears that the peripheral vasoconstriction component of the baroreflex is not affected by aging. Logically, there are at least 2 other areas in which aging could adversely affect the baroreflex. One is the baroreceptors themselves in which stiffened vessels could limit the stretch of the baroreceptors (which detect stretch, not pressure) and therefore reduce the gain of the system. The other is the processing of the baroreceptor input in the brain. There is no current evidence that baroreceptor output changes with age, and the fact that changes in sympathetic nervous system output are unaltered by age argues against a central nervous system deficit in the baroreflex. Lastly, the decreased response to ␤-receptor stimulation may also be responsible for decreased resting renin and angiotensin levels in the elderly and attenuated increases in renin and angiotensin in response to upright posture.27 The aldosterone response to corticotropin is not diminished with age, so it is presumed that aged kidneys, like the rest of the body, have a reduced response to ␤-receptor stimulation. In contrast, vasopressin levels increase with age, and the elderly increase their vasopressin levels more than do young adults in response to increased serum osmolarity.28 Increased Systemic Vascular Resistance and Sympathetic Nervous System Activity With age, systemic vascular resistance increases.29 A variety of mechanisms may contribute to the increase, including the arterial stiffening that decreases the compliance of the thoracic aorta and forces pressure to higher levels as the aorta accepts the stroke volume. That aortic stiffness could affect resistance may seem odd; after all, a metal pipe is very stiff yet may have low resistance to flow. However, impedance to blood flow is a dynamic phenomenon because blood flow is not constant, at least in the arteries. Arterial pressure must increase more in older people to accommodate the pulsatile nature of blood flow. This increase alters the calculation of vascular resistance when defined as mean arterial pressure (minus central venous pressure) divided by cardiac output. At the cellular level, aging is associated with decreased nitric oxide production in endothelial cells of both conduit and resistance vessels.30,31 Nitric oxide destruction is enhanced with age because of increased levels of oxygen free radicals from agerelated impairment of free radical scavenging. The response to circulating vasodilators is impaired, at least in part because less nitric oxide is produced in response to the dilators. Sympathetic nerve activity may also affect vascular resistance by changing the diameter of the resistance vessels, primarily the arterioles. Also, sympathetic nervous system activity increases with age as suggested by increased sympathetic nerve activity in skeletal muscle and by higher levels of circulating norepinephrine. There is some disagreement as to the mechanism of the increased norepinephrine levels. Evidence exists for (1) increased release of norepinephrine from the nerve terminals because of increased nerve activity, (2) an increase in the

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Fig 5. Both age and chronic hypertension are shown to diminish the baroreflex. The strength of the baroreflex (y-axis) is defined as the log of the change in the R-R interval (milliseconds) divided by the change in the systolic blood pressure. (Reprinted with permission from Gribbin et al.25)

percent of released norepinephrine reaching the general circulation (increased “spillover”), and (3) a decrease in the metabolism or reuptake of norepinephrine, but most experts agree that at least part of the increase in norepinephrine levels is because of increased release.32-35 Other observations corroborate the hypothesis that increased sympathetic nervous system activity can increase vascular resistance. Stimuli that increase sympathetic nervous system activity appear to produce at least as much vasoconstriction in older as in young adults. For example, exercise causes generalized vasoconstriction in nonexercising limbs, and this response appears to be greater in older adults.36 The rise in circulating norepinephrine during exercise is greater in elderly subjects as well. The cold pressor test produces the same increase in sympathetic nervous system outflow and in forearm vasoconstriction regardless of age.26,36 Despite these observations, it appears that a higher infusion rate of an alpha-vasoconstrictor must be administered to older subjects to achieve the same degree of vasoconstriction as in young subjects.37,38 Changes in Vagal Activity A given dose of atropine increases heart rate much less in older adults than in young adults, despite similar initial and final volumes of distribution and a slower metabolism in the

elderly.39,40 One possible explanation is lower basal vagal tone in older adults, thereby limiting the increase in heart rate that can be achieved by blocking the vagal tone. Such a contention is supported by diminished heart rate variability in older adults.41 Heart rate variability has a low-frequency component, controlled by the sympathetic nervous system, and a highfrequency component, controlled by the parasympathetic nervous system. Both components diminish with age. The decrease in low-frequency variability can likely be explained by the decreased response to ␤-receptor stimulation, whereas a decrease in vagal activity with age could explain the decrease in the high-frequency component. After a myocardial infarction, patients with poor heart rate variability are at increased risk of death over the next several years.42 Even in healthy adults, the loss of heart rate variability has been proposed as a marker for physiologic aging.43 The Inherent Instability of the Aged Cardiovascular System It should be clear that most of the changes associated with aging are at least moderately detrimental to blood pressure stability. Perhaps the most dramatic consequence of aging is the sensitivity to volume status of the aged cardiovascular system. The elderly heart becomes more dependent on cardiac filling at the same time it becomes more difficult to maintain steady

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unlike young adults, show postural hypotension. The combination of mild hypovolemia plus acute blood redistribution, despite the fact that less redistribution likely occurred with the older subjects, either caused a decrease in cardiac performance greater than occurred in young adults or was beyond what the reflex mechanisms could respond to adequately or both. For the interested reader, there are some excellent reviews on the physiology of cardiovascular aging.45,46 HEMODYNAMIC INSTABILITY DURING ANESTHESIA

Fig 6. Passive 60° tilt is applied to healthy young (solid circles) and elderly (open circles) subjects when normally hydrated (solid lines) and after diuresis and salt restriction left both groups depleted of approximately 2 kg of water and 100 mEq of sodium (dotted lines). In the normovolemic state, both age groups maintained systolic blood pressure effectively. Under conditions of mild hypovolemia, the young adults still responded effectively to the tilt, but the elderly subjects averaged more than a 20-mmHg decrease in blood pressure. Asterisk indicates change from prediuresis response at p < 0.02. (Reprinted with permission from Shannon et al.44)

cardiac filling volumes and pressures. Failure to maintain an adequate end-diastolic volume causes a significant decline in cardiac performance, especially in the presence of diminished compensatory inotropic enhancement. Myocardial and venous stiffening narrow the range of acceptable filling pressures and body blood volumes. Too little blood fails to generate filling pressures that produce an adequate end-diastolic volume. Too much blood and filling pressures rapidly increase to where adverse consequences occur, such as pulmonary congestion. Changes in sympathetic activity may have less effect on the heart but still affect the blood vessels and still shift the distribution of blood volume to or from the heart, thereby causing significant changes in cardiac performance in addition to the effect on vascular resistance. The sensitivity to body volume status can be illustrated when young and old adults are subjected to a tilt test under normovolemic and hypovolemic conditions.44 A tilt test raises the individual from the supine position without the opportunity for the subject to use their leg muscles, which could improve venous blood return to the heart. The goal of the tilt is to cause dependent blood pooling and cardiac hypovolemia and then monitor the body’s response. When performed under normovolemic conditions, healthy elderly maintain their blood pressure as effectively as young adults (Fig 6). When the tilt test is repeated after salt restriction and diuretics have induced mild hypovolemia, the elderly,

Given the preceding discussion, it should not be surprising that older patients show more hypotension and greater blood pressure lability during anesthesia than do young adults.47,48 What is surprising, however, is how little formal investigation has been performed on the differences in the cardiovascular response to anesthesia between young and elderly adults, especially during general anesthesia. Appropriate comparison of the response to general anesthesia is complicated by the need to adjust anesthetic dose for pharmacologic and pharmacokinetic changes with age. Presumably, the removal of sympathetic nervous system activity plays a major role in the response of the elderly patient to either a general or a spinal anesthetic. Decreases in vascular resistance, decreases in contractility, decreases in heart rate, and the shifting of blood away from the heart and into the gut and limbs are all potential consequences of decreased sympathetic tone and all can lower blood pressure. The higher the preanesthetic sympathetic tone, the greater the degree of expected hypotension. If the elderly indeed have higher sympathetic tone than young adults, then the degree of hypotension should be greater. Such a hypothesis has been indirectly examined with neuraxial anesthesia. Conventional wisdom suggests that spinal anesthesia, even if the block level is high, produces only a modest decrease in blood pressure in young, healthy subjects via approximately 10% decreases in both cardiac output and vascular resistance.49 In the presence of mostly high

Fig 7. The hemodynamic response to high spinal anesthesia is shown in elderly men with cardiac disease. Most of the decrease in mean arterial blood pressure (MAP) was because of a decrease in systemic vascular resistance (SVR) with only a modest contribution from a decrease in cardiac output (CO). The decrease in cardiac output was because of a decrease in stroke volume (SV) but not heart rate (HR). The decrease in stroke volume was entirely because of a decrease in left ventricular end-diastolic volume (EDV), but the decrease was partially compensated for by an increase in the ejection fraction (EF). (Reprinted with permission from Rooke et al.50)

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spinal anesthesia in men from 59 to 80 years of age, mean arterial pressure decreased by 33% because of a 26% decrease in vascular resistance but only a 10% decrease in cardiac output (Fig 7).50 Also observed were significant shifts of blood from the left ventricle to the legs and mesentery, but stroke volume was not proportionately decreased because of an increase in the ejection fraction. Although the patients in this study had cardiac disease, many had normal left ventricular function so it is possible that the effects of aging and a sedentary lifestyle were more important than the cardiac disease. In a study of healthier elderly patients, spinal blockade at an average T6 level produced an approximate decrease in vascular resistance of at least 21%.51 Both these studies lack young control subjects. A study of epidural anesthesia with ropivacaine without epinephrine that included both age groups showed a 29% decrease in mean arterial pressure in the older group (above 60 years old) compared with only 12% in the younger (18-40 years old) subjects.52 Unfortunately, the block height was also much higher in the older subjects (T4 v T8 on average). Blood pressure lability during general anesthesia is likely the result of changes in the depth of anesthesia versus the sympathetic nervous system activity in response to changes in the surgical stimulus. Achieving the proper balance is often difficult because the surgical stimulus can change much more quickly than the depth of anesthesia. One strategy, often favored by the author, is to maintain the anesthetic deep enough to block the response to most any anticipated surgical stimulus and cover periods of low surgical stimulus and consequent hypotension with pressors. How anesthetic depth is maintained may influence the degree of hypotension. The use of opioids to decrease the amount of inhalation agent may minimize hypotension. Others prefer to use adjuncts, primarily ␤-blockers, to minimize the hemodynamic response when a lighter depth of anesthesia is used in comparison to what would be needed in the absence of the ␤-blockade. No matter how skilled the delivery of the anesthetic, sooner or later hypotension in the elderly will be encountered. In young subjects, the response is frequently fluid administration; but that may not be the appropriate therapy for the elderly. Volume administration before spinal anesthesia in the elderly does lessen the blood pressure decrease but ultimately does not appear to reduce the incidence of hypotension or the need for vasopressor therapy.53,54 Similarly, fluid administration alone often fails to treat hypotension adequately during neuraxial blockade and is less effective than vasopressors.55,56 Although fluid administration increased stroke volume to levels above baseline, the ability to increase vascular resistance by the vasopressors provided the more effective therapy. Furthermore, volume loading, at least in patients with coronary artery disease, may be associated with worsened left ventricular function as assessed by echocardiography.57 Of course, vasopressors, at least phenylephrine, may have adverse effects too, including decreased left ventricular function or even myocardial ischemia.58,59 It can easily be argued that the ideal therapy does not exist. The perfect drug for the hypotensive elderly patient would reliably increase vascular resistance, shift blood from the periphery back to the central circulation to restore stroke volume, and provide just enough ␤-1 agonism to maintain left ventricular function yet avoid tachycardia. In the absence of the

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perfect pressor, the author administers volume when there is clinical evidence of hypovolemia and uses phenylephrine for nearly all other circumstances unless there is evidence of poor ventricular function. In some circumstances when hypotensive anesthesia is desirable and an epidural anesthetic is in use, an intravenous infusion of epinephrine should be considered.60 The technique, popularized primarily for hip surgery, provides the desirable effects of an increased cardiac output yet a lowered blood pressure, presumably because the epinephrine not only increases cardiac output via ␤-1 receptor stimulation but also vasodilation via ␤-2 receptor stimulation. Similar effects occur when epinephrine is present in the epidural anesthetic; however, infusions are easier to titrate. PERIOPERATIVE MYOCARDIAL ISCHEMIA AND CARDIAC MORTALITY

Most, if not all, perioperative myocardial infarctions are likely the result of clot formation at the site of a coronary plaque that may or may not have been sufficiently occlusive to produce ischemia before the infarction. It can be argued that plaque formation is a disease process and not an inevitable result of aging, and therefore coronary disease and its clinical manifestations are beyond the scope of this review. There is one aspect of ischemia, however, that appears to be related to aging and not disease. The phenomenon of ischemic preconditioning provides protection against infarction from prolonged, but not indefinite, periods of myocardial ischemia. This protection may not be present in older people. Ischemic preconditioning is usually shown by applying a brief (eg, 5 minutes) period of ischemia to a portion of the heart followed by a period of reperfusion (eg, 5-60 minutes), then making that portion of the heart ischemic for a period of time long enough (eg, 40 minutes) to cause some, but not all, of the at-risk tissue to infarct. The presence of an initial ischemic event reduces the size of the infarct in comparison to what the same prolonged ischemic period would cause in the absence of the preconditioning.61 The protective mechanism behind preconditioning appears to involve adenosine triphosphate– dependent K channels whose action can be enhanced with adenosine and inhibited by glyburide.62 Delayed preconditioning also exists whereby noninfarction ischemic events confer some protection from the adverse consequences of ischemic events that occur several days later.63 The mechanism behind delayed preconditioning is less well understood. Preconditioning may be involved in a variety of clinical situations. Warmup angina describes the patient who exercises to the point of angina, rests, and then can achieve a higher level of exertion the second time around before experiencing angina. Warmup angina has been duplicated in the controlled circumstances of treadmill exercise in which ischemia can be documented with ST-segment changes. After the first period of exertion, subsequent exertion was associated with longer times before ST changes and a higher systolic pressure-rate product before ischemia.64 Unfortunately, age diminishes the improved performance of the second (and any subsequent) periods of exertion. Around age 60 the increase in the duration of exertion began to decline and by age 75 no improvement could be shown.65

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Fig 8. The protective effect of angina within 48 hours of a myocardial infarction is present for patients less than 65 years of age (adult) but not for patients over 65 (elderly). Adults who experienced angina shortly before their infarctions had markedly lower incidences of death and heart failure. Elderly patients, however, had the same high rate of complications regardless of whether they had angina within 48 hours of their infarctions; *p < 0.01; **p < 0.02. (Modified with permission from the American College of Cardiology Foundation. J Am Coll Cardiol 30:947-954, 1997.66)

Considerably more distressing is the possibility that ineffective preconditioning may contribute to elderly patients suffering more complications after myocardial infarction. In a retrospective analysis of 500 patients who were admitted for treatment of an acute myocardial infarction, patients younger than 65 had markedly reduced rates of in-house mortality, heart failure, and ventricular fibrillation if they had experienced angina within 48 hours of their myocardial infarction in comparison to patients under 65 who did not experience angina.66 In contrast, prior angina conferred no benefit for patients older than 65 for any complication. Furthermore, the complication rates for in-house death and heart failure in the elderly patients were as high or higher than the rates in younger adults without antecedent angina (Fig 8). This study cannot be considered definitive, however. It is retrospective, and there were differences between the younger and elderly adults, most notably the fact that thrombolytic therapy was less likely to be used in elderly patients. Nevertheless, the cumulative data of this and other studies suggest that at least part of the increased mortality and morbidity of coronary disease in the elderly is because of the loss of ischemic preconditioning. VOLUME STATUS AND CONGESTIVE HEART FAILURE

Heart failure is a well-known risk factor for perioperative cardiovascular complications. Systolic dysfunction is invari-

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ably the result of a disease process such as coronary artery or valvular disease but not so diastolic dysfunction. The predisposition to diastolic dysfunction of the aged heart complicates fluid management in the elderly. Volume overload can raise filling pressures to levels capable of causing symptoms of congestive heart failure more easily in the elderly, and hypovolemia can more easily result in decreased cardiac output and even hypotension. The importance of diastolic dysfunction cannot be overemphasized. It is estimated that of patients over 65 years of age with congestive heart failure, up to half have reasonable systolic function (⬎40% ejection fraction).67 The incidence of heart failure from diastolic dysfunction increases with age and is largely responsible for the 10% prevalence of heart failure in people over 80 years old. When heart failure is caused by isolated diastolic dysfunction, there is generally evidence of systolic hypertension and ventricular hypertrophy. These findings emphasize the contribution of hypertrophic muscle to delayed relaxation and the contribution of systolic hypertension to the development of hypertrophy. In fact, there is increasing realization that isolated systolic hypertension is a major risk factor for both heart failure and stroke and should be aggressively treated, especially because isolated systolic hypertension constitutes more than 60% of all cases of hypertension in patients over 65.68 In a study of more than 4,300 patients over age 50 (average age 66) undergoing major noncardiac surgery, the incidence of postoperative heart failure was 1% and equaled half of the total cardiac complications.69 In addition to patients with obvious risk factors such as preexisting heart failure or a perioperative myocardial infarction, those at greatest risk for postoperative failure are elderly patients with a history of poorly controlled hypertension and who have had surgeries with major fluid shifts. Furthermore, the elderly have diminished renal function and may not eliminate excess fluid as quickly as young adults once mobilization of third-space fluid commences. Careful and frequent examination for signs of fluid overload should guide diuretic therapy. ARRHYTHMIAS

Aging compromises the pacemaker and conduction systems. Sinus node pacemaker cells are reduced to as little as 10% of young adult levels.46 With sinoatrial node dysfunction comes the increased risk of bradycardia and even sick-sinus syndrome. The atrioventricular (AV) node maintains its cell population with age, but the AV node conduction time lengthens with accompanying P-R prolongation. The number of Purkinje fibers decreases with age, although not nearly as severely as for the SA node. Fibrosis and other age-related changes to the atrium predispose the elderly to atrial fibrillation, as does the fact that bradycardia, if present, enhances the initiation of atrial fibrillation.70 Atrial fibrillation is a particularly common and often nettlesome arrhythmia. Atrial fibrillation increases in prevalence 2-fold every decade, affecting up to 10% of people over age 80.70 It is now clear that some patients with atrial fibrillation frequently alternate between sinus rhythm and atrial fibrillation. Atrial fibrillation in the elderly may be asymptomatic, especially if there is intrinsic rate control from AV nodal dysfunction. If initial discovery of atrial fibrillation is made shortly

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before surgery, should surgery proceed or be postponed for further workup? Probably the most important test would be an echocardiogram. Certainly, it would not be wise to proceed with elective surgery if an echocardiogram found some cardiac abnormality that affected the patient’s perioperative management, especially if treatment could lower that risk. If a cardiac thrombus were found, the stress of surgery could make it worse or lead to an embolus if the patient spontaneously reverted to sinus rhythm. If the patient were a candidate for elective cardioversion, it could be argued that a purely elective case should be postponed because the patient will be easier to manage if in sinus rhythm. The onset of atrial fibrillation after surgery is certainly well appreciated in cardiothoracic surgery, but it is common in elderly patients after other types of surgery as well. As with any new onset, initial therapy is aimed at control of the ventricular response. Digoxin, seemingly the mainstay of rate control, may not be a good choice perioperatively because digoxin loses its efficacy in situations of low vagal/high sympathetic tone. The importance of postoperative anticoagulation when atrial fibrillation develops intraoperatively or postoperatively and the controversy over appropriate prophylaxis for the prevention of atrial fibrillation have been recently reviewed.71 Ventricular ectopy increases with age even in the absence of cardiac disease, whereas the increased incidence of ventricular tachycardia and fibrillation appear to be disease related and not directly because of aging.72 All forms of heart block, including bundle-branch block, are more common in the elderly but appear to carry an adverse prognosis only if associated with overt cardiac disease, such as usually the case with Mobitz type II block and often the case with third-degree block and left bundle-branch block. However, the most common cause of third-degree block in the elderly remains idiopathic degenerative disease of the conduction system. PERIOPERATIVE STROKE

Having surgery increases the risk of stroke. After identifying more than 1,450 patients with ischemic stroke and an equal number of matched control patients, it was determined that the stroke patients had a higher incidence of a surgical procedure within one month of their stroke.73 When surgeries other than cardiac, vascular, and neurologic were examined, the odds ratio was 3.0 for having a stroke within 30 days of surgery in comparison to no surgery. The risk of perioperative stroke increases with age and may reach a 3% incidence or more in patients 80 years and older.74 Presumably heightened coagulability may play a role in perioperative stroke just as it may with

perioperative myocardial infarction. Another contributory mechanism, especially in the elderly, is that of atrial fibrillation and the risk of embolic stroke. In at least 1 (small) series of perioperative stroke, atrial fibrillation was present in 33% of the cases.75 Given the propensity for older patients to show hemodynamic instability during surgery and anesthesia, could intraoperative hypotension be a contributory mechanism for perioperative stroke? The evidence is indirect, but all of it argues against such a mechanism. First of all, most strokes occur postoperatively; that is, there is a clear period after surgery in which the patient has a normal neurologic status, then worsens later on.76 The median occurrence is 2 days postoperatively. Second, the incidence of hypotension is no higher in stroke patients than in case-matched controls having surgery without stroke.76 Third, if hypotension were a prominent cause, borderzone infarcts would be expected to occur more often than specific vascular bed infarcts, and border-zone infarcts should occur more often when hypotension is present. Neither expectation has been found to occur.76 Fourth, the incidence of stroke during deliberate hypotensive anesthesia is low, and no higher than in subjects having the same surgery without deliberate hypotension.74 Even when careful psychometric testing is performed, patients subjected to deliberate hypotension perform as well as the patients randomized to less severe or no hypotension.74,77 CONCLUSION

Cardiovascular aging is predominantly manifested by increased tissue stiffness and fibrosis, decreased response to ␤-receptor stimulation, increased sympathetic nervous system activity at rest and in response to stimuli, and the loss of ischemic preconditioning. The consequences of these and other changes are myriad, but all lead to a decrease in patient reserve. In otherwise healthy patients, the reduced reserve may not be very damaging. When added to the effects of chronic disease and the stress of surgery, the effects of aging increase the instability of the system and increase the likelihood of adverse events. Hemodynamic instability is the most common problem noted in the perioperative period, although it is debatable just how severe the consequences of the instability are given current levels of anesthetic care. However, the inevitable stress of surgery with its attendant fluid shifts and enhanced coagulation, when coupled with such changes as stiff veins, diastolic dysfunction, and loss of ischemic preconditioning, clearly place the elderly patient at increased risk of adverse cardiovascular events, including myocardial infarction, heart failure, and stroke.

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