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Homeostatic Fragility in the Elderly
Geriatric Cardiology
Homeostatic Fragility in the Elderly Naftali Stern, M . D . , * and Michael L. Tuck, M . D. t A major physiology textbook defines homeostasis as the maintenance of static or constant conditions in the internal envir~nment.~'In practical clinical terms, the long list of physiologic functions relevant to the maintenance of organic "well-being" may be narrowed down to preservation of tissue oxygenation and adequate water and electrolyte environment. In addition to the cumulative increase in various s~ecific organic diseases with advancing age, aging per se is accompanied by multiple alterations in physiologic function that hinder the efficacy of homeostatic regulatory processes. A large body of data accumulated mostly within the past 15 years in different medical disciplines not only has confirmed that aging is associated with increased honleostatic fragility but also has unveiled some of the underlying mechanisms involved.
TISSUE OXYGENATION In the most general sense, tissue oxygenation depends on appropriate oxygen uptake by red blood cells in the lungs (respiratory mechanisms) and the adequate delivery of blood to peripheral tissues, a function of cardiac output and arterial pressure.
Aging and Respiratory Mechanisms It is well established that arterial oxygen tension declines with age in healthy subjects.77 This is believed to result from an age-dependent increase in ventilation perfusion mismatch33and does not, in itself, reflect chronic obstructive lung disease. With advancing age, pulmonary function diminishes, leading to changes consis-
tent with "lower airway obstruction."" In fact, many spirometry parameters used in clinical pulmonary medicine, such as vital capacity, FEV,, peak expiratory flow rate, maximal midexpiratory flow rate, and maximal expiratory flow, show an age-dependent decline3' and should be corrected routinely for age. Stiffening of the chest wall, weakening of respiratory muscles, and a steady decline of pulmonary elastic recoil are all observed with aging. Various conditions not specifically related to aging per se such as disorders leading to upper airway obstruction (for example, nasal polyps, deviated septum) or to the distortion of the thoracic cage (for example, kyphoscoliosis, kyphosis) may have an aggravating cumulative effect on agedependent respiratory defects. Besides local mechano-elastic factors, control of breathing is also affected by aging. Chemoreceptor responsiveness is relatively blunted in the elderly. Both hypercapneic and hypoxic ventilatory remanses are markedlv diminished in older in. ividuals, an effect i n d e ~ e n d e n tof lung mechanics. " A decrease in mechanoreceptor responsiveness has also been shown.83Finally, aging is associated with a steadv increase in the ilcidvence of sleep-related breathing disorders.". 54 Depending on the population studied and methods used to diagnose sleep-related breathing disorders. as much as 30 G 60 Der cent of the elderly population manifests some of the sleep-related breathing disorder^.^. 54 TO appreciate the potential toll of this common abnormality in the elderly, it should be recognized that a typical patient having 12 to 25 apneic-hypopneic episodes per sleep hour will experience 240,000 to 500,000 hypoxemic spells, arousals, and pulmonary and systemic arterial pressure spikes in a 10-year period. Indeed, younger subjects with the sleep apnea
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*Assistant Professor o f Medicine, University of California School o f Medicine, Los Angeles; StaffPhysician, Endocrinology Department, Sepulveda Veterans Administration Medical Center, Sepulveda, California tProfessor of Medicine, University of California School o f Medicine, Los Angeles; Chief, Endocrinology-Metabolism, Sepulveda Veterans Administration Medical Center, Sepulveda, California Cardiology Clinics-Vol.
4, No. 2, May 1986
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syndrome have increased incidence of hypertension27.35, 96 that is often reversed along with the correction of sleep apnea achieved by weight reduction surgery.48In the elderly, however, hypertension appears to be evenly distributed between subjects with and without sleeprelated breathing disorders.55 Under regular daily circumstances, the "homeostatic" implications of the respiratory abnormalities reviewed earlier are probably minimal. However. the common occurrence of minor ailments such as upper or lower respiratory tract infection often unveils the enhanced vulnerability of elderly subjects with impaired compensatory respiratory mechanisms. In addition, the increased sensitivity of the elderly to "benign" agents such as benzodiazepines may be better understood in light of the worsening of central respiratory depression in susceptible awake individual^^^, 69, 76 and the induction of an astonishing increase in the number of apneic episodes in elderly patients with mild sleeprelated breathing disorders. 14.56 Aging and Cardiac Output A complete assessment of the aging heart is beyond the scope of this article. However, a number of age-related changes that could hinder homeostatic adaptation to daily activities will be highlighted. Normal function of the left ventricle depends on (1) appropriate filling of this chamber (preload), that is, end-diastolic volume; (2) the contractile capacity of the myocardium; and (3) the vascular impedance to blood ejected by the contracting left ventricular myocardium (afterload). Preload. The rate of diastolic filling in subjects in the 65- to 80-year-old age group is roughly 50 per cent of the rate measured in the 25- to 45-year-old age group.21Thus, although at rest the end-diastolic volume is normal even in the elderly,70decreased diastolic filling rates in the elderly may potentially result in reduced end-diastolic volume and, hence, diminished stroke volume occurring during periods of increased heart rate such as that induced bv physical activity, assumption of upright posture, or onset of fever or stress. Myocardial Contractility. The myocardial capacity to develop force does not appear to be affected by aging per se.45Although there is both in vitro and in vivo evidence for a moderate (15 to 20 per cent) prolongation of myocardial contraction time,30, the cardiovascular functional implications of this phenomenon in the aged are not clear. Minor reductions in
myocardial contractility, as reflected by increased end-diastolic volume (that is, increased myocardial fiber length), have been reported in older individuals subjected to concomitant betaadrenergic blockade and alI;ha-adrenergic pressor stress.44Thus, under these hardly physiologic conditions, the aging heart appears to rely more on length-dependent (Frank-Starling) mechanisms to develop the appropriate increment in contractile force than does the younger heart. Afterload. Even though it appears that total peripheral resistance is not grossly modified with advancing age, the following lines of evidence support the concept that a significant, if subtle, rise in vascular impedance does accompany aging: 1. Systolic and, to a lesser extent, diastolic arterial pressure rises steadily with age36.64. 70 (Fig. 1). 2. Arterial elasticity, particularly that of the aortic wall, declines, as evidenced by lowered ,~ intra-aortic presretraction c a p a ~ i t yincreased sure change per arterial radius change,24 and enhanced pulse wave velocity." 3. Left ventricular wall thickness is strongly related to age,21which suggests that an adaptation to a long-standing increase in afterload has taken place. In addition to alterations in left ventricular function per se, a major factor is the ageassociated decline in the maximal heart rate response to exercise. Whereas basal heart rates in the elderly do not differ significantly from those in younger individuals, the mean heart rate in response to a "maximum workload" is 174 k 4 beats per minute in the 25- to 44-yearold age group, but only 143 + 4 beats per minute in the 65- to 79-year-old age group.93 Sympathetic activity rises with age in normal subjects, as reflected by higher basal circulating norepinephrine level@ (Fig. 2) as well as by enhanced norepinephrine response to upright posture and isometric exercise (handgri~).~' Furthermore, maximal plasma norepinephrine levels measured during maximum treadmill exercise show a positive correlation with age.87 Thus, the reduced heart rate response to exercise in the elderly must be related to decreased chronotropic responsiveness to adrenergic stimuli. Indeed, a decline both in the number of beta-adrenergic receptors7' (Fig. 3) and in postreceptor adenylate cyclase activation41with aging has been reported in humans. That the reduction in maximal heart rate is a function of attenuated beta-adrenergic responsiveness rather than of nonadrenergic mechanisms is
Homeostatic Fragility in the Elderly
Figure 1. Systolic blood pressure as a function of age. (From Rodenheffer, R. J., et al. : Exercise cardiac output is maintained with advancing age in healthy human subjects: Cardiac dilation and increased stroke volume compensate for diminished heart rate. Circulation, 69:203, 1984; with permission.)
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Figure 2. Plasma norepinephrine as a function of age. (From Lake, C. R., et al.: Age-adjusted plasma norepinephrine levels are similar in normotensive and hypertensive subjects. N. Engl. J. Med., 296:208209, 1977; with permission.) 0 .
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Figure 3. Lymphocyte beta-adrenergic receptors as a function of age. (From Schocken, D. H., and Roth, G. S.: Reduced beta adrenergic receptor concentrations in aging man. Nature, 2672356-858, 1977; with permission.)
supported by observations that nonadrenergic stimuli are capable of eliciting indistinguishable chronotropic responses in the young and elderly alike.97 What is the integrated effect of these agerelated changes on cardiac capacity to adapt to circumstances threatening homeostasis? In the healthy older individual, the decline in the capacity to increase heart rate in response to exercise is well comvensated for bv an increase in stroke volume. 70 L ~ h u scardiac' , output does not decline with aging, even at workloads as high " as 125 W.70The needed increase in stroke volume during exercise in the elderly who fail to achieve "sufficient" increase in heart rate can be appropriately met by resorting to FrankStarling mechanisms. With each workload level. exercising elderly subjects exhibit much larger end-diastolic left ventricular volumes, thereby facilitating the generation of sufficiently augmented contractile force and stroke volume to compensate for the blunted increase in heart rate. Overall, the aging healthy heart manifests remarkable functional adavtation to alterations associated with normal aging and is not normally responsible for serious impairment of homeostatic regulatory processes. u
Arterial Pressure Aging is associated with a steady, gradual rise in systolic and diastolic arterial pressure, even within the normal range.36,64- 70 FUrthermore, there is a well-documented age-related rise in Al. the incidence of essential h y p e r t e n ~ i o n .88~ ~
though it is true that circulating norepinephrine levels also rise with age, several lines of evidence suggest that hyGeAension in the elderly is not "neurogenic." First, plasma norepinephrine increases with age in normotensive individuals but not in patients with essential hyperten~ i o n Second, .~~ contrary to findings in young and middle-aged hypertensive subjects, in whom plasma catecholamines are positively related to arterial blood pressure,13 an inverse relationship has been noted in older hypertensive individuals. 20, s2 Finally, using multiple sampling throughout the 24-hour cycle, we have recently shown that elderly subjects with essential hypertension in fact have lower circulating levels of norepinephrine, epinephrine, and dopamine than do age-matched normotensive individualss2 (Fig. 4A). This contrasts with the observations in younger hypertensive subjects, in whom 24-hour norepinephrine levels are clearly higher than in their normotensive agematched counterpartss6 (Fig. 4B). Of major interest is the issue of aging and adaptation of arterial pressure or vasopressorldilator mechanisms to acute changes commonly encountered in daily life, such as posture, exercise, and sleep. Postural hypotension is common in the elderly. Mild to moderate orthostasis, that is, a postural fall in systolic pressure of at least 20 mm Hg, is encountered in roughly a quarter of an ambulant elderly population, and a severe drop in systolic arterial pressure, that is, a decrease of 40 mm Hg or more. has been observed in 5 ver cent of the e l d e r l ~which ,~ reflects major derangements of blood pressure regulation in this age group. u
Homeostatic Fragility in the Elderly
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Figure 4. A, Twenty-four-hour plasma norepinephrine levels in older hypertensive and normotensive men. B, Twentyfour-hour plasma norepinephrine levels in young hypertensive and normotensive men. (A, from Stern, N . , et al.: Dissociation of 24-hour catecholamine levels from blood pressure in older men. Hypertension, 7:1023-1029, 1985; with permission. B, from Tuck, M . L., et al.: Enhanced 24-hour norepinephrine in young patients with essential hypertension. Am. J. Cardiol., 55:112-115, 1985; with permission.)
The maintenance of arterial pressure at a relatively constant level so that acute increases or decreases are offset effectively is governed mainly by baroreflex arc mechanisms. Thus, during lowering of intra-arterial pressure, baroreceptors located in the left atrium, carotid sinus, and large arteries are subjected to reduced stretching and are turned off, resulting in stimulation of central vasomotor regulatory centers that are otherwise tonically inhibited. The effector mechanisms activated by these centers include the sympathetic nervous system, the renin-angiotensin axis, and vasopressin release. Aging affects not only baroreceptor sensitivity but also each of these efferent limbs of the baroreflex arc. A number of studies have shown that baroreflex sensitivity diminishes with age.26 56, 78
Most investigations of baroreflex function have relied on demonstration of a reduction of heart rate in response to pressor agents; the effect has been less pronounced in the elderly. Indirect data also support the concept of diminished baroreflex-dependent mechanisms in the elderly in response to depressor stimuli. Decreased cardiovascular response rates to drugs that reduce blood pressure have been shown in older i n d i v i d ~ a l s .Likewise, ~~ Vlachakis and associatesg0have reported significant reduction in the normal pulse rate increments following hypotensive maneuvers such as exposure to heat and administration of the vasodilator trimethaphan camsylate in elderly hypertensive subjects. Finally, increments in heart rate in response to upright posture diminish with aging. 65
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Plasma norepinephrine response to upright posture rises steadily with advancing age," suggesting that the afferent limb of the baroreceptor reflex is fully functional during hypotensive stimuli in the elderly. Thus, despite claims to the contrarv. ,, there is no direct evidence that orthostatic hv~otension results from submaxi, ma1 activation of the baroreflex arc in otherwise healthy elderly individuals. As already stated, the sympathetic response to upright posture in the elderly -appears to be intact if not actually exaggerated. Because the sympathetic response is most likely the major mechanism normally preventing orthostatic hypotension, it is possible that diminished peripheral response to catecholamines plays a role in postural hypotension in this age group. There is abundant evidence for loss of beta-adrenergic receptor activity in various tissues with aging.l0, 43, 55, " Propranolol, a beta-adrenergic receptor blocker, reduces heart rate to a lesser extent in older subjects.1° An age-related decrease in the ability of isoproterenol, a beta-adrenergic agonist, to increase heart rate has been reported.43 However, pressor response to endogenous sympathetic stimulation should depend more on alpha-adrenergic response. Whether or not aging is indeed associated with changes in pressor response to alpha-adrenergic stimulation is currently unknown, although a recent study has documented that during epinephrine infusion, older men have smaller increases in systolic arterial pressure than younger individual^.'^ A decreased number of platelet alpha-adrenergic receptors has been reported in aged subject^,^ but it could not be confirmed subsequently.', 60 Activation of the renin-angiotensin system in response to standing is also affected by aging. The incidence of subnormal plasma renin activity (PRA) responses to low-sodium diet and upright posture shows a positive correlation with patients' age and diastolic pressure in It is now patients with essential hyperten~ion.'~ apparent that even though the reduction of PRA with aging is more pronounced in hypertensive subiects, " . elderly normotensive individuals also show an age-related decline in the renin-angiotensin axis.12. 31, 61. 90 For example, 33 per cent of normotensive subjects in the 70- to 79-yearold age group display hyporesponsive PRA, but this is uncommon in younger individuals.12 Thus, blunted PRA and, hence, angiotensin I1 response to postural changes may contribute to the pathogenesis of orthostatic hypotension in the elderly. Finally, even though the release of vasopressin is not normally considered necessary to prevent a drop in arterial pressure in response &
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to standing, it is known that vasopressin secretion rises in young subjects assuming the upright posture,74presumably through activation of left atrial baroreceptors. In fact, the volumepressure-baroreceptor pathway is a more powerful (although not as sensitive) activator of vasopressin release than the osmoreceptor-de'~ individuals may fail pendent p a t h ~ a y . Elderly to show the normal postural rise in vasopressin levels, even in the presence of symptomatic orthostatic hypotension. Because the same individuals have normal norepinephrine response to standing (suggesting an intact afferent limb of the baroreflex arc), Rowe and Robertson have inferred that the defect must be located at a central nervous system site between the vaso75 motor center and the posterior pit~itary.'~, Although the abnormalities just outlined often remain "subclinical," they may also be accentuated acutely with dramatic clinical presentations in the presence of such common superimposed conditions as pyrexia, mild dehydration, varicose veins, and the use of diuretics or nitrates. Particularly worrisome is the high incidence of orthostatic hypotension in the elderly hypertensive subjects in whom hypotensive drug therapy has been recently initiated. Not only is the effectiveness of baroreceptors diminished in elderly subjects with long-standing hypertension, but also the normal autoregulatory mechanisms maintaining cerebral blood flow constant until mean arterial pressure falls to 60 mm Hg have been "reset," so that the lower pressure limit of autoregulation rises. Thus, sharp falls in blood pressure that are not counterbalanced effectively by baroreceptor activation and/or release of catecholamines, angiotensin 11, and perhaps vasopressin are often associated in these patients with reduced cerebral perfusion, presenting as lightheadedness, dizziness, falls, or, in the extreme case, distinct cerebrovascular catastrophies. 34 Blood pressure irregularities during sleep in the elderly have begun to attract attention only recently. In younger age groups, the incidence of sleep apnea among hypertensives is much higher than among age-matched control^.^^^ 96 Case series studies of subjects with sleep-related breathing disorders report a 50 per cent It has also been incidence of hyperten~ion.~' shown in a large-scale study that snoring, a fairly reliable clinical correlate of sleep apnea, ~ ~ concern is associated with h y p e r t e n ~ i o n .Of are reports of systemic hypertensive spikes during apneic episodes in younger individuals, presumably related to acute sympathetic re. ~ ~ elderly subjects, parsponse to a ~ n e aSome ticularly those with essential hypertension, also 253
Homeostatic Fragility i n t h e Elderly
have nocturnal episodic elevations of arterial blood pressure.82In fact, it has been suggested that in a subgroup of elderly hypertensives with established target organ disease, the normal circadian rhythm of blood pressure is completely blunted.40A recent finding is the occurrence of hypotensive nocturnal episodes in normotensive elderly subjects with sleep-related breathing disorders. The average nadir of mean arterial pressure in these subjects was 53 mm Hg, well below levels (greater than 60 mm Hg) that assure effective autoregulation of cerebral blood flow." The fact that the hypotensive nocturnal episodes were not chronologically related to apneic-hypopneic episodes in these subjects suggests a basic derangement in blood pressure regulation during sleep, the nature of which remains to be determined. Regardless of the precise underlying mechanism, these subjects could be particularly susceptible to ischemic episodes during sleep.
WATER AND ELECTROLYTE ENVIRONMENT Water Homeostasis and Aging Aging effects water economy at the renal, the osmoreceptor-posterior pituitary, and perhaps hypothalamic levels. Renal physiology is markedly modified in the elderly healthy individual: (1)Renal blood flow declines steadily with age,94 and this is almost fully accounted for by a selective decline in cortical blood flow with relative sparing of the medullary blood (2) The number of nephrons appears to decline with age.74(3) There is a linear decline in renal function beginning at the fourth decade of life, with creatinine clearance decreasing by an average of 8 ml per minute per 1.73 m3 per decade thereafter.72The main clinical implication is that extreme caution is required in the administration of drugs with known renal excretion or with established nephrotoxicity. There is an age-related decline in the kidney's ability to concentrate urine effectively in response to fluid d e ~ r i v a t i o n .Following ~~ 12 hours of water deprivation, mean urinary osmolarity is about 25 per cent lower in older subjects when compared with that in younger control^.^^^ 77 Indirect evidence suggests that this submaximal concentration capacity results from a renal defect rather than from insufficient vasopressin release. First, Helderman and associates32have shown an age-related increase
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in vasopressin release from the posterior pituitary in response to rising plasma osmolarity during infusion of hypertonic saline solution. Second, even though submaximal vasopressin infusions result in comparable rises in urinary osmolarity in young and old individual^,^^ an age-dependent decrease in urinary concentration capacity becomes apparent when higher doses of vasopressin are used.58It is currently unclear whether this relative "vaso~ressinresistance'' results from vasopressin-receptor-related mechanisms, increased splute load imposed on the fewer remaining nephrons, or decreased medullary osmolarity. Complicating the reduced ability to concentrate urine in the elderly is the common occurrence of clinical conditions associated with clouded sensorium during which fluid intake is diminished. Thirst may be impaired even in the apparently normal elderly individual, further subjecting this age group to the risks of severe volume contraction and hypernatremia. Of h articular interest is the observation that some patients with previous cerebrovascular events have an impaired sense of thirst in the face of preserved mental status and ability to communicate, leading to recurrent life-threatening d e h y d r a t i ~ n .Both ~ ~ acute and chronic hypernatremia exceeding 160 mEq per liter are associated with high mortality rates (60 to 70 per cent) in the adult population. When the reduced ability of the elderly to conserve sodium (discussed later) is also. considered, it becomes obvious whv the elderlv are so sensitive even to minor forms of volume depletion, such as that imposed in preparation for radiocontrast studies. 71 In parallel to the diminished ability to concentrate urine, the elderly populatioi also has impaired ability to form dilute urine. Lindeman and colleagues have shown that the maximum diluting capacity declines steadily, with the mean minimum osmolarities being 52 + 3, 74 t 6, and 92 & 11 mosmol per liter in young, middle-aged, and old individuals, respecti~ely.~ ' Although a diluting defect could lead to hyponatremia, which is not a rare occurrence, especially in chronic care f a ~ i l i t i e s ,it~ ~ is generally believed that inappropriate secretion of vasopressin rather than a renal dilution defect is the most common cause of hyponatremia in the e l d e r l ~ Other .~ than the increased incidence of "idiopathic" inappropriate ADH secretion in the e l d e r l ~ , ~many ' intercurrent ailments known to induce this svndrome. such as pneumonia, stroke, and multiple acute and chronic intrathoracic or intracranial processes,
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are encountered in this age group. Because diuretics further diminish the renal capacity to excrete a water load, the common occurrence of diuretic-induced hyponatremia in the elderly is not surprising. Other commonly used drugs enhancing the release of vasopressin (barbiturates, anesthetic agents, clofibrate, carbamazepine, amitriptyline, vincristine, and cyclophosphamide) or enhancing its renal effects (chlorpropamide) may also precipitate water retention and hyponatremia in the susceptible elderly individual. Sodium and Potassium Economy Disagreement exists regarding the ability of the senescent kidney to conserve sodium. When older subjects are shifted from a regular diet to a low-sodium diet, the re-establishment of sodium balance (that is, the time required for the excreted urinary sodium to reach a steady state) is markedly delayed compared with younger subjects (half-time for sodium balance being -31 hours versus - 18 hours in subjects over 60 years and under 25 years of age, respectively).16 However, the significance of this observation has been questioned, as one study has demonstrated that 6 days of sodium restriction resulted in indistinguishable weight reduction in young and elderly Recently, a preliminary report has confirmed that elderly individuals show decreased capacity of sodium conservation when placed on a sodium-restricted diet and that this is accompanied by a somewhat greater weight reduction. lg Normally, the renin-angiotensin-aldosterone axis plays a major role in sodium economy in response to sodium depletion. Overall, the renin-angiotensin system displays decreased basal activity and reduced sensitivity to changes in sodium homeostasis in the elderly.1231. 84, As the role of renal nerves and beta-adrenergic mechanisms in stimulation of renin release is well established, it is possible that reduced PRA in the elderly reflects an additional example of decreased beta-adrenergic responsivity with aging. Alternatively, it appears that plasma inactive renin rises steadily with age,49which raises the possibility of an alteration in the activation of renin. An age-related decline in the basal plasma aldosterone has also been noted in normotensive individuals, as well as a reduced aldosterone responsiveness to upright posture, diuretics, and sodium restriction.12, 29 This probably reflects the concomitant blunting of the PRA response, as the glomerulosa
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response to another stimulator of aldosterone secretion, ACTH, is not affected by aging.92 Whether the delayed renal adaptation to sodium restriction is indeed related to sluggish aldosterone response or to other factors such as renal Na-K-ATPase is unknown at present. There is some evidence that Na-K-ATPase activitv declines with age in red blood cells18 and the myocardium,68and the possibility of a similar decline in the kidney has been raised.63 Although the reduced capacity of the elderly to excrete salt load such as during excessive administration of intravenous saline solution or dietary sodium is widely recognized by clinicians. no oublished studies are available addressing t i e effect of age on the ability to enhance urinary sodium excretion appropriately in resoonse to acute or chronic sodium challenge. In practice, in the absence of overt or subclinical myocardial or renal disease, some weight gain and transient peripheral edema may be the onlv conseauences of careless or inadvertent excessive exposure to sodium. The agedependent reduction in renal blood flow and glomerular filtration rate may explain the increased susceptibility of the elderly to volume expansion. The susceptibility of the elderly to volume/sodium expansion does not result from an a priori increased blood volume, plasma volume, or exchangeable sodium, as these parameters are not affected by age in normal subjects.Vinally, whether or not renal blood flow appropriately increases in response to a sodium load in the elderly, as is seen in the young, has not been established. The combination of declining: renal function, reduction in the number of nephrons (and hence, tubular mass), and reduced activity of the renin-aldosterone svstem renders elderlv subjects more sensitive to a potassium load. Thus, even though the healthy older individual is normokalemic, h~perkalemia may evolve more readilv in resoonse to excessive ~otassium challenge by intravenous fluids and potassiumsparing diuretics which either directly antagonize the effect of the alreadv diminished " levels of circulating mineralocorticoids (spironolactone) or impair the tubular excretion of potassium by mineralocorticoid-independent oathwavs (amiloride). Acute reductions in , ilomerular filtration rate may more readily precipitate hyperkalemia in the elderly with diminished,renal function. The svndrome of hvooren, inemic hv~eraldosteronism with low-grade , hyperkalemia is seen more commonly in the older age groups.38 Finally, it has been known for almost 20 years that the elderly have an acquired tubular defect u
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in urine acidification manifested as reduced excretion of an acute anlinonium chloride load.'. The clinical implications of this dysfunction are not entirely clear, but it is conceivable that it may contribute to and impair the recovery from metabolic acidosis of unrelated etiology.
REFERENCES 1. Abrass, I., KO, T., and Scarpace, P. J.: Platelet alpha adrenergic receptor function in aging. Clin. Res., 32:479A, 1984. 2. Adler, S., Lindeman, R. D., Yiengst, M. J . , et al.: Effect of acute acid loading on urinary acid excretion by the aging human kidney. J. Lab. Clin. Med., 72278-289, 1968. 3. Agarwal, B. N . , and Cabebe, F. G.: Renal acidification in elderly subjects. Nephron, 26:291-295, 1980. 4. Ancoli-Israel, S., Kripke, D. S., Mason, W., et al.: Sleep apnea and nocturnal myoclonus in a senior population. Sleep, 4:349-358, 1981. 5. Aschoff, L.: Lectures in Pathology. New York, Paul Hoeber, 1924. 6. Beretta-Piccoli, C . , and Weidman, P.: Circulatory volume in essential hypertension. Relationships with age, blood pressure, exchangeable sodium, aldosterone and catecholamines. Miner. Electrolyte Metab., 10:292-300, 1984. 7. Bichet, D. G., and Schreier, R. W.. Renal function and disease in the aged. In Schreier, R. W. (ed.): Clinical Internal Medicine in the Aged. Philadelphia, W. B. Saunders Company, 1982, pp. 211-221. 8. Brodde, 0. E., Analuf, M., Grabeu, N., et al.: Agedependent decrease of alpha,-adrenergic receptor number in human platelets. Eur. J. Pharmacol., 81:345-345, 1980. 9. Caird, F. I., Andrews, G. R., and Kennedy, R. D.: Effect of posture on blood pressure in the elderly. Br. Heart J., 35527-530, 1973. 10. Conway, J., Whaler, R., and Sannerstedt, R.: Sympathetic nervous activity during exercise in relation to age. Cardiovasc. Res., 5:577-581, 1981. 11. Corskadon, N., and Demment, W. C.: Respiration during sleep in the aged human. J. Gerontol., 36:420-423, 1981. 12. Crane, M. G . , and Harris, J. J.: Effect of aging on renin activity and aldosterone excretion. J. Lab. Clin. Med., 87:949-959, 1976. 13. DeQuattro, V. L., Miura, Y., Lurvey, A., et al.: Increased plasma catecholamine concentrations and vas deferens norepinephrine biosynthesis in men with elevated blood pressure. Circ. Res., 36:118124, 1974. 14. Dolly, T. R., and Block, A. J.: Effects of flurazepam on sleep disordered breathing and nocturnal oxygen disaturation in asymptomatic subjects. Am. J. Med., 73:239-243, 1982. 15. Dontas, A. S . , Marketos, S. G., and Papamayiotau, P.: Mechanisms of renal tubular defect in old age. Postgrad. Med. J . , 48:295-303, 1972. 16. Epstein, M., and Hollenberg, N. K.: Age as a deterininant of renal sodium conservation in normal man. J. Lab. Clin. Med., 87:411-417, 1976. 17. Flood, C., Gherondache, C., Ficus, G., et al.: The metabolism and secretion of aldosterone in elderly subjects. J. Clin. Invest., 46:961-966, 1967. 18. Gambert, S. R., and Duthie, E. H., Jr.: Effect of age on red cell membrane sodium-potassium dependent
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38. Knochel, J. P.: The syndrome of hyporenineinic hypoaldosteronism. Annu. Rev. Med., 30:145-153, 1979. 39. Knudson, R. J., Clark, D. F., Kennedy, T. C., et al.: The effect of age alone on mechanical properties of the normal adult human lung. J. Appl. Physiol., 43:1054-1062, 1977. 40. Kobrin, I., Dunn, F. G., Oigman, W., et al.: Essential hypertension in the elderly: Circulation variation of arterial pressure. In Weber, M. A,, and Dryers, J. I. M. (eds.): Ambulatory Blood Pressure Monitoring. Boston, Martinus Nijhoff Publishing, 1984, pp. 157162. 41. Krall, J. F., Connely, M., Weisbart, R., et al.: Agerelated elevation of plasma catecholamine concentration and reduced responsiveness of lymphocyte adenylate cyclase. J. Clin. Endocrinol. Metab., 52:863867, 1981. 42. Kronenberg, R. S., and Drage, C. W.: Attenuation of ventilatory and heart rate responses to hypoxemia and hypercapnea with aging in normal men. J. Clin. Invest., 52:1812-1819, 1973. 43. Lakatta, E . G.: Alterations in the cardiovascular system that occur in advanced age. Fed. Proc., 38:163-170, 1980. 44. Lakatta, E. G. : Age-related alterations in cardiovascular response to adrenergic mediated stress. Fed. Proc., 39:3173-3177, 1980. 45. Lakatta, E . G., and Yin, F. C. P.: Myocardial aging: Functional alterations and related cellular mechanisms. Am. J. Physiol., 242:H927-H941, 1982. 46. Lake, C. R., Ziegler, M. G., Coleman, M. D., et al.: Age-adjusted plasma norepinephrine levels are similar in normotensive and hypertensive subjects. N. Engl. J. Med., 296:208-209, 1977. 47. Landowne, M.: The relation between intra-arterial pressure and impact pulse wave velocity with regard to age and arteriosclerosis. J. Gerontol., 13:153-162, 1958. 48. Lavie, P., Ben-Yosef, R., and Rubin, A,: Prevalence of sleep apnea syndrome among patients with essential hypertension. Am. Heart J., 108:373-376, 1984. 49. Leutcher, J. A,, Kramer, F. B., Wilson, D. M., et al.: Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N. Engl. J. Med., 312:1412-1417, 1985. 50. Lindeman, R. D., Lee, T. D., Yiengst, M. J., et al.: Influence of age, renal disease, hypertension, diuretics and calcium on the antidiuretic response to suboptimal infusions of vasopressin. J. Lab. Clin. Med., 68:206-223, 1966. 51. Lugaresi, E., Criginotta, E., Coccagano, G., et al.: Some epidemiological data on snoring and cardiocirculatory disturbances. Sleep, 3221-224, 1980. 52. MacDonald, R. K., Solomon, D. H., and Shock, N. W.: Aging as a factor in the renal hemodynamic changes induced by standardized pyrogen. J. Clin. Invest., 30:457-462, 1951. 53. Maggi, A., Schmidt, M. J., Ghetti, B., et al.: Effects of aging on neurotransmitter receptor binding in rat and human brain. Life Sci., 24:367-374, 1979. 54. McGinty, D., Littner, M., Beahm, E., et al.: Sleep related breathing disorders in older men: A search for underlying mechanisms. Neurobiol. Aging, 3:899-903, 1982. 55. McGinty, D., Beahm, E., Stern, N., et al.: Occult nocturnal hypotension in older men with sleeprelated breathing disorders. Sleep Research, 14:190, 1985. 56. Mendelson, W. B., Garnett, D., and Gillin, J. C.:
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Homeostatic Fragility in the Elderly 76. Rudolf, M., Geddis, D. M., and Turner, J.: Decrease of central respiratory drive by nitrazepam. Thorax, 33:97-100, 1978. 77. Sabini, C. A,, Grassi, V., Solinas, E., et al.: Arterial oxygen tension in relation to age in healthy subjects. Respiration, 25:3-10, 1968. 78. Schocken, D. H. D., and Roth, G. S.: Reduced beta adrenergic receptor concentrations in aging man. Nature, 267356-858, 1977. 79. Shimada, K., Kitazumi, T., Sadakaue, N., et al.: Agerelated changes of baroreflex function, plasma norepinephrine and blood pressure. Hypertension, 7:113-117, 1985. 80. Sowers, J. R., Rubenstein, L. Z., and Stern, N.: Plasma norepinephrine responses to posture and isometric exercise increase with age in the absence of obesity. J. Gerontol., 38:315-317, 1983. 81. Spurgeon, H. A,, Steinbach, M. F., and Lakatta, E. G.: Chronic exercise prevents characteristic agerelated changes in rat cardiac contraction. Am. J. Physiol., 244:H513-H518, 1983. 82. Stern, N., Beahin, E., McGinty, D., eta].: Dissociation of 24-hour catecholamine levels from blood pressure in older men. Hypertension, 7:1023-1029, 1985. 83. Tack, M., Altose, M. D., and Cherniack, N. S.: Effect of aging on the perception of resistive ventilatory loads. Am. Rev. Respir. Dis., 126:463-467, 1982. 84. Tilkian, A. G., Guilleminault, C., Schroeder, J. S., et al.: Hemodyuamics in sleep induced apnea: Studies during wakefulness and sleep. Ann. Intern. Med., 85:714-719, 1976. 85. Tuck, M. L., Williams, G. H . , Dluhy, R. G., et al.: Relation of age, diastolic pressure and known duration of hypertension to presence of low renin hypertension. Am. J. Cardiol., 33:632-637, 1973. 86. Tuck, M. L., Stern, N., and Sowers, J. R.: Enhanced 24-hour norepinephrine in young patients with essential hypertension. Am. J. Cardiol., 55112-115, 1985. 87. Tzankoff, S. P., Fleg, J. L., Norris, A. H., et al.: Agerelated increase in serum catecholamine levels during exercise in healthy adult men. Physiologist, 23:50A, 1980.
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Homeostatic Fragility in the Elderly Naftali Stern, M . D . , * and Michael L. Tuck, M . D. t A major physiology textbook defines homeostasis as the maintenance of static or constant conditions in the internal envir~nment.~'In practical clinical terms, the long list of physiologic functions relevant to the maintenance of organic "well-being" may be narrowed down to preservation of tissue oxygenation and adequate water and electrolyte environment. In addition to the cumulative increase in various s~ecific organic diseases with advancing age, aging per se is accompanied by multiple alterations in physiologic function that hinder the efficacy of homeostatic regulatory processes. A large body of data accumulated mostly within the past 15 years in different medical disciplines not only has confirmed that aging is associated with increased honleostatic fragility but also has unveiled some of the underlying mechanisms involved.
TISSUE OXYGENATION In the most general sense, tissue oxygenation depends on appropriate oxygen uptake by red blood cells in the lungs (respiratory mechanisms) and the adequate delivery of blood to peripheral tissues, a function of cardiac output and arterial pressure.
Aging and Respiratory Mechanisms It is well established that arterial oxygen tension declines with age in healthy subjects.77 This is believed to result from an age-dependent increase in ventilation perfusion mismatch33and does not, in itself, reflect chronic obstructive lung disease. With advancing age, pulmonary function diminishes, leading to changes consis-
tent with "lower airway obstruction."" In fact, many spirometry parameters used in clinical pulmonary medicine, such as vital capacity, FEV,, peak expiratory flow rate, maximal midexpiratory flow rate, and maximal expiratory flow, show an age-dependent decline3' and should be corrected routinely for age. Stiffening of the chest wall, weakening of respiratory muscles, and a steady decline of pulmonary elastic recoil are all observed with aging. Various conditions not specifically related to aging per se such as disorders leading to upper airway obstruction (for example, nasal polyps, deviated septum) or to the distortion of the thoracic cage (for example, kyphoscoliosis, kyphosis) may have an aggravating cumulative effect on agedependent respiratory defects. Besides local mechano-elastic factors, control of breathing is also affected by aging. Chemoreceptor responsiveness is relatively blunted in the elderly. Both hypercapneic and hypoxic ventilatory remanses are markedlv diminished in older in. ividuals, an effect i n d e ~ e n d e n tof lung mechanics. " A decrease in mechanoreceptor responsiveness has also been shown.83Finally, aging is associated with a steadv increase in the ilcidvence of sleep-related breathing disorders.". 54 Depending on the population studied and methods used to diagnose sleep-related breathing disorders. as much as 30 G 60 Der cent of the elderly population manifests some of the sleep-related breathing disorder^.^. 54 TO appreciate the potential toll of this common abnormality in the elderly, it should be recognized that a typical patient having 12 to 25 apneic-hypopneic episodes per sleep hour will experience 240,000 to 500,000 hypoxemic spells, arousals, and pulmonary and systemic arterial pressure spikes in a 10-year period. Indeed, younger subjects with the sleep apnea
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*Assistant Professor o f Medicine, University of California School o f Medicine, Los Angeles; StaffPhysician, Endocrinology Department, Sepulveda Veterans Administration Medical Center, Sepulveda, California tProfessor of Medicine, University of California School o f Medicine, Los Angeles; Chief, Endocrinology-Metabolism, Sepulveda Veterans Administration Medical Center, Sepulveda, California Cardiology Clinics-Vol.
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syndrome have increased incidence of hypertension27.35, 96 that is often reversed along with the correction of sleep apnea achieved by weight reduction surgery.48In the elderly, however, hypertension appears to be evenly distributed between subjects with and without sleeprelated breathing disorders.55 Under regular daily circumstances, the "homeostatic" implications of the respiratory abnormalities reviewed earlier are probably minimal. However. the common occurrence of minor ailments such as upper or lower respiratory tract infection often unveils the enhanced vulnerability of elderly subjects with impaired compensatory respiratory mechanisms. In addition, the increased sensitivity of the elderly to "benign" agents such as benzodiazepines may be better understood in light of the worsening of central respiratory depression in susceptible awake individual^^^, 69, 76 and the induction of an astonishing increase in the number of apneic episodes in elderly patients with mild sleeprelated breathing disorders. 14.56 Aging and Cardiac Output A complete assessment of the aging heart is beyond the scope of this article. However, a number of age-related changes that could hinder homeostatic adaptation to daily activities will be highlighted. Normal function of the left ventricle depends on (1) appropriate filling of this chamber (preload), that is, end-diastolic volume; (2) the contractile capacity of the myocardium; and (3) the vascular impedance to blood ejected by the contracting left ventricular myocardium (afterload). Preload. The rate of diastolic filling in subjects in the 65- to 80-year-old age group is roughly 50 per cent of the rate measured in the 25- to 45-year-old age group.21Thus, although at rest the end-diastolic volume is normal even in the elderly,70decreased diastolic filling rates in the elderly may potentially result in reduced end-diastolic volume and, hence, diminished stroke volume occurring during periods of increased heart rate such as that induced bv physical activity, assumption of upright posture, or onset of fever or stress. Myocardial Contractility. The myocardial capacity to develop force does not appear to be affected by aging per se.45Although there is both in vitro and in vivo evidence for a moderate (15 to 20 per cent) prolongation of myocardial contraction time,30, the cardiovascular functional implications of this phenomenon in the aged are not clear. Minor reductions in
myocardial contractility, as reflected by increased end-diastolic volume (that is, increased myocardial fiber length), have been reported in older individuals subjected to concomitant betaadrenergic blockade and alI;ha-adrenergic pressor stress.44Thus, under these hardly physiologic conditions, the aging heart appears to rely more on length-dependent (Frank-Starling) mechanisms to develop the appropriate increment in contractile force than does the younger heart. Afterload. Even though it appears that total peripheral resistance is not grossly modified with advancing age, the following lines of evidence support the concept that a significant, if subtle, rise in vascular impedance does accompany aging: 1. Systolic and, to a lesser extent, diastolic arterial pressure rises steadily with age36.64. 70 (Fig. 1). 2. Arterial elasticity, particularly that of the aortic wall, declines, as evidenced by lowered ,~ intra-aortic presretraction c a p a ~ i t yincreased sure change per arterial radius change,24 and enhanced pulse wave velocity." 3. Left ventricular wall thickness is strongly related to age,21which suggests that an adaptation to a long-standing increase in afterload has taken place. In addition to alterations in left ventricular function per se, a major factor is the ageassociated decline in the maximal heart rate response to exercise. Whereas basal heart rates in the elderly do not differ significantly from those in younger individuals, the mean heart rate in response to a "maximum workload" is 174 k 4 beats per minute in the 25- to 44-yearold age group, but only 143 + 4 beats per minute in the 65- to 79-year-old age group.93 Sympathetic activity rises with age in normal subjects, as reflected by higher basal circulating norepinephrine level@ (Fig. 2) as well as by enhanced norepinephrine response to upright posture and isometric exercise (handgri~).~' Furthermore, maximal plasma norepinephrine levels measured during maximum treadmill exercise show a positive correlation with age.87 Thus, the reduced heart rate response to exercise in the elderly must be related to decreased chronotropic responsiveness to adrenergic stimuli. Indeed, a decline both in the number of beta-adrenergic receptors7' (Fig. 3) and in postreceptor adenylate cyclase activation41with aging has been reported in humans. That the reduction in maximal heart rate is a function of attenuated beta-adrenergic responsiveness rather than of nonadrenergic mechanisms is
Homeostatic Fragility in the Elderly
Figure 1. Systolic blood pressure as a function of age. (From Rodenheffer, R. J., et al. : Exercise cardiac output is maintained with advancing age in healthy human subjects: Cardiac dilation and increased stroke volume compensate for diminished heart rate. Circulation, 69:203, 1984; with permission.)
AGE lyearsl
.
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Figure 2. Plasma norepinephrine as a function of age. (From Lake, C. R., et al.: Age-adjusted plasma norepinephrine levels are similar in normotensive and hypertensive subjects. N. Engl. J. Med., 296:208209, 1977; with permission.) 0 .
23
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Naftali Stern and Michael L. Tuck
Figure 3. Lymphocyte beta-adrenergic receptors as a function of age. (From Schocken, D. H., and Roth, G. S.: Reduced beta adrenergic receptor concentrations in aging man. Nature, 2672356-858, 1977; with permission.)
supported by observations that nonadrenergic stimuli are capable of eliciting indistinguishable chronotropic responses in the young and elderly alike.97 What is the integrated effect of these agerelated changes on cardiac capacity to adapt to circumstances threatening homeostasis? In the healthy older individual, the decline in the capacity to increase heart rate in response to exercise is well comvensated for bv an increase in stroke volume. 70 L ~ h u scardiac' , output does not decline with aging, even at workloads as high " as 125 W.70The needed increase in stroke volume during exercise in the elderly who fail to achieve "sufficient" increase in heart rate can be appropriately met by resorting to FrankStarling mechanisms. With each workload level. exercising elderly subjects exhibit much larger end-diastolic left ventricular volumes, thereby facilitating the generation of sufficiently augmented contractile force and stroke volume to compensate for the blunted increase in heart rate. Overall, the aging healthy heart manifests remarkable functional adavtation to alterations associated with normal aging and is not normally responsible for serious impairment of homeostatic regulatory processes. u
Arterial Pressure Aging is associated with a steady, gradual rise in systolic and diastolic arterial pressure, even within the normal range.36,64- 70 FUrthermore, there is a well-documented age-related rise in Al. the incidence of essential h y p e r t e n ~ i o n .88~ ~
though it is true that circulating norepinephrine levels also rise with age, several lines of evidence suggest that hyGeAension in the elderly is not "neurogenic." First, plasma norepinephrine increases with age in normotensive individuals but not in patients with essential hyperten~ i o n Second, .~~ contrary to findings in young and middle-aged hypertensive subjects, in whom plasma catecholamines are positively related to arterial blood pressure,13 an inverse relationship has been noted in older hypertensive individuals. 20, s2 Finally, using multiple sampling throughout the 24-hour cycle, we have recently shown that elderly subjects with essential hypertension in fact have lower circulating levels of norepinephrine, epinephrine, and dopamine than do age-matched normotensive individualss2 (Fig. 4A). This contrasts with the observations in younger hypertensive subjects, in whom 24-hour norepinephrine levels are clearly higher than in their normotensive agematched counterpartss6 (Fig. 4B). Of major interest is the issue of aging and adaptation of arterial pressure or vasopressorldilator mechanisms to acute changes commonly encountered in daily life, such as posture, exercise, and sleep. Postural hypotension is common in the elderly. Mild to moderate orthostasis, that is, a postural fall in systolic pressure of at least 20 mm Hg, is encountered in roughly a quarter of an ambulant elderly population, and a severe drop in systolic arterial pressure, that is, a decrease of 40 mm Hg or more. has been observed in 5 ver cent of the e l d e r l ~which ,~ reflects major derangements of blood pressure regulation in this age group. u
Homeostatic Fragility in the Elderly
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Older Hyperlenwves
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HYPERTENSIVE SUBJECTS
a NoRMoTENslvE SUBJECTS
TIME
Figure 4. A, Twenty-four-hour plasma norepinephrine levels in older hypertensive and normotensive men. B, Twentyfour-hour plasma norepinephrine levels in young hypertensive and normotensive men. (A, from Stern, N . , et al.: Dissociation of 24-hour catecholamine levels from blood pressure in older men. Hypertension, 7:1023-1029, 1985; with permission. B, from Tuck, M . L., et al.: Enhanced 24-hour norepinephrine in young patients with essential hypertension. Am. J. Cardiol., 55:112-115, 1985; with permission.)
The maintenance of arterial pressure at a relatively constant level so that acute increases or decreases are offset effectively is governed mainly by baroreflex arc mechanisms. Thus, during lowering of intra-arterial pressure, baroreceptors located in the left atrium, carotid sinus, and large arteries are subjected to reduced stretching and are turned off, resulting in stimulation of central vasomotor regulatory centers that are otherwise tonically inhibited. The effector mechanisms activated by these centers include the sympathetic nervous system, the renin-angiotensin axis, and vasopressin release. Aging affects not only baroreceptor sensitivity but also each of these efferent limbs of the baroreflex arc. A number of studies have shown that baroreflex sensitivity diminishes with age.26 56, 78
Most investigations of baroreflex function have relied on demonstration of a reduction of heart rate in response to pressor agents; the effect has been less pronounced in the elderly. Indirect data also support the concept of diminished baroreflex-dependent mechanisms in the elderly in response to depressor stimuli. Decreased cardiovascular response rates to drugs that reduce blood pressure have been shown in older i n d i v i d ~ a l s .Likewise, ~~ Vlachakis and associatesg0have reported significant reduction in the normal pulse rate increments following hypotensive maneuvers such as exposure to heat and administration of the vasodilator trimethaphan camsylate in elderly hypertensive subjects. Finally, increments in heart rate in response to upright posture diminish with aging. 65
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Plasma norepinephrine response to upright posture rises steadily with advancing age," suggesting that the afferent limb of the baroreceptor reflex is fully functional during hypotensive stimuli in the elderly. Thus, despite claims to the contrarv. ,, there is no direct evidence that orthostatic hv~otension results from submaxi, ma1 activation of the baroreflex arc in otherwise healthy elderly individuals. As already stated, the sympathetic response to upright posture in the elderly -appears to be intact if not actually exaggerated. Because the sympathetic response is most likely the major mechanism normally preventing orthostatic hypotension, it is possible that diminished peripheral response to catecholamines plays a role in postural hypotension in this age group. There is abundant evidence for loss of beta-adrenergic receptor activity in various tissues with aging.l0, 43, 55, " Propranolol, a beta-adrenergic receptor blocker, reduces heart rate to a lesser extent in older subjects.1° An age-related decrease in the ability of isoproterenol, a beta-adrenergic agonist, to increase heart rate has been reported.43 However, pressor response to endogenous sympathetic stimulation should depend more on alpha-adrenergic response. Whether or not aging is indeed associated with changes in pressor response to alpha-adrenergic stimulation is currently unknown, although a recent study has documented that during epinephrine infusion, older men have smaller increases in systolic arterial pressure than younger individual^.'^ A decreased number of platelet alpha-adrenergic receptors has been reported in aged subject^,^ but it could not be confirmed subsequently.', 60 Activation of the renin-angiotensin system in response to standing is also affected by aging. The incidence of subnormal plasma renin activity (PRA) responses to low-sodium diet and upright posture shows a positive correlation with patients' age and diastolic pressure in It is now patients with essential hyperten~ion.'~ apparent that even though the reduction of PRA with aging is more pronounced in hypertensive subiects, " . elderly normotensive individuals also show an age-related decline in the renin-angiotensin axis.12. 31, 61. 90 For example, 33 per cent of normotensive subjects in the 70- to 79-yearold age group display hyporesponsive PRA, but this is uncommon in younger individuals.12 Thus, blunted PRA and, hence, angiotensin I1 response to postural changes may contribute to the pathogenesis of orthostatic hypotension in the elderly. Finally, even though the release of vasopressin is not normally considered necessary to prevent a drop in arterial pressure in response &
413
to standing, it is known that vasopressin secretion rises in young subjects assuming the upright posture,74presumably through activation of left atrial baroreceptors. In fact, the volumepressure-baroreceptor pathway is a more powerful (although not as sensitive) activator of vasopressin release than the osmoreceptor-de'~ individuals may fail pendent p a t h ~ a y . Elderly to show the normal postural rise in vasopressin levels, even in the presence of symptomatic orthostatic hypotension. Because the same individuals have normal norepinephrine response to standing (suggesting an intact afferent limb of the baroreflex arc), Rowe and Robertson have inferred that the defect must be located at a central nervous system site between the vaso75 motor center and the posterior pit~itary.'~, Although the abnormalities just outlined often remain "subclinical," they may also be accentuated acutely with dramatic clinical presentations in the presence of such common superimposed conditions as pyrexia, mild dehydration, varicose veins, and the use of diuretics or nitrates. Particularly worrisome is the high incidence of orthostatic hypotension in the elderly hypertensive subjects in whom hypotensive drug therapy has been recently initiated. Not only is the effectiveness of baroreceptors diminished in elderly subjects with long-standing hypertension, but also the normal autoregulatory mechanisms maintaining cerebral blood flow constant until mean arterial pressure falls to 60 mm Hg have been "reset," so that the lower pressure limit of autoregulation rises. Thus, sharp falls in blood pressure that are not counterbalanced effectively by baroreceptor activation and/or release of catecholamines, angiotensin 11, and perhaps vasopressin are often associated in these patients with reduced cerebral perfusion, presenting as lightheadedness, dizziness, falls, or, in the extreme case, distinct cerebrovascular catastrophies. 34 Blood pressure irregularities during sleep in the elderly have begun to attract attention only recently. In younger age groups, the incidence of sleep apnea among hypertensives is much higher than among age-matched control^.^^^ 96 Case series studies of subjects with sleep-related breathing disorders report a 50 per cent It has also been incidence of hyperten~ion.~' shown in a large-scale study that snoring, a fairly reliable clinical correlate of sleep apnea, ~ ~ concern is associated with h y p e r t e n ~ i o n .Of are reports of systemic hypertensive spikes during apneic episodes in younger individuals, presumably related to acute sympathetic re. ~ ~ elderly subjects, parsponse to a ~ n e aSome ticularly those with essential hypertension, also 253
Homeostatic Fragility i n t h e Elderly
have nocturnal episodic elevations of arterial blood pressure.82In fact, it has been suggested that in a subgroup of elderly hypertensives with established target organ disease, the normal circadian rhythm of blood pressure is completely blunted.40A recent finding is the occurrence of hypotensive nocturnal episodes in normotensive elderly subjects with sleep-related breathing disorders. The average nadir of mean arterial pressure in these subjects was 53 mm Hg, well below levels (greater than 60 mm Hg) that assure effective autoregulation of cerebral blood flow." The fact that the hypotensive nocturnal episodes were not chronologically related to apneic-hypopneic episodes in these subjects suggests a basic derangement in blood pressure regulation during sleep, the nature of which remains to be determined. Regardless of the precise underlying mechanism, these subjects could be particularly susceptible to ischemic episodes during sleep.
WATER AND ELECTROLYTE ENVIRONMENT Water Homeostasis and Aging Aging effects water economy at the renal, the osmoreceptor-posterior pituitary, and perhaps hypothalamic levels. Renal physiology is markedly modified in the elderly healthy individual: (1)Renal blood flow declines steadily with age,94 and this is almost fully accounted for by a selective decline in cortical blood flow with relative sparing of the medullary blood (2) The number of nephrons appears to decline with age.74(3) There is a linear decline in renal function beginning at the fourth decade of life, with creatinine clearance decreasing by an average of 8 ml per minute per 1.73 m3 per decade thereafter.72The main clinical implication is that extreme caution is required in the administration of drugs with known renal excretion or with established nephrotoxicity. There is an age-related decline in the kidney's ability to concentrate urine effectively in response to fluid d e ~ r i v a t i o n .Following ~~ 12 hours of water deprivation, mean urinary osmolarity is about 25 per cent lower in older subjects when compared with that in younger control^.^^^ 77 Indirect evidence suggests that this submaximal concentration capacity results from a renal defect rather than from insufficient vasopressin release. First, Helderman and associates32have shown an age-related increase
207
in vasopressin release from the posterior pituitary in response to rising plasma osmolarity during infusion of hypertonic saline solution. Second, even though submaximal vasopressin infusions result in comparable rises in urinary osmolarity in young and old individual^,^^ an age-dependent decrease in urinary concentration capacity becomes apparent when higher doses of vasopressin are used.58It is currently unclear whether this relative "vaso~ressinresistance'' results from vasopressin-receptor-related mechanisms, increased splute load imposed on the fewer remaining nephrons, or decreased medullary osmolarity. Complicating the reduced ability to concentrate urine in the elderly is the common occurrence of clinical conditions associated with clouded sensorium during which fluid intake is diminished. Thirst may be impaired even in the apparently normal elderly individual, further subjecting this age group to the risks of severe volume contraction and hypernatremia. Of h articular interest is the observation that some patients with previous cerebrovascular events have an impaired sense of thirst in the face of preserved mental status and ability to communicate, leading to recurrent life-threatening d e h y d r a t i ~ n .Both ~ ~ acute and chronic hypernatremia exceeding 160 mEq per liter are associated with high mortality rates (60 to 70 per cent) in the adult population. When the reduced ability of the elderly to conserve sodium (discussed later) is also. considered, it becomes obvious whv the elderlv are so sensitive even to minor forms of volume depletion, such as that imposed in preparation for radiocontrast studies. 71 In parallel to the diminished ability to concentrate urine, the elderly populatioi also has impaired ability to form dilute urine. Lindeman and colleagues have shown that the maximum diluting capacity declines steadily, with the mean minimum osmolarities being 52 + 3, 74 t 6, and 92 & 11 mosmol per liter in young, middle-aged, and old individuals, respecti~ely.~ ' Although a diluting defect could lead to hyponatremia, which is not a rare occurrence, especially in chronic care f a ~ i l i t i e s ,it~ ~ is generally believed that inappropriate secretion of vasopressin rather than a renal dilution defect is the most common cause of hyponatremia in the e l d e r l ~ Other .~ than the increased incidence of "idiopathic" inappropriate ADH secretion in the e l d e r l ~ , ~many ' intercurrent ailments known to induce this svndrome. such as pneumonia, stroke, and multiple acute and chronic intrathoracic or intracranial processes,
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are encountered in this age group. Because diuretics further diminish the renal capacity to excrete a water load, the common occurrence of diuretic-induced hyponatremia in the elderly is not surprising. Other commonly used drugs enhancing the release of vasopressin (barbiturates, anesthetic agents, clofibrate, carbamazepine, amitriptyline, vincristine, and cyclophosphamide) or enhancing its renal effects (chlorpropamide) may also precipitate water retention and hyponatremia in the susceptible elderly individual. Sodium and Potassium Economy Disagreement exists regarding the ability of the senescent kidney to conserve sodium. When older subjects are shifted from a regular diet to a low-sodium diet, the re-establishment of sodium balance (that is, the time required for the excreted urinary sodium to reach a steady state) is markedly delayed compared with younger subjects (half-time for sodium balance being -31 hours versus - 18 hours in subjects over 60 years and under 25 years of age, respectively).16 However, the significance of this observation has been questioned, as one study has demonstrated that 6 days of sodium restriction resulted in indistinguishable weight reduction in young and elderly Recently, a preliminary report has confirmed that elderly individuals show decreased capacity of sodium conservation when placed on a sodium-restricted diet and that this is accompanied by a somewhat greater weight reduction. lg Normally, the renin-angiotensin-aldosterone axis plays a major role in sodium economy in response to sodium depletion. Overall, the renin-angiotensin system displays decreased basal activity and reduced sensitivity to changes in sodium homeostasis in the elderly.1231. 84, As the role of renal nerves and beta-adrenergic mechanisms in stimulation of renin release is well established, it is possible that reduced PRA in the elderly reflects an additional example of decreased beta-adrenergic responsivity with aging. Alternatively, it appears that plasma inactive renin rises steadily with age,49which raises the possibility of an alteration in the activation of renin. An age-related decline in the basal plasma aldosterone has also been noted in normotensive individuals, as well as a reduced aldosterone responsiveness to upright posture, diuretics, and sodium restriction.12, 29 This probably reflects the concomitant blunting of the PRA response, as the glomerulosa
-
172
response to another stimulator of aldosterone secretion, ACTH, is not affected by aging.92 Whether the delayed renal adaptation to sodium restriction is indeed related to sluggish aldosterone response or to other factors such as renal Na-K-ATPase is unknown at present. There is some evidence that Na-K-ATPase activitv declines with age in red blood cells18 and the myocardium,68and the possibility of a similar decline in the kidney has been raised.63 Although the reduced capacity of the elderly to excrete salt load such as during excessive administration of intravenous saline solution or dietary sodium is widely recognized by clinicians. no oublished studies are available addressing t i e effect of age on the ability to enhance urinary sodium excretion appropriately in resoonse to acute or chronic sodium challenge. In practice, in the absence of overt or subclinical myocardial or renal disease, some weight gain and transient peripheral edema may be the onlv conseauences of careless or inadvertent excessive exposure to sodium. The agedependent reduction in renal blood flow and glomerular filtration rate may explain the increased susceptibility of the elderly to volume expansion. The susceptibility of the elderly to volume/sodium expansion does not result from an a priori increased blood volume, plasma volume, or exchangeable sodium, as these parameters are not affected by age in normal subjects.Vinally, whether or not renal blood flow appropriately increases in response to a sodium load in the elderly, as is seen in the young, has not been established. The combination of declining: renal function, reduction in the number of nephrons (and hence, tubular mass), and reduced activity of the renin-aldosterone svstem renders elderlv subjects more sensitive to a potassium load. Thus, even though the healthy older individual is normokalemic, h~perkalemia may evolve more readilv in resoonse to excessive ~otassium challenge by intravenous fluids and potassiumsparing diuretics which either directly antagonize the effect of the alreadv diminished " levels of circulating mineralocorticoids (spironolactone) or impair the tubular excretion of potassium by mineralocorticoid-independent oathwavs (amiloride). Acute reductions in , ilomerular filtration rate may more readily precipitate hyperkalemia in the elderly with diminished,renal function. The svndrome of hvooren, inemic hv~eraldosteronism with low-grade , hyperkalemia is seen more commonly in the older age groups.38 Finally, it has been known for almost 20 years that the elderly have an acquired tubular defect u
-
\
L
&
Homeostatic Fragiliity in the Elderly
in urine acidification manifested as reduced excretion of an acute anlinonium chloride load.'. The clinical implications of this dysfunction are not entirely clear, but it is conceivable that it may contribute to and impair the recovery from metabolic acidosis of unrelated etiology.
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