There are a lot of old people. In the 2010 United States census, patients older than the age of age 65 years comprised 13% of the U.S. population or 40,300,000 people.1 It is important that anesthesiologists understand the differences in pharmacology and physiology in elderly patients in order to be able to properly use anesthetic and analgesic drugs and compensate for aging-related functional decline in major organ systems. Some fortunate individuals remain physically vigorous until very late in life, whereas others deteriorate physically at a younger age. The cumulative effects of smoking, alcohol, and environmental toxins can accelerate the deterioration of aging in exposed individuals. Thus, it is not surprising that variability in physiology increases throughout life.2 Increased physiologic variability results in increased pharmacokinetic and pharmacodynamic variability in elderly subjects.3 The clinical result of this increased variability is an increased incidence of adverse drug reactions in elderly patients.4 Thus, elderly patients require more careful attention to drug titration. The elderly have in common with the newborn limited physiologic reserve.
Aging and the Cardiovascular System
Increasing age is associated with increasing cardiac morbidity. Aging is associated with an increasing prevalence of cardiovascular disease and decreasing cardiovascular functional reserve.5 Heart failure is the most frequent cause of hospitalization in patients older than 65 years of age. However, it is important to separate the cardiovascular effects of aging from those of common diseases with increased prevalence in the elderly, such as atherosclerosis, hypertension, and diabetes mellitus. The decline in cardiac function that occurs with aging in the healthy individual appears to be related, in part, to decreasing functional demand. Indeed, when exercise and low-calorie diet are maintained into the later decades, the decline in cardiovascular function is markedly attenuated.6 It has been suggested that cardiovascular function is directly related to skeletal muscle mass. Aging also has discrete effects on the heart, large vessels, endothelial function, cardiac conduction system, and the cardiovascular autonomic response (Fig. 46-1).6
Heart
The heart increases in size during aging as a result of concentric ventricular hypertrophy. This occurs in response to the increase in left ventricular afterload. This increase in afterload occurs as the result of fibrosis and endothelial damage, which increase arterial stiffness and reduce the capacity for nitric oxide–induced vasodilation. Hypertrophy of cardiac myocytes occurs and accounts for a 30% increase in left ventricular wall thickness. Meanwhile, the number of cardiac myocytes is decreased due to necrosis and apoptosis. Despite these changes, resting systolic function tends to be well preserved in healthy individuals. However, the heart rate response to severe exercise is diminished. As a result, increases in cardiac output in response to severe exertion are attenuated by approximately 20% to 30%.
Cardiac dysfunction in aging is largely related to impaired diastolic left ventricle function with increased prevalence of diastolic heart failure.7 There is an age-related increase in cardiac connective tissue that, when combined with ventricular hypertrophy, increases wall stiffness and reduces diastolic compliance. Ventricular filling in the elderly is especially dependent on active diastolic relaxation. In this process, calcium is removed from troponin C binding sites, triggering the dissociation of actin and myosin, thus facilitating isometric relaxation. Active diastolic relaxation uses approximately 15% of the energy consumed during the cardiac cycle. This process is significantly impaired in the elderly and exacerbates the adverse effects of ventricular hypertrophy on diastolic filling. As such, the elderly heart is markedly dependent on the atrial “kick” for adequate ventricular preload. It is estimated that atrial contraction contributes approximately 30% of ventricular filling in the elderly versus 10% in younger individuals. Because of the importance of atrial contraction, and because filling is delayed by reduced ventricular compliance, ventricular filling is typically not complete until very late in diastole. Tachycardia and shortened diastolic intervals are associated with marked decreases in ventricular preload in the elderly. Atrial fibrillation is a common rhythm in the elderly. Loss of the atrial kick is particularly poorly tolerated by elderly patients because of decreased capacitance of the left ventricle from the previously noted changes. Perioperative events that reduce venous return, such as hypovolemia, positive pressure ventilation, and increased venous capacitance, may be accompanied by significant decreases in cardiac output. Conversely, excessive perioperative increases in blood volume or decreases in contractility can precipitate congestive cardiac failure. Diastolic dysfunction is now recognized as a major contributor to cardiovascular disease in the elderly population and is exacerbated by several coexisting diseases8,9(Table 46-1).
It is difficult to distinguish systolic dysfunction from diastolic dysfunction during routine clinical evaluation. Furthermore, routine preoperative echocardiographic indices of function such as left ventricular ejection fraction will fail to identify diastolic dysfunction. However, diastolic filling can be evaluated by comparing Doppler echocardiographic measurements of mitral valve inflow velocities during the early and late (atrial contraction) phases of diastole. Dyspnea in the elderly may indicate congestive cardiac failure and/or pulmonary disease.
Large Vessels
Structural changes in the large vessels are an important element of the aging process and contribute significantly to the age-related changes in the heart described earlier.10 The large vessels become elongated, tortuous, and dilated in the elderly. Their intima and media are thickened, causing these vessels to be less distensible. The normal cushioning function of the large vessels is impaired; causing accelerated and enhanced pulse wave propagation. In the elderly, the pulse wave is reflected back from the peripheral circulation and augments systolic pressure. In young adults, the reflected pulse wave generally has lower amplitude and its return from the peripheral circulation is delayed such that diastolic rather than systolic pressure is augmented. As a result, diastolic pressure tends to be lower in the elderly than in younger individuals. Thus, in the elderly, both systolic pressure and pulse pressure are increased and left ventricular afterload is elevated. All of the aforementioned age-related vascular structural changes are accelerated in the presence of hypertension or atherosclerosis.
Endothelial Function
The vascular endothelium is an important regulator of vasomotor response, coagulation, fibrinolysis, immunomodulation, and vascular growth and proliferation. Endothelial dysfunction is an important element in the early pathogenesis of atherosclerosis, diabetes mellitus, and systemic hypertension.11 Aging is associated with altered endothelial structure and function, even in the absence of disease. Reactive oxygen species, such as superoxide anions, have been implicated in age-related endothelial dysfunction. Endothelial dysfunction is accelerated by smoking, diabetes, hypertension, and hyperlipidemia. In the elderly, endothelial nitric oxide release is decreased in all vascular beds, including the coronary circulation.12 Furthermore, the vasodilator response to nitric oxide of the adjacent vascular smooth muscle is also reduced. Vasodilator responses to β2 agonists and vasoconstrictor responses to α-adrenergic stimulation are similarly attenuated in the elderly. Thus, age-related endothelial dysfunction can be characterized as a decrease in the ability of the endothelium to dilate or contract blood vessels in response to physiologic and pharmacologic stimuli.
Conduction System
There are several important age-related structural and functional changes in the cardiac conduction system.5 The sinoatrial node undergoes a progressive change over time such that the proportion of pacemaker cells decreases from 50% in late childhood to less than 10% at 75 years. The sinoatrial node, atrioventricular node, and conduction bundles also become infiltrated with fibrous and fatty tissue. These changes are responsible for the increased incidence of first- and second-degree heart block, sick sinus syndrome, and atrial fibrillation in the elderly. The development of atrial fibrillation is also facilitated by left atrial enlargement, which typically accompanies aging in otherwise healthy individuals. Otherwise, healthy elderly men also experience an age-related increase in the prevalence, frequency, and complexity of ventricular ectopy.
Autonomic and Integrated Cardiovascular Responses
Aging is associated with increased norepinephrine entry into the circulation and deficient catecholamine reuptake at nerve endings. Therefore, elevated circulating concentrations of norepinephrine are usual, generating chronically increased adrenergic receptor occupancy. However, the cardiovascular response to increased adrenergic stimulation is attenuated by downregulation of postreceptor signaling and reduced contractile response of the myocardium. The number of the β-adrenergic receptors is reduced in the elderly myocardium.7 The decreased chronotropic and inotropic response of elderly patients to β-adrenergic drugs also has a contribution from downstream changes in the mechanism by which binding at the receptor is coupled to cyclic adenosine monophosphate. The response to exogenously administered β agonists, such as isoproterenol, is similarly attenuated. Receptor downregulation is responsible for the age-related decline in maximum heart rate during exercise. Indeed, receptor downregulation in the elderly makes their cardiovascular function similar to that of a younger individual who has received β-adrenergic antagonists.
Orthostatic hypotension is common in the elderly and is associated with syncope, falls, and cognitive decline. Impaired baroreceptor reflexes and attenuated peripheral vasoconstriction are partially responsible. Hypovolemia and salt depletion also contribute and are the result of iatrogenic diuretic administration or increased atrial natriuretic peptide release. Orthostatic hypotension is more common in patients who are hypertensive at baseline. It is difficult to separate the effects of aging per se from those of age-related chronic increases in systolic pressure. Straining against a closed glottis (Valsalva maneuver) typically produces a decrease in venous return and cardiac output. The normal baroreceptor response to this maneuver includes an increase in heart rate and peripheral vascular tone and restoration of blood pressure. However, this response is markedly attenuated in the elderly. Age-related impairment of baroreceptor responses makes hypotension more likely after the initiation of positive pressure ventilation, particularly in the presence of hypovolemia. Similarly, neuraxial local anesthetic–induced sympathetic blockade is more likely to be accompanied by hypotension in the presence of an impaired baroreceptor response. In the Irish Longitudinal Aging Study, antidepressants and β blockers were associated with orthostatic hypotension, and hypnotics and sedatives worsened preexisting orthostatic intolerance.13 Antihypertensive drugs that did not act through β-adrenergic blockade were not associated with orthostatic hypotension. These findings should be considered in the mobilization of elderly patients who may have received these drugs in the perioperative period.
Anesthetic and Ischemic Preconditioning in the Aging Heart
It is now recognized that, under certain circumstances, exposure to volatile anesthetics (anesthetic preconditioning) or several brief periods of ischemia (ischemic preconditioning) may enhance tolerance to subsequent ischemia, enhance cardiac function, and reduce infarction size.14 Because the incidence of atherosclerosis and coronary artery disease is age-related, the elderly would seem be most likely to benefit from a preconditioning strategy. However, both anesthetic and ischemic preconditioning may be markedly attenuated in the elderly, potentially explaining the difficulty of translating promising preclinical results to treatment.15,16 Furthermore, potent volatile drugs may induce significant cardiovascular depression in this age group. Therefore, the use of preconditioning strategies in this age group is uncertain.
Aging and the Respiratory System
The respiratory system undergoes a multifactorial decline in functional reserve with aging (Tables 46-2 and 46-3).17 Under normal circumstances, this decrease in respiratory function is not associated with significant limitation of daily activity. However, decreased respiratory reserve may be unmasked by illness, surgery, anesthesia, and other perioperative events. Common respiratory diseases and the effects of smoking and environmental pollution frequently exacerbate the decline in respiratory function with aging. The anticipation and amelioration of their effects is critically important to anesthetic management in the elderly, as postoperative respiratory complications result in 40% of perioperative deaths in patient older than 65 years.18
Respiratory System Mechanics and Architecture
The chest wall becomes less compliant with aging, presumably related to changes in the thoracic skeleton and a decline in costovertebral joint mobility. These changes produce a restrictive functional impairment. The noncompliant thoracic cage makes intercostal muscle activity less efficient. Therefore, the diaphragm and abdominal muscles assume a greater role in tidal breathing. However, diaphragmatic function declines with age, predisposing the elderly to respiratory fatigue when required to significantly increase minute ventilation. Although the diaphragm does not appear to undergo significant atrophy or change in muscle fiber type with aging, it does occupy a flatter position and therefore has a less favorable mechanical advantage. These changes predispose the elderly to respiratory insufficiency in the setting of high regional anesthesia.
Aging is associated with a loss of lung elasticity that is responsible for a decrease in lung recoil, thus making the lung more distensible. Changes in surfactant function may also contribute to age-related changes in lung compliance. The net result of these changes in the elastic properties of the lung and chest wall is an increase in intrapleural pressure that significantly impacts on respiratory function. Intrapleural pressure is a critical determinant of small airway caliber. Increased intrapleural pressures increase the tendency for small airway collapse to occur, thus causing gas trapping and/or expiratory airflow limitation.
Lung Volumes and Capacities
Vital Capacity
Vital capacity (VC) is the volume generated when a maximal inspiration is followed by a maximal expiration. There is a progressive loss of VC with aging that results from increased chest wall stiffness, decreased lung elastic recoil, and decreased respiratory muscle strength.
Residual Volume
The residual volume is the volume remaining in the lungs after a maximal expiration. In young individuals, the residual volume is determined primarily by ability of the expiratory muscles to overcome the elastic recoil properties of the lung and chest wall. However, in the elderly, dynamic airway closure also limits expiration. Therefore, aging is associated with a progressive increase in residual volume of up to 10% per decade (Fig. 46-2).19
Total Lung Capacity
Total lung capacity is the sum of the residual volume and the VC. Thus, the combined effect of the decline in VC and increase in residual volume is that the total lung capacity remains relatively constant with aging.
Functional Residual Capacity
The functional residual capacity (FRC) is the volume remaining in the lungs at the end of a normal expiration. The FRC is the volume at which the elastic recoil forces of the lung and chest wall are at equilibrium. The opposing recoil forces of the lung and chest wall generate the subatmospheric intrapleural pressure. Aging is associated with a progressive increase in FRC that occurs as a result of the decreased elastic recoil force of the lungs. However, the increase in FRC is less than would be predicted from the change in lung elastic recoil alone. This is because the increased stiffness of the chest wall counteracts the increase in lung volume.
Closing Capacity
Airway closure may occur in small airways (<1 mm) whose caliber is determined by their transmural pressure. Airway closure typically occurs in dependent areas of the lung where the surrounding intrapleural pressure is likely to be greater. In young adults, airway closure occurs only at low lung volumes (approximately 10% of VC). Thus, airway closure is unlikely during normal tidal breathing. However, as intrapleural pressure increases with age, airway closure occurs at progressively greater lung volumes. Indeed, in the elderly, airway closure occurs at approximately 40% of the VC reflecting lung volumes that exceed FRC. Although the FRC increases by up to 3% per decade, closing capacity increases at a greater rate. Thus, gas exchange impairment due to shunting in regions of airway closure is typical in the elderly during normal tidal breathing. The supine position is associated with a decrease in FRC when compared to the standing position. In this regard, the supine position makes airway closure during normal tidal breathing more likely. Indeed, airway closure may occur during tidal breathing as early as the mid-40s in the supine position.
Expiratory Flow
There is a progressive decline in forced exhaled volume in 1 second (FEV1) and forced vital capacity (FVC) with age that is independent of smoking or environmental exposure. Age-related loss of lung elastic recoil predisposes to dynamic airway collapse during forced expiratory maneuvers. Expiratory muscle strength also declines with age.
Diffusing Capacity and Alveolar-to-Arterial Oxygen Gradient
Gas exchange efficiency declines with aging as a result of increasing intrapulmonary shunting and decreasing lung diffusing capacity. The result is a linear decline in resting supine PaO2 between early adulthood and 65 years of age (Fig. 46-3).20 Small airway closure causes ventilation to perfusion (V/Q) mismatch and shunting. Cardiac output is often decreased in the elderly to the extent that mixed venous oxygen tension is decreased. Thus, even modest amounts of shunting may produce a significant decrease in PaO2 because of the contribution of desaturated venous blood. The diameter of the alveolar ducts is increased and their respective alveoli are wider and shallower. These architectural changes significantly reduce alveolar surface area. As a result, diffusing capacity for carbon monoxide may decline by up to 50% between early adulthood and 80 years of age.
Upper Airway Protective Reflexes
Cough effectiveness is reduced in the elderly because of diminished reflex sensitivity and impaired muscle function. Cough reflex attenuation is associated with an increased incidence of aspiration pneumonia. The mechanisms of cough reflex impairment include desensitization of airway epithelial irritant receptors and impaired swallowing.21 Smoking causes airway sensory nerve neuropeptide depletion and nicotine inhibits C fiber transmission in the lower respiratory tract.22 Coexisting medical conditions that are associated with cough reflex suppression include stroke, laryngectomy, and Parkinson disease. General anesthetics inhibit the cough reflex through inhibition of central respiratory neurons.23 Care is needed during intubation and extubation of patients with risk factors for impaired airway protection.
Control of Breathing, Chemoreceptors, and Integrated Responses
The cardiorespiratory responses to hypoxia and hypercarbia are mediated via central and peripheral chemoreceptors. The increases in heart rate and minute ventilation in response to elevations in PaCO2 or decreases in PaO2 are markedly attenuated in the elderly. The attenuated ventilatory response is multifactorial and reflects decreased peripheral chemoreceptor sensitivity, reduced respiratory muscle activity, decreased respiratory mechanical efficiency, and general respiratory deconditioning. These important protective reflexes are further attenuated by the administration of opioids and sedative/hypnotic drugs. Thus, the elderly are at particular risk from life-threatening respiratory depression in the perioperative period. In a recent report, investigators found that the risk of opioid-induced ventilatory depression increased with increasing age, with patients 61 to 70 years of age having 2.8 times the risk of ventilatory depression compared with patients 16 to 45 years old.24 Although the risk of respiratory depression from opioids is greater in the elderly, the same is not true for all opioid side effects. Opioids are a major cause of postoperative nausea and vomiting in young and middle-aged patients, increasing the risk nearly four-fold25; age was not a risk factor for nausea and vomiting in other reports.24 In fact, age may actually decrease the risk of nausea and vomiting; one group of investigators reported a 13% decrease in the risk of postoperative nausea and vomiting with each additional decade of life.26
Sleep Disordered Breathing
The incidence of sleep disordered breathing increases with age, especially in men. It is estimated that approximately 20% of elderly people have clinically significant obstructive sleep apnea.27 The prevalence of snoring is highest in the seventh decade and is associated with an increased risk of stroke and heart disease. Morbidity associated with sleep apnea includes systemic and pulmonary hypertension, dysrhythmias, myocardial infarction, stroke, sudden death, and automobile accidents. In addition, obstructive sleep apnea doubles the risk for postoperative delirium in the elderly.28
Thermoregulation in the Elderly
There is ample evidence that hyperthermia and hypothermia in the elderly are poorly tolerated and that extreme cold and heat stress are associated with increased mortality compared to younger individuals.29However, it is not clear whether the greater susceptibility to thermal stress is related to aging per se or to underlying socioeconomic conditions, general fitness, activity levels, and the effects of coexisting disease in the elderly.
Resting Core Temperature
Aging is associated with a greater variability in core temperature. Indeed, it is estimated that up to 10% of people greater than 65 years of age have early morning core temperatures of less than 35.5°C (Table 46-4). However, when the effects of coexisting disease, socioeconomic circumstances, and medication are eliminated, there is no evidence of declining body temperature with advancing age in healthy individuals under thermoneutral conditions. Circadian temperature variations are not significantly different in the healthy elderly compared to younger individuals.
Response to Cold Stress
The elderly do not have a normal response to cold stress. The usual physiologic response to cold stress is to decrease heat loss by peripheral vasoconstriction and to increase heat production via shivering and nonshivering thermogenesis. Aging is associated with attenuated vasoconstrictor responses to cold. The inability to efficiently conserve heat in the elderly is exacerbated by the age-related decrease in skeletal muscle mass. Loss of skeletal muscle mass is responsible for the age-related decline in basal heat production. It is estimated that resting heat production declines by 20% between the ages of 30 and 70 years. There is a significant gender-related difference in cold stress response in the elderly. Mortality during cold weather is higher in men compared to age-matched women. It is likely that the higher percentage of body fat and lower surface area-to-mass ratio in females is responsible for this difference. The attenuated cold stress responses of the elderly are further diminished by general and regional anesthesia. Perioperative hypothermia is very likely in the elderly patient unless active measures are taken to maintain normothermia.
Gastrointestinal Function in the Elderly
Liver
Although aging is associated with a decrease in liver mass and hepatic blood flow, hepatocellular metabolic function appears to be relatively well preserved throughout life. Protein synthetic function may be diminished in some elderly individuals, particularly those with poor nutritional intake. Reduced serum albumin concentrations will affect drug binding. On the other hand, the concentration of another important drug-binding protein, α-1-acid glycoprotein, is typically increased in the elderly. Hepatic synthesis of plasma cholinesterase may be diminished, particularly in men. There is evidence of an increase in the duration of mivacurium activity but not succinylcholine with age.30
Although hepatic enzyme function may be qualitatively normal in the elderly, the reduction in hepatic mass and blood flow is responsible for a significant decrease in first-pass metabolism of several drugs that are important in the aging population.31 Because first-pass metabolism is reduced, the oral bioavailability of propranolol and labetalol are increased in the elderly. Conversely, prodrugs, such as the angiotensin-converting enzyme (ACE) inhibitor enalapril, require activation by the liver before they exert their pharmacologic effect. Therefore, the bioavailability of these drugs may be decreased in the elderly.
Gastroesophageal Physiology
Gastric emptying of solid material appears to be relatively normal in the healthy elderly population. However, gastric emptying of liquids may be delayed compared to younger individuals.32 Emptying of both liquids and solids is commonly delayed in the presence of certain coexisting diseases that are common with aging such as gastroesophageal reflux disease (GERD) (Table 46-5). However, the typical symptoms of GERD seen in the younger population (heartburn and regurgitation) are less frequent in the elderly, making diagnosis more difficult. Dysphagia, vomiting, respiratory symptoms, weight loss, and anemia are more common presenting symptoms in the elderly. Several medications that are commonly prescribed in the elderly population predispose to GERD by decreasing lower esophageal sphincter tone (Table 46-6).
Renal Function in the Elderly
Aging is accompanied by a decrease in the cortical nephron population and a reduction in renal mass. Renal blood flow and glomerular filtration rate (GFR) both decline with age.31 The average male GFR is 125 mL per minute. This value decreases by approximately 1 mL/min/yr after the age of 40 years as a result of the decline in nephron population and hyalinization of cortical afferent arterioles. The medullary nephron population is relatively preserved, and age-related vascular changes in the medulla are minimal. Despite the significant decline in GFR with aging, the serum creatinine concentration increases minimally because there is also an age-related decrease in skeletal muscle mass. Although renal function is diminished in the elderly, it is sufficient to maintain homeostasis under normal physiologic conditions. However, the renal response to common perioperative stresses may be insufficient to maintain homeostasis.31 Although the elderly individual is able to maintain acid–base balance under every day physiologic conditions, the response to increased acid loads such as during ischemia and sepsis is attenuated due to impaired renal tubular ammonium secretion.
The elderly are at risk for both dehydration and free water overload because of impaired renal responses. Urine concentrating ability is critically dependent upon the presence of a hypertonic renal medulla. However, medullary perfusion is relatively increased in the elderly, resulting in a washout of solute and a reduction in osmolality in that region. Thus, the collecting tubules are not exposed to the usual concentration gradient necessary to produce concentrated urine.33 Reduced numbers of cortical nephrons also contribute to impaired salt conservation. This suboptimal renal response to dehydration is compounded by age-related deficiencies in thirst mechanisms. Water deprivation is associated with a reduced thirst response in elderly subjects despite significant increases in plasma osmolality.34 As a result of these factors, the elderly are at enhanced risk of dehydration.
The response to free water excess is similarly attenuated in the elderly. This is particularly relevant because the perioperative neuroendocrine stress response is associated with arginine vasopressin (antidiuretic hormone) release and water retention. When combined with iatrogenic hypotonic fluid administration, these factors make the elderly patient particularly susceptible to perioperative free water overload and hyponatremia.
Skeletal Muscle Mass and Aging
Aging is associated with a significant decline in neuromuscular performance. Loss of neuromuscular function causes functional disability and loss of independence.35 By the seventh and eighth decades, maximal voluntary contractile strength is reduced by 20% to 40%. Neuromuscular decline results predominantly from loss of skeletal muscle mass, which declines by approximately 40% between the ages of 20 and 60 years (sarcopenia). However, strength losses with aging may be attenuated by continued physical activity, particularly resistance training. The decline in muscle function is multifactorial (Table 46-7). Diminished skeletal muscle mass has significant implications for the elderly patient in the perioperative period (Table 46-8).
Neurophysiology of Aging
The elderly demonstrate increased sensitivity to benzodiazepines, opioids, and volatile anesthetic drugs. The minimum alveolar concentration (MAC) of potent volatile anesthetic drugs is decreased by approximately 25% at 80 years of age when compared to MAC values obtained at 40 years of age.36 The addition of nitrous oxide is more effective in reducing the requirements for potent inhaled anesthetic drugs in the elderly.
Perhaps as a function of limited neurologic reserve, the elderly are at risk for postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) that are strong risks factor for mortality.37 POD is a syndrome of fluctuating consciousness, inattention, memory impairment, and perceptual abnormalities that typically occurs after a lucid interval of 1 to 3 days after emergence from general anesthesia. In comparison to the validated criteria for POD, the definition of POCD is much looser. One of the largest studies, International Study of Postoperative Cognitive Dysfunction 1 described POCD in 26% of elderly patients 1 week after anesthesia and 10% after 3 months using a variety of well-recognized tests.38
Although POCD and POD are distinct syndromes, there are a large number of risk factors for POCD and POD that overlap, which suggests a shared pathogenesis. POD is equally common after both regional and general anesthesia, whereas POCD may be more common after general anesthesia.39 The pathophysiology of acute POD in the elderly is undetermined. However, a neuroinflammatory response exacerbated by a faulty blood–brain barrier is thought to be mechanistically important. Surgical trauma induces an inflammatory response, which leads to an inflammatory cascade mediated by cytokines and macrophages in the central nervous system resulting in POCD.40
Although POCD is a risk factor for early mortality, in an 11-year follow-up of the ISPOCD cohort, it was not found to be a risk factor for dementia. As the population ages and requires more surgical intervention, the pathogenesis of this syndrome and its best management are important areas for investigation.
Pain and Aging
Pain is a part of daily life for many elderly patients, with about 50% of patients older than the age of 70 years reporting chronic pain.41 Elderly patients are particularly more prone to chronic pain than younger people.42 There are some interesting differences between young and older subjects in their response to experimental pain. There is some evidence that older patients are more sensitive to experimental pain, which may be explained, at least in part, by a reduction in the endogenous analgesic response to pain, possibly mediated by reduced production of β-endorphin in response to noxious stimulation.43,44 Older patients experience a more prolonged hyperalgesia following capsaicin injection compared with younger subjects. However, older patients appear to also require a higher intensity of noxious stimulation before first reporting pain.45 Some of the differences between studies may also depend on exactly which pain pathways are activated during the assessment. Chakour and colleagues46 demonstrated that pain transmission via C fibers was unchanged in young versus elderly subjects. However, there was a substantial reduction in pain transmission via Ad fibers. Thus, the relative perceptions of pain in elderly subjects versus younger subjects were influenced by the extent of pain transmission via Aδ fibers.
As a general rule, elderly patients are more sensitive to opioids. Electroencephalographic studies of subjects treated with fentanyl, alfentanil, sufentanil, and remifentanil support a 50% dose reduction for elderly patients.47–50Aging results in less important pharmacokinetic effects of these drugs with variable reports of small reductions in clearance.
In contrast, morphine and meperidine have active metabolites, which accumulate in the elderly.
Morphine is metabolized by glucuronidation into two metabolites, morphine-3-glucuronide, which is mostly inactive, and morphine-6-glucuronide, which is itself a potent analgesic. Although the potency of intrathecal morphine-6-glucuronide is 650-fold higher than that of morphine, morphine-6-glucuronide crosses the blood–brain barrier very slowly, so slowly that it is unlikely that it contributes to the acute analgesia provided by morphine. However, with chronic administration, the levels of morphine-6-glucuronide will rise to pharmacologically active concentrations.51 Morphine-6-glucuronide is eliminated by the kidneys. Creatinine clearance is reduced with advancing age. Thus, morphine-6-glucuronide will accumulate more in elderly patients, necessitating a reduction in dose of chronically administered morphine. Of course, if the patient has renal insufficiency, it might be better to select an opioid without an active metabolite.
Elderly patients have reduced meperidine clearance, resulting in a longer half-life for meperidine. Meperidine will accumulate in elderly subjects with repeated administration.52 A worrisome aspect of meperidine is the toxic metabolite, normeperidine. Renal excretion of normeperidine was particularly reduced in elderly patients. The result is that normeperidine will likely accumulate with repeated doses in elderly patients.53 Because normeperidine is highly epileptogenic, meperidine is probably a poor choice for patient-controlled analgesia or other forms of continuous opioid delivery in elderly patients.
The alterations in physiology and pharmacology discussed earlier make the anesthetic management of elderly patients more challenging. The increasing elderly population requiring surgery makes knowledge of these factors critical. With careful drug titration and pre- and postoperative management, even the extreme elderly can safely undergo surgery in order to improve the quality of their lives.
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