Fig. 16.1
Histologic sections of normal lung from a nonsmoking (a) 22-year-old homicide victim, and (b) a 75-year-old individual (hematoxylin and eosin stain, 2×)
The destruction of alveolar walls results in small alveoli coalescing to form larger sacs. Consequently, the lungs have less elasticity and less natural recoil to hold small airways open as lung volumes change with respiration [12, 13]. Airways from the level of bronchioles to the alveolar ducts lack a cartilaginous support. Without a semirigid structure to keep them open during passive exhalation, these airways depend on the elastic recoil of the lung parenchyma to prevent collapse at low lung volumes (Fig. 16.2). There is an age-related decrease in the diameter of small bronchioles from the fourth decade that is consistent with decreased compliance [14]. In the older patient, these dependent airways close at a higher lung volume than in younger subjects. The physiologic consequence of these changes is increasing ventilation perfusion (V/Q) mismatching with advancing age. A progressive hypoxemia develops as the number of alveoli gradually decreases and anatomic dead space increases [15].
Fig. 16.2
(a) The change in static recoil of the lung measured at 60% of total lung capacity. The decrease in recoil with age is apparent. Atrophy of pulmonary parenchyma results in less elastic recoil to hold open small airways at low tidal volumes. (b) Increasing ventilation-perfusion mismatching occurring with age leads to lower resting PaO2. The resting arterial tension was determined by the equation PaO2 (mm Hg) = 143.6 − (0.39 × age) − (0.56 × BMI) − (0.57 × PaCO2), assuming a BMI of 25 and PaCO2 of 40 mm Hg. (a) Based on data from Turner et al. [13] (b) Based on data from Cerveri et al. [15]
The increased closing volume makes it more likely an older patient will experience hypoxia at some time in the perioperative period. Older patients experience hemoglobin desaturation at a faster rate because of greater V/Q mismatching. In the operating room, the transfer of oxygen is not as efficient when using positive pressure ventilation in the supine position as it is when breathing spontaneously. The combination of altered ventilatory response to hypoxia, sedation from residual inhalational agents, and analgesics increases the risk of hypoxia after general anesthesia. The likelihood of hypoxia is further compounded if pulmonary disease is superimposed on age-related changes.
An age-related mismatching of pulmonary ventilation and perfusion may influence the uptake of volatile anesthetic agents. Areas of the lung that are well ventilated but with less perfusion will contribute more anesthetic gas and can be expected to cause a more rapid increase in the ratio of alveolar (FA) to inspired (FI) agent concentrations. However, there is little evidence to confirm this. In the absence of grossly abnormal pulmonary function, the small increase in the FA/FI ratio caused by a progressive V/Q mismatch is probably offset by a lower metabolic rate, and hence lower ventilation and perfusion per kilogram body weight in the elderly. It is difficult to demonstrate any difference in anesthetic uptake attributable to age alone in normal patients (Edmond Eger, personal communication, 2005). However, patients with chronic pulmonary obstructive disease from emphysema, chronic bronchitis, or asthma will have a slower increase in the alveolar concentration (FA) of volatile anesthetic agents (Fig. 16.3).
Fig. 16.3
The effect of pulmonary disease on the increase of alveolar concentration (FA) compared with inspired concentration (FI) versus time. The increase in FA/FI is slower in subjects with pulmonary disease (Adapted from Gloyna [166]. With permission from Wolters Kluwer Health)
There is no evidence that an obstruction to diffusion of anesthetic agents develops with age. Alveolar thickening from unusual disorders such as idiopathic pulmonary fibrosis or common problems such as lung congestion from cardiac failure should slow diffusion of anesthetic gases, but it is not likely that this results in a slower increase in the partial pressure of the inhalational agent in pulmonary venous blood.
Any change in V/Q mismatching has a more pronounced effect on inhalational agents with low blood/gas partition (B/G) coefficients [16]. This includes sevoflurane, desflurane, and the inorganic compound nitrous oxide (Table 16.1). Lu et al. [17] measured sevoflurane concentration in arterial and jugular venous blood samples in patients during cardiac surgery. Their study population consisted of 10 patients between the ages of 51 and 73 years who received a constant 3.5% inspired sevoflurane concentration for 1 h. It took 40 min before the concentration of sevoflurane in venous blood became equal to the arterial blood. The arterial sevoflurane concentration was also approximately 40% less than the end-tidal expired sevoflurane. Thus, the end-tidal sevoflurane concentration did not reliably reflect the parallel concentration of sevoflurane in the brain. The equilibration between arterial blood and brain tissues takes four times longer than predicted and sevoflurane uptake in the brain takes approximately 1 h [17]. Because of the changes slowing uptake, it should also be anticipated there will be slower elimination of inhalational anesthetics from altered pulmonary function [18].
Table 16.1
Physical properties of inhalational agents including nitrous oxide
Agent | Molecular weighta, b (g) | Boilinga point (°C) | Vapor pressurea, c | Partition coefficient | Recovered as metabolitese (%) | ||
|---|---|---|---|---|---|---|---|
Oil/gasa | Blood/gas | Fat/bloodd | |||||
Halothane  | 197.4 | 50 | 243 | 224 | 2.3 | 51 | 11–25 |
Enflurane  | 184.5 | 57 | 172 | 98.5 | 1.91 | 36 | 2.4 |
Isoflurane  | 184.5 | 49 | 238 | 90.8 | 1.4 | 45 | 0.2 |
Desflurane  | 168 | 24 | 669 | 19 | 0.45 | 27 | 0.02 |
Sevoflurane  | 200 | 59 | 157 | 53.4 | 0.60 | 48 | 5.0 |
Nitrous oxide  | 44 | −88 | 38,770 | 1.4 | 0.47 | 2.3 | 0 |
Alveolar ventilation does not change with age. However, there are changes that lead to degrees of V/Q mismatching and changes in the control of minute ventilation in response to hypoxia and hypercarbia. The normal partial pressure of carbon dioxide in arterial blood is 4.6–5.3 kPa (34.5–39.8 mm Hg) in older patients [19, 20]. With advancing age, the control of ventilation is less sensitive. The normal response to hypercarbia is an increase in the minute ventilation. In young individuals, there is a profound response, about 2–5 L/min per torr carbon dioxide [21, 22]. Where the response to rebreathing carbon dioxide is 3.4 L/min in men whose average age is 26 years, the response is only 1.8 L/min in men who are about 70 years of age [23]. The likelihood of respiratory acidosis from impaired ventilation after general anesthesia is, therefore, greater but it is not documented.
The ventilatory response to hypoxia greatly diminishes with advanced age [23]. When combined with the sedative effect of inhalational anesthetics, the profoundly impaired drive to increase minute ventilation in response to hypoxia leaves the elderly patient at risk for hypoxia. This may contribute to the numerous instances of respiratory complications in the recovery period including hypoxia hypoventilation and atelectasis [24]. Therefore, less-soluble inhalational anesthetic drugs for elderly patients are reasonable choices. Transporting elderly patients with supplemental oxygen from the operating room to the postanesthesia care unit (PACU) is prudent. Generous use of supplemental oxygen and close monitoring while in the PACU are imperative.
Influence of the Aging Cardiovascular System
The major cardiovascular changes occurring with age include impaired pump function and atherosclerotic changes in the vasculature. These changes occur independently of diseases that can affect the heart and peripheral vasculature. The most common cardiovascular problems are hypertension, arteriosclerosis, atherosclerotic vascular, and coronary disease. Angina pectoris and myocardial ischemia leading to myocardial infarction are frequent myocardial events [25]. The incidence of cardiac arrhythmia increases with age, the most common conduction abnormalities being ventricular conduction defects, first degree atrial-ventricular block, atrial fibrillation, ST-T wave abnormalities, major Q-wave and QS-wave abnormalities and in addition, evidence of left ventricle hypertrophy [26]. Heart failure is a common problem in the elderly, the incidence and prevalence increasing with age. The incidence of heart failure in individuals older than 65 years is increasing with 20–30 cases per 1000 persons older than 80 years of age [27, 28]. Approximately half of congestive heart failure cases occur in patients with preserved systolic function, a problem now recognized as diastolic dysfunction [29]. Diastolic dysfunction is common and is as predictive of eventual death as systolic failure. This problem is found frequently in association with coronary artery disease and ventricular hypertrophy [30]. This is likely due to aggravating subendocardial myocardial ischemia. The association of diastolic dysfunction with common cardiac disease, and its association with aging is an additional factor that may affect hemodynamic responses to fluid shifts, anesthetics, and other perioperative drugs.
Aside from being the frequent target of disease, the cardiovascular system experiences a decline in function with age. Measuring cardiac performance during exercise is often used as a surrogate for surgical stress. One general measure of cardiac function, the maximum oxygen transport or VO2-max, decreases at the rate of approximately 1% per year after age 30 [31–33]. It is tempting to rely on cardiac output as a way of assessing the effect of age. However, changes in cardiovascular function are variable and not easily attributed to a single cause. Cardiac output has several determinants, and, as a single index, it is not an adequate measure to understand anesthetic effects in the elderly.
In healthy older subjects, the peripheral flow of blood decreases and peripheral vascular resistance increases in comparison to younger counterparts. Physical conditioning does not alter these changes [34] (Fig. 16.4). Increasing vascular resistance may explain some decrease in cardiac output, but decreases in cardiac output may also result from decrement in the chronotropic response, systolic, and diastolic function. There is general agreement that the maximum heart rate response decreases with age. The maximum cardiac stroke volume does not change very much as a result of age alone, but it may decrease for several reasons, such as ventricular hypertrophy, stiffening of the ventricular wall, lower preload, and higher afterload. By carefully matching the physical abilities of older master athletes with younger competitive runners, Hagberg et al. [35] demonstrated that the decrease in VO2-max occurring with age is attributable only to a decreased maximal heart rate. There was no change in the stroke volume and arterial-venous oxygen difference to account for lower cardiac output [35]. The influence of age on cardiac function is seen when normal subjects are stressed. The left end diastolic volume index (LEDVI) does not normally decrease with age, and exercise or stress increases LEDVI via β-adrenergic stimulation. This is the Frank–Starling mechanism and with advanced age, increasing the end-diastolic volume, and thus the stroke volume and cardiac output, compensate for diminished ability to increase the heart rate (Fig. 16.5) [36].
Fig. 16.4
Cardiovascular changes occurring with age in healthy male subjects. Femoral blood flow decreases (a) and peripheral vascular resistance increases (b) with age. The effect of age on these variables is not influenced by exercise conditioning. (c) Age-related changes in cardiac output are minor ((a, b) Reprinted from Dienno et al. [34]. With permission from John Wiley and Sons, (c) Based on data from Dienno et al. [34])
Fig. 16.5
The action of increasing workload on cardiac function as a function of advancing age. Each point is the slope of a coefficient for each physiologic parameter measured in a group of normal subjects ranging in age from 25 to 79 years. The subjects performed stationary bicycle work while hemodynamic measurements were taken and worked to the point of exhaustion. An increase or decrease in the slope coefficient with increasing workload indicates an increasing or decreasing effect of age. CO cardiac output, EDV end-diastolic volume, ESV end-systolic volume, SBP systolic blood pressure, EF ejection fraction, HR heart rate (Reprinted with permission from Rodeheffer et al. [118]. With permission from Wolters Kluwer Health)
Cardiac output is determined by the heart rate and stroke volume. Altered uptake and distribution of inhalational anesthetic agents result when cardiac pump function decreases. Patients with decreased cardiac output have a slower systemic circulation time that is matched with a slower circulation through the pulmonary circuit. During general anesthesia, slower pulmonary circulation provides more time for volatile anesthetic agents to diffuse into the blood. Pulmonary venous blood can attain a higher partial pressure of anesthetic gas under these circumstances than anticipated. Thus, the effect of lower cardiac output is greater delivery of anesthetic drug to the myocardium and the central nervous system. Generally, this effect occurs with the more soluble anesthetics such as halothane and enflurane . The action of low cardiac output increasing uptake is attenuated by anesthetics with a lower B/G solubility. This favors the use of low-solubility agents such as desflurane and sevoflurane.
A slower systemic circulation also slows delivery of anesthetic agents to target tissues including the central nervous system (Fig. 16.6). The clinical result is a slower onset of anesthesia. However, with the most soluble inhalational agents, a lower cardiac output means arterial blood will convey a higher partial pressure of anesthetic agent to the central nervous system, and, consequently, with greater drug delivery, the anesthetic effect may be more profound. Low cardiac output in patients with cardiac disease exaggerates this effect. Volatile anesthetic agents can cause a cycle of myocardial depression leading to increased uptake, increased alveolar concentration, and further depression of cardiac output. Therefore, the potential cardiac depressant effect of volatile anesthetics is significant.
Fig. 16.6
Reduced cardiac output results in slower pulmonary circulation and allows for the diffusion of more anesthetic agent into the blood. This results in a more rapid increase in the partial pressure of agent in the blood, greater delivery to the central nervous system, and a more profound onset of anesthesia. This is more likely with the very soluble anesthetic agents. However, the onset of action may be delayed compared with patients with normal cardiac output (Adapted from Gloyna [166]. With permission from Wolters Kluwer Health)
Anesthetics may decrease stroke volume by depressing contractility or slowing the rate. Bradycardia is encountered in many clinical situations and it is often a simple problem to treat. An advantage of newer volatile anesthetics is that they generally cause little change in heart rate or they tend to increase it slightly at higher concentrations (Fig. 16.7). In younger patients, tachycardia results from abrupt increases in desflurane administration above 1 minimal alveolar concentration (MAC) (Fig. 16.8). A similar but less-pronounced response also occurs with isoflurane [37]. The depression of myocardial contractility by anesthetic agents is a more important consideration. Global cardiac depression is most likely with halothane, enflurane, and to some extent, isoflurane. These drugs are more soluble in blood than either desflurane or sevoflurane and can have a greater effect for this reason (Table 16.2).
Fig. 16.7
(a) Hemodynamic effects of desflurane (DES) during controlled ventilation in young volunteer subjects. The subjects received no other drugs. MAC minimal alveolar concentration. (b) Hemodynamic effects of isoflurane during controlled ventilation in young volunteer subjects. Measurements were made during the first and fifth hours of continuous anesthesia and demonstrate small changes occurring in the heart rate response with prolonged anesthesia ((a) Based on data from Cahalan et al. [165]. (b) Based on data from Stevens et al. [45])
Fig. 16.8
A transient increase in heart rate, blood pressure, and sympathetic activity occurs with isoflurane and desflurane when the concentrations are increased rapidly to more than 1 minimal alveolar concentration. Several interventions have been described to effectively counter this occurrence, including avoiding the “over pressuring” technique. HR heart rate, MAP mean arterial pressure (Reprinted from Weiskopf et al. [37]. With permission from Wolters Kluwer Health, Inc.)
Table 16.2
The influence of halothane or enflurane on myocardial contractility, EES, in a canine model and during coronary artery bypass surgery
Canine model | CABG surgery | |||
|---|---|---|---|---|
Halothane (n = 7) | Enflurane (n = 7) | |||
Control | 10.1 ± 0.6 | 15.2 ± 0.4 | Control | 11.5 ± 2.0 |
1% | 6.7 ± 0.4 | 12.3 ± 0.6 | 60% N2O | 9.0 ± 2.2 |
2% | 4.2 ± 0.5 | 9.3 ± 0.5 | 0.5% halothane | 8.1 ± 2.4 |
Predicting how patients with combined pulmonary and cardiac disease will respond during general anesthesia with volatile anesthetics is difficult. Clinicians can expect slower induction and longer emergence from inhalational anesthesia. It is also likely these patients will have greater hemodynamic instability during anesthesia.
Influence of Body Composition Changes
A primary factor influencing inhalational agent pharmacokinetics is the change in body composition. These include a reduction in the skeletal muscle mass and an increase in the total body fat content [38]. Although there is considerable variation, the general trend is for an increase in the percentage of body fat (Fig. 16.9). The change in body composition is greater for men, with about 25% of their total body mass being fat. For older women, the total body fat content averages 35% [39]. As total body fat increases with age, the proportion of total body water also decreases.
Fig. 16.9
The change in body composition occurring with age. Data from the Fels Longitudinal Study including men (a) (n = 102) and women (b) (n = 108) for subjects not selected because of any known criteria related to body composition. Women have a greater percent of body fat than men at all ages. Men have an increasing trend in body weight and percent body fat. Women tend to lose fat-free mass as they become older (Based on data from Guo et al. [38])
Fat tissue has a great capacity to retain lipid-soluble drugs. For those inhalational agents with greater lipid solubility, the volume of distribution increases (Tables 16.1 and 16.3). Fat acts as a reservoir for volatile agents, resulting in the accumulation of inhalational agents during maintenance and delaying emergence. Depending on many variables, including the lipid solubility of the agent, less blood flow to fat tissue than other tissues, and the duration of anesthesia, an increase in the proportion of body fat may prolong emergence. Although the changes in body fat composition are greater in men and women have a greater percent body fat at all ages, there is no indication of a gender difference with the pharmacokinetics of inhalational anesthetic agents.
Table 16.3
Pharmacokinetics of newer volatile anesthetic agents
Agent | MAC | B/Ga | FGFb |  (min−1) | Cl12 c(mLvapor kg−1 min−1) | vdss c (mLvap/kgbw) |
|---|---|---|---|---|---|---|
Sevoflurane | 2.1 | 0.69 | 2 | 0.117 (0.070–0.344) | 13.0 (9.8–22.4) | 1748 (819–8997) |
Isoflurane | 1.2 | 1.4 | <1 | 0.158 (0.065–0.583) | 30.7 (15.9–38.7) | 4285 (1509–9640) |
Desflurane | 6 | 0.42 | <1 | 0.078 (0.029–0.186) | 7.0 (4.4–11.1) | 698 (408–1917) |
The lipid-soluble drugs redistribute slowly from fat tissue so their effect may be prolonged. The loss of skeletal muscle mass has a significant impact on drug pharmacokinetics because this tissue receives a large portion of the blood supply. As the body fat content increases, a smaller part of each circulating blood volume perfuses this tissue and it diminishes the volume of distribution for the agents that are not very lipid soluble.
Most body fat resides in subcutaneous and abdominal areas. However, body fat may be heterogeneous and various anatomic fat stores may differ in their capacity to act as a reservoir for lipid-soluble drugs [40]. Subcutaneous fat that develops from excessive eating may function differently from the epicardial or mesenteric fat that is present even in very lean individuals. How this might affect the uptake and retention of lipid-soluble inhalational agents is yet to be determined.
The steady-state volume of distribution, Vdss, is greatest [41] for isoflurane and least with desflurane (Table 16.3). The movement of volatile agent from the central to peripheral compartments is fastest for desflurane and intermediate for sevoflurane, whereas isoflurane is the slowest. It is not just the greater solubility of isoflurane that accounts for its Vd being six times that of desflurane. Isoflurane increases blood flow to tissues such as skeletal muscle, a tissue with large storage capacity [41, 42].
The partial pressure of anesthetic permitting wakefulness, the MAC-awake value, determines the emergence from general anesthesia. The MAC-awake value for all volatile anesthetics is about one-third the MAC value. A slow, continued release of volatile agent from fat tissue can maintain a partial pressure of agent in the blood causing excessive sedation, respiratory depression, and contribute to postanesthesia delirium. This action may contribute to a greater incidence of postoperative complications and prolonged stays in the PACU.
The increasing proportion of body fat suggests an advantage with the less-soluble volatile anesthetic drugs. Emergence from general anesthesia has been studied by comparing desflurane and isoflurane anesthesia in elderly patients. Compared with isoflurane anesthesia, signs of early recovery and endotracheal tube removal occurred in approximately half the time with desflurane. Emergence was also faster than with intravenous anesthesia [43]. For short procedures (less than 2 h), patients reached signs of early recovery and experienced endotracheal tube removal sooner with desflurane compared with [44] sevoflurane.
Influence of Renal Changes
Renal atrophy occurs with age, mainly through the loss of cortical nephrons. The kidney loses about 20% of its mass by age 80, and functional changes accompany renal atrophy. Most subjects experience a decrease in renal blood flow, glomerular filtration rate (GFR), and creatinine clearance. The reduction in renal blood flow probably results from cardiovascular changes in addition to renal changes [45]. However, the Baltimore Longitudinal Study of Aging showed that a decline in the GFR is not inevitable because 30% of healthy individuals have no decrease in GFR with age [46]. The plasma creatinine level varies with the muscle mass and with age-related changes in body composition accompanying the aging process. Thus, it is better to evaluate renal function in the elderly using the Cockroft–Gault formula [(140 − age) × weight (kg)/Cr × 72] than simply using the plasma creatinine value [47] (Fig. 16.10).
Fig. 16.10
The relationship between serum creatinine and creatinine clearance by age. The glomerular filtration rate (GFR) decreases most individuals after age 30 but a decline in GFR is not inevitable. The graphs are standardized for a 70 kg male with values calculated using the Cockroft–Gault formula (Based on data from Hughes et al. [39])
All volatile anesthetic agents in clinical use are fluorinated ether compounds. The constellation of renal changes may place the older patient at greater risk for [48] fluoride toxicity (Table 16.1). Inorganic free fluoride ions form during metabolism of these agents by the hepatic cytochrome P-450 enzyme system. Toxic levels of free fluoride produce a high output, vasopressin-resistant form of acute renal failure [49]. This disorder was first reported with methoxyflurane in 1966.
The only inhalation agents used today that can produce enough fluoride to be of concern are enflurane, isoflurane, and sevoflurane [50–52]. The threshold fluoride level for causing mild defects in renal concentrating ability is 50 μmol/L [53]. Experiments with cultured collecting duct cells indicate mitochondria may be the target of the free fluoride ion [54].
Whether fluoride toxicity results from the use of modern inhalational anesthetics is in doubt. Concern surrounded the use of sevoflurane because about 5% of it is metabolized by the cytochrome P-450 2E1 isoform [55]. Of that, 3.5% appears in the urine as free fluoride ion [56]. This is less than the fluoride production from methoxyflurane metabolism but more than that seen with either enflurane or isoflurane.
The likelihood of fluoride toxicity has been questioned because fluoride levels greater than 50 μg/L were reached in studies comparing sevoflurane and enflurane administration in humans, yet they did not demonstrate nephrotoxicity [57]. The mean fluoride level in patients receiving sevoflurane was 47 μmol/L, twice the 23 μmol/L level in patients that received prolonged enflurane anesthesia. More than 40% of subjects having prolonged sevoflurane anesthesia had plasma fluoride levels greater than 50 μmol/L, with no impairment of renal concentrating ability. The results of this study should be cautiously extrapolated to the elderly because it included only young volunteers in their mid-twenties [58]. Neither enflurane nor halothane produced a further decrease of renal function in patients with moderate renal insufficiency [59]. Enflurane is now used infrequently for general anesthesia. There are no clinical reports that actively assert that enflurane should be avoided in elderly patients with renal insufficiency.
A toxic fluoride threshold more likely will be met with prolonged exposure to isoflurane than halothane. The peak plasma level of fluoride occurs 24 h after an average 10-h administration of isoflurane. This is equivalent to 19.2 MAC hours of isoflurane exposure. With this level of exposure, 40% of patients studied had fluoride levels slightly greater than 50 μmol/L. In contrast, similar exposure to halothane produced lower fluoride levels with the highest plasma levels occurring at the end of the surgical cases. Among elderly patients with renal insufficiency, no further deterioration of renal function resulted with the use of isoflurane, enflurane, or sevoflurane anesthesia [60]. Desflurane poses very little risk to patients with renal insufficiency because so very little of it is metabolized [61].
Sevoflurane breaks down in the alkaline environment of the carbon dioxide absorber to form fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether, or Compound A. This happens particularly at low total gas flows. Like free fluoride ions, compound A is also nephrotoxic. The production of Compound A is increased with greater production and absorption of carbon dioxide because the degradation of sevoflurane increases with absorber temperature [58–64]. The combination favoring production of Compound A includes not only increased CO2 absorption but also absorber temperature, decreased CO2 washout, and high levels of sevoflurane [23, 65, 66]. Compound A is clearly nephrotoxic in the laboratory, but it is not certain whether any instances of renal failure occurred from using sevoflurane. In patients with normal renal function and ranging in age from 30 to 69 years, Compound A accumulated during anesthesia with 1 LPM gas flows. Yet, there was no difference detected in clinical or biochemical markers of renal function when those patients were compared with subjects receiving isoflurane anesthesia [67]. Compound A does not accumulate in breathing circuits or carbon dioxide absorbers when gas flows are 5 L/min, but because of the potential for Compound A formation, sevoflurane is not recommended for use at less than 2 LPM fresh gas flow [68]. Nevertheless, no differences in biochemical markers were noted among patients receiving sevoflurane at low-flow (1 L/min), high-flow (5–6 L/min), or low-flow isoflurane anesthesia, and no evidence of renal toxicity exists [69]. Furthermore, in older patients with moderately impaired renal function , sevoflurane anesthesia does not cause apparent injury to the renal tubules [70], and low-flow anesthesia with sevoflurane does not result in any greater change in blood urea nitrogen, creatinine , or creatinine clearance than isoflurane [71].
Influence of Hepatic Changes
There is a similar atrophy of the liver that is accompanied by a reduction in hepatic blood flow [72–74]. Decreased hepatic blood flow results in diminished metabolism of drugs that rely on hepatic clearance. The decrease in hepatic blood flow seems responsible for the decreased hepatic metabolism of drugs and not changes in hepatic enzyme activity [75].
The newer inhalational agents are not extensively metabolized. Of all the volatile agents, halothane is the most extensively transformed with approximately 20% of it metabolized in the liver [76]. The other agents in common use are metabolized to a much lesser extent. Approximately 5% of sevoflurane, 2.4% of enflurane, 0.2% of isoflurane, and 0.02% of desflurane are metabolized [16, 77–79] (Table 16.1). Metabolism of halothane, isoflurane, and desflurane produces trifluoroacetic acid. The amount of this metabolite produced is lowest with desflurane [76, 80–83].
The hepatic-function changes associated with aging are probably important only for halothane and sevoflurane because the other agents undergo only minimal transformation. The loss of hepatic tissue with age may be associated with decreased metabolism of the volatile agents, but this is not documented. If decreased metabolism of these drugs occurs, it is probably not clinically significant.
Volatile anesthetic agents have a variable effect on liver function . Sevoflurane decreases production of fibrinogen, transferrin, and albumin in cultured hepatocytes more than exposure to halothane, isoflurane, or enflurane does [84]. However, enflurane causes greater depression of albumin synthesis than sevoflurane. The effects of desflurane on hepatic synthesis are not known. It is not anticipated that it would have much effect because so little of it is metabolized [85].
Many drugs bind to plasma proteins, and several intravenous anesthetic drugs are carried in the blood bound to plasma proteins. Albumin is a carrier for many drugs, and low blood concentrations of albumin are frequently encountered in elderly patients. This probably contributes to the exaggerated effects of many drugs in older subjects because of the greater fraction of unbound free drug. There is no evidence suggesting that volatile agents rely on protein binding for transport or that the increased sensitivity to volatile anesthetics works through this mechanism.
The Pharmacodynamics of Inhalational Agents in the Elderly
The introduction of halogenated ethers with progressively lower solubility characterizes the era of modern agents. As the solubility of newer agents approaches that of nitrous oxide, the result is a more rapid uptake and faster elimination of the drug. Theoretically, low solubility and faster uptake also allow greater control of anesthetic blood levels during the maintenance phase of anesthesia. Faster elimination with low-solubility agents should provide for a rapid emergence from anesthesia. Inhalational agents used for general anesthesia include isoflurane, sevoflurane, desflurane, halothane, and enflurane. For practical purposes, the first three warrant most consideration because they represent the majority of volatile agents used. The properties of the inhalational agents are found in Table 16.1.
Aging and the MAC
The classic expression of pharmacodynamic effect for volatile anesthetic agents is the MAC. MAC is the minimal alveolar concentration of a volatile drug at 1 atm that prevents movement in 50% of subjects following surgical incision [86]. The concentrations of volatile agents defined by MAC values are usually not enough for adequate anesthesia during surgical cases. Frequently, about 1.3 times MAC, or essentially an ED95 dose of anesthetic, is needed [87].
For adult subjects, the MAC is 1.15% for isoflurane, 6% for desflurane, and 1.85% for sevoflurane . As patients age, MAC decreases for all the volatile drugs, generally occurring at approximately 6% per decade [88]. The decrease in drug requirement does not follow a linear relationship but accelerates after 40–50 years of age. This phenomenon also applies to intravenous anesthetic drugs in which the pharmacokinetics of injected drugs changes substantially with age [89]. Guedel [90] was the first to note that inhalational anesthetic requirements decrease with age. This has subsequently been documented for halothane [91], isoflurane, [92] enflurane, desflurane [93, 94], and sevoflurane [95]. The mathematic relationship of MAC, age, end-expired concentration of anesthetic agent, and the contribution by nitrous oxide has been determined [96]. A nomogram for estimating age-related changes in MAC is available (Fig. 16.11).
