The onset of effect of NMBAs is determined by, in addition to their potency, the time that it takes them to get to the neuromuscular junction. The speed with which they are delivered to the neuromuscular junction is influenced by circulation to the muscles and cardiac output. Once the neuromuscular blocking agent arrives at the muscle, it must diffuse into the neuromuscular junction and bind with the acetylcholine receptor to cause neuromuscular blockade. In geriatric patients, although there are some differences as to the extent (Table 20.1), increased age is generally associated with a slower onset of neuromuscular block when doses of 2 × ED₉₅ (two times the dose that causes, on average, 95% neuromuscular block) or greater are administered. Differences in onset are more apparent when doses that do not cause complete NMB are examined [24] (Fig. 20.2). The administration of doses causing complete paralysis allows only for the determination of the time required to achieve 100% neuromuscular block. Administration of smaller doses (<ED₉₅) allows the time required for the compound to actually have its maximal effect to be measured. While the greater time required for maximal effect in the elderly may be attributable to a decreased cardiac output, physically active, healthy geriatric patients do not necessarily have a decline in cardiac function [29, 30].

In a study in patients over the age of 65 years who were receiving oxygen-nitrous oxide-isoflurane anesthesia, cisatracurium (0.1 mg/kg) was administered after induction of anesthesia [31]. Onset of block was slower in elderly individuals than in young adults (3 versus 4 min, respectively). Pharmacodynamic modeling demonstrated that biophase equilibration was slower in the elderly than in young adults (0.06 versus 0.071, respectively), and the authors attributed the slower onset of neuromuscular block to the slower biophase equilibration. The relative contributions of decreased cardiac output and slower biophase equilibration remain to be determined.

The slower onset of NMB in geriatric patients may result in overdosing of the NMBAs. In an effort to shorten the onset of effect, larger or additional doses of NMBAs may be administered. The larger doses result in an increased duration of action of the neuromuscular blocking agent. Furthermore, for those compounds that are eliminated through hepatic and renal mechanisms, the larger doses and administration of subsequent doses result in cumulation so that each subsequent dose lasts longer than those administered previously [32]. This progressive prolongation of effect occurs because recovery of neuromuscular function begins during redistribution of NMBAs, such as pancuronium or vecuronium, out of the plasma and into storage sites rather than during elimination of the compound from the body. With subsequent doses, the earlier doses are reentering the plasma for elimination. The drug effect, therefore, is a combination of the effects of the recently administered relaxant and a portion of the earlier doses as both contribute to plasma concentration. This effect is more pronounced with the long-acting pancuronium than with the intermediate-acting vecuronium.

Aging, even in healthy elderly patients, is accompanied by decreases in hepatic and renal blood flow and function [33, 34]. Because the majority of nondepolarizing neuromuscular blocking agents are eliminated through some combination of these means, alterations in pharmacokinetics and duration of effect are to be expected. Alterations in the pharmacodynamics of nondepolarizing compounds as a result of changes in the pharmacokinetics associated with the normal process of aging may be difficult to distinguish from concomitant disease processes.

Of the long-acting neuromuscular blocking agents, pancuronium is the only one that is available for clinical use. These long-acting compounds generally depend primarily on the kidney for their elimination from the body (Table 20.2). It is not surprising, therefore, that they have a longer duration of action in geriatric patients. As found in the majority of studies of these compounds, their prolonged duration of action can be attributed to a prolonged elimination half-life and a decreased clearance, when compared to young adults (Table 20.3).

This is true for pancuronium, which, while still clinically available, is used relatively infrequently. McLeod [36] demonstrated a decrease in the clearance of pancuronium with increasing age. In a later study, Duvaldestin [19] studied the pharmacokinetics and dynamics of pancuronium in young and elderly adults and found that recovery intervals were prolonged by at least 60% in the elderly. The clearance of pancuronium was decreased more than 30% in the elderly, from 1.8 in young adults to 1.2 mL/min/kg (Fig. 20.3). Because the volume of distribution in the elderly was the same as in young adults, the decrease in clearance was accompanied by a doubling of the elimination half-life from 107 to 201 min.

In contrast to the dependence of the long-acting NMBAs on the kidney for their elimination, the intermediate-acting compounds are eliminated from the body primarily through other mechanisms (Table 20.2). These include hepatic elimination, ester hydrolysis, and Hofmann degradation. In addition to decreases in renal function and blood flow, aging is associated with decreases in hepatic blood flow and hepatocellular function [26, 27, 37]. One would expect, therefore, that compounds relying on either of these means of elimination from the body would have altered pharmacokinetics. In contrast, clearance by Hofmann elimination is independent of end-organ function, and aging should have little impact on the pharmacokinetics of compounds eliminated through this mechanism.

Vecuronium was the first of the intermediate-acting nondepolarizing NMBAs to be introduced into clinical practice. Although it is eliminated primarily in the bile [38, 39], 20–25% of the compound is eliminated unchanged in the urine. The action of vecuronium in the elderly has been studied by four different groups of investigators [16, 20, 39, 40], and the results regarding pharmacokinetics and pharmacodynamics have not been consistent. d’Hollander and colleagues [39] examined the rate of recovery from vecuronium-induced NMB in geriatric patients. Recovery rates were compared to those in patients under the age of 40 and those between 40 and 60 years of age. The 10–25% and 25–75% recovery intervals, the time to recover from 10% to 25% and 25% to 75% baseline muscle strength, respectively, were significantly prolonged in the elderly patients. Additionally, less vecuronium was required to maintain 90% neuromuscular block for a period of 90 min in the elderly patients than it was in the younger individuals [39]. McCarthy [40] reported very similar findings with the clinical duration of action (the time from administration of an NMBA to 25% recovery of baseline muscle strength) of vecuronium being significantly prolonged in the elderly following administration of a bolus dose.

Rupp [20] studied the pharmacokinetics and dynamics of vecuronium in elderly patients in whom an infusion of the NMBA had been discontinued once 70–80% NMB had been achieved. The clearance and volume of distribution of vecuronium in patients older than 70 years of age were approximately 30% less than what was found in younger adults. Elimination half-life and the 25–75% recovery interval, however, were similar in young adult and elderly patients. Lien [16] found that the 5–25% and 25–75% recovery intervals were approximately three times longer in elderly patients than in young adults following administration of a single intravenous dose of vecuronium. The clearance of vecuronium was half as fast in the elderly as it was in young adult patients (2.6 vs 5.6 mL · kg⁻¹, respectively) and elimination of the compound was slower in geriatric patients (78 and 125 min for young adult and elderly patients, respectively). The authors concluded that the prolonged duration of action of vecuronium in elderly patients is attributable to its decreased clearance in this patient population, supporting the findings of d’Hollander and colleagues [39]. The decreased clearance is not inconsistent with the findings of Rupp et al. [20]

Like vecuronium, rocuronium is an intermediate-acting nondepolarizing NMBA with a steroidal structure. Similar to vecuronium, the kidney is not its primary means of elimination from the body. However, while it does not depend on the kidney for its elimination, clearance of rocuronium is decreased and its mean residence time is prolonged in patients with renal failure [37]. As with vecuronium, the behavior of this compound in aged patients has been studied by different groups of investigators [22, 26, 27]. In the case of rocuronium, however, the results are more similar across the studies. Baykara et al. [27] reported that recovery of the first response in the train of four after administration of 1 mg/kg was slower in the elderly than in young adults. Bevan et al. [22] found, in a study of repeat bolus doses of rocuronium, that the clinical duration of action and the 25–75% recovery intervals were prolonged in elderly patients. With repeated doses of 0.1 mg/kg rocuronium administered at 25% recovery of twitch height, the duration of action increased in the elderly patients but not in the young adult patients. Matteo et al. [26] studied the pharmacokinetics and pharmacodynamics of rocuronium in geriatric patients following a 0.6 mg/kg dose and found that in patients between the ages of 70–78 years, clearance was decreased by 27%. Not unexpectedly, the 25–75% recovery interval was increased from 13 min in the young adults to 22 min in the elderly patients.

In contrast to NMBAs with a steroidal structure, atracurium depends on neither the kidney nor the liver as its primary means of elimination. It undergoes ester hydrolysis and the base and temperature catalyzed process of Hofmann elimination (Table 20.2). Because the elimination of atracurium is not end-organ dependent, the physiologic changes associated with aging would not be expected to affect its pharmacokinetics and recovery profile. As they had done with vecuronium, d’Hollander and colleagues [41] studied atracurium in patients over the age of 60 years. In this study, patients received an infusion of atracurium to maintain 90% depression of neuromuscular function for 90 min. The dose of relaxant required to maintain this depth of paralysis was calculated in the age groups studied (older than 60 years, 40–60 years, and younger than 40 years of age). There were no differences among the groups in either their 10–25% and 25–75% recovery intervals or the amount of relaxant necessary to maintain 90% twitch suppression.

Slight changes in the pharmacokinetics of atracurium in elderly patients, however, have been reported. Kent et al. [42] administered 0.6 mg/kg atracurium to elderly and young adult patients and found no difference in clearance and the volume of distribution between the two patient groups. There was, however, a small but significant difference in the elimination half-life. The elimination half-life of atracurium was prolonged by 15% in elderly patients, from 20 to 23 min. Kitts et al. [35] administered an infusion of atracurium to achieve 70% neuromuscular block. As described by Kent [42], elimination half-life was prolonged in the elderly. Because clearance was not affected by advanced age, the increase in elimination half-life was attributable to a larger volume of distribution in elderly patients. Most recently, Parker et al. [43] found that its elimination half-life was prolonged and clearance decreased in elderly patients. The results of Kitts, Kent, and Parker support the finding by Fisher et al. [44] that in addition to Hofmann elimination and ester hydrolysis, renal and hepatic mechanisms contribute to the elimination of the compound. Despite these pharmacokinetic differences in elderly patients, however, the dynamics of neuromuscular blockade with atracurium are not different in the young and elderly [35, 41].

Cisatracurium is one of the ten isomers that comprise atracurium. Similar to atracurium, it is eliminated primarily through Hofmann elimination. Renal clearance accounts for 16% of its elimination from the body [45]. As with atracurium, small changes have been found in the pharmacokinetics of this compound in elderly patients. Ornstein et al. [28] described a prolongation of its half-life of 4 min (21.5 versus 25.5 min in young and elderly patients, respectively) and an increase in its volume of distribution (108 versus 126 mL · kg⁻¹ in young and elderly patients, respectively). Clearance was unchanged with advanced age. Sorooshian et al. [31] also found that clearance was unaffected by advanced age. The volume of distribution in the elderly, however, was larger. Both studies found no difference in recovery of neuromuscular function after administration of 0.1 mg/kg cisatracurium. In a later study, Pühringer et al. [46] also noted the lack of effect of small changes in pharmacokinetics of cisatracurium on the duration of action of the compound in the elderly. Patients received 0.15 mg/kg cisatracurium to induce neuromuscular blockade and 0.03 mg/kg boluses to maintain neuromuscular blockade. The clinical duration of action after the initial dose and the time to return to a train-of-four ratio of 0.8 following the last dose of cisatracurium were the same in young adults and those older than 65 years of age.

While no longer widely clinically available, mivacurium is the only available nondepolarizing neuromuscular blocking agent with a short duration of action that was used for a significant period of time. Like succinylcholine, it is metabolized by butyrylcholinesterase (BChE) and is dependent on neither hepatic nor renal function for its elimination. Recovery from mivacurium-induced block is prolonged in the elderly [47]. In this study, patients received either a bolus of 0.15 mg/kg mivacurium and were allowed to recover or, following the bolus, were given an infusion to maintain 90% suppression of neuromuscular response to stimulation. All recovery parameters were prolonged by approximately 30% in elderly patients. The amount of mivacurium required to maintain neuromuscular blockade was also reduced (3.7 versus 5.5 μg/kg/min in the elderly and young, respectively). Goudsouzian et al. [48] also found that elderly patients required a lower infusion rate to maintain a stable depth of block. A study of the kinetics of mivacurium in the elderly does not explain the prolongation of recovery observed in this patient population [49]. The investigators found that the half-life and clearances of the three isomers of mivacurium, cis-trans, trans-trans, and cis-cis, were not different in elderly patients. The volume of distribution of the relaxant was, however, larger in the elderly.

Plasma cholinesterase activity is reduced in the elderly [50] and mivacurium requirements are inversely related to BChE activity [51] in that patients with higher BChE activity require higher mivacurium infusion rates to maintain the desired depth of block than patients with lower BChE activity. When mivacurium is used in geriatric patients, lower infusion rates are required to maintain a stable depth of NMB and, if administered as repeated boluses, longer dosing intervals would be anticipated.

Residual NMB is a risk whenever a nondepolarizing NMBA is administered. The incidence of residual NMB, defined as a train-of-four ratio < 0.90, has been reported to be as high as 62% [52]. While it occurs in both young and elderly patients, residual neuromuscular block appears to be a more frequent occurrence in geriatric patients [53, 54]. An increased frequency of residual NMB in this patient population occurs because of a combination of factors including relative overdosing because of a slower onset of effect, a decreased clearance, decreased muscle mass, and increased variability in the duration of action of NMBAs [55–57].

Residual NMB is well recognized as being associated with adverse events [58–61]. One prospective trial of patient outcome after general anesthesia that included the use of NMBAs (vecuronium, atracurium, or pancuronium) [58] demonstrated that elderly patients who received pancuronium were likely to enter the postanesthesia care unit (PACU) with a train-of-four ratio less than 0.7 more frequently than the younger adult patients, regardless of the NMBA they received. Additionally, these patients were more likely to develop postoperative pulmonary complications than patients who had arrived to the postanesthesia care unit with a train-of-four ratio ≥ 0.7. More recently, Pietraszewski [54] found that elderly patients were more likely to have hypoxia and inadequate recovery of neuromuscular function in the PACU. The one patient in this relatively small study who developed postoperative pneumonia was elderly, and the cause of the complication was determined to be residual paralysis. In a larger trial, Murphy [53] found that although younger patients received larger doses of rocuronium, residual NMB occurred more commonly in geriatric patients. Elderly patients with residual NMB were more likely to develop airway obstruction and hypoxemia before reaching the PACU and to report symptoms of muscle weakness than elderly patients who had adequate recovery of neuromuscular function. This finding is not unexpected as residual NMB interferes with the coordination of swallowing [62, 63] and the response of the carotid body chemoreceptor to hypoxia [64]. Consistent with the results of Berg’s study [58], there was a trend toward longer hospital stays and more pulmonary complications in the geriatric population with residual NMB. Cedborg [65] found 1 year earlier that residual paralysis in geriatric volunteers resulted in an increase in both the severity and frequency of pharyngeal dysfunction.