ORIGINAL ARTICLES
Distribution, Elimination, and Action of Vecuronium in the Elderly Cynthia A. Lien, MD, Richard s. Matteo, MD, Eugene Omstein, PhD, MD, Arthur E. Schwartz,
MD,
and Jaime Diaz
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York
The effects of age on the pharmacokinetics and pharmacodynamics of vecuronium in eight elderly patients aged 72-86 yr and eight younger adults aged 26-48 yr undergoing elective surgical procedures under nitrous oxide-fentanyl anesthesia were studied. Vecuronium (0.1 mg/kg) was given as an intravenous bolus, and the ulnar nerve was stimulated with a square-wave impulse of 0.2-ms duration. The response to stimulation a t a frequency of 0.1 Hz was measured and recorded with a force displacement transducer applied to the thumb. Spontaneous recovery was significantlylonger in elderly patients than in
T
here have been conflicting reports in the elderly of the pharmacokinetics and pharmacodynamics of vecuronium, a nondepolarizing muscle relaxant of intermediate duration of action. D'Hollander et al. (1)in a study of patients older than 60 yr and two groups of younger patients found that spontaneous recovery indexes from 10% to 25% and from 25% to 75% twitch height were significantly longer in the older patients. Although they did not study kinetics, their results suggested decreased elimination of the drug in elderly patients. Rupp et al. (2,3) examined the pharmacokinetics and pharmacodynamics of vecuronium in eld y patients given an l discontinued once infusion of vecuronium that k fas twitch tension had decreased'to 20%-30% of control. Elderly patients (>70 yr d d ) had significantly decreased plasma clearances and volumes of distribution, whereas elimination half-life of vecuronium and recovery index (25%-75% of control) were not significantly different, when compared with that of their younger counterparts. They concluded that "healthy elderly patients d o not appear to represent a popula-
Accepted for publication February 20, 1991. Address correspondence to Dr. Lien, Department of Anesthesiology, The New York Hospital, Cornell Medical Center, 525 East 68th Street, New York, NY 10021. 01991 by the International Anesthesia Research Society 0003-2999/911$3.50
younger patients (50% recovery time, 97.1 ? 29 vs 39.8 +- 14 min, mean L SD; recovery index [25%75%], 49.4 +- 11 vs 15.0 ? 8 min). In addition, in elderly patients elimination half-life of vecuronium was significantly prolonged (125 & 55 vs 78 * 21 min, P = 0.04) and plasma clearance reduced (2.6 t 0.6 vs 5.6 ? 3.2 mL.kg-'.min-', P = 0.049). The prolonged duration of action of vecuronium in the elderly surgical patients thus appears to be secondary to altered pharmacokinetics consistent with an age-related decrease in renal and hepatic functions. (Anesth Analg 1991;73:3942)
tion distinctly different from younger adults in their pharmacokineticipharmacodynamic response." The present study was undertaken to obtain additional data on the distribution, elimination, and action of vecuronium in elderly patients with the intention of clarifying and reconciling the conflicting reports of vecuronium in elderly surgical patients.
Methods After institutional review board approval, informed consent was obtained from eight young (aged 2& 48 yr) and eight elderly (aged 72-86 yr) ASA physical status 1-111 patients undergoing elective neurosurgical procedures. Patients with hepatic, renal, or neuromuscular disease and those taking medications known to affect neuromuscular transmission were eliminated from the study. Patients were premedicated with oral diazepam (10 mg) and with intramuscular glycopyrolate (0.2 mg) at the discretion of their anesthesiologists. In the operating room, electrocardiograms, pulse oximeters, blood pressure cuffs, capnographs, and esophageal temperature probes were used for monitoring. After preoxygenation, anesthesia was induced with fentanyl (4-7 pglkg), midazolam (20-100 pglkg), droperidol (1040 pgikg), and thiopental (2-5 mglkg). 39
40
ANESTH ANALG
LIEN ET AL. VECURONIUM IN THE ELDERLY
1991;73:3942
Ventilation with nitrous oxide and oxygen (70%:30%) was controlled using an anesthesia face mask. The ulnar nerve was stimulated at the wrist through surface electrodes with a supramaximal square-wave impulse of 0.2-ms duration. The stimulus was delivered at a frequency of 0.1 Hz from a Grass S8 stimulator in conjunction with a Grass stimulation isolation unit. Response to stimulation was measured and recorded with a force displacement transducer (Grass model FT-10) applied to the thumb. Once the baseline adduction response of the thumb was obtained, patients were given vecuronium (0.1 mgkg) as an intravenous bolus. After vecuronium was administered, the trachea was intubated and mechanical ventilation was instituted and adjusted to maintain normocarbia. Anesthesia was maintained with 70% nitrous oxide, 30% oxygen, and a continuous fentanyl infusion of 2-3 pg.kg-l.h-'. After the twitch response had returned to at least 90% of the baseline, atracurium was given if further muscle relaxation was required. Esophageal temperature was maintained between 34.8 and 36.6"C with warming blankets. Heparinized blood samples were obtained from an indwelling arterial catheter just before the administration of vecuronium and 1, 3, 5, 10, 15, 20, 30, 45, 60, 75,90, 120, 150, 180, 210, 240, 300, and 360 min after its administration. These samples were immediately placed in tubes containing 1 M sodium phosphate buffer at a pH of 4.0. The ratio of blood to buffer was 4:l. Additional samples were drawn between the timed lunetic samples as warranted by return of twitch response. The plasma was separated and frozen. At a later date, the samples were prepared for analysis using an anion exchange column (Bakerbond specially made by J.T. Baker, Phillipsburg, N.J.). Vecuronium concentration was determined by the spectrofluorometric method described by Kersten et al. (4). The maximum sensitivity of this method is 25 ng/mL with the coefficients of variation no more than 6%. The times to 5%, 25%, 50%, and 75% recovery of twitch height were recorded, and the 5%-25% and 25%-75% recovery indexes were determined. The plasma concentration versus time-course curves for each patient were fit to both biexponential and triexponential equations, using weighted nonlinear leastsquares regression analysis (5). A weighting function of 1/x: was used. The best fit for the data was then determined by the method of Boxenbaum et al. (6). Pharmacokinetic values were calculated using standard methods for bolus intravenous iniection of a drug. The fema1e:male ratios were compared using analysis. The recovery indices, recovery times, and pharmacokinetic values were compared between the elderly and control groups using Student's two-tailed t-tests for unpaired data. The concentration-time data points were compared in the two groups using re-
Table 1. Demographics and Intraoperative Conditions of the Study Populations Young
P
Elderly ~
Sex (F:M)
3:5 81 2 14 35.9 2 0.4 29 t 2
Weight (kg) Temperature ("C) ETco, (mm Hg)
4:4 71 2 14 35.7 2 0.7 29 2 7
0.642 0.200 0.536 0.855
ETco,, end-tidal carbon dioxide tension Values are mean i SD.
Table 2. Recovery Times and Recovery Indices Young Time to recovery (min) 5% 25% 50% 75% Recovery index (min) 5%-25% 25%-75 70 Valuec are mean
21.1 2 32.0 2 39.8 47.9 2
*
7.3 11.6 13.5 15.6
10.7 2 5.2 15.0 2 8.0
Elderly
P
47.3 2 15.5 73.8 t- 24.4 97.1 f 29.3 123.1 t 33.3
0.001 0.001 0.0002 0.0001
27.8 2 18.0 49.4 ? 11.4
0.032 0.0001
2 SD
peated measures analysis of variance. The threshold for statistical significance was P < 0.05.
Results The age of the young control group was 41 5 7 yr (mean ? SD) and that of the elderly patients 77 -+ 4 yr. There were no significant differences between the two study populations in terms of sex, weight, intraoperative ETco,, and temperature (Table 1). The return of twitch and the recovery indexes were significantly longer in the elderly than in the younger patients (Table 2). Figure 1 demonstrates the plasma time-concentration data (? SD) for each of the groups. At 60 min, the plasma concentration of vecuronium in the elderly group of patients became significantly greater than the plasma concentration in the control group. The statistical significance of this difference continued throughout the remainder of the study. Plasma decay curves for both groups were best described by biexponential equations. In the elderly, elimination half-life of vecuronium was significantly prolonged and clearance of vecuronium was decreased (Table 3).
2
~
i
~
~
~
The distribution and elimination of drugs in the elderly may be altered by a multitude of physiologic changes that accompany the aging process. These
~
LIEN E T A L . VECURONIUM IN THE ELDERLY
ANESTH ANALG 1991;73:3942
10000~
1''
0
60
120
180 240 Time (minutes)
300
360
Figure 1. Plasma concentration versus time-course in elderly (0-0)and in younger (0-0) patients after a single intravenous dose (0.1 mgikg) of vecuronium. Values are mean 2 SD; I I = 8 in each group except at 360 min where II = 5 for elderly and J I = 6 for younger patients.
Table 3. Pharmacokinetic Variables Variables t,,, elim (min) Clp (mL.kg-'.min-') Vi (Likg) Vd area (Likg)
Young 78 5.6 0.08 0.49
21 3.2 0.02 2 0.02
2 2
*
Elderly 125 2 2.6 ? 0.08 0.44
* *
55 0.6 0.01 0.01
P 0.040 0.049 0.474 0.335
f,,2 elim, half-life of elimination; Clp, plasma clearance, Vi, initial volume of distribution; Vd area, volume of distribution. Values are mean 5 SD.
41
They found that the recovery indices of both 10%25% and 25%-75% were significantly prolonged in the group greater than 60 yr of age. Although they did not study kinetics, their results suggested decreased elimination of the drug in elderly patients. Rupp et al. (2,3) looked at both the pharmacokinetics and pharmacodynamics of vecuronium in the elderly. Their patients were given a continuous infusion of 2.5 pg.kg-'.minp' of vecuronium until the twitch tension was 20%-30% of control, at which point the infusion was terminated. Elderly patients (>70 yr old) had significantly decreased plasma clearances and volumes of distribution, whereas elimination half-life of vecuronium and recovery indices (25%75% of control) were not significantly different from younger counterparts. It was concluded that "healthy elderly patients do not appear to represent a population distinctly different from younger adults in their pharmacokineticlpharmacodynamic response." In contrast, the data presented in this study demonstrate prolonged recovery after an intravenous bolus of vecuronium, prolonged elimination half-life, and decreased clearance of vecuronium in the elderly. Although in the study of Rupp et al. (2,3), the reported kinetic and dynamic data obtained in younger patients (25%-75% recovery index, 10 t 1 min; elimination half-life, 70 20 min; clearance, 5.2 0.8 mL.kg-'.min-l; volume of distribution at steady state (Vd,,), 244 ? 38 mL/kg) are not that dissimilar from values reported in this study, there are significant differences in the data obtained for the elderly patients, including a recovery index of 11 1 min and an elimination half-life of 58 k 10 min versus the values of 49.4 t 11.4 and 125 55 min obtained in this study, respectively. There are several reasons that the results of this study may differ from those of Rupp et al. Differences in anesthetic technique (nitrous oxide-halothane used by Rupp's group as opposed to nitrous oxide-fentanyl used in this study) is a possible reason. A nitrous oxide-halothane anesthetic may cause prolonged recovery times when compared with the return of twitch during a nitrous oxide-narcotic technique. As the recovery indices in Rupp's study are appreciabljr less than those in this study, it is unlikely that anesthetic technique accounts for the differences observed. In addition, as the elderly patients in both Rupp's and our study received the same anesthetic as their respective controls, the anesthetic agents should not be a factor within each study. A major difference between the two studies is the method of vecuronium administration. In this study, 0.1 mg/kg of vecuronium was given as an intravenous bolus. This dose was sufficient to cause complete muscle paralysis in all patients, and twitch did not return to 5% of the control value for 21.1 ? 7.3 min (mean t SD) in the younger patients and 47.3 ?
*
*
*
changes include decreases in lean body mass, in total body water, in glomerular filtration and renal blood flow, in splanchnic blood flow, and in serum albumin levels, and increases in fat. The long-acting nondepolarizing muscle relaxants pancuronium (7,8), metocurine (9), and d-tubocurarine (9) have prolonged durations of action in the elderly related to decreased elimination of these drugs through the kidneys. The elimination of vecuronium is, in addition to being effected by the kidneys, highly dependent on hepatic clearance; 40% of a vecuronium dose is eliminated unchanged in the bile within 24 h after its administration (10). As aging is associated with reductions of both splanchnic and renal blood flows (11,12), one would expect duration of action and the elimination of vecuronium also to be prolonged in the elderly. Previous studies (1-3) have yielded conflicting results as to the pharmacodynamics of vecuronium in the elderly. DHollander et al. (1) studied recovery rates in patients older than 60 yr and compared them with results obtained in two younger groups of patients after the discontinuation of a continuous infusion of vecuronium adjusted to maintain twitch height constant at 10% of baseline for at least 90 min.
*
42
ANESTH ANALG 1991;73:39-42
LIEN ET AL. VECURONIUM IN THE ELDERLY
15.5 min in the elderly. Because return of twitch clearly occurred during the elimination phase of the drug in our study, a decrease of plasma clearance of vecuronium should produce a delay in recovery time. This indeed is what was observed in the elderly patients in this study. In contrast, Rupp et al. infused vecuronium until the twitch was 20%-30% of the control value, stopped the infusion, and began his measurements. No indication was given of the total dose of muscle relaxant given to the patients. The elderly may have received less relaxant to achieve the desired end point. If the elderly patients received a smaller dose of vecuronium than the younger controls, the possibility exists that Rupp et al. were looking at recovery during the redistribution phase rather than during the elimination phase. This could account for their surprising report that the clearance of vecuronium is significantly decreased in elderly patients although there is no difference in recovery time between the younger and elderly patients. In support of this theory, Fisher and Rosen (13), using computer simulation, determined the effect of the relaxant dose on the duration of action of the relaxants. They clearly demonstrated that when a moderate dose of vecuronium (40 pg/kg) is administered, recovery occurs during the drug’s distribution phase. As drug dose is increased, recovery of twitch occurs further into the elimination phase. These data can also be used to explain the finding of D’Hollander et al. after a prolonged infusion of vecuronium (90 min at a steady-state 90% depression of twitch response). In that study, elderly patients required a significantly longer period of time for return of twitch height from 25% to 75% of baseline value. Clearly in D’Hollander’s study, a large vecuronium dose was administered to the patients and a return of twitch response occurred during the elimination phase. Although D’Hollander et al. did not measure drug concentration nor calculate pharmacokinetic values, their results are clearly compatible with a decreased plasma clearance of vecuronium in elderly patients. Studies by Bell et al. (14) and O’Hara et al. (15) demonstrated no differences in the dose-response relationships of vecuronium in the elderly and in the young. In both studies, a single-dose methodology was used to compare the potency of the muscle relaxant in these two groups. Their results, because of study design, reflect the distribution of the muscle relaxant rather than its elimination. The distribution of a drug is, in turn, closely related to its volume of distribution. That there is no significant difference in the volumes of distribution between the elderly and the young patients in this study provides a clear pharmacokinetic explanation of why both Bell et al. and O’Hara et al. reported
no differences in the dose-response relationship of vecuronium between the two age groups. Our finding that the action of vecuronium is prolonged in the elderly is clearly in agreement with that of D’Hollander et al. The prolongation of vecuronium action appears to be secondary to decreased drug elimination in older patients, consistent with ageassociated decreases in hepatic and renal blood flows. The results of this study suggest that anesthesiologists should expect the action of vecuronium to be prolonged in the elderly surgical patient and emphasize the need to administer carefully and to monitor closely the effects of neuromuscular blocking agents in these patients. The authors acknowledge with gratitude the aid of Dr. Michael J. Avram, Assistant Professor, Department of Anesthesia, Northwestern University Medical School, in establishing the spectrofluorometric method of analysis of vecuronium in our laboratory.
References 1. D’Hollander AA, Massaux F, Nevelsteen M, Agoston S. Age2.
3. 4. 5. 6. 7.
8.
9.
10. 11.
12.
13. 14. 15.
dependent dose-response relationship of Org NC45 in anaesthetized patients. Br J Anaesth 1982;54:653-6. Rupp SM, Castagnoli KP, Fisher DM, Miller RD. Pancuronium and vecuronium pharmacokinetics and pharmacodynamics in younger and elderly adults. Anesthesiology 1987;67:45-9. Rupp SM, Fisher DM, Miller RD, Castagnoli K. Pharmacokinetics and pharmacodynamics of vecuronium in the elderly. Anesthesiology 1983;59:A270. Kersten UW, Meijer DKF, Agoston S. Fluorometric and chromatographic determination of pancuronium bromide and its metabolites in biological materials. Clin Chim Acta 1973;44:5946. Dixon W, Brown M, Engelman L, et al. BMDP Statistical Software. Berkeley: University of California Press, 1983:29C-304. Boxenbaum HG, Riegelman S, Elashoff RM. Statistical estimation in pharmacokinetics. J Pharmacokinet Biopharm 1974;2:12348. McLeod K, Hull CJ, Watson MJ. Effects of aging on the pharmacokinetics of pancuronium. Br J Anaesth 1979;51:435-8. Duvaldestin P, Saada J, Berger JL, D’Hollander A, Desmonts JM. Pharmacokinetics, pharmacodynamics and dose-response relationships of pancuronium in control and elderly subjects. Anesthesiology 1982;56:3640. Matteo RS, Backus WW, McDaniel DD, et al. Pharmacokinetics and pharmacodynamics of d-tubocurarine and metocurine in the elderly. Anesth Analg 1985;64:22-8. Bencini AF, Scaf AHJ, Sohn YJ, Kersten-Kleef UW, Agoston S. Hepatobiliary disposition of vecuronium bromide in man. Br J Anaesth 1986;58:98E-95. Bender AD. The effect of increasing age on the distribution of peripheral blood flow in man. J Am Geriatr Soc 1965;13:192-8. Leithe ME, Hermiller JB, Magorien RD, Unverferth DV, Leier CV. The effect of age on central and regional hemodynamics. Gerontology 1984;30:240-6. Fisher DM, Rosen JI. A pharmacokinetic explanation for increasing recovery time following larger or repeated doses of nondepolarizing muscle relaxants. Anesthesiology 1986;65:286-91. Bell PF, Mirakhur RK, Clarke RSJ. Dose-response studies of atracurium, vecuronium and pancuronium in the elderly. Anaesthesia 1989;44:925-7. OHara DA, Fragen RJ, Shanks CA. The effects of age on the dose-response curves for vecuronium in adults. Anesthesiology 1985;63:542-4.
Distribution, Elimination, and Action of Vecuronium in the Elderly Cynthia A. Lien, MD, Richard s. Matteo, MD, Eugene Omstein, PhD, MD, Arthur E. Schwartz,
MD,
and Jaime Diaz
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York
The effects of age on the pharmacokinetics and pharmacodynamics of vecuronium in eight elderly patients aged 72-86 yr and eight younger adults aged 26-48 yr undergoing elective surgical procedures under nitrous oxide-fentanyl anesthesia were studied. Vecuronium (0.1 mg/kg) was given as an intravenous bolus, and the ulnar nerve was stimulated with a square-wave impulse of 0.2-ms duration. The response to stimulation a t a frequency of 0.1 Hz was measured and recorded with a force displacement transducer applied to the thumb. Spontaneous recovery was significantlylonger in elderly patients than in
T
here have been conflicting reports in the elderly of the pharmacokinetics and pharmacodynamics of vecuronium, a nondepolarizing muscle relaxant of intermediate duration of action. D'Hollander et al. (1)in a study of patients older than 60 yr and two groups of younger patients found that spontaneous recovery indexes from 10% to 25% and from 25% to 75% twitch height were significantly longer in the older patients. Although they did not study kinetics, their results suggested decreased elimination of the drug in elderly patients. Rupp et al. (2,3) examined the pharmacokinetics and pharmacodynamics of vecuronium in eld y patients given an l discontinued once infusion of vecuronium that k fas twitch tension had decreased'to 20%-30% of control. Elderly patients (>70 yr d d ) had significantly decreased plasma clearances and volumes of distribution, whereas elimination half-life of vecuronium and recovery index (25%-75% of control) were not significantly different, when compared with that of their younger counterparts. They concluded that "healthy elderly patients d o not appear to represent a popula-
Accepted for publication February 20, 1991. Address correspondence to Dr. Lien, Department of Anesthesiology, The New York Hospital, Cornell Medical Center, 525 East 68th Street, New York, NY 10021. 01991 by the International Anesthesia Research Society 0003-2999/911$3.50
younger patients (50% recovery time, 97.1 ? 29 vs 39.8 +- 14 min, mean L SD; recovery index [25%75%], 49.4 +- 11 vs 15.0 ? 8 min). In addition, in elderly patients elimination half-life of vecuronium was significantly prolonged (125 & 55 vs 78 * 21 min, P = 0.04) and plasma clearance reduced (2.6 t 0.6 vs 5.6 ? 3.2 mL.kg-'.min-', P = 0.049). The prolonged duration of action of vecuronium in the elderly surgical patients thus appears to be secondary to altered pharmacokinetics consistent with an age-related decrease in renal and hepatic functions. (Anesth Analg 1991;73:3942)
tion distinctly different from younger adults in their pharmacokineticipharmacodynamic response." The present study was undertaken to obtain additional data on the distribution, elimination, and action of vecuronium in elderly patients with the intention of clarifying and reconciling the conflicting reports of vecuronium in elderly surgical patients.
Methods After institutional review board approval, informed consent was obtained from eight young (aged 2& 48 yr) and eight elderly (aged 72-86 yr) ASA physical status 1-111 patients undergoing elective neurosurgical procedures. Patients with hepatic, renal, or neuromuscular disease and those taking medications known to affect neuromuscular transmission were eliminated from the study. Patients were premedicated with oral diazepam (10 mg) and with intramuscular glycopyrolate (0.2 mg) at the discretion of their anesthesiologists. In the operating room, electrocardiograms, pulse oximeters, blood pressure cuffs, capnographs, and esophageal temperature probes were used for monitoring. After preoxygenation, anesthesia was induced with fentanyl (4-7 pglkg), midazolam (20-100 pglkg), droperidol (1040 pgikg), and thiopental (2-5 mglkg). 39
40
ANESTH ANALG
LIEN ET AL. VECURONIUM IN THE ELDERLY
1991;73:3942
Ventilation with nitrous oxide and oxygen (70%:30%) was controlled using an anesthesia face mask. The ulnar nerve was stimulated at the wrist through surface electrodes with a supramaximal square-wave impulse of 0.2-ms duration. The stimulus was delivered at a frequency of 0.1 Hz from a Grass S8 stimulator in conjunction with a Grass stimulation isolation unit. Response to stimulation was measured and recorded with a force displacement transducer (Grass model FT-10) applied to the thumb. Once the baseline adduction response of the thumb was obtained, patients were given vecuronium (0.1 mgkg) as an intravenous bolus. After vecuronium was administered, the trachea was intubated and mechanical ventilation was instituted and adjusted to maintain normocarbia. Anesthesia was maintained with 70% nitrous oxide, 30% oxygen, and a continuous fentanyl infusion of 2-3 pg.kg-l.h-'. After the twitch response had returned to at least 90% of the baseline, atracurium was given if further muscle relaxation was required. Esophageal temperature was maintained between 34.8 and 36.6"C with warming blankets. Heparinized blood samples were obtained from an indwelling arterial catheter just before the administration of vecuronium and 1, 3, 5, 10, 15, 20, 30, 45, 60, 75,90, 120, 150, 180, 210, 240, 300, and 360 min after its administration. These samples were immediately placed in tubes containing 1 M sodium phosphate buffer at a pH of 4.0. The ratio of blood to buffer was 4:l. Additional samples were drawn between the timed lunetic samples as warranted by return of twitch response. The plasma was separated and frozen. At a later date, the samples were prepared for analysis using an anion exchange column (Bakerbond specially made by J.T. Baker, Phillipsburg, N.J.). Vecuronium concentration was determined by the spectrofluorometric method described by Kersten et al. (4). The maximum sensitivity of this method is 25 ng/mL with the coefficients of variation no more than 6%. The times to 5%, 25%, 50%, and 75% recovery of twitch height were recorded, and the 5%-25% and 25%-75% recovery indexes were determined. The plasma concentration versus time-course curves for each patient were fit to both biexponential and triexponential equations, using weighted nonlinear leastsquares regression analysis (5). A weighting function of 1/x: was used. The best fit for the data was then determined by the method of Boxenbaum et al. (6). Pharmacokinetic values were calculated using standard methods for bolus intravenous iniection of a drug. The fema1e:male ratios were compared using analysis. The recovery indices, recovery times, and pharmacokinetic values were compared between the elderly and control groups using Student's two-tailed t-tests for unpaired data. The concentration-time data points were compared in the two groups using re-
Table 1. Demographics and Intraoperative Conditions of the Study Populations Young
P
Elderly ~
Sex (F:M)
3:5 81 2 14 35.9 2 0.4 29 t 2
Weight (kg) Temperature ("C) ETco, (mm Hg)
4:4 71 2 14 35.7 2 0.7 29 2 7
0.642 0.200 0.536 0.855
ETco,, end-tidal carbon dioxide tension Values are mean i SD.
Table 2. Recovery Times and Recovery Indices Young Time to recovery (min) 5% 25% 50% 75% Recovery index (min) 5%-25% 25%-75 70 Valuec are mean
21.1 2 32.0 2 39.8 47.9 2
*
7.3 11.6 13.5 15.6
10.7 2 5.2 15.0 2 8.0
Elderly
P
47.3 2 15.5 73.8 t- 24.4 97.1 f 29.3 123.1 t 33.3
0.001 0.001 0.0002 0.0001
27.8 2 18.0 49.4 ? 11.4
0.032 0.0001
2 SD
peated measures analysis of variance. The threshold for statistical significance was P < 0.05.
Results The age of the young control group was 41 5 7 yr (mean ? SD) and that of the elderly patients 77 -+ 4 yr. There were no significant differences between the two study populations in terms of sex, weight, intraoperative ETco,, and temperature (Table 1). The return of twitch and the recovery indexes were significantly longer in the elderly than in the younger patients (Table 2). Figure 1 demonstrates the plasma time-concentration data (? SD) for each of the groups. At 60 min, the plasma concentration of vecuronium in the elderly group of patients became significantly greater than the plasma concentration in the control group. The statistical significance of this difference continued throughout the remainder of the study. Plasma decay curves for both groups were best described by biexponential equations. In the elderly, elimination half-life of vecuronium was significantly prolonged and clearance of vecuronium was decreased (Table 3).
2
~
i
~
~
~
The distribution and elimination of drugs in the elderly may be altered by a multitude of physiologic changes that accompany the aging process. These
~
LIEN E T A L . VECURONIUM IN THE ELDERLY
ANESTH ANALG 1991;73:3942
10000~
1''
0
60
120
180 240 Time (minutes)
300
360
Figure 1. Plasma concentration versus time-course in elderly (0-0)and in younger (0-0) patients after a single intravenous dose (0.1 mgikg) of vecuronium. Values are mean 2 SD; I I = 8 in each group except at 360 min where II = 5 for elderly and J I = 6 for younger patients.
Table 3. Pharmacokinetic Variables Variables t,,, elim (min) Clp (mL.kg-'.min-') Vi (Likg) Vd area (Likg)
Young 78 5.6 0.08 0.49
21 3.2 0.02 2 0.02
2 2
*
Elderly 125 2 2.6 ? 0.08 0.44
* *
55 0.6 0.01 0.01
P 0.040 0.049 0.474 0.335
f,,2 elim, half-life of elimination; Clp, plasma clearance, Vi, initial volume of distribution; Vd area, volume of distribution. Values are mean 5 SD.
41
They found that the recovery indices of both 10%25% and 25%-75% were significantly prolonged in the group greater than 60 yr of age. Although they did not study kinetics, their results suggested decreased elimination of the drug in elderly patients. Rupp et al. (2,3) looked at both the pharmacokinetics and pharmacodynamics of vecuronium in the elderly. Their patients were given a continuous infusion of 2.5 pg.kg-'.minp' of vecuronium until the twitch tension was 20%-30% of control, at which point the infusion was terminated. Elderly patients (>70 yr old) had significantly decreased plasma clearances and volumes of distribution, whereas elimination half-life of vecuronium and recovery indices (25%75% of control) were not significantly different from younger counterparts. It was concluded that "healthy elderly patients do not appear to represent a population distinctly different from younger adults in their pharmacokineticlpharmacodynamic response." In contrast, the data presented in this study demonstrate prolonged recovery after an intravenous bolus of vecuronium, prolonged elimination half-life, and decreased clearance of vecuronium in the elderly. Although in the study of Rupp et al. (2,3), the reported kinetic and dynamic data obtained in younger patients (25%-75% recovery index, 10 t 1 min; elimination half-life, 70 20 min; clearance, 5.2 0.8 mL.kg-'.min-l; volume of distribution at steady state (Vd,,), 244 ? 38 mL/kg) are not that dissimilar from values reported in this study, there are significant differences in the data obtained for the elderly patients, including a recovery index of 11 1 min and an elimination half-life of 58 k 10 min versus the values of 49.4 t 11.4 and 125 55 min obtained in this study, respectively. There are several reasons that the results of this study may differ from those of Rupp et al. Differences in anesthetic technique (nitrous oxide-halothane used by Rupp's group as opposed to nitrous oxide-fentanyl used in this study) is a possible reason. A nitrous oxide-halothane anesthetic may cause prolonged recovery times when compared with the return of twitch during a nitrous oxide-narcotic technique. As the recovery indices in Rupp's study are appreciabljr less than those in this study, it is unlikely that anesthetic technique accounts for the differences observed. In addition, as the elderly patients in both Rupp's and our study received the same anesthetic as their respective controls, the anesthetic agents should not be a factor within each study. A major difference between the two studies is the method of vecuronium administration. In this study, 0.1 mg/kg of vecuronium was given as an intravenous bolus. This dose was sufficient to cause complete muscle paralysis in all patients, and twitch did not return to 5% of the control value for 21.1 ? 7.3 min (mean t SD) in the younger patients and 47.3 ?
*
*
*
changes include decreases in lean body mass, in total body water, in glomerular filtration and renal blood flow, in splanchnic blood flow, and in serum albumin levels, and increases in fat. The long-acting nondepolarizing muscle relaxants pancuronium (7,8), metocurine (9), and d-tubocurarine (9) have prolonged durations of action in the elderly related to decreased elimination of these drugs through the kidneys. The elimination of vecuronium is, in addition to being effected by the kidneys, highly dependent on hepatic clearance; 40% of a vecuronium dose is eliminated unchanged in the bile within 24 h after its administration (10). As aging is associated with reductions of both splanchnic and renal blood flows (11,12), one would expect duration of action and the elimination of vecuronium also to be prolonged in the elderly. Previous studies (1-3) have yielded conflicting results as to the pharmacodynamics of vecuronium in the elderly. DHollander et al. (1) studied recovery rates in patients older than 60 yr and compared them with results obtained in two younger groups of patients after the discontinuation of a continuous infusion of vecuronium adjusted to maintain twitch height constant at 10% of baseline for at least 90 min.
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ANESTH ANALG 1991;73:39-42
LIEN ET AL. VECURONIUM IN THE ELDERLY
15.5 min in the elderly. Because return of twitch clearly occurred during the elimination phase of the drug in our study, a decrease of plasma clearance of vecuronium should produce a delay in recovery time. This indeed is what was observed in the elderly patients in this study. In contrast, Rupp et al. infused vecuronium until the twitch was 20%-30% of the control value, stopped the infusion, and began his measurements. No indication was given of the total dose of muscle relaxant given to the patients. The elderly may have received less relaxant to achieve the desired end point. If the elderly patients received a smaller dose of vecuronium than the younger controls, the possibility exists that Rupp et al. were looking at recovery during the redistribution phase rather than during the elimination phase. This could account for their surprising report that the clearance of vecuronium is significantly decreased in elderly patients although there is no difference in recovery time between the younger and elderly patients. In support of this theory, Fisher and Rosen (13), using computer simulation, determined the effect of the relaxant dose on the duration of action of the relaxants. They clearly demonstrated that when a moderate dose of vecuronium (40 pg/kg) is administered, recovery occurs during the drug’s distribution phase. As drug dose is increased, recovery of twitch occurs further into the elimination phase. These data can also be used to explain the finding of D’Hollander et al. after a prolonged infusion of vecuronium (90 min at a steady-state 90% depression of twitch response). In that study, elderly patients required a significantly longer period of time for return of twitch height from 25% to 75% of baseline value. Clearly in D’Hollander’s study, a large vecuronium dose was administered to the patients and a return of twitch response occurred during the elimination phase. Although D’Hollander et al. did not measure drug concentration nor calculate pharmacokinetic values, their results are clearly compatible with a decreased plasma clearance of vecuronium in elderly patients. Studies by Bell et al. (14) and O’Hara et al. (15) demonstrated no differences in the dose-response relationships of vecuronium in the elderly and in the young. In both studies, a single-dose methodology was used to compare the potency of the muscle relaxant in these two groups. Their results, because of study design, reflect the distribution of the muscle relaxant rather than its elimination. The distribution of a drug is, in turn, closely related to its volume of distribution. That there is no significant difference in the volumes of distribution between the elderly and the young patients in this study provides a clear pharmacokinetic explanation of why both Bell et al. and O’Hara et al. reported
no differences in the dose-response relationship of vecuronium between the two age groups. Our finding that the action of vecuronium is prolonged in the elderly is clearly in agreement with that of D’Hollander et al. The prolongation of vecuronium action appears to be secondary to decreased drug elimination in older patients, consistent with ageassociated decreases in hepatic and renal blood flows. The results of this study suggest that anesthesiologists should expect the action of vecuronium to be prolonged in the elderly surgical patient and emphasize the need to administer carefully and to monitor closely the effects of neuromuscular blocking agents in these patients. The authors acknowledge with gratitude the aid of Dr. Michael J. Avram, Assistant Professor, Department of Anesthesia, Northwestern University Medical School, in establishing the spectrofluorometric method of analysis of vecuronium in our laboratory.
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dependent dose-response relationship of Org NC45 in anaesthetized patients. Br J Anaesth 1982;54:653-6. Rupp SM, Castagnoli KP, Fisher DM, Miller RD. Pancuronium and vecuronium pharmacokinetics and pharmacodynamics in younger and elderly adults. Anesthesiology 1987;67:45-9. Rupp SM, Fisher DM, Miller RD, Castagnoli K. Pharmacokinetics and pharmacodynamics of vecuronium in the elderly. Anesthesiology 1983;59:A270. Kersten UW, Meijer DKF, Agoston S. Fluorometric and chromatographic determination of pancuronium bromide and its metabolites in biological materials. Clin Chim Acta 1973;44:5946. Dixon W, Brown M, Engelman L, et al. BMDP Statistical Software. Berkeley: University of California Press, 1983:29C-304. Boxenbaum HG, Riegelman S, Elashoff RM. Statistical estimation in pharmacokinetics. J Pharmacokinet Biopharm 1974;2:12348. McLeod K, Hull CJ, Watson MJ. Effects of aging on the pharmacokinetics of pancuronium. Br J Anaesth 1979;51:435-8. Duvaldestin P, Saada J, Berger JL, D’Hollander A, Desmonts JM. Pharmacokinetics, pharmacodynamics and dose-response relationships of pancuronium in control and elderly subjects. Anesthesiology 1982;56:3640. Matteo RS, Backus WW, McDaniel DD, et al. Pharmacokinetics and pharmacodynamics of d-tubocurarine and metocurine in the elderly. Anesth Analg 1985;64:22-8. Bencini AF, Scaf AHJ, Sohn YJ, Kersten-Kleef UW, Agoston S. Hepatobiliary disposition of vecuronium bromide in man. Br J Anaesth 1986;58:98E-95. Bender AD. The effect of increasing age on the distribution of peripheral blood flow in man. J Am Geriatr Soc 1965;13:192-8. Leithe ME, Hermiller JB, Magorien RD, Unverferth DV, Leier CV. The effect of age on central and regional hemodynamics. Gerontology 1984;30:240-6. Fisher DM, Rosen JI. A pharmacokinetic explanation for increasing recovery time following larger or repeated doses of nondepolarizing muscle relaxants. Anesthesiology 1986;65:286-91. Bell PF, Mirakhur RK, Clarke RSJ. Dose-response studies of atracurium, vecuronium and pancuronium in the elderly. Anaesthesia 1989;44:925-7. OHara DA, Fragen RJ, Shanks CA. The effects of age on the dose-response curves for vecuronium in adults. Anesthesiology 1985;63:542-4.
