Acta Anaesthesiol Scand 2002; 46: 684691 Printed in Denmark.

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Copyright C Acta Anaesthesiol Scand 2002 ACTA ANAESTHESIOLOGICA SCANDINAVICA

0001-5172

Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients

D. STERGAARD1, J. VIBY-MOGENSEN2, N. A. PEDERSEN1, H. HOLM1 and L. T. SKOVGAARD3
1

Department of Anaesthesia, Gentofte University Hospital, 2Department of Anaesthesia, Rigshospitalet, 3Department of Biostatistics, University of Copenhagen, Denmark

Background: Mivacurium is hydrolyzed by plasma cholinesterase, and is therefore less dependent on liver metabolism and renal elimination than other neuromuscular blocking drugs. This might favor the use of mivacurium in elderly patients. The purpose of this study was to compare the pharmacodynamics and the pharmacokinetics of the three isomers of mivacurium and their metabolites in young adult and elderly patients. Methods: Sixty-four patients were included in a doseresponse study, in which 32 young adults and 32 elderly patients received one of four doses of mivacurium. An additional bolus dose of mivacurium to a total of 0.1 mg/kg was given followed by a continuous infusion adjusted to maintain a 9199% neuromuscular block. The times to maximum block and different levels of recovery were measured using mechanomyography and train-of-four (TOF) nerve stimulation. Thirty-two patients were randomly selected for the pharmacokinetic study. Venous samples were taken for determination of the three mivacurium isomers and the metabolites. Results: The estimated ED95 were 0.053 and 0.061 mg/kg in young adults and elderly patients, respectively (NS). The median infusion rate did not differ, but duration to a TOF ratio of

0.7 was signicantly longer in elderly patients than in young adult patients (21.0 vs. 16.5 min). No statistically signicant difference between the age groups in clearance and elimination half-life of the isomers was seen. The half-lives of the metabolites were signicantly prolonged in the elderly patients. Conclusion: There were no signicant differences in the potency or infusion requirements between the adult and elderly patients, but the rate of recovery was signicantly, though only moderately prolonged, in the elderly patients. No signicant difference in clearance was seen but the elimination half-lives of the metabolites was longer in the elderly patients.

Received 9 August 2001, accepted for publication 8 February 2002

Key words: age factors; butyrylcholinesterase; cholinesterase; doseresponse curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers.
c Acta Anaesthesiologica Scandinavica 46 (2002)

papers have described the pharmacodynamics of mivacurium following bolus doses and continuous infusions. Most of these studies were performed in young adults (15), with only a few in elderly patients (68). The pharmacokinetics of mivacurium has been described in young healthy adults (9, 10), whereas pharmacokinetic data of elderly patients are sparse (11). As mivacurium is rapidly hydrolyzed by plasma cholinesterase (pChe) (12) it is less dependent on liver metabolism and renal elimination than some other non-depolarizing neuromuscular blocking drugs. This might favor the use of mivacurium in elderly patients who may have a variable decrease in their glomerular ltration rate. On the other hand, lean body mass and total body water decrease with age, both of which may affect the pharmacokinetics of mivacurium. So far only one pharmacokinetic study of mivacurium has been performed in elderly patients, which indicated a reduced clearance
EVERAL

of the two active isomers of mivacurium (11). No studies of mivacurium metabolites pharmacokinetics have been reported in elderly patients. The purpose of the present study was to evaluate both the pharmacodynamics of mivacurium and the pharmacokinetics of the three mivacurium isomers and their metabolites, in young adult and elderly patients.

Patients and methods

Seventy patients, ASA physical status 12, scheduled for elective ear or nose operations entered the study. Thirty-ve were young adult patients (1840 years) and 35 were elderly patients (age 65 years). Before induction of anesthesia a blood sample was taken, and according to the biochemical analysis all patients had normal pChe phenotype and low to normal pChe activity (13). Females of childbearing potential and

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patients with a history of neuromuscular, cardiovascular, renal or hepatic disorders were excluded from the study, as were patients receiving drugs that might affect the neuromuscular transmission. All patients gave their informed consent, and the local Ethics Committee approved the study. Premedication consisted of diazepam 0.10.2 mg/kg orally. Anesthesia was induced with fentanyl 14 mg/ kg, diazepam 0.050.15 mg/kg and thiopentone 36 mg/kg, and maintained with 66% nitrous oxide in oxygen and supplementary doses of fentanyl and diazepam. Perioperative monitoring included electrocardiogram, pulseoximetry, capnography and non-invasive blood pressure every minute for the rst 3 min following mivacurium administration and every 5 min thereafter. The blood pressure cuff and the intravenous line used for drug and uid administration were on the same arm. Ventilation was adjusted to maintain normocapnia (end tidal CO2 4.55.6 kPa). The rectal and peripheral skin temperatures were measured and maintained at greater than 35C and 32C, respectively (14). After the induction of anesthesia, a second intravenous line was inserted in the arm for blood sampling (used for monitoring) and a third line in the foot for mivacurium infusion. The mechanical twitch was recorded using a Myograph 2000 (Biometer International, Denmark). The ulnar nerve was stimulated at the wrist using surface electrodes and 1-Hz single twitch stimulation (14). When supramaximal stimulation was achieved and the response to stimulation was stable for 5 min the stimulation pattern was changed to train-of-four (TOF).

twitch height of the rst twitch (T1) in two TOF trains). Tracheal intubation was performed at a maximum T1 depression following this second bolus dose. Following the spontaneous recovery of the T1 510% of start control value, a continuous infusion of mivacurium was started at an initial rate of 6 mg/kg/min. It was subsequently adjusted to maintain a neuromuscular block within the range of 9199% T1 depression. At the end of the surgical procedure the neuromuscular block was allowed to recover spontaneously. Neuromuscular monitoring The maximum T1 depression following the rst dose of mivacurium and all recovery data were calculated using start control values (14). Monitoring was continued until both 90% T1 recovery and a TOF ratio of 0.70 were obtained. The time from the second mivacurium dose injection to the rst response to TOF and duration to 10, 25 and 90% T1 recovery to a TOF ratio of 0.70 were determined. The interval 2575% (time from 25 to 75% T1 recovery) after the end of the infusion were measured (14).

Pharmacokinetics
Sixteen young adult and 16 elderly patients with an expected anesthetic duration of more than 90 min were randomly selected for the pharmacokinetic study. Later, three patients (two young adult and one elderly) were excluded because of insufcient blood sampling. In six young adult and in three elderly patients the plasma concentration data for the cis-trans isomer during the infusion were close to or below the lower limit of quantication of the plasma assay; these data were excluded. Plasma concentrations of mivacurium Venous blood samples (5 ml) were collected immediately before mivacurium administration, 1.2 and 5 min following the initial dose, and before and at 1, 2, 5, 10 and 20 min following the second bolus dose. Blood samples were also collected immediately before and at 1, 2, 5, 10, 15, 20 and 30 min after the start of the mivacurium infusion, and at 30 min intervals during the infusion. If the infusion rate was changed, blood samples were collected immediately before and at 1, 2 and 5 min following the change. Three samples were also taken at 5 min intervals before the infusion was terminated. Additional samples were collected immediately before and at 1, 2, 5, 10, 15, 30, 45, 60, 120, 180, 240 and 360 min after the infusion was terminated. In less than 10 s the blood samples were transferred into a vacutainer containing a cholinesterase in-

Pharmacodynamics
Doseresponse study According to the protocol 32 young adult and 32 elderly patients were allocated to receive one of four different doses of mivacurium: 0.04, 0.06, 0.08, or 0.09 mg/kg. After including six patients receiving the 0.08 and the 0.09 mg/kg doses it became clear, however, that these doses resulted in a complete response to TOF nerve stimulation abolition. The doses were therefore reduced to 0.03 and 0.05 mg/kg, respectively. The six patients who had received the 0.08 and 0.09 mg/kg doses were excluded from the doseresponse study and replaced by another six randomly selected patients. Continuous infusion study In 65 patients an additional bolus dose of mivacurium was given up to a total of 0.1 mg/kg, when maximum block was achieved following the initial dose (equal

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D. stergaard et al.

hibitor (phospholine iodide). The samples were centrifuged and the plasma was decented and frozen at 70C. The ratio of the cis-cis, cis-trans and trans-trans isomers in the clinical trial material used was approximately 5.8, 35.5 and 58.8%, respectively (data are from the certicate of analysis, Glaxo Wellcome). The concentration of each of the three isomers were determined by a stereospecic high performance liquid chromatographic method with uorometric detection and a stepped gradient (by the Department of Bioanalysis and Drug Metabolism, Glaxo Wellcome Research Laboratories, Beckingham, UK). The drug assay was automated (ASPEC, Gilson). The coefcient of variation was 12% and the lowest level of quantication was 2.5 ng/ml. Calibration was linear over the range 51000 ng/ml (15). Pharmacokinetic data The plasma concentrations of the individual isomers were used to construct plasma concentration vs. time prole of the drug. Non-compartmental pharmacokinetic parameters were determined for individual patient assay data. Cmax (the maximum concentration) was taken directly from the plasma concentrations. AUC 0-t (area under the plasma concentration vs. time curve from zero to the last measurable concentration at time t) for both isomers and metabolites were calculated by the linear trapezoidal method, taking the plasma concentration at the time of injection to be zero. The elimination rate constant (l) was estimated by log-linear regression for the terminal slope of the concentration vs. time prole. The value of l was used to extrapolate concentrations beyond the last measurable concentration: Ct to innite time. The elimination half-life (t1/2l ln2/l) and the AUC0- (area under the plasma concentration curve vs. time curve from zero to time innity (AUC0- AUC0-t Ct/l) for the isomers and metabolites, the total plasma clearance (CL dose/ AUC0-), the clearance at steady state (Clss rate of infusion/concentration at steady state) and the volume of distribution (VDl CL/l) for the isomers were calculated.

Summary statistics (mean, SD), median, range and 95%CI were used to describe the neuromuscular data. The efcacy data were reasonably normally distributed. Comparisons between age groups were based on t-tests with a pooled variance estimate. P0.05 was used to dene a statistically signicant difference. An overall mean infusion rate was calculated for each age group from the average infusion rates of the individual patients. Pearsons correlation coefcient was used to evaluate whether a linear relationship existed between the infusion rate and the pChe activity.

Results
Table 1 shows the demographic and biochemical data. All patients were within 20% of their ideal body weight (14). No statistically signicant differences in weight, height or pChe activity were seen between the groups. Estimated creatinine clearances were signicantly lower in the elderly than in the young adults: 62 (17) vs. 121 (24) ml/min (mean, SD).

Pharmacodynamic data
Doseresponse study There was no statistically signicant difference in the potency of mivacurium in the young adult and elderly patients. The estimated ED50 and ED95 were 0.030 mg/kg and 0.053 mg/kg, and 0.033 mg/kg and 0.061 mg/kg, in young adult and elderly patients, respectively. In Fig. 1 the composite doseresponse lines and the condence limits are given. Continuous infusion study There was no statistically signicant difference in duration of infusion or mean infusion requirement in the two groups of patients (Table 2). A stable 9199% T1 depression was obtained after the rst four 5-min periods both in the young adult and elderly patients, with a median infusion rate of 6.0 mg/kg/min in both groups of patients for the rst 105 min. Only a few patients received an infusion for more than 120 min. A correlation was found between the pChe activity and the infusion rate of mivacurium (r0.43; P0.001). Spontaneous recovery from the neuromuscular block was signicantly prolonged in the elderly patients compared with the young adult patients (Table 2). All patients were able to maintain headlift for 5 s before leaving the operation theater and again at discharge from the recovery room. An adverse reaction possibly related to mivacurium was only seen in one patient, who had had two brief

Statistical analyses
To determine mivacuriums potency, the T1 depressions (%) were transformed into probits and plotted against the logarithm of the mivacurium dose. The doseresponse relationship was determined separately for the two age groups by linear regression analysis. Probit values of 0% and 100% T1 depression were replaced by 0.5% and 99.5% values, respectively (14).

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Mivacurium in adults and elderly patients

Table 1
Demographic and biochemical data in young adult (1840 years) and elderly patients (65 years). Group Young adults Elderly Number of patients 35 35 Males/ Females 9/26 17/18 Age years 31 (1840) 72 (6583) Weight kg 74.8 (53105) 70.4 (4895) Height cm 178 (160192) 171 (154190) Plasma cholinesterase activity U/l 799 (3861221) 807 (4471734) Dibucaine n 84 (8285) 85 (8486)

Medians and ranges are given. Reference values for plasma cholinesterase activity and for the dibucaine number are 6601620 U/L and 79 87 L, respectively (13).

Table 2
Infusion requirements, duration of action and recovery data in young adult (1840 years) and elderly patients (65 years). Group 75% Young adults Elderly Duration of infusion min 86 (25227) 95 (28207) Median infusion rate mg/kg/min 6.0 (4.610.6) 6.0 (3.810.6) Duration 10% 3.9 (012.5) 5.0 (015.9) 25% 6.0 (1.416.7) 8.5 (020.9)* 90% 16.7 (9.431.9) 21.6 (9.343.9)* Duration TOF 0.70 16.5 (9.531.5) 21.0 (8.438.5)* Interval 2575% 7.2 (3.614.0) 10.6 (6.220.0)*

Median (ranges) and number of patients (n) are given. Data are presented according to the good clinical research practice (GCRP) rules for pharmacodynamic studies in neuromuscular blocking agents (14). *Signicant difference in recovery from the neuromuscular block between the two groups (P0.05). TOF, train-of-four ratio.

episodes of mild bronchospasme, which were successfully treated with terbutaline. Pharmacokinetic study During the continuous infusion of mivacurium a new steady state plasma concentration was achieved for the cis-trans and the trans-trans isomers within 10 min of infusion rate changes. Contrary to this, the plasma concentration of the cis-cis isomer never reached steady state. Therefore, no steady state clearance for this isomer could be estimated. No signicant difference in the concentration of the cis-cis isomer at the end of the infusion was found between the young adult and elderly patients: 70 and 60 ng/ml, respectively. Table 3 summarizes the pharmacokinetic data of the three isomers. No statistical signicant difference in Cmax and AUC was seen in the young adult and elderly patients, although there was a trend towards higher Cmax values in the young adult patients. No statistical signicant difference in the clearances of the three isomers was seen in the young adult and elderly patients. There was a statistically signicant correlation between the pChe activity and the clearance of the cis-trans ( r0.42; P0.04) and trans-trans (r0.50; P0.006) isomers, but not of the cis-cis isomer (r0.12; P0.54)Table 3. There was a trend towards a longer elimination half-life in the elderly for all isomers, but this was not

statistically signicant. The 95%CI for the cis-cis, cistrans and the trans-trans isomer was 0.771.57, 0.72 2.04 and 0.922.86, respectively; indicating that the elimination half-life could have been from 57186% longer in the elderly patients. All isomers showed small volumes of distribution during the elimination phase. The data is, however, severely affected by the poor characterization of the terminal phase in some patients and by high estimates for plasma clearances. The higher VD estimates for the elderly patients were only statistically signicant for the trans-trans isomer, most probably because of the large variances found for the other isomers. The plasma concentration of the cis quarternary alcohol metabolite was too low to allow for reliable estimates of the half-life or AUC data. For the three other metabolites, the plasma concentration increased during the infusion period and Cmax occurred near the end of the infusion (Table 4). For all metabolites, Cmax was dependent on the duration of infusion. No signicant differences were seen in Cmax between the young adult and elderly patients. The plasma concentrations of the three major metabolites were measurable for 6 h with a bi-exponential decline following the termination of the mivacurium infusion. The elimination half-lives for the three major metabolites were prolonged by approximately 30% in the elderly patients. This difference was statistically signicant for the two monoester metabo-

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D. stergaard et al.
Table 3
Estimated maximum concentration (Cmax), area under curve (AUC0), steady state concentration (Css), steady state clearance CLss, total clearance (CL), elimination half-life (t1/2l) and volume of distribution during the terminal elimination phase (VDl) of each isomer in 14 young adult (1840 years) and 15 elderly patients (65 years). Isomer Cis-cis Young Adults Elderly Cis-trans Young adults Elderly Trans-trans Young adults Elderly Cmax ug/ml 101 (77170) 76 (42144) 192 (67390) 107 (27518) 448 (179791) 308 (831069) AUC0 ng/ml hour 191 (51321) 152 (38435) 42 (1275) 28 (5131) 124 (34196) 82 (44364) Css ng/ml Clss ml/kg/min Cl ml/kg/min 4.4 (3.05.5) 4.5 (2.79.8) 94 (51144) 133 (47167) 51 (3098) 67 (29135) t1/2l min 56 (3575) 65 (15131) 2.1 (1.16.1) 2.6 (1.29.5) 2.7 (0.49.0) 4.3 (1.49.5) VDl l/kg 0.31 (0.240.54) 0.37 (0.200.96) 0.32 (0.121.17) 0.50 (0.102.55) 0.19 (0.060.49) 0.44* (0.101.10)

25 (1043) 17 (954) 67 (32114) 46 (34148)

92 (53190) 133 (57264) 53 (32121) 77 (33141)

Medians and ranges are given. *Statistically signicant difference, P0.05.

lites (cis and trans 879) (Table 4). The relative exposure to each metabolite per unit dose was estimated by dividing the AUC by the total dose. The average relative exposure was 20% higher in the elderly than in the young adult patients. This difference was statistically signicant for all metabolites.

Discussion
The primary pharmacodynamic ndings are that there was no difference in potency or infusion requirements of mivacurium in the young adult and elderly

patients, but that the elderly patients had a signicantly slower rate of spontaneous recovery of neuromuscular block. Pharmacokinetically, the clearances and the elimination half-lives did not differ signicantly in the two age groups, but the volume of distribution increased in the elderly patients. Also, the elimination half-lives of the metabolites were signicantly longer in the elderly patients.

Pharmacodynamics
We used the single dose method to determine the doseresponse relationship (the potency) of mivacuri-

Fig. 1. Scatterplot of the probit transformed twitch depression and the logarithm of the dose in young adult patients (A) and elderly patients (B). The composite doseresponse lines (slope 6.427 and 7.098) and the condence intervals are given.

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Mivacurium in adults and elderly patients

um because a cumulative dose technique tends to underestimate the potency of a short-acting drug such as mivacurium (16). The ED95 found by us in young adults are in good agreement with the results of previous studies in adult patients using TOF stimulation, as in this study (3, 4). We found no statistically signicant difference in potency between the two age groups; neither did Valinthout et al. (7). Our estimated ED95 in both the young adult and elderly patients (0.053 and 0.061 mg/kg, respectively) is, however, lower than those found by Valinthout et al. (0.091 and 0.096 mg/kg, respectively) (7). These differences might be caused by differences in methodologies. The mean infusion rate (6 mg/kg/min) required to maintain a 9199% neuromuscular block did not differ between the young adult and elderly patients for the rst 105 min. Only a few of the elderly patients received a longer infusion. The infusion requirement found in young adults is comparable to data from other studies in adults during narcotic anesthesia (3, 4, 6, 16), but slightly higher than reported by Goudsouzian et al. (8). This can be explained by differences in methodology as Goudsouzian et al. used EMG. Servin et al. (11), Dahaba et al. (17) and Goudsouzian et al. (8) all found lower infusion requirements in elderly compared with young adult patients, and also found that the necessary infusion rate seemed to decrease with time. The duration of infusion was, however, longer (4 h) (8, 17). A correlation was found between the pChe activity and the infusion rate of miva-

curium both in the young adult and elderly patients; the higher the pChe activity the higher the infusion rate. This is in accordance with previous studies (2, 18). The times to different levels of T1 recovery in the young adult patients were comparable to those reported previously (9). The spontaneous recovery time was signicantly prolonged in the elderly compared with the young adult patients. This is in agreement with the ndings of Maddineni et al. (6) and Servin et al. (11). Whether or not a difference of 510 min in recovery time is clinically relevant is, however, open to discussion. Plasma cholinesterase activity may decrease with age (13). The prolonged recovery time in the elderly cannot, however, be explained by differences in pChe activity because we did not nd any statistically signicant difference in pChe activity between the two age groups.

Pharmacokinetics
In elderly patients there was a trend towards lower Cmax values. One might speculate if the time to Cmax was longer than 2 min in some of the elderly patients and Cmax actually occurred within the 3-min period where no blood samples were drawn. This would affect the area under the curve, and hence the clearance of mivacurium in elderly patients would have been overestimated.

Total and steady state clearance

The clearances we found in the young adult patients are in agreement with data from studies using the same technique (i.v. sampling) (9, 19, 20) and somewhat higher than in studies using arterial sampling (10, 11). The differences might be explained by the different sampling techniques. We used venous sampling and only limited sampling immediately after the injection of mivacurium. Hence, the initial part of the area under the plasma concentration curve could have been underestimated, and consequently the plasma clearances and the volume of distributions are overestimated. Lacroix et al. (10) reported the clearances of the trans-trans and the cis-trans to be overestimated by 66 and 90%, respectively, whereas that of the cis-cis isomer was overestimated by only 10%. The importance of arterial sampling is of major importance following a bolus dose and of less importance during a continuous infusion. No statistically signicant difference in the clearance of the three isomers was seen between the two groups of patients. Because of the large variation in clearances found between the individual patients we cannot exclude a type 2 error. Elderly patients often

Table 4
Estimated maximum concentration (Cmax)), elimination half-lives (t1/2l) and area under curve AUC/dose of each mivacurium metabolite in 14 young adult (1840 years) and 15 elderly patients (65 years). Cmax ng/ml Cis monoester Young adults Elderly Trans monoester Young adults Elderly Trans alcohol Young adults Elderly 435 (194564) 424 (209839) 683 (3231051) 666 (3391240) 617 (2501752) 599 (3181215) t1/2lmin AUC/dose ml/h 1660 (12472368) 2026* (13843464) 2112 (16793381) 2661* (15964365) 1800 (9433237) 2208* (13683288)

87 (63103) 107* (37174) 58 (4283) 78* (33134) 44 (2895) 61 (25107)

Medians and ranges are given. *Statistically signicant difference between groups, P0.05.

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D. stergaard et al.

have a longer circulation time than do young adults, and this might cause an even greater decrease in the area under the rst moment curve and an even larger overestimation of the plasma clearance and the volume of distribution of the individual isomers of mivacurium. Our data is in contrast to Servin et als (11) ndings of a 50% reduction in clearance of the active isomers in elderly patients. The reduction in clearance did not, however, cause a markedly impaired elimination because of a simultaneous decrease in the distribution volume at steady state. In accordance with previous studies (9, 19, 20) we found a relationship between the pChe activity and the clearances of the active isomers. For the cis-cis isomer there was only a weak correlation with pChe activity, and most probably the clearance of this isomer is predominantly renal (21).

the young adult patients than reported, following a single dose of mivacurium (10). A statistical signicant higher metabolite exposure in the elderly group was seen, when calculated as the AUC dose per unit dose. This is probably the result of prolonged half-life in the elderly group. The metabolites, however, have low pharmacological activity, and the higher metabolite exposure in the elderly patients probably has no clinical importance (24).

Relationship between pharmacodynamic and pharmacokinetic data

We found a statistically signicant longer duration of action and recovery time of mivacurium in the elderly patients, whereas no difference in potency or infusion requirements was seen. Most likely, the prolonged recovery time in the elderly patients is a result of altered pharmacokinetics of mivacurium, although we were unable to detect a difference in elimination half-lives for the three isomers of mivacurium. An increased elimination half-life reects a longer stay of mivacurium in the body, and hence a longer duration of action. This is in accordance with an increased volume of distribution for the trans-trans isomer. A signicantly increased elimination half-life of the cis- and trans monoester metabolite was seen. However, this is probably of no clinical importance because metabolites have low pharmacological activity (24). In a combined pharmacodynamic and pharmacokinetic study, Servin et al. (11) also found a prolonged duration of action in elderly patients, as well as a decreased clearance of active isomers. Despite the decrease in clearance, the elimination of mivacurium was not markedly modied because of a simultaneous decrease in the distribution volume at steady state.

Elimination half-life
The elimination half-lives in young adults found in our study were consistent with the ndings of Lien et al. and Head Rapson et al. (9, 19, 20). There was no statistically signicant trend towards higher elimination half-life values of the three isomers in the elderly patients. However, as the data varied largely between the patients and for the cis-trans isomer it was difcult to obtain a sufcient number of samples before the lower plasma assay limit of quantication was reached.

Volume of distribution
The VDl observed in the young adult patients is comparable with previously reported data (9). In elderly patients, the volume of distribution during the terminal phase (VDl) for the trans-trans isomer was signicantly increased. Also, there was a tendency towards a higher VDl for the cis-trans and the cis-cis isomers. The volume of distribution for many drugs, for example cisatracurium, is known to increase in elderly patients (22, 23). The increased volume of mivacurium distribution in the elderly is in contrast with the ndings of Servin et al. (11), who reported a decreased Vdss in elderly patients.

Conclusion
The potency and mean infusion rate required to maintain a stable level of neuromuscular block for at least 105 min are similar in young adult and elderly patients. Recovery from neuromuscular block is signicant, though only moderately prolonged in elderly patients. These pharmacodynamic ndings cannot readily be explained by our pharmacokinetic ndings, but are most probably the result of longer elimination isomer half-lives. The clearance and the elimination half-lives of the three mivacurium isomers are similar in young adult and elderly patients, but the elimination half-lives of the cis- and trans-monoester metabolites are longer in elderly patients.

Metabolites
The plasma concentrations of all metabolites increased during the infusion. No signicant difference in Cmax was found between the two age groups. However, the elimination half-lives for the three major metabolites were 2040% longer in the elderly patients. This might be a result of a lower renal clearance in the elderly patients. We found shorter elimination half-lives of the trans monoester and trans alcohol in

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Acknowledgements
The study was supported by a grant from Glaxo Wellcome. The pharmacokinetic analysis was performed by Glaxo Wellcome, UK, and the authors thank Graham Ridout, Glaxo Wellcome, UK for support and advice concerning the pharmacokinetic analysis. Also we thank Bodil Mathiesen, Rigshospitalet, for performing the pChe analysis. 13.

14.

References
1. Savarese JJ, Ali HH, Basta SJ, Embree PB, Scott RPF, Sunder N et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). Anesthesiology 1988: 68: 723 732. 2. Ali HH, Savarese JJ, Embree PB, Basta SJ, Stout RG, Bottros LH et al.. Clinical pharmacology of mivacurium chloride (BW B1090U) infusion: comparison with vecuronum and atracurium. Br J Anaesth 1988: 61: 541546. 3. Caldwell JE, Kitts JB, Heier T, Fahey MR, Lynam DP, Miller RD. The doseresponse relationship of mivacurium chloride in humans during nitrous oxide- narcotic anesthesia in adult surgical patients. Anesthesiology 1989: 70: 3135. 4. Diefenbach C, Mellinghoff H, Lynch J, Buzello W. Mivacurium: doseresponse relationship and administration by repeated injection or infusion. Anesth Analg 1992: 74: 420423. 5. stergaard D, Jensen FS, Jensen E, Skovgaard LT, Viby Mogensen J. Inuence of plasma cholinesterase activity on recovery from mivacurium-induced neuromuscular blockade in phenotypically normal patients. Acta Anaesthesiol Scand 1992: 36: 702706. 6. Maddineni VR, Mirakhur RK, McCoy EP, Sharpe TD. Neuromuscular and haemodynamic effects of mivacurium in elderly and young patients. Br J Anaesth 1994: 73: 608 612. 7. Vanlinthout LEH, Booij LDHJ, van Egmond J, Robertson EN. Age related differences in magnitude and complete recovery of mivacurium induced neuromuscular block. Anesthesiology 1995: 83: A897. 8. Goudsouzian N, Chakravorti S, Denman W, Schwartz A, Yang HS, Cook DR. Prolonged mivacurium infusion in young and elderly adults. Can J Anesth 1997: 44: 955962. 9. Lien CA, Schmith VD, Embree PB, Belmont MR, Wargin WA, Savarese JJ. The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1994: 80: 12961302. 10. Lacroix M, Donati F, Varin F. Pharmacokinetics of mivacurium isomers and their metabolites in healthy volunteers after intravenous bolus administration. Anesthesiology 1997: 86: 322330. 11. Servin F, Lavaut E, Peytavin G, Farinotti R, Desmonts JM. A pharmacokinetic and dynamic study of mivacurium infusion in elderly patients. Anesthesiology 1997: 87: A855. 12. Cook DR, Stiller RL, Weakly JN, Chakravorti S, Brandom BW, Welch RM. In vitro metabolism of mivacurium chloride

15.

16.

17.

18.

19.

20.

21. 22.

23.

24.

(BW B1090U) and succinylcholine. Anesth Analg 1989: 68: 452456. Jensen FS, Skovgaard LT, Viby-Mogensen J. Identication of human plasma cholinesterase variants in 6688 individuals using biochemical analysis. Acta Anaesthesiol Scand 1995: 39: 157162. Viby-Mogensen J, Engbk J, Eriksson LI, Gramstad L, Jensen E, Jensen FS, Koscielniak-Nielsen Z, Skovgaard LT, stergaard D. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996: 40: 5974. Viby-Mogensen J, stergaard D, Donah F, Fisher D, Hunter J, Kampmann JP, Kopman A, Proost JH, Rasmussen SN, Skovgaard LT, Varin F, Wright PMC. Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP). Acta Anaesthesiol Scand 2000: 44: 11681180. rding H, Skovgaard LT, Engbk J, Viby-Mogensen. Dose response curves for vecuronium during halothane and neurolept anaesthesia: Single bolus versus cumulative method. Acta Anaesthesiol Scand 1985: 29: 121124. Dahaba AA, Rehak PH, List WF. A comparison of mivacurium infusion requirements between young and elderly adult patients. Eur J Anaesthesiol 1996: 13: 4348. Hart PS, McCarthy GJ, Brown R, Lau M, Fisher D. The effect of plasma cholinesterase activity on mivacurium infusion rates. Anesth Analg 1995: 80: 760763. Head-Rapson AG, Devlin JC, Parker CJR, Hunter JM. Pharmacokinetics of the three isomers of mivacurium and pharmacodynamics of the chiral mixture in hepatic cirrhosis. Br J Anaesth 1994: 73: 613618. Head-Rapson AG, Devlin JC, Parker CJR, Hunter JM. Pharmacokinetics and pharmacodynamics of the three isomers of mivacurium in health, in end-stage renal failure and in patients with impaired renal function. Br J Anaesth 1995: 75: 3136. Parker CJR, Hunter JM. The pharmacokinetics of mivacurium anaesthetic. Pharmacol Rev 1995: 3: 168175. Ornstein E, Lien CA, Matteo MD, Ostapkovich ND, Diaz J, Wolf KB. Pharmacodynamics and pharmacokinetics of cisatracurium in geriatric surgical patients. Anesthesiology 1996: 84: 520525. Sorooshian SS, Stafford MA, Eastwood NB, Boyd AH, Hull CJ, Wright PMC. Pharmacokinetics and pharmacodynamics of cisatracurium in young and elderly patients. Anesthesiology 1996: 84: 10831091. Belmont MR, Rubin LA, Lien CA, Tjan J, Savarese JJ. Mivacurium anaesthetic. Anaesthetic Pharmacol Rev 1995: 3: 156 167.

Address: Doris stergaard Department of Anesthesiology Herlev University Hospital 2730 Herlev Denmark e-mail: dooe/herlevhosp.kbhamt.dk

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