Since its introduction in 1995, sevoflurane has gained popularity for use in children. Sevoflurane is less irritating to the respiratory tract than halothane and facilitates rapid and pleasant inhaled anesthesia induction  with less bradycardia and myocardial depression . More importantly for ambulatory pediatric surgery, sevoflurane provides rapid emergence from anesthesia .
Prompt recovery is required from neuromuscular blocking drugs in ambulatory surgery, which makes mivacurium an appropriate choice for muscle relaxation. The interaction between mivacurium and inhaled anesthetics has been described , but there are no studies evaluating the requirements for mivacurium with various depths of sevoflurane anesthesia or the influence of sevoflurane on the recovery from neuromuscular block in children. These are particularly relevant if halothane is replaced by sevoflurane because halothane has much less effect on the intensity of blockade or dose requirements with mivacurium than other inhaled anesthetics, such as isoflurane .
The purpose of this study was to determine the dose requirements of mivacurium administered by continuous infusion to maintain 90%-95% neuromuscular block during sevoflurane 0.5 and 1 age-adjusted minimum alveolar anesthetic concentrations (MACs), compared with balanced anesthesia. Recovery after the mivacurium infusion was also measured. Similar studies were undertaken in adult patients. Plasma cholinesterase (PChE) activity was measured to examine the relationships between mivacurium requirement and recovery from neuromuscular blockade.
After institutional approval and written, informed consent from patients or parents, we studied 75 pediatric (2-12 yr) and 75 adult (20-65 yr) ASA physical status I or II patients undergoing elective surgery. Only those of normal body weight and height (children within the 5th-95th percentile range on normal growth charts) and adults with a body mass index between 20 and 30, scheduled for surgery of at least 1-h duration, were included. Pregnant women; patients with a history of hypersensitivity to dairy products, asthma, epilepsy, neuromuscular disease, or drug abuse; or those who had recently taken medication affecting neuromuscular transmission were excluded.
Routine preoperative care and premedication were administered at the discretion of the anesthesiologist. Baseline values for blood pressure and heart rate were measured preoperatively. Standard monitoring during anesthesia, including pulse oximetry, PETCO2, automated blood pressure, electrocardiogram, and body temperature, were continued throughout the procedure.
Neuromuscular transmission was monitored by using an electromyograph (EMG) (Relaxograph: Datex, Helsinki, Finland). Surface electrodes were applied over the ulnar nerve on the forearm. Recording electrodes were placed on the hand to record the EMG response of the adductor pollicis, and the arm was secured. A skin thermistor was taped to the hand close to the monitoring site, and the arm was wrapped in a blanket to reduce cooling. Skin temperature was maintained >32[degree sign]C; central temperature, measured at the axilla (children) or esophagus (adults), was maintained >35[degree sign]C. Supramaximal square wave train-of-four (TOF) stimulation at 2.0 Hz and 0.2-ms duration was delivered to the ulnar nerve every 10 s, and the evoked EMG response of the adductor pollicis was recorded. Monitoring began 2-3 min before the administration of mivacurium and continued until the end of anesthesia. Assessments of recovery (times to T1 25%, 75%, 90%, 95%, and TOF 0.7) were made using the final EMG baseline as a reference to calculate neuromuscular recovery .
In each age group, the 75 patients were randomized by a computer-generated assignment to three groups of 25 patients to receive propofol-opioid anesthesia with the addition of 0, 0.5 or 1.0 MAC sevoflurane, respectively. An infusion of isotonic sodium chloride solution was established before the induction of anesthesia. Blood was withdrawn (after the induction of anesthesia but before the administration of mivacurium in children; before the induction of anesthesia in adults) for PChE estimation using butryl thiocholine as the substrate (Boehringer, Mannheim, Germany).
In children, anesthesia was induced with 5 mg/kg propofol, 0.02 mg/kg atropine, 0.3 mg/kg lidocaine, and 2 [micro sign]g/kg fentanyl IV, followed by tracheal intubation without the use of muscle relaxants. If IV cannulation was difficult in an awake child, inhalation of nitrous oxide or sevoflurane in oxygen was allowed before insertion of the cannula, followed by the same IV induction sequence when the end-tidal sevoflurane had dissipated. As soon as neuromuscular monitoring was established, an initial bolus dose of 0.25 mg/kg mivacurium (2 x 95% effective dose) IV was given. Anesthesia was maintained with inhalation of N2 O/O2 (2:1) and positive pressure ventilation to maintain normocarbia. A propofol infusion (200 [micro sign]g [center dot] kg-1 [center dot] min-1) initially was titrated to maintain heart rate and systolic blood pressure within 10% of baseline. Fentanyl increments (0.5-2 [micro sign]g/kg), and other drugs, such as midazolam, droperidol, anticholinergic drugs, and opioids, were administered as indicated.
According to randomization, sevoflurane inhalation was introduced 2-3 min after the initial mivacurium bolus (T1 <5%). Sevoflurane was adjusted to maintain end-tidal concentrations at 0, 0.5, or 1.0 MAC based on age-adjusted MAC concentrations for sevoflurane. Sevoflurane MAC in oxygen is higher in children than in adults: 2.6% (1-3 yr), 2.5% (3-12 yr), 2.1% (40 yr), 1.6% (60 yr) [6,7]. Propofol administration was discontinued or reduced as clinically indicated after the addition of sevoflurane. When neuromuscular blockade had recovered to T1 5% after the mivacurium bolus, an infusion of mivacurium, initially 10 [micro sign]g [center dot] kg-1 [center dot] min-1, was adjusted every 2-3 min to maintain a constant 90%-95% neuromuscular blockade. Changes in infusion rate and the cumulative doses of mivacurium delivered were recorded at 5-min intervals. Mivacurium infusion was discontinued at the end of surgery. The end-tidal sevoflurane concentration was maintained at the assigned level until spontaneous neuromuscular recovery reached a TOF ratio of 0.7, then anesthesia was terminated as clinically indicated.
In adults, general anesthesia was induced with 1.5-3.0 mg/kg propofol, 0.02 mg/kg atropine, 0.3 mg/kg lidocaine, 2 [micro sign]g/kg fentanyl, and 0.2 mg/kg mivacurium (2 x 95% effective dose in adults) IV to facilitate tracheal intubation. Maintenance of anesthesia was similar to that in children, but the propofol infusion was started at the lower rate of 50-150 [micro sign]g [center dot] kg-1 [center dot] min-1. In all other respects, the same study protocol was followed for children and adults.
The sample size estimate of 25 subjects in each of the three parallel groups was based on a two-sided test of statistical significance at P < 0.05 and was designed to detect a between-concentration difference of 40% in the infusion rate of mivacurium with a power of >or=to80%. Efficacy variables (onset time, duration, and recovery indices) and demographic data (age, height, weight) in adults and children were compared by using one-way analysis of variance at each concentration of sevoflurane (0, 0.5, and 1 MAC), followed by the multiple comparison tests of Bonferroni, Tukey, and Scheffe. Similar analyses were used to compare infusion rates at 5-min intervals in each of the three groups. Two-factor (time and sevoflurane concentration group) repeated-measures analysis of variance was used to identify sequential differences in infusion rates. Categorical demographic data (gender, ASA physical status) were compared using Pearson's chi squared test, as well as Fisher's exact test. Comparisons between children and adults of infusion rates at 5-min intervals at each sevoflurane concentration, and of efficacy variables were made using Student's t-test. Correlations between PChE activity and onset, infusion rate, and recovery indices of mivacurium neuromuscular block were made using least squares linear regression analysis (Statview[registered sign]; Abacus Concepts Inc., Berkeley, CA). A statistical significance level of P < 0.05 was chosen. All data are expressed as mean values +/- SD (range) except as otherwise stated.
All 75 children successfully completed the study. Seven adult patients were excluded from complete analysis: one because of clindamycin therapy and six because of block reversal, for clinical reasons, before all recovery data had been obtained and/or a lack of recovery data. Partial data analysis was available for all subjects, so that the primary analysis was based on the intent to treat population. Recovery data were not available in two cases, so that the intent to treat population was reduced by two subjects.
Within the age groups, there were no differences among the sevoflurane groups in demographic variables (age, weight, height, ASA physical status, gender) (Table 1). Similarly, there were no differences among drug groups for PChE concentration (Table 1) or initial systolic/diastolic blood pressures, heart rate, or temperature. The number of male versus female subjects was similar in children (34 vs 41), but most of the adults (73 of 75) were female. PChE activity was greater in children than in adults (9.15 +/- 1.65 vs 6.52 +/- 1.86 KU/L; P < 0.0001) (Table 1). Although the duration of surgery was similar in children and adults, the duration of anesthesia, time of mivacurium infusion, total dose, and average infusion rate of mivacurium were less in children (P < 0.05) (Table 1).
Mivacurium administration data are shown in Figure 1 for 5-min intervals up to 50 min, after which there were too few subjects in each group (<10) to make valid comparisons. During the first 10 min of infusion, there was a sevoflurane-dependent decrease in the rate required to maintain 90%-95% block in adults. At 30 min, there were still differences among the groups. Reduction in mivacurium requirement in the 1.0 MAC group was approximately 50% of that in the 0 MAC group (Figure 1). The pattern was similar in children, except that the mivacurium requirement was greater than that in adults at each time. At 30 min, the infusion rate in each of the groups of children was approximately double that of adults (Table 2). After 10 min, the rate continued to decrease in children given sevoflurane, by >50% between 10 and 45 min (Figure 1).
After the initial equipotent doses of mivacurium, onset of neuromuscular block and recovery to T1 were more rapid in children than in adults (P < 0.001) but were not different among sevoflurane groups. After stopping the mivacurium infusion, recovery was slower with sevoflurane (P < 0.01) in children and adults (Table 2). Recovery was slower in adults than in children for each measured level of TOF at each sevoflurane dose (P < 0.01, Table 2). The differences were considerable: mean time to TOF 0.7 recovery in children was prolonged from 9.8 +/- 2.5 min at 0 MAC to 19.4 +/- 6.3 min at 1.0 MAC, compared with 19.9 +/- 5.4 and 32.9 +/- 9.8 min, respectively, in adults (P < 0.0001) (Table 2).
PChE activity correlated with infusion rate, onset time, and recovery times (recovery index, time to TOF 0.7 recovery) from neuromuscular block (Table 3, Figure 2 and Figure 3).
The principal findings of this study were that, to maintain 90%-95% neuromuscular block with an infusion of mivacurium, the rate of administration was higher in children than in adults and that the requirement for mivacurium was decreased in the presence of sevoflurane. After 30 min, the infusion rate in children was approximately double that in adults and, in both, 1 MAC sevoflurane reduced the infusion rate by a further 50%. Reduction in infusion rate with sevoflurane in adults was primarily accomplished within 10 min of its introduction, whereas the requirement continued to decrease for at least 45 min in children. In addition, after the mivacurium infusion, the rate of recovery of neuromuscular function was more rapid in children than in adults, and the recovery rate was slowed by sevoflurane in a dose-related manner in both age groups. Finally, PChE activity was correlated with the infusion rate and the rate of recovery of neuromuscular block.
Markakis et al.  examined brief targeted infusions of mivacurium to attain approximately 50% and 90% neuromuscular block in adults and children to determine the relationship between dose and PChE activity . They determined that higher infusion rates were required in children than in adults to maintain the same level of neuromuscular block. In other studies using balanced anesthesia, the doses to maintain 90%-95% block [4,9,10] were similar to those in the balanced anesthesia group in our study. There are no reports of mivacurium infusion in children during sevoflurane anesthesia. In comparisons that have been made using other inhaled anesthetic drugs, the need for mivacurium was reduced by approximately one-third by 1 MAC halothane and by approximately 70% by 1 MAC isoflurane . Isoflurane delays recovery from mivacurium neuromuscular block . Previous studies in adults demonstrated that the potentiating effect of sevoflurane was similar to that of isoflurane concentrations on neuromuscular block produced by atracurium, vecuronium, or pancuronium . These observations are compatible with those of the present study, in which mivacurium requirements were reduced by 50%-70% in the presence 1 MAC sevoflurane in both children and adults.
In general, our results are in agreement with previous reports of the potentiation of nondepolarizing neuromuscular blockade by inhaled anesthesia. Kaplan et al.  reported prolongation of recovery after 0.2 mg/kg mivacurium administered during 1 MAC sevoflurane anesthesia in children. Like other inhaled anesthetic drugs, reversal of vecuronium neuromuscular block with neostigmine or edrophonium is impaired in the presence of sevoflurane, and this is more marked with sevoflurane than with isoflurane [14,15]. This observation is of limited importance when mivacurium is used for neuromuscular blockade because pharmacological reversal is seldom required, at least in children [16,17].
There is considerable dispute concerning the role of PChE in determining mivacurium requirements in children. As in previous studies , we found that PChE concentration was higher in children than in adults and that children required larger doses of mivacurium to achieve the same degree of neuromuscular block (Table 1). Although Lien et al.  showed that the clearance of the trans-trans and cis-trans isomers correlated with PChE concentration, several authors have described little  or no  relationship between the mivacurium infusion rates required to maintain constant block and the PChE level. However, most investigations involved fewer subjects with a narrower age range than those in the present study; hence, a more limited range of PChE concentrations. Hart et al.  used a different approach. By targeting brief steady-state infusions to approximately 50% and 90% twitch depression and estimating the infusion rates that would have produced 50% (IR50) and 90% (IR90) twitch depression, they found that infusion rates were related to PChE concentration and that approximately 50% of the variability in infusion rates was a function of variability in PChE in adults. In a similar study in children, these authors established a relationship between PChE for IR50, but not IR90, twitch depression. They concluded that variability of PChE could account for only 22% of the variability in infusion rates . In the present study, we confirmed the importance of PChE in determining the rate of mivacurium infusion. Using linear regression analysis for all subjects, we established relationships between PChE and infusion rate and recovery indices for mivacurium (Table 3). Up to 40% of the pharmacodynamic variation of mivacurium may be explained as a function of variation of PChE activity.
An unexpected finding of the present study was the progressive reduction in mivacurium requirements in children who received sevoflurane. In adults, little alteration in infusion rate was observed after 10 min (Figure 1, Table 2). It was anticipated that the rapid equilibration of sevoflurane would avoid the slow achievement of steady-state neuromuscular block previously experienced with an atracurium infusion during enflurane anesthesia . There was no evidence of limb cooling, reduced intensity of block, or abnormality of monitoring. One explanation for this finding might be the accumulation of the cis-cis isomer of mivacurium that does not undergo hydrolysis by PChE. In the presence of increased PChE, more of this isomer might be produced, and because it is eliminated slowly, this could lead to a more prolonged block and, therefore, to a reduced infusion requirement. However, continued reduction in mivacurium requirement was not seen during balanced anesthesia in children when a greater amount of mivacurium had been infused producing, presumably, even greater amounts of the cis-cis isomer. Similarly, Goudsouzian et al.  were unable to demonstrate any clinical effect of the isomer in prolonged infusions of mivacurium (>4 h) in adults. Such debate will not be resolved until simultaneous pharmacokinetic and pharmacodynamic measurements are made so that neuromuscular sensitivity can be expressed in terms of plasma concentration, rather than assumed by the dose administered. During enflurane anesthesia, the plasma concentration of atracurium, administered by constant infusion, progressively increased . A similar finding with mivacurium during sevoflurane anesthesia would lead to a decreasing need for mivacurium.
When mivacurium infusion is used to maintain stable neuromuscular blockade in children, approximately twice the adult dose is required. If used in the presence of sevoflurane, the mivacurium requirement is reduced according to sevoflurane dose: at 1 MAC concentrations, the infusion rate is reduced by approximately 70% in children and 50% in adults. As with other inhaled anesthetics, recovery of neuromuscular function is prolonged in the presence of sevoflurane. Further studies are needed to determine the rate of recovery when administration of sevoflurane is stopped at the same time as, or soon after, mivacurium.
In conclusion, mivacurium neuromuscular blockade is potentiated by sevoflurane in children and in adults. This effect leads to a reduction in the mivacurium dose necessary to produce a stable block and leads to prolonged recovery when stopped. Children require approximately twice the dose of mivacurium necessary for adults during balanced and sevoflurane anesthesia. Some 40% of the variability in mivacurium behavior may be explained as a function of PChE activity.
1. Taivainen T, Tiainen P, Meretoja OA, et al. Comparison of the effects of sevoflurane and halothane on the quality of anaesthesia and serum glutathione transferase alpha and fluoride in paediatric patients. Br J Anaesth 1994;73:590-5.
2. Holzman RS, van der Velde ME, Kaus SJ, et al. Sevoflurane depresses myocardial contractility less than halothane during induction of anesthesia in children. Anesthesiology 1996;85:1260-7.
3. Sarner JB, Levine M, Davis PJ, et al. Clinical characteristics of sevoflurane in children. Anesthesiology 1995;82:38-46.
4. Meretoja OA, Wirtavuori K, Taivainen T, Olkkola KT. Time course of potentiation of mivacurium by halothane and isoflurane in children. Br J Anaesth 1996;76:235-8.
5. Meretoja OA, Theroux M. Can final EMG baseline be used as a reference to calculate neuromuscular recovery? Acta Anaesthesiol Scand 1997;41:492-6.
6. Katoh T, Ikeda K. Minimum alveolar concentration of sevoflurane in children. Br J Anaesth 1992;68:139-41.
7. Scheller MS, Saidman LJ, Partridge BL. MAC of sevoflurane in humans and the New Zealand White rabbit. Can J Anaesth 1988;35:153-6.
8. Markakis DA, Hart PS, Lau M, et al. Does age or pseudocholinesterase activity predict mivacurium infusion rate in children? Anesth Analg 1996;82:39-43.
9. Meretoja OA, Taivainen T, Wirtavouri K, Olkkonen KT. Pharmacology of mivacurium in infants. Br J Anaesth 1994;73:490-3.
10. Meretoja OA, Olkkola KT. Pharmacodynamics of mivacurium in children using a computer-controlled infusion. Br J Anaesth 1993;71:232-7.
11. Jalkanen L, Meretoja O. The influence of the duration of isoflurane anaesthesia on neuromuscular effects of mivacurium. Acta Anaesthesiol Scand 1997;41:248-51.
12. Vanlinthout LEH, Booij LHDJ, Van Egmond J, Robertson EN. Effect of isoflurane and sevoflurane on the magnitude and time course of neuromuscular block produced by vecuronium, pancuronium and atracurium. Br J Anaesth 1996;76:389-95.
13. Kaplan RF, Garcia M, Hannallah RS. Mivacurium-induced neuromuscular blockade during sevoflurane and halothane anaesthesia in children. Can J Anaesth 1995;42:16-20.
14. Morita T, Tsukagoshi H, Sugaya T, et al. Inadequate antagonism of vecuronium-induced neuromuscular block by neostigmine during sevoflurane or isoflurane anesthesia. Anesth Analg 1995;80:1175-80.
15. Morita T, Kurosaki D, Tsukagoshi H, et al. Sevoflurane and isoflurane impair edrophonium reversal of vecuronium-induced neuromuscular block. Can J Anaesth 1996;43:799-805.
16. Bevan JC, Tousignant C, Stephenson C, et al. Dose responses for neostigmine and edrophonium as antagonists of mivacurium in adults and children. Anesthesiology 1996;84:354-61.
17. Bevan DR, Kahwaji R, Ansermino JM, et al. Residual block after mivacurium with or without edrophonium reversal in adults and children. Anesthesiology 1996;84:362-7.
18. Davis L, Britten JJ, Morgan M. Cholinesterase: its significance in anaesthetic practice. Anaesthesia 1997;52:244-60.
19. Lien CA, Schmith VD, Embreee PB, et al. The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1994;80:1296-302.
20. Ostergaard D, Jensen FS, Jensen E, et al. Influence of plasma cholinesterase activity on recovery from mivacurium-induced neuromuscular blockade in phenotypically normal patients. Acta Anaesthesiol Scand 1992;36:702-6.
21. Hart PS, McCarthy GJ, Brown R, et al. The effect of plasma cholinesterase activity on mivacurium infusion rates. Anesth Analg 1995;80:760-3.
22. Withington DE, Donati F, Bevan DR, Varin F. Potentiation of atracurium neuromuscular blockade by enflurane: time-course of effect. Anesth Analg 1991;72:469-73.
23. Goudsouzian N, Chakravorti S, Denman W, et al. Prolonged mivacurium infusion in young and elderly adults. Can J Anaesth 1997;44:955-62.
© 1998 International Anesthesia Research Society
24. Reference not provided.