Mivacurium chloride in infants and children

Mivacurium has been little studied in infants and children without a volatile anaesthetic agent. We analysed onset time and maximal neuromuscular response after mivacurium 0.1 mg/kg, and the infusion requirement of mivacurium to maintain a 50, 90, or 95% neuromuscular block in 76 infants and children under N₂O-O₂ alfentanil anaesthesia. Furthermore, we assessed the time course of potentiation of 1 MAC end-tidal halothane or isoflurane on the infusion requirement of mivacurium. Neuromuscular response was recorded by adductor pollicis electromyogram. The onset time of mivacurium was shorter in infants than in children (2.1 ± 0.6 and 3.2 ± 0.9 min (mean±SD); P =0.0001). The dose potency of mivacurium did not depend on the age of a paediatric patient. The estimated ED₉₅ of mivacurium was 136±46 μg/kg. The mivacurium requirement to maintain a 50, 90, or 95% neuromuscular block averaged 340, 730, and 900 μg/kg/h, respectively. Halothane and isoflurane decreased this hourly requirement by 35 and 70%, respectively. The decrease in the mivacurium infusion requirement was fastest in the youngest children. In conclusion, mivacurium is easy to administer as bolus doses or continuous infusion in paediatric patients because its potency is similar in all patients from 1 month to 15 years of age. Halothane and isoflurane produce their maximal potentiation of neuromuscular block only after 30–60 min of administration. This potentiation is similar in magnitude in all patients, but takes place fastest in the youngest children.     

Mivacurium chloride: a study to evaluate its use during propofol–nitrous oxide anaesthesia

We assessed the neuromuscular and cardiovascular effects of mivacurium chloride, a neuromuscular blocking agent, in 33 patients during propofol-nitrous oxide anaesthesia. Neuromuscular function was assessed with supramaximal stimuli of the ulnar nerve, using surface electrodes at the wrist, with repeat trains of four. Mivacurium given as a bolus of 0.15 mg.kg-1 (ED95 x 2) was found to be haemodynamically stable. Intubating conditions assessed at 2 and 2.5 min were either good or excellent. All patients developed a block of 100% in a mean (SD) time of 105 (34) s. There were mean (SD) intervals of 12 (2.4) min before the reappearance of the first twitch of the train of four (T1) following the bolus dose, and 15.8 (3.1) min for the T1 to reach 25% of its control value (TC). Seventeen patients received an infusion of mivacurium to maintain neuromuscular blockade (T1:TC 10-20%) with a mean (SD) infusion rate of 6.9 (2.2) micrograms.kg-1.min-1. Recovery from neuromuscular blockade was assessed with spontaneous offset or augmented with edrophonium following either the initial bolus or an infusion. Following a bolus it took a mean (SD) of 26.2 (3.7) min for the fourth twitch of the train of four (T4):T1 ratio to reach 0.7. In patients receiving an infusion with spontaneous offset it took a mean (SD) time of 12.0 (2.2) min to reach the T4:T1 ratio of 0.7 from a T1:TC value of 8.8. Edrophonium significantly decreased the recovery time in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mivacurium in children with Duchenne muscular dystrophy

The authors retrospectively reviewed their experience with mivacurium for neuromuscular blockade in seven children with Duchenne muscular dystrophy. Mivacurium was administered to seven children ranging in age from 8.3 to 14.4 years and in weight from 29 kg to 68 kg during either posterior spinal fusion or lower extremity release. An initial bolus dose of 0.2 mg·kg^?1 was followed by a continuous infusion. Neuromuscular blockade was monitored with a standard twitch monitor and the TOF (2 Hz for 2 s). Complete suppression of all four twitches occurred in 1.5 to 2.6 min. The continuous infusion was started with the return of the first twitch and adjusted to maintain one twitch. Time to recovery of the first twitch varied from 12 to 18 min. Continuous infusion requirements varied from 3 to 20 μg·kg^?1 with an average for the case of less than 10 μg·kg^?1 min^?1 in five of the seven patients. A moderate increase in sensitivity to mivacurium in this patient population is suggested by a decrease in infusion requirements and a prolonged effect following the initial dose.     

Mivacurium in special patient groups

In special patient groups, drug response may be different from that in the healthy adult patient. Mivacurium dose requirements vary with age, and children require larger doses to obtain any given degree of block, but the elderly often require smaller doses. However, the dose requirements of the neonate do not necessarily differ greatly from those of the adult. There is a relationship between the duration of action of a bolus dose – as well as infusion requirements to maintain block – and the plasma cholinesterase activity. Patients with renal disease may have a decreased cholinesterase activity and may require smaller doses of mivacurium. Patients with severe liver disease may have a marked decrease in cholinesterase activity, and in these patients a substantially smaller dose of the drug may be needed to obtain and maintain any given degree of block. If the variation in dose requirements is kept in mind and the degree of block appropriately monitored, mivacurium may be used with safety in special patient groups, such as children, the elderly, or those with renal or hepatic impairment.     

Mivacurium-induced neuromuscular blockade in patients with atypical plasma cholinesterase

The duration of action of mivacurium was evaluated during a modified neurolept anaesthesia in 17 patients heterozygous for the usual and the atypical plasma cholinesterase (pChe) gene (E^a₁E^a₁) and in five patients homozygous for the atypical gene (E^a₁E^a₁). The response to train-of-four nerve stimulation was recorded using a Myograph 2000. Five heterozygous patients were given a small dose of mivacurium 0.03 mg kg bw^-1 intravenously (Group 1). The mean (range) suppression of the first twitch in the train-of-four response (T₁) was 91% (69–100%). The time to 90% T₁ recovery was 23.9 min (14.0–31.3 min). Twelve other heterozygous patients (Group 2) received mivacurium 0.2 mg kg bw^-1 (2.5 * ED₉₅). In these patients the time to 100% T₁ suppression was 1.4 min (1.1–2.0 min). The time to reappearance of the T₁ response, to 90% T₁ recovery, and the recovery index (25.3 min (14.5–34.5), 45.5 min (30.9–59.2), and 9.8 min (6.8–19.6), respectively) were significantly longer than reported in phenotypically normal patients. Five patients homozygous for the atypical gene (Group 3) were given 0.03 mg kg bw^-1 mivacurium. The time to reappearance of T₁ response following this low dose of mivacurium ranged from 26–128 min. In all five patients the neuromuscular block was successfully antagonized with neostigmine preceded by atropine. In conclusion, mivacurium-induced neuromuscular blockade was moderately prolonged in patients heterozygous for the usual and the atypical gene for plasma cholinesterase. Patients homozygous for the atypical plasma cholinesterase gene appear to be markedly sensitive to mivacurium.     

Influence of plasma cholinesterase activity on recovery from mivacurium-induced neuromuscular blockade in phenotypically normal patients

The significance of plasma cholinesterase (pChe) activity for the duration of action of mivacurium in phenotypically normal patients was evaluated in 35 patients during neurolept anaesthesia. The response to train-of-four nerve stimulation was recorded using a Myograph 2000. Ten patients with normal pChe (Group I) and five patients with decreased pChe activity (Group 2) were given a small test dose of mivacurium 0.03 mg kg-1. Mivacurium 0.1 mg kg-1 was administered following spontaneous recovery from the first dose. The mean suppression of the height of the first (T1) of the train-of-four responses following mivacurium 0.03 mg kg-1 patients with normal and decreased enzyme activity was 40% and 56%, respectively, and the mean T1 suppression after mivacurium 0.1 mg kg-1 was 100% in both groups. The times to different levels of twitch height recovery following the 0.1 mg kg-1 dose did not differ between the two groups of patients. Another 20 patients with normal or decreased pChe activity (Group 3) were given mivacurium 0.2 mg kg-1. In this group the time to maximum block was 1.4 min (1.0-4.0) mean (range) and the time to reappearance of the T1 response was 15.0 min (7.4-22.7) (range). An inverse relationship was found between the patients' pChe activity and the time to first response. It is concluded that mivacurium is short-acting in patients with normal pChe phenotype and normal to low-normal pChe activity. No patient with very low pChe activity was included in the study. A prolonged response to mivacurium may, however, be expected in these patients.     

The duration of action of mivacurium is prolonged if preceded by atracurium or vecuronium

We studied 45 patients (ASA I-II) during propofol-alfentanil-N₂O-O₂ anaesthesia to determine if recovery from neuromuscular block induced by mivacurium is influenced differently by prior injection of atracurium or vecuronium. Neuromuscular function was monitored by adductor pollicis EMG. Patients were randomized to receive two dosesof either mivacurium (150 and 70 μg kg^-1), atracurium (350 and 75 μg kg^-1) or vecuronium (70 and 15 μg kg^-1) followed by a final dose of mivacurium 70 μg kg^-1. The second and third doses of the muscle relaxants were administered at 25–30% recovery of the E₁ (first EMG response in the train-of-four series). Following the final dose of mivacurium, the EMG response recovered to 25 and 95% in 10.4±3.9 and 19.7±5.7 min (mean±SD), respectively, if mivacurium was the only muscle relaxant. Respective times were 100% longer if mivacurium had been preceded by atracurium (23.8 ± 3.3 and 39.8±6.9 mm) or vecuronium (22.6±3.5 and 44.1 ±7.9 min) ( P =0.000l). The 25–75% recovery times in the three groups were 4.9±1.0, 8.7±2.4 and 10.5±2.5 min, respectively ( P =0.0001). Our results indicate that there is no benefit in giving mivacurium at the end of surgery after peroperative use of atracurium or vecuronium.     

The pharmacodynamics and pharmacokinetics of mivacurium in children

BACKGROUND: In children, onset time and duration of action of mivacurium are shorter than in adults. Some suggest that this is due to differences in plasma cholinesterase (pChe), whereas others indicate that there is no difference. The purpose of this study was to evaluate the pharmacodynamics and pharmacokinetics of mivacurium in phenotypically normal children aged 3-6 and 10-14 years old, respectively. METHODS: Ten children aged 3-6 years and 10 children aged 10-14 years were studied during halothane anaesthesia. Before induction of anaesthesia, a blood sample was drawn to measure the pChe activity and phenotype. The neuromuscular block was monitored at the thumb using train-of-four (TOF) nerve stimulation every 12 s and mechanomyography. The times to different levels of neuromuscular recovery following mivacurium 0.2 mg/kg were recorded. The concentrations in venous blood of the three isomers and the metabolites of mivacurium were measured. RESULTS: No statistically significant difference was found in pChe activity or in the pharmacodynamics of mivacurium. The onset time was 1.4 min (0.8-1.9) median (range) and 1.3 min (1.1-1.9) and the time to first response to TOF nerve stimulation was 9.6 min (6.5-12.6) and 10.5 min (7.0-14.0) in young and older children, respectively. The pharmacokinetic data were too sparse to allow analysis of the two age groups separately (8 and 8 patients), hence the data were pooled. The median clearances of the cis-cis, the cis-trans, and the trans-trans isomer were 5.5, 51.0 and 30.5 ml/kg/min, respectively. CONCLUSION: Our data indicate that there are no major differences in pharmacodynamics or pharmacokinetics of mivacurium between young (3-6 years) and older (10-14 years) children.     

Synergism between mivacurium and pancuronium in adults

Mivacurium could be a useful agent as a final dose of a muscle relaxant following pancuronium if only additivily exists between these agents. We examined the interaction between mivacurium and pancuronium in 70 patients (ASA I-II) during propofol-alfentanil-N₂O-C₂ anaesthesia. Neuromuscular function was monitored by adductor pollicis EMG.
Firstly we established dose-response curves for mivacurium and pancuronium. Thereafter, 20 patients received a combination of 0.5 times the ED₅₀ doses of mivacurium and pancuronium (cMP) determined in the first part of this study. Patients were randomized to receive the cMP to the same IV-line (n=10) or to two separate IV-lines in opposite hands (n=10).
ED₅₀ values for mivacurium and pancuronium were 57.7 and 37.1 μg kg^-1, respectively. Maximal neuromuscular block following the cMP was 91.8 ±5.0% (mean±SD). This was highly significantly different from the estimated 50% NMB if only additivity exists between mivacurium and pancuronium ( P =0.0001). After the cMP, the 25 75% recovery rime was 9.4± 1.3 min and the time to train-of-four ratio of 0.70 was 35.8±5.4 min. There was no statistical difference in any recorded neuromuscular parameter between the two subgroups receiving mivacurium and pancuronium to the same or to opposite hands ( P >040).
We conclude that a significant synergism exists between mivacurium and pancuronium which may indicate that mivacurium does not produce a short-acting NMB if given after pancuronium. We do not recommend using mivacurium together with pancuronium.     

Mivacurium infusion requirement and spontaneous recovery of neuromuscular transmission in children anaesthetized with nitrous oxide and fentanyl,halothane, isoflurane or sevoflurane

BACKGROUND: Forty children, aged 3-11 years, ASA I or II, were allocated at random to receive N2O/O2-fentanyl or 1 MAC halothane, isoflurane or sevoflurane-N2O/O2 anaesthesia. Mivacurium was used for muscle relaxation. METHODS: Electromyographic response of the adductor pollicis to train-of-four (TOF) stimulation, 2 Hz for 2 s, applied to the ulnar nerve at 10-s intervals was recorded using the Relaxograph (Datex, Helsinki, Finland). An intubating dose of mivacurium, 0.2 mg.kg-1 was given, and when T1 returned to 5%, muscle relaxation was maintained by continuous infusion of mivacurium, adjusted manually to maintain a stable 90-99% block. RESULTS: Halothane, isoflurane and sevoflurane groups had lower infusion requirements for mivacurium than the N2O-fentanyl group (P=0.000083). Mivacurium requirement was 18.8 +/- 6.8, 10.8 +/- 4.2, 6.9 +/- 3.9 and 9.6 +/- 5.6 microg.kg-1.min-1 for children receiving N2O/O2-fentanyl, halothane, isoflurane and sevoflurane anaesthesia, respectively. CONCLUSIONS: Spontaneous recovery from T1=10% to TOF ratio=0.7 was insignificantly prolonged from 6.3 to 12.5 min in the fentanyl group to 7-16.5 min in children anaesthetized with inhalational anaesthetics.     

Comparison of the neuromuscular effects of mivacurium and suxamethonium in infants and children

We compared both the time course of neuromuscular blockade and the cardiovascular side-effects of suxamethonium and mivacurium during halothane and nitrous oxide anaesthesia in infants 2–12 months and children 1–12 years of age. Equipotent doses of mivacurium and suxamethonium were studied; 2.2×ED₉₅ was used in four groups of infants and children, while 3.4×ED₉₅ was used in two groups of children. Onset of neuromuscular block in infants was not significantly faster with suxamethonium than with mivacurium ( P =0.2). In all infants given suxamethonium, intubating conditions were excellent, while, in 6/10 infants given mivacurium, intubating conditions were excellent. Onset of complete neuromuscular block in children was significantly faster with suxamethonium, 0.9 min compared with mivacurium, 1.4 min ( P ×0.05). Increasing the dose of suxamethonium or mivacurium in children to 3.4×ED₉₅ did not change the onset of neuromuscular block. Recovery of neuromuscular transmission to 25% of initial twitch height (T₂₅) in infants and children was significantly faster after suxamethonium than after mivacurium, at 2.5 and 6 min, respectively ( P ×0.05). In children given 3.4×ED₉₅ of suxamethonium or mivacurium, recovery from neuromuscular block was almost identical with the dose of 2.2×ED₉₅, with spontaneous recovery to T₂₅ prolonged by only 0.5 min. No infant or child had hypotension after the mivacurium bolus dose.     

Recovery from mivacurium-induced neuromuscular blockade after neurosurgical procedures of long duration

Study Objective: To determine if recovery following prolonged (5 hours in length or greater) infusions of mivacurium is different from recovery after single bolus administration.

Design: open-labelled, controlled study.

Setting: Inpatient neurosurgical service at a university hospital.

Patients: 36 patients between the ages of 18 to 65 without significant history of renal, hepatic, cardiac, or metabolic disease undergoing neurosurgical procedures. 21 patients had craniotomies or skull base procedures of an estimated length of 5 hours or greater; 15 patients (control) underwent short neurosurgical operations (two hours or less).

Interventions: Intravenous (IV) mivacurium 0.15 mg/kg was given with stable general anesthesia with 70% nitrous oxide in oxygen, 0.2% to 0.3% end-tidal isoflurane, and continuous infusion of fentanyl. The control group was allowed to recover spontaneously after single bolus administration while neuromuscular blockade was maintained in the study group with a continuous infusion of mivacurium until 30 minutes before completion of surgery, at which time the infusion was discontinued and neuromuscular function was allowed to recover spontaneously.

Measurements and Main Results: The evoked compound electromyogram of the adductor pollicis brevis muscle was measured during stimulation of the ulnar nerve at 2 Hz for 2 seconds at 10-second intervals. Measurements included time to 50% and 90% depression of twitch (T₁ of the TOF response), time to T₁ equal to 25% (T₁25), 50% (T₁50), and 75% (T₁75) of baseline, and TOF ratio (TR) at 10%, 25%, 50%, and 75% recovery. Recovery index (RI), which is T₁75 minus T₁25, was also determined. All mivacurium infusion rates decreased during surgery. Recovery rates were significantly longer in the long infusion (LI) group than the control group. RI was also increased in the LI group compared with the single bolus control (11.3 ± 1.2 minutes vs. 7.1 ± 0.8 minutes p < 0.05).

Conclusions: Recovery following mivacurium by prolonged continuous infusion was slower than that observed after single bolus administration in this patient population. Clinically, this increased time to recovery may be insignificant.     

Plasma cholinesterase activity and duration of action of mivacurium in phenotypically normal patients

BACKGROUND: The short duration of action of mivacurium is due to its rapid hydrolysis by plasma cholinesterase (pChe). In patients with normal phenotype, low pChe activity because of, for instance, disease or intake of drugs may prolong the duration of action of mivacurium. The purpose of this study was to evaluate the relationship between pChe activity and the duration of action of mivacurium 0.2 mg/kg in phenotypically normal patients. MATERIAL: Forty-three adult patients with normal pChe phenotype and low or normal pChe activity, undergoing a variety of surgical procedures were included in the study with their informed consent and Ethics Committee approval. The neuromuscular block was monitored using TOF stimulation every 12 s and mechanomyography. The time to reappearance of the first response to TOF stimulation was measured. RESULTS: The patients pChe activities ranged from 45 to 1272 U/l (normal range 660-1620 U/l) and the time to first response to TOF from 8.1 to 62.7 min. An inverse relationship between enzyme activity and duration of action of mivacurium was found. The relationship was described by the equation: log10 (time) =alpha- beta log10 (pChe), where alpha (SD) is 2.547 (0.186) and beta (SD) 0.454 (0.069). CONCLUSION: In patients with phenotypically normal pChe, prediction of the duration of action of mivacurium is possible from the patients actual pChe activity. In patients with pChe activities below the normal range, the time to reappearance of the first response to TOF stimulation may vary from 10 to 180 min Only patients with pChe activities <220 U/l had a significantly prolonged duration of action of mivacurium.     

The effect of halothane on mivacurium infusion requirements in adult surgical patients

Background: The extent of interaction between volatile anaesthetics and neuromuscular blocking agents depends both on the inhalational anaesthetic and the muscle relaxant. Halothane has the weakest potentiating effect on neuromuscular blocking drugs and previous studies of the interaction between halothane and mivacurium have been contradictory. We were interested in determining the effect of different levels of halothane-nitrous oxide anaesthesia on infusion requirements of mivacurium. Methods: Sixty adult surgical patients were studied. Anaesthesia was induced with thiopentone and fentanyl and intubation facilitated with mivacurium 0.15 mg kg^-1. The patients were randomly assigned to one of four study groups. The control group received nitrous oxide in oxygen (2: 1) supplemented with fentanyl, while in the other groups halothane was administered at different end-tidal concentrations: 0.19% (Group 2), 0.37% (Group 3), 0.74% (Group 4), corresponding to 0.25, 0.5 and 1.0 MAC of halothane. Neuromuscular block was kept at 95% with a closed-loop feedback infusion of mivacurium and monitored with electromyography. Plasma cholinesterase concentrations and dibucaine numbers were determined. Results: Mivacurium infusion requirements (mean±SD) were 7.5±3.1 μg kg^-1 min^-1 with nitrous oxide-fentanyl anaesthesia. In the groups receiving 0.25, 0.5 or 1.0 MAC of halothane the steady-state infusion rates of mivacurium were reduced to 6.3±2.8, 5.6±1.4 and 5.7±2.5 μg-kg^-1min^-1 (P < 0.05), respectively. There was a linear relationship between mivacurium infusion requirements and plasma cholinesterase activity. Conclusion: Halothane anaesthesia reduces mivacurium infusion requirements by 15–25% compared to nitrous oxide-fentanyl anaesthesia. Interindividual differences in the extent of this interaction are great.     

Rocuronium in infants, children and adults during balanced anaesthesia

We studied 20 infants, 20 children and 20 adults during balanced anaesthesia to compare the neuromuscular blocking effects of rocuronium in these age groups. Neuromuscular function was recorded by adductor pollicis emg and a cumulative log-probit dose-response curve of rocuronium was established. Thereafter, full spontaneous recovery of the neuromuscular function was recorded. Onset time of the first dose of rocuronium was shorter in children than in infants or adults. The potency of rocuronium was greatest in infants and least in children; the ED₅₀ doses (mean ± SD) being 149 ± 36 μg˙kg^?1 in infants, 205 ± 52 μg˙kg^?1 in children and 169 ± 47 μg˙kg^?1 in adults (P<0.05 between infants and children) and the ED₉₅ doses being 251 ± 73 μg˙kg^?1, 409 ± 71 μg˙kg^?1 and 350 ± 77 μg˙kg^?1, respectively (P<0.05 between all groups). The emg recovery following an average 94.5 ± 4.8% neuromuscular blockade established by rocuronium was roughly similar in all study groups. Thus, one ED₉₅ dose of rocuronium, unlike vecuronium, acts as an intermediate-acting agent in all age groups.     

Prolonged mivacurium neuromuscular block in children

The authors report two cases of prolonged neuromuscular block after administration of mivacurium in children with previously undiagnosed plasma cholinesterase deficiency related to homozygous atypical genotype. Their anaesthetic management is described as well as determination of the phenotype of both children and their family.     

Onset and duration of action of rocuronium in children receiving chronic anticonvulsant therapy

The onset and time course of action of rocuronium in normal children and children receiving anticonvulsant drugs for prolonged periods was characterized. A single bolus dose of 0.6 mg.kg-1 rocuronium was administered i.v. to seven nonepileptic patients on no medication, and eight patients on chronic anticonvulsant therapy consisting of either phenytoin, carbamazepine, or both who were age and weight matched. Neuromuscular transmission was monitored by the evoked compound electromyography of the thenar muscles using train of four stimulation every 20 s. Recovery times of the first twitch to 10%, 25%, 50%, 75% and 100% of baseline values and recovery index were obtained. The onset times were 1.05+/-0.5 and 1.41+/-0.5 min for the control and anticonvulsant groups respectively and were not significantly different. Children receiving chronic anticonvulsant therapy had significantly shorter recovery index than the control group (control 10.4+/-5.1 min, anticonvulsant 4.8+/-1.7 min, P<0.05). Furthermore, the duration of recovery to 10%, 50%, 75% and 100% of baseline T1 values was less in the anticonvulsant drug group. Our data confirm resistance to rocuronium in children on chronic anticonvulsant drugs.