Inhibitor Report for: Mivacurium

BACKGROUND: Mivacurium is a short-acting non-depolarizing muscle relaxant, which is hydrolyzed by butyrylcholinesterase. The neuromuscular block (NMB) can be antagonized with cholinesterase inhibitors (CHEI), but the short duration of action of mivacurium questions the need. This systematic review evaluated if the use of CHEIs (neostigmine, pyridostigmine or edrophonium) facilitates reversal of mivacurium-induced NMB. METHOD: Randomized controlled trials and crossover-studies comparing spontaneous recovery with CHEI reversal in patients with mivacurium-induced NMB, assessed with quantitative neuromuscular monitoring, were included. Mean time from injection of the CHEI or allowing of spontaneous recovery to an endpoint representing full recovery was used as outcome. First response to train-of-four nerve stimulation (T1 ) described the level of NMB for administration of the CHEI. Moderate NMB refers to T1 >/= 5% and deeper NMB refers to T1 < 5%. Systematic critical appraisal was performed using the Scottish Intercollegiate Guidelines Network guidelines. Overall quality assessment was done using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Sixteen studies with data from 546 patients were included. Low quality of evidence was found that neostigmine and edrophonium administered at moderate NMB accelerated recovery with up to approximately 5.5-6.5 and 6.5-9.0 minutes, respectively. At deeper NMB only edrophonium accelerated recovery. The effect of neostigmine was not clarified at deeper mivacurium-induced NMB. No studies with reversal by pyridostigmine were identified. CONCLUSION: Low quality of evidence supports that neostigmine and edrophonium accelerate the recovery of mivacurium-induced NMB with 5-6.5 and 6-9.0 minutes respectively, when administered at moderate NMB. At deeper NMB only edrophonium accelerated the recovery.

Mivacurium is a new nondepolarizing muscle relaxant of the benzylisoquinoline type. Its short duration of action is due to rapid breakdown by plasma cholinesterase. The dose of mivacurium which produces 95% inhibition of twitch response (ED95) is between 60 and 80 micrograms/kg. Thus, mivacurium is 0.8 times and four times as potent as vecuronium and atracurium, respectively. With 2-3 x ED95, tracheal intubation can be accomplished within 2.5 min of intravenous injection. The ensuing DUR25% (time from injection to 25% recovery of control twitch tension) is twice as long as with suxamethonium and about half as long as with equipotent doses of atracurium or vecuronium. For muscle relaxation during long surgical procedures, mivacurium has been used as a continuous infusion. The average 6-min recovery index after infusion of mivacurium is particularly favourable for flexible control of muscle paralysis, whereas the recovery indices after infusion of atracurium or vecuronium are 15-30 min. In conclusion, mivacurium will close the pharmacodynamic gap between suxamethonium and the nondepolarizing muscle relaxants of intermediate duration of action. It will probably also be a suitable alternative to suxamethonium in elective cases.

Mivacurium chloride (BW B1090U) is a new, short-acting non-depolarizing neuromuscular blocking agent. It is a synthetic bis-benzylisoquinolinium diester, which is hydrolysed rapidly by plasma cholinesterase. This study compares mivacurium, atracurium and vecuronium by continuous i.v. infusion. The duration of mivacurium infusion ranged from 29.5 to 286 min. The steady state infusion rates necessary to maintain 95 (SEM 4)% twitch suppression were: mivacurium 8.3 (0.7) micrograms kg-1 min-1; atracurium 7.9 (0.4) micrograms kg-1 min-1; vecuronium 1.2 (0.3) micrograms kg-1 min-1. Following infusions of mivacurium, various recovery times (for example: 25-75%, 6.9 (0.3) min; 25-95%, 11.0 (0.4) min; 5-95% 14.5 (0.4) min) did not differ significantly from those following single bolus doses. Recovery times following cessation of mivacarium infusions were approximately 50% of those for equivalent durations of infusion of atracurium (10.9 (0.3) min for 25-75% recovery and 26.6 (0.4) min for 5-95% recovery). For vecuronium, corresponding recovery times were 13.8 (0.9) and 32.0 (1.2) min, respectively. Comparative recovery times for mivacurium were 40-50% of those for vecuronium. There was a significant correlation between the infusion rate of mivacurium required to maintain 95% twitch depression and the plasma cholinesterase activity of individual subjects.

BACKGROUND: Mivacurium is a short-acting non-depolarizing muscle relaxant, which is hydrolyzed by butyrylcholinesterase. The neuromuscular block (NMB) can be antagonized with cholinesterase inhibitors (CHEI), but the short duration of action of mivacurium questions the need. This systematic review evaluated if the use of CHEIs (neostigmine, pyridostigmine or edrophonium) facilitates reversal of mivacurium-induced NMB. METHOD: Randomized controlled trials and crossover-studies comparing spontaneous recovery with CHEI reversal in patients with mivacurium-induced NMB, assessed with quantitative neuromuscular monitoring, were included. Mean time from injection of the CHEI or allowing of spontaneous recovery to an endpoint representing full recovery was used as outcome. First response to train-of-four nerve stimulation (T1 ) described the level of NMB for administration of the CHEI. Moderate NMB refers to T1 >/= 5% and deeper NMB refers to T1 < 5%. Systematic critical appraisal was performed using the Scottish Intercollegiate Guidelines Network guidelines. Overall quality assessment was done using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Sixteen studies with data from 546 patients were included. Low quality of evidence was found that neostigmine and edrophonium administered at moderate NMB accelerated recovery with up to approximately 5.5-6.5 and 6.5-9.0 minutes, respectively. At deeper NMB only edrophonium accelerated recovery. The effect of neostigmine was not clarified at deeper mivacurium-induced NMB. No studies with reversal by pyridostigmine were identified. CONCLUSION: Low quality of evidence supports that neostigmine and edrophonium accelerate the recovery of mivacurium-induced NMB with 5-6.5 and 6-9.0 minutes respectively, when administered at moderate NMB. At deeper NMB only edrophonium accelerated the recovery.

BACKGROUND The authors previously showed that children require larger infusion rates of mivacurium than adults to maintain target twitch depression. Here, they determined whether there are differences between children and adults in mivacurium's pharmacokinetic and pharmacodynamic properties. METHODS: Twenty-seven patients aged 1-58 yr were anesthetized with nitrous oxide and isoflurane. Cholinesterase activity and adductor pollicis twitch tension in response to train-of-four stimuli were measured. Mivacurium was infused, targeting 90% twitch depression. When twitch was stably depressed 85%-95% for 10 min with no change in infusion rate for 15 min, plasma was sampled to determine concentrations of mivacurium's stereoisomers. Clearance of the trans-trans (Cl(trans-trans)) and cis-trans (Cl(cis-trans)) isomers was determined as the mivacurium infusion rate (adjusted for isomer composition) divided by the concentration of that isomer. Using the Hill equation, assuming equipotency of the trans-trans and cis-trans isomers, and ignoring the contribution of the nonpotent cis-cis isomer, the authors estimated the steady state plasma concentration yielding 90% twitch depression, C90. The effect of age on cholinesterase activity, the infusion rate depressing twitch tension by 90% (IR90), C90, Cl(trans-trans), and Cl(cis-trans) was determined using linear regression. RESULTS: Cholinesterase activity, IR90, and C90 did not vary with age. Both Cl(trans-trans) (r2 = 0.19, P = 0.01) and Cl(cis-trans) (r2 = 0.19, P = 0.02) decreased with age. CONCLUSION: Clearance of mivacurium's potent isomers is larger in younger patients, consistent with the larger mivacurium infusion requirement in children than in adults reported previously.

INTRODUCTION Recent developments in both the quantitative evaluation of neuromuscular blockade and new muscle relaxants are reviewed. With respect to nerve stimulation, neuromuscular recording, and definition of parameters, the results of the 1994 Copenhagen International Consensus Conference are highlighted. Future clinical studies should adhere to these standards. MUSCLE RELAXANTS: Rocuronium, cisatracurium, and mivacurium are new muscle relaxants that were released for clinical use in 1995/1996. Of these, rocuronium has the shortest time of onset, whereas its recovery characteristics closely resemble those of vecuronium. Rocuronium is five times less potent than vecuronium. Twice the ED95 of rocuronium provides good or excellent intubating conditions within 60 to 90 s. Slight vagolytic effects were reported following injection of 0.6 mg/kg rocuronium, while histamine release was not observed. Cisatracurium is one of the ten steroisomers of atracurium. It is five times as potent as the chiral mixture while having a similar pharmacodynamic and -kinetic profile. Up to eight times the ED95 did not cause significant histamine release or clinically relevant cardiovascular effects. Mivacurium is a short-acting nondepolarizing benzylisoquinoline muscle relaxant that undergoes rapid break-down by plasma cholinesterase (PChE). Its duration of action is about one-half as long as that of equipotent doses of atracurium and vecuronium and three times as long as succinylcholine. Mivacurium has a moderate histamine-releasing potential. In patients with atypical or reduced PChE activity, the duration of action of mivacurium is prolonged.

BACKGROUND: Reversal of neuromuscular blockade induced with pancuronium, d-tubocurarine, or doxacurium is achieved using smaller doses of neostigmine in adults than in children. Also, pancuronium- and doxacurium-induced blockade is reversed with smaller doses of edrophonium in children than in adults. The purpose of this study was to compare the spontaneous and neostigmine- and edrophonium-assisted recovery of mivacurium-induced neuromuscular block in adults and children. METHODS: Fifty-four adults, aged 40.1 +/- 10.9 yr, and 54 children, aged 4.9 +/- 0.7 yr, physical status ASA 1-2, were studied during propofol/fentanyl/nitrous oxide anesthesia. A Datex relaxograph was used to monitor the electromyographic response of the adductor pollicis to train-of-four stimulation of the ulnar nerve every 10 s. After induction of anesthesia, 0.2 mg x kg(-1) intravenous mivacurium was administered followed by an infusion to maintain 90-95% T1 block. At the end of surgery, one of four doses of neostigmine (5, 10, 20, and 50 micrograms x kg(-1)) or edrophonium (100, 200, 400, and 1,000 micrograms x kg(-1)) or placebo was given, by random allocation, when T1 had recovered to 10%. Values of T1 and train-of-four were measured for 10 min. RESULTS: Spontaneous recovery proceeded more rapidly in children than in adults. At 10 min, T1 had recovered to 97 +/- 2% (SD) in children compared with 69 +/- 11% in adults and train-of-four to 84 +/- 5% versus 30 +/- 13% (P<0.0001). In children, 10 min after reversal, recovery of T1 and train-of-four was not different from control after edrophonium and was enhanced only by the larger doses of neostigmine. In adults, recovery was accelerated by both edrophonium and neostigmine. Five minutes after reversal, recovery was improved by either drug in adults and in children. CONCLUSIONS: Spontaneous recovery from mivacurium- induced neuromuscular block is more rapid in children than in adults. Ten minutes after attempted reversal, recovery is accelerated by edrophonium and usually by neostigmine in adults but not in children. Thus, when reversal is required, edrophonium may be preferred to neostigmine.

Mivacurium is a short-acting nondepolarising muscle relaxant of the benzylisoquinoline type undergoing rapid breakdown by plasma cholinesterase. With 2.5 fold ED95, tracheal intubation can be accomplished within 2-3 min following injection. The ensuing DUR 25% (i.e. time from injection to 25% recovery of control twitch tension) is three times as long as with succinylcholine and about half as long as with equipotent doses of atracurium and vecuronium. The principal side effects of mivacurium are facial flushing and a transient fall in blood pressure due to a moderate histamine release following doses of 3-4 times the ED95. In patients with end stage liver or renal disease as well as in patients with atypical plasma cholinesterase the duration of action of mivacurium is prolonged. Rocuronium is a steroidal non-depolarising neuromuscular blocking agent chemically related to vecuronium. Compared with the latter, rocuronium is less potent, has a shorter onset of action, and no cumulative effects. Adequate intubating conditions are achieved within 60 to 90 s after i.v. injection of twice the ED95. Its elimination from the blood occurs primarily via liver uptake, while renal elimination is about 10 to 30%. Slight vagolytic effects are reported following injection of 0.6 mg/kg rocuronium, while histamine release is unlikely to occur. Atracurium is a mixture of ten stereoisomers. One of them, cis-atracurium, is five times as potent as the chiral mixture while having a similar pharmacodynamic and kinetic profile. It does not cause significant histamine release or clinically relevant cardiovascular effects at doses up to 8 times the ED95. Laudanosine release seems to be less with cis-atracurium than with atracurium.

Neostigmine antagonism after suxamethonium followed by mivacurium chloride bolus and infusion was studied. Thirty ASA group I or II patients were given mivacurium 0.15 mg/kg followed by infusion during nitrous oxide-enflurane-pethidine anaesthesia. Train of four (TOF) stimuli were applied to the ulnar nerve at the wrist and TOF twitch height and ratio measured by TOF-GUARD nerve stimulator. Mivacurium infusion was titrated to give a 90% block of first twitch height. Patients were randomized into two groups. Group I patients recovered from the mivacurium block spontaneously while Group II patients were given neostigmine 0.05 mg/kg and atropine 0.02 mg/kg. Time to reach train of four ratio (TOFR) of 25%, 50% and 70% were measured. This study demonstrated a mean infusion rate of 5.1 +/- 1.8 micrograms/kg/min to maintain a 90% neuromuscular block. In the spontaneous recovery group, time to reach TOFR of 25%, 50% and 70% were 9.3 +/- 2.7 min, 13.5 +/- 3.0 min and 16.7 +/- 3.0 min respectively while the corresponding times in the neostigmine group were 5.2 +/- 1.7 min, 10.9 +/- 2.2 min and 16.1 +/- 7.4 min respectively. There were significant differences in the time taken to TOFR of 25% (P < 0.0001) and 50% (P < 0.05) but no difference in the time taken for TOFR to return to 70%. We concluded that mivacurium is suitable for use in caesarean section despite a decrease in plasma cholinesterase activity. Neostigmine antagonism is not required as a routine.

PURPOSE To examine the influence of anticholinesterase drugs neostigmine and edrophonium (which have different effects on plasma cholinesterase activity) administered for antagonism of neuromuscular block on the duration of action of mivacurium (a neuromuscular blocking drug metabolised by plasma cholinesterase). METHODS: This was a randomized study where mivacurium 0.15 mg.kg-1 was administered to a control group or after administration of neostigmine 40 micrograms.kg-1 or edrophonium 1 mg.kg-1 (n = 10 for each group) administered 10 min earlier for antagonism of atracurium-induced neuromuscular block. Neuromuscular block was measured by stimulation of the ulnar nerve in a train-of-four mode (TOF) and measuring the force of contraction of the adductor pollicis muscle. Baseline plasma cholinesterase activity was estimated before drug administration in all the groups and following anticholinesterase administration. RESULTS: The times to recovery of T1 (first response in the TOF) to 25 and 90% of control and of the TOF ratio to 0.7 after 0.15 mg.kg-1 of mivacurium were 47, 65 and 70 min in the neostigmine group; 25, 36 and 36 min in the edrophonium group and 17, 29 and 27 min respectively in the control group (P < 0.01). The plasma cholinesterase activity (PCHE) after neostigmine decreased from 6596 to 1959 U.L-1 (P < 0.001) but there was no change after edrophonium (6140 to 6396 U.L-1).
CONCLUSIONS: The duration of action of mivacurium is prolonged by previous administration of neostigmine and this is most likely to be due to inhibition of PCHE activity.

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 x ED95 was used in four groups of infants and children, while 3.4 x 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 < or = 0.05). Increasing the dose of suxamethonium or mivacurium in children to 3.4 x 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 < or = 0.05). In children given 3.4 x ED95 of suxamethonium or mivacurium, recovery from neuromuscular block was almost identical with the dose of 2.2 x ED95, with spontaneous recovery to T25 prolonged by only 0.5 min. No infant or child had hypotension after the mivacurium bolus dose.

Mivacurium is a new nondepolarizing muscle relaxant of the benzylisoquinoline type. Its short duration of action is due to rapid breakdown by plasma cholinesterase. The dose of mivacurium which produces 95% inhibition of twitch response (ED95) is between 60 and 80 micrograms/kg. Thus, mivacurium is 0.8 times and four times as potent as vecuronium and atracurium, respectively. With 2-3 x ED95, tracheal intubation can be accomplished within 2.5 min of intravenous injection. The ensuing DUR25% (time from injection to 25% recovery of control twitch tension) is twice as long as with suxamethonium and about half as long as with equipotent doses of atracurium or vecuronium. For muscle relaxation during long surgical procedures, mivacurium has been used as a continuous infusion. The average 6-min recovery index after infusion of mivacurium is particularly favourable for flexible control of muscle paralysis, whereas the recovery indices after infusion of atracurium or vecuronium are 15-30 min. In conclusion, mivacurium will close the pharmacodynamic gap between suxamethonium and the nondepolarizing muscle relaxants of intermediate duration of action. It will probably also be a suitable alternative to suxamethonium in elective cases.

We investigated the interaction between mivacurium and succinylcholine when mivacurium was administered during the early recovery from succinylcholine block. We studied 40 adult patients during propofol-alfentanil-N2O-O2 anesthesia. Neuromuscular function was monitored using an electromyographic method (Relaxograph, Datex, Helsinki, Finland). Patients randomly received either 1.0 mg/kg of succinyl-choline followed by 0.15 mg/kg of mivacurium when the first twitch (T1) during succinylcholine block recovered to 5%, or 0.15 mg/kg of mivacurium without succinylcholine. Serum cholinesterase activity was lower than normal range in two patients and higher than normal range in four patients, but the dibucaine number value was normal in every patient. The mean onset time (3.8 +/- 0.9 min) (mean +/- SD) or maximal neuromuscular block (96.6% +/- 7.2%) of mivacurium did not differ between the groups. The T1 recovery times of mivacurium were slightly shorter (P < 0.05) after succinylcholine administration than without it. During recovery of mivacurium block, the fade was significantly greater, i.e., the train-of-four (TOF) ratio was lower, after succinylcholine administration than without it. Recovery index (T1 25%-75%, mean 4.7 +/- 1.3 min) and the time from the administration of mivacurium to the recovery of TOF ratio 0.7 (mean 20.4 +/- 5.1 min) were not different between the groups. In conclusion, in healthy patients succinylcholine has negligible effects on a subsequent mivacurium-induced neuromuscular block.

Mivacurium is a relatively new short-acting nondepolarizing neuromuscular blocker. A recommended dose of 0.15-0.2 mg kg-1 provides tracheal intubating conditions within 2.5 min and duration of action of 15-30 min, making it a possible alternative to suxamethonium for short procedures requiring tracheal intubation. However, in common with suxamethonium its metabolism depends primarily on plasma cholinesterase and its duration of action is prolonged in patients with reduced plasma cholinesterase activity. We present a case of unexpected prolonged neuromuscular block in a child with previously undiagnosed plasma cholinesterase deficiency.

Although mivacurium is eliminated by plasma cholinesterase, previous investigations have revealed either no relationship or limited correlation between mivacurium infusion rates (IRs) and plasma cholinesterase activity. Assuming that such a relationship should exist, we used a novel approach to better demonstrate the relationship in humans. Fourteen isoflurane-anesthetized adults underwent standard neuromuscular monitoring. Mivacurium was then infused at 1.0 micrograms.kg-1.min-1 until twitch tension stabilized. The IR was then adjusted, using the Hill equation, to produce approximately steady state 50% (n = 14) or 90% (n = 13) twitch depression. Using these values for IR and steady-state twitch depression, the IRs expected to produce 50% and 90% twitch depression (IR50 and IR90, respectively) were estimated by on nonlinear regression. Both IR50 (r2 = 0.51, P < 0.005) and IR90 (r2 = 0.48, P < 0.01) were related to plasma cholinesterase activity; the coefficient of the Hill equation did not vary with plasma cholinesterase activity. We conclude that mivacurium IRs are, as expected, influenced by the activity of the enzyme responsible for its elimination.

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.

Recovery from the effects of muscle relaxants can occur either spontaneously by their metabolism in the body or by elimination via the normal excretion pathways, or by the administration of pharmacologic antagonists. The decision as to whether spontaneous recovery should be allowed to take place or pharmacologic reversal should be induced depends upon several factors, principal among them being the duration of action of the muscle relaxant used, its dose, and the time that is available. The recovery times of most relaxants, including atracurium and vecuronium, are such as to require antagonism if adequate recovery is to be attained quickly. An agent such as mivacurium may, however, allow complete spontaneous recovery to take place without the use of antagonists.

We report a case of prolonged neuromuscular block after administration of mivacurium 0.2 mg kg-1 to a 16-yr-old patient where the duration of block was 2.5 h. The interesting points in this case were that the patient had homozygous atypical plasma cholinesterase deficiency (both parents had a normal phenotype) following liver transplantation. Investigations showed low plasma cholinesterase activity (343 iu litre-1; normal 600-1400) and dibucaine number was 25 (normal 76-83). Despite possessing atypical enzyme normally associated with markedly prolonged duration of suxamethonium, on two occasions the patient received suxamethonium and responded normally. This had not previously been reported. The patient demonstrated prolonged block with mivacurium as a result of atypical enzyme (despite normal metabolism of suxamethonium).

The effectiveness of neostigmine 40 micrograms/kg for antagonism of two different levels of neuromuscular blockade, induced by a bolus dose of mivacurium 0.15 mg/kg, was studied in 45 patients. The patients were anaesthetized with thiopentone, fentanyl, nitrous oxide in oxygen, and enflurane. Neostigmine was administered at either 10% recovery of the twitch height (TH10) at the adductor pollicis muscle (n = 14) or upon reappearance of the first response at the orbicularis oculi muscle (OO1) after train-of-four (TOF) stimulation (n = 16), the latter representing a deeper degree of neuromuscular blockade. Fifteen of the 45 patients did not receive neostigmine (control group). Neostigmine administration at OO1 rather than at TH10 at the adductor pollicis muscle caused reversal of neuromuscular blockade to occur 8 min earlier and shortened the time to reach 25% recovery of the twitch height (TH25) at the adductor pollicis muscle by about 5 min, compared with the control group. However, the time needed to reach a T4/T1 ratio > or = 0.8 was similar in both the early and late neostigmine administration groups, being 9 min faster than in the control group. It can be concluded that there is no advantage in administering neostigmine at profound neuromuscular blockade to achieve clinically adequate recovery (T4/T1 ratio > or = 0.8). However, the time between injection of mivacurium and TH25 may be shortened by using neostigmine at profound neuromuscular blockade, a procedure which may be useful in case of unpredictably difficult intubation, since diaphragmatic movements usually reappear at TH25.

We have studied the pharmokinetics of cis-trans, trans-trans and cis-cis mivacurium in 10 healthy subjects and 11 patients with mild or moderate hepatic cirrhosis, during nitrous oxide-oxygen-isoflurane anaesthesia. Mivacurium 15 micrograms kg-1 min-1 was infused for 10 min (total dose 0.15 mg kg-1) and the plasma concentration of the three isomers measured at regular intervals for 190 min. The electromyographic response to the drug was also measured. Compartmental analysis of the resulting isomer profiles was undertaken: one- and two-compartment models were fitted to derive clearance, volume of distribution and half-life. Clearance of the cis-trans and trans-trans isomers was reduced significantly in the cirrhotic compared with the healthy group: cis-trans (median (range)) 44 (15-121) ml kg-1 min-1 vs 95 (57-213) ml kg-1 min-1 (P < 0.05); trans-trans 32 (12-64) ml kg-1 min-1 vs 70 (34-101) ml kg-1 min-1 (P < 0.05). The difference in the clearance of the cis-cis isomer in the cirrhotic (4.2 (2.9-12.1) ml kg-1 min-1) compared with the healthy group (5.2 (2.9-8.9) ml kg-1 min-1) was not significant with this sample size. Clearance of each isomer correlated significantly with plasma cholinesterase activity: cis-trans r = 0.73, P < 0.001; trans-trans r = 0.69, P < 0.001; cis-cis r = 0.48, P < 0.05.

Ten healthy patients and 25 patients with cirrhosis of the liver (10 Child's A, 10 Child's B and 5 Child's C) received a bolus dose of mivacurium chloride 150 micrograms kg-1. The electromyographic response was monitored throughout anaesthesia until recovery of the first twitch of the train-of-four (TOF) (T1/T0) to at least 85% and the TOF ratio (T4:T1) to at least 80%. There was no significant difference between the two groups in the onset of neuromuscular block, but recovery was prolonged in the cirrhotic group compared with the healthy patients (respective mean times to recovery of T1/T0: to 5% = 20.2 vs 11.2 min (P < 0.05); to 10% = 23.8 vs 13.4 min (P < 0.005); to 25% = 28.4 vs 16.6 min (P < 0.005); to 50% = 41.1 vs 20.1 min (P < 0.005); to 75% = 43.8 vs 24.9 min (P < 0.005). Recovery of T4:T1 to 70% = 48.1 vs 27.4 min (P < 0.005)). Recovery was most prolonged in the Child's C patients. Mean plasma cholinesterase activity was less in the cirrhotic compared with the healthy group (mean 582 (SD 254) iu litre-1 vs 1125 (303) iu litre-1) (P < 0.001) and there was a significant negative correlation between plasma cholinesterase activity and all the indices of recovery (P < 0.001 for all except recovery index (P < 0.01)). We conclude that patients with hepatic cirrhosis may be sensitive to mivacurium, which could be explained, at least in part, by the lesser plasma cholinesterase activity.

Mivacurium is a potent nondepolarising neuromuscular blocking agent which is structurally related to the benzylisoquinolinium compound, atracurium. Mivacurium has a short duration of action due to its rapid elimination by plasma cholinesterase. When administered to essentially healthy adult patients receiving nitrous oxide-narcotic anaesthesia, the recommended intubating dose (2 x ED95) usually provides clinically effective neuromuscular block for approximately 15 to 20 minutes and spontaneous recovery is 95% complete within about 25 to 30 minutes. When administered to paediatric patients aged 2 to 12 years, the recommended intubating dose of mivacurium produces approximately 10 minutes of clinically effective neuromuscular block. The clinical duration of action of mivacurium is shorter than that of the other nondepolarising blockers atracurium and vecuronium, although it is still longer than that of the depolarising blocker suxamthonium (succinylcholine). The recommended intubating dose usually produces good or excellent conditions for tracheal intubation within 2 to 2.5 minutes in adult patients, although intubation times are longer than those for a standard intubating dose of suxamethonium. Thus far, mivacurium has not demonstrated a cumulative neuromuscular blockade when administered to patients with normal plasma cholinesterase activity. Furthermore, due to the intrinsically faster rate of recovery, pharmacological reversal with anticholinesterases is less likely to be indicated with mivacurium than for other, longer-acting, nondepolarising blockers. Benzylisoquinolinium compounds such as mivacurium have the potential to release histamine and cause cardiovascular instability. Interpatient variability in the susceptibility to histamine release is to be expected, although the recommended intubating dose has produced minimal haemodynamic effects in clinical trials to date. Prolonged neuromuscular block is likely in patients with markedly reduced plasma cholinesterase activity. In particular, patients homozygous for the atypical plasma cholinesterase gene are extremely sensitive to the neuromuscular blocking effects of mivacurium and should not receive the drug. In summary, a single bolus dose of mivacurium can be recommended for use in adult and paediatric patients undergoing nonemergency tracheal intubation and/or during short surgical procedures. For maintenance of neuromuscular block, mivacurium can be administered as multiple bolus doses or as a continuous infusion. In particular, the lack of a significant cumulative effect renders the drug suitable for the maintenance of neuromuscular blockade during extended surgical procedures of unpredictable length.

People with genetic variants of cholinesterase respond abnormally to succinylcholine, experiencing substantial prolongation of muscle paralysis with apnea rather than the usual 2-6 min. The structure of usual cholinesterase has been determined including the complete amino acid and nucleotide sequence. This has allowed identification of altered amino acids and nucleotides. The variant most frequently found in patients who respond abnormally to succinylcholine is atypical cholinesterase, which occurs in homozygous form in 1 out of 3500 Caucasians. Atypical cholinesterase has a single substitution at nucleotide 209 which changes aspartic acid 70 to glycine. This suggests that Asp 70 is part of the anionic site, and that the absence of this negatively charged amino acid explains the reduced affinity of atypical cholinesterase for positively charged substrates and inhibitors. The clinical consequence of reduced affinity for succinylcholine is that none of the succinylcholine is hydrolyzed in blood and a large overdose reaches the nerve-muscle junction where it causes prolonged muscle paralysis. Silent cholinesterase has a frame shift mutation at glycine 117 which prematurely terminates protein synthesis and yields no active enzyme. The K variant, named in honor of W. Kalow, has threonine in place of alanine 539. The K variant is associated with 33% lower activity. All variants arise from a single locus as there is only one gene for human cholinesterase (EC 3.1.1.8). Comparison of amino acid sequences of esterases and proteases shows that cholinesterase belongs to a new family of serine esterases which is different from the serine proteases.

Mivacurium chloride (BW B1090U) is a new, short-acting non-depolarizing neuromuscular blocking agent. It is a synthetic bis-benzylisoquinolinium diester, which is hydrolysed rapidly by plasma cholinesterase. This study compares mivacurium, atracurium and vecuronium by continuous i.v. infusion. The duration of mivacurium infusion ranged from 29.5 to 286 min. The steady state infusion rates necessary to maintain 95 (SEM 4)% twitch suppression were: mivacurium 8.3 (0.7) micrograms kg-1 min-1; atracurium 7.9 (0.4) micrograms kg-1 min-1; vecuronium 1.2 (0.3) micrograms kg-1 min-1. Following infusions of mivacurium, various recovery times (for example: 25-75%, 6.9 (0.3) min; 25-95%, 11.0 (0.4) min; 5-95% 14.5 (0.4) min) did not differ significantly from those following single bolus doses. Recovery times following cessation of mivacarium infusions were approximately 50% of those for equivalent durations of infusion of atracurium (10.9 (0.3) min for 25-75% recovery and 26.6 (0.4) min for 5-95% recovery). For vecuronium, corresponding recovery times were 13.8 (0.9) and 32.0 (1.2) min, respectively. Comparative recovery times for mivacurium were 40-50% of those for vecuronium. There was a significant correlation between the infusion rate of mivacurium required to maintain 95% twitch depression and the plasma cholinesterase activity of individual subjects.

Mivacurium chloride (BW B1090U), a bis-benzylisoquinolinium diester compound, was found to undergo hydrolysis in vitro by purified human plasma cholinesterase in a pH-stat titrator at 88% of the rate of succinylcholine at pH 7.4, 37 degrees C and 5 microM substrate concentration. In 72 consenting ASA Physical Status I-II patients receiving nitrous oxide/oxygen-narcotic-thiopental anesthesia, the neuromuscular blocking effect of mivacurium was assessed following bolus doses from 0.03 to 0.30 mg/kg, as well as during and following continuous infusions from 35 to 324 min in length. The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.08 mg/kg. At 0.1 mg/kg, 96% block developed, onset to maximum block required 3.8 +/- 0.5 min, and recovery to 95% twitch height occurred 24.5 +/- 1.6 (SE) min after injection. At 0.25 mg/kg, onset was 2.3 +/- 0.3 min; 95% recovery developed within 30.4 +/- 2.2 min, an increase in duration of action of only 24% versus 150% higher dosage. Comparative recovery indices from 5 to 95% or from 25 to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.3 mg/kg (range 12.9 to 14.7 and 6.6 to 7.2 min, respectively). In 38 patients who received mivacurium by continuous infusion (duration 88.1 +/- 7.1/47.1 min, SE/SD) for maintenance of 95 +/- 4% twitch inhibition, the mean 5-95% and 25-75% recovery indices after discontinuation of infusion were 14.4 +/- 0.6 and 6.5 +/- 0.3 min (P greater than 0.5 vs. all single bolus doses). The train-of-four (T4) ratio, within 2.6 +/- 0.5 min after 95% twitch recovery following bolus doses, averaged 79.5 +/- 1.8% (n = 32). Similarly, after discontinuation of infusions, the T4 ratio reached 73.4 +/- 1.9% within 3.4 +/- 1.9 min after 95% twitch recovery (n = 33). Antagonism of residual block was seldom indicated, but, to test ease of reversal, eight patients electively received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at 67 to 93 (76.6 +/- 3.5) % block. Twitch returned to 95% of control within 4.5 to 9.5 (6.3 +/- 0.5) min after neostigmine. Mivacurium may offer increased versatility in providing clinical muscle relaxation in a variety of situations. Further studies seem appropriate.