Substrate Report for: Mivacurium

The present study was designed to determine the time-course of recovery of the train-of-four (TOF) ratio during spontaneous recovery from mivacurium-induced block. Fifteen patients, free of neuromuscular disease, undergoing general endotracheal anaesthesia with isoflurane were studied. After anaesthetic induction, patients received a bolus dose of mivacurium 0.15 mg.kg-1. The TOF was then recorded continuously every 12 sec with a mechanogram (adductor pollicis monitor). When the TOF ratio recovered spontaneously to 0.9, an additional 0.05 mg.kg-1 of mivacurium was given. The durations required for recovery from a TOF ratio of 0.3 to 0.7 (DUR0.3-0.7) and from a TOF ratio of 0.3 to 0.9 (DUR0.3-0.9) were determined. The DUR0.3-0.7 averaged 7.0 +/- 2.5 min (range 3.4-12.2 min). The DUR0.3-0.9 averaged 11.8 +/- 3.9 min (range 6.0-20.2 min). There was no evidence of prolongation of recovery times (cumulation) following repeated dosing. The present data indicate that, in patients with normal cholinesterase activity (clinical duration 7-25 min), waiting 20 min beyond the time when fade is no longer apparent by visual or tactile evaluation is sufficient to attain a TOF ratio greater than 0.7-0.9 during spontaneous recovery from mivacurium, and may enable anaesthetists to avoid antagonism of mivacurium-induced block.

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 chloride (Mivacron) is a new benzylisoquinolinium choline-like diester neuromuscular blocking drug with an onset of action at equipotent doses that is comparable to atracurium and vecuronium but slower than succinylcholine. Its clinical duration (injection-25% recovery and injection-95% recovery) is twice that of succinylcholine but one-half to one-third that of atracurium and vecuronium. Mivacurium is easy to use as a continuous infusion and when used this way its recovery characteristics are unchanged. It is readily antagonized by anticholinesterase drugs. The ED95 in adults under narcotic-based anesthesia is 0.07-0.08 mg/kg. At twice the ED95 (0.15 mg/kg) onset time is about 2 to 3 minutes, duration to 25% recovery is 15 to 20 minutes, and 5-95% recovery time about 14 minutes. The mean infusion rate in adults is 6 micrograms/kg/min (range 2-15) with a 5-95% recovery time of 14 minutes. Enflurane and isoflurane require a 20-30% decrease in dosage; halothane, enflurane, and isoflurane prolong the duration of mivacurium 25-30%. The ED95 in children 2 to 12 years of age is slightly higher (0.09-0.11 mg/kg) with a faster onset and shorter duration. In these young patients, a dose of 0.2 mg/kg has an onset comparable to succinylcholine. Being chemically related to atracurium, mivacurium may cause histamine release. When administered rapidly at doses of 0.2 mg/kg or greater in adults, histamine release and transient hypotension have been observed. Doses of 0.2 mg/kg or higher are not recommended by the manufacturer. Mivacurium is metabolized by plasma cholinesterase. In vitro, the rate is about 70% that of succinylcholine. In patients with normal or slightly less than normal plasma cholinesterase activity, no prolonged durations of action have been observed. In patients heterozygous for the atypical gene and at a dose of 0.2 mg/kg, 50% prolongation has been shown. Those individuals homozygous for the atypical gene are exquisitely sensitive to mivacurium and have a markedly prolonged blockade that is readily reversible. In these patients and those with acquired deficiencies, mivacurium should not be used. The duration of action in elderly patients is comparable to that in the young, while in prerenal transplant patients, its duration is prolonged by about 50%, and in prehepatic transplant patients, duration of block is increased threefold. Mivacurium possesses the advantages of short duration, unchanged recovery characteristics following infusions (without phase II block or tachyphylaxis), and precise control.

BACKGROUND: The duration of action for many pharmaceutical agents is dependent on their breakdown by endogenous hydrolytic enzymes. Dietary factors that interact with these enzyme systems may alter drug efficacy and time course. Cholinesterases such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) hydrolyze and inactivate several anesthetic drugs, including cocaine, heroin, esmolol, local ester anesthetics, and neuromuscular blocking drugs. Natural glycoalkaloid toxins produced by plants of the family Solanaceae, which includes potatoes and tomatoes, inhibit both AChE and BuChE. Here the authors assess the extent to which two solanaceous glycoalkaloids (SGAs), alpha-solanine and alpha-chaconine, can alter the effects of neuromuscular blocking drugs and cholinesterase inhibitors in vivo and in vitro.
METHODS: Inhibition of purified human AChE and BuChE by SGAs, neuromuscular blocking drugs, and cholinesterase inhibitors was assessed by an in vitro colorimetric cholinesterase assay. In vivo experiments were carried out using anesthetized rabbits to test whether SGAs affect recovery from mivacurium-induced paralysis.
RESULTS: SGAs inhibited human BuChE at concentrations similar to those found in serum of individuals who have eaten a standard serving of potatoes. Coapplication of SGAs (30-100 nm) with neuromuscular blocking drugs and cholinesterase inhibitors produced additive cholinesterase inhibition. SGA administration to anesthetized rabbits inhibited serum cholinesterase activity and mivacurium hydrolysis. In addition, SGA prolonged the time needed for recovery from mivacurium-induced paralysis (149 +/- 12% of control; n = 12).
CONCLUSIONS: These findings support the hypothesis that inhibition of endogenous enzyme systems by dietary factors can influence anesthetic drug metabolism and duration of action. Diet may contribute to the wide variation in recovery time from neuromuscular blockade seen in normal, healthy individuals.

We compared the dose-response relationship and the neuromuscular blocking effects of mivacurium during infusions of esmolol in 40 anaesthetised rabbits. Train-of-four stimuli were applied every 10 s to the common peroneal nerve and the force of contraction of the tibialis anterior muscle was measured. Plasma cholinesterase activity decreased by 13% after esmolol infusion. The ED95 of mivacurium increased significantly from 29 (4.8) micrograms.kg-1 with placebo to 61 (9.8) micrograms.kg-1 during esmolol 100 micrograms.kg-1.min-1, 49 (8.2) micrograms.kg-1 during esmolol 300 micrograms.kg-1.min-1 and 54 (7.3) micrograms.kg-1 during esmolol 500 micrograms.kg-1.min-1, respectively (p < 0.001). The duration of neuromuscular block with mivacurium 0.16 mg.kg-1 was prolonged by 30% with esmolol due to diminished plasma cholinesterase activity (p < 0.05). Heart rate and mean arterial blood pressure decreased by 15% with esmolol (p < 0.05). The results of this study show that, in rabbits, esmolol decreased plasma cholinesterase activity, antagonised the neuromuscular blocking potency of mivacurium and prolonged its neuromuscular blocking effect.

Mivacurium is a short-acting, nondepolarising muscle relaxant of the benzylisoquinoline type that undergoes rapid breakdown by plasma cholinesterase. After 2.5 times the ED95 (0.2 mg/kg), 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. The principal side effects of mivacurium are facial flushing and a transient fall in blood pressure due to moderate histamine release following doses 3-4 times the ED95. In patients with end-stage liver or renal disease as well as those with atypical plasma cholinesterase, the duration of action of mivacurium is prolonged.

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.

This review discusses concepts of isomers, stereoisomers, chirality, and enantiomers as applied to drugs used in anaesthesia. The inhalational anaesthetics enflurane and isoflurane are examples of stereoisomers. A chiral centre is formed when a carbon or quaternary nitrogen atom is connected to four different atoms. A molecule with one chiral centre is then present in one of two possible configurations termed enantiomers. A racemate is a mixture of both enantiomers in equal proportions. Many of the drugs used in anaesthesia are racemic mixtures (the inhalation anaesthetics, local anaesthetics, ketamine, and others). The shape of the atracurium molecule is comparable to that of a dumb-bell:the two isoquinoline groups representing the two bulky ends connected by an aliphatic chain. In each isoquinoline group there are two chiral centres, one formed by a carbon and the other by a quaternary nitrogen atom. From a geometric point of view, the connections from the carbon atom to a substituted benzene ring and from the quaternary nitrogen to the aliphatic chain may point in the same direction (cis configuration) or in opposite directions (trans configuration). The two isoquinoline groups in atracurium are paired in three geometric configurations: cis-cis, trans-trans, or cis-trans. However, the two chiral centres allow each isoquinoline group to exist in one of four stereoisometric configurations. In the symmetrical atracurium molecule, the number of possible stereoisomers is limited to ten. Among these, 1 R-cis, 1'R-cis atracurium was isolated and its pharmacologic properties studied. This isomer, named cis-atracurium, offers clinical advantages over the atracurium mixture, principally due to the lack of histamine-releasing propensity and the higher neuromuscular blocking potency. The ester groups appear in one of two steric configurations true and reverse esters. In the true esters, oxygen is positioned between the nitrogen atom and the carbonyl group, while in the reverse esters in its positioned on the other side of the carbonyl group. True esters, suxamethonium and mivacurium, are hydrolysed by the enzyme plasma cholinesterase (butyrylcholinesterase), albeit at different rates. The more rapid degradation of suxamethonium is responsible for its fast onset and short duration of action in comparison with mivacurium. The reverse esters, atracurium, cisatracurium, and remifentanil, are hydrolysed by nonspecific esterases in plasma (carboxyesterases). Remifentanil is hydrolysed rapidly; the degradation leads to its inactivation and short duration of action. Cis-atracurium is preferentially degraded and inactivated by a process known as Hofmann elimination. In a second step, one of the degradation products, the monoester acrylate, is hydrolysed by a nonspecific esterase.

Plasma cholinesterase (PCE) is an enzyme necessary for the metabolism of certain anesthetic-related medications. Individuals with abnormal cholinesterase activity (e.g., insufficient quantity of functional PCE or atypical PCE genotypes) may exhibit a prolonged paralytic response to the muscle relaxants succinylcholine and mivacurium. A review of perianesthesia nursing considerations and treatment modalities relating to patients presenting with this interesting clinical picture will be offered.

BACKGROUND: The metabolic hydrolysis of mivacurium (and succinylcholine) is markedly impaired in the presence of hereditary or acquired defects of pseudocholinesterase. Clinical reports are conflicting as to the utility of anticholinesterases, in the reversal of mivacurium paralysis. In the current study, the role of exogenous cholinesterases and/or of anticholinesterase, neostigmine, in the reversal of deep mivacurium-induced paralysis, was studied. The rat phrenic-diaphragm preparation, in a fixed volume of Krebs solution, was chosen to eliminate the confounding effects on the dissipation of neuromuscular effects caused by hydrolysis, elimination, and redistribution of the drug. METHODS: In the phrenic-diaphragm preparation, mivacurium was administered to obtain >90% single twitch inhibition. Single twitch responses (0.1 Hz) were monitored for 60 min, after which the response to train-of-four stimulation was tested. The reversal of mivacurium by 0.5, 1.0, or 2.0 units/ml of (true) acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase and by neostigmine, 0.1, 1.0, or 10.0 micrograms/ml tested. The efficacy of human plasma cholinesterase, 1 unit/ml in combination with each of the above neostigmine concentrations, also was examined. The reversal of succinylcholine-induced paralysis by the acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase (1 unit/ml) alone and in the presence of neostigmine (10.0 micrograms/ml) was additionally tested as a positive control. A train-of-four ratio > 0.75 was considered adequate reversal. RESULTS: Acetylcholinesterase was a poor hydrolyzer of mivacurium, as bioassayed by reversal of paralysis. Bovine pseudocholinesterase in concentrations of 0.5 and 1.0 units/ml did not effectively reverse single twitch and train-of-four responses by 60 min, but bovine pseudocholinesterase (2 units/ml) and all concentrations of human plasma cholinesterase did. Neostigmine alone, tested at all concentrations, was an incomplete reversal drug. Clinical or therapeutic concentrations (0.1 and 1.0 micrograms/ml) of neostigmine did not, but pharmacologic concentrations (10 micrograms/ml) interfere with the efficacy of human plasma cholinesterase (1 unit/ml). Bovine pseudocholinesterase and human plasma cholinesterase equally reversed the effects of succinylcholine but acetylcholinesterase did not, whereas the addition of 10 micrograms/ml neostigmine to the enzymes inhibited the reversal of succinylcholine. CONCLUSIONS: Human plasma cholinesterase will reverse mivacurium more effectively than bovine pseudocholinesterase, but both will effectively reverse succinylcholine. Acetylcholinesterase has no effects on either relaxant. The anticholinesterase neostigmine was an incomplete reversal drug. Pharmacologic concentrations of anticholinesterases do, while clinical or therapeutic concentrations do not, completely inhibit the metabolic activity of pseudocholinesterases.

The present study was designed to determine the time-course of recovery of the train-of-four (TOF) ratio during spontaneous recovery from mivacurium-induced block. Fifteen patients, free of neuromuscular disease, undergoing general endotracheal anaesthesia with isoflurane were studied. After anaesthetic induction, patients received a bolus dose of mivacurium 0.15 mg.kg-1. The TOF was then recorded continuously every 12 sec with a mechanogram (adductor pollicis monitor). When the TOF ratio recovered spontaneously to 0.9, an additional 0.05 mg.kg-1 of mivacurium was given. The durations required for recovery from a TOF ratio of 0.3 to 0.7 (DUR0.3-0.7) and from a TOF ratio of 0.3 to 0.9 (DUR0.3-0.9) were determined. The DUR0.3-0.7 averaged 7.0 +/- 2.5 min (range 3.4-12.2 min). The DUR0.3-0.9 averaged 11.8 +/- 3.9 min (range 6.0-20.2 min). There was no evidence of prolongation of recovery times (cumulation) following repeated dosing. The present data indicate that, in patients with normal cholinesterase activity (clinical duration 7-25 min), waiting 20 min beyond the time when fade is no longer apparent by visual or tactile evaluation is sufficient to attain a TOF ratio greater than 0.7-0.9 during spontaneous recovery from mivacurium, and may enable anaesthetists to avoid antagonism of mivacurium-induced block.

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.

The effect of reduced plasma cholinesterase (ChE) activity in response to normothermic cardiopulmonary bypass (CPB) on mivacurium neuromuscular block was studied in nine patients anesthetized with propofol/fentanyl. Mivacurium was injected intravenously as an initial bolus of 150 micrograms/kg; repeat doses of 75 micrograms/kg were given when the evoked twitch tension attained 75% of control. With the institution of CPB, the previously normal ChE activity was reduced by 42% and remained low until the end of the procedure. The times of onset (time from the end of injection to maximum neuromuscular block) of the maintenance doses of mivacurium were 26% longer during than before or after CPB (P < 0.05). Their DUR25% (time from end of injection to recovery of neuromuscular transmission to 25% of control) were 13 +/- 3 min (means +/- SD) before, 14 +/- 4 min during, and 16 +/- 4 min (P < 0.05) after CPB. It is concluded, that, although markedly reducing the patient's previously normal ChE activity, normothermic CPB had little effect on the time characteristics of mivacurium neuromuscular block.

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 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.

BACKGROUND Mivacurium, a nondepolarizing muscle relaxant, is metabolized by plasma cholinesterase. Although edrophonium does not alter plasma cholinesterase activity, we have observed that doses of edrophonium that antagonize paralysis from other nondepolarizing muscle relaxants are less effective with mivacurium. We speculated that edrophonium might after metabolism of mivacurium, thereby hindering antagonism of paralysis. Accordingly, we determined the effect of edrophonium on neuromuscular function and plasma mivacurium concentrations during constant mivacurium infusion. METHODS: We infused mivacurium to maintain 90% depression of adductor pollicis twitch tension and then gave edrophonium in doses ranging from 125-2,000 micrograms/kg without altering the mivacurium infusion. Peak twitch tension after edrophonium was determined to estimate the dose of edrophonium antagonizing 50% of twitch depression for antagonism of mivacurium; plasma cholinesterase activity and mivacurium concentrations before and after edrophonium were measured. Additional subjects were given 500 micrograms/kg edrophonium to antagonize continuous infusions of d-tubocurarine and vecuronium. RESULTS: With mivacurium, edrophonium increased twitch tension in a dose-dependent manner: the dose of edrophonium antagonizing 50% of twitch depression was 2,810 micrograms/kg. The largest dose of edrophonium (2,000 micrograms/kg) produced only 45 +/- 7% antagonism. Edrophonium, 500 micrograms/kg, antagonized mivacurium markedly less than it antagonized d-tubocurarine and vecuronium. Edrophonium increased plasma concentrations of the two potent stereoisomers of mivacurium 48% and 79%, these peaking at 1-2 min; plasma cholinesterase activity was unchanged. CONCLUSIONS: Edrophonium doses that antagonize d-tubocurarine and vecuronium are less effective in antagonizing the neuromuscular effects of mivacurium during constant infusion. Edrophonium increases plasma mivacurium concentrations, partly or completely explaining its limited efficacy; the mechanism by which edrophonium increases mivacurium concentrations remains unexplained. Our results demonstrate that antagonism of mivacurium by edrophonium is impaired, and therefore we question whether edrophonium should be used to antagonize mivacurium.

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.

BACKGROUND Mivacurium chloride is a bis-benzylisoquinolinium nondepolarizing neuromuscular blocking agent, hydrolyzed by butyrylcholinesterase (PCHE). The dose-response relationships for PCHE after mivacurium have not been studied. Therefore, this study was designed to establish dose-response relationships for PCHE as an antagonist of mivacurium-induced neuromuscular blockade. METHODS: Forty-eight physical status 1 adults were given 0.15 mg/kg mivacurium during fentanyl-thiopental-nitrous oxide-isoflurane anesthesia. Train-of-four (TOF) stimulation was applied to the ulnar nerve every 12 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height (T1) reached 10% of its initial control value, exogenous PCHE equivalent to activity present in 2.5, 5, 7.5, 15, or 25 ml/kg of human plasma was administered by random allocation to 40 patients. Neuromuscular function in another eight subjects was allowed to recover spontaneously. Two blood samples were taken for determination of plasma cholinesterase activity. The first sample was taken before induction of anesthesia, and the second sample was taken when the TOF ratio had recovered to 0.75. Dibucaine and fluoride numbers were determined from the first assay. RESULTS: Administration of PCHE produced significant increases in PCHE activity in all patients. The larger the dose, the greater was the resultant plasma activity. Human PCHE produced a dose-dependent antagonism of mivacurium-induced neuromuscular blockade and the recovery times correlated inversely with PCHE activity (P < 0.01). The recovery of T1 was greater (P < 0.01) and time to attain a TOF ratio of 0.75 was shorter (P < 0.01) with any dose of PCHE than that observed in the spontaneous recovery group. After the administration of exogenous PCHE equivalent to activity present in 25 ml/kg of human plasma, recovery of TOF ratio to 0.75 or more was observed in all patients in less than 10 min and time to attain a TOF ratio of 0.75 was 55% shorter than the spontaneous recovery group (8.4 [7.1-9.7] vs. 18.7 [15.4-22] min; mean and 95% confidence intervals). CONCLUSIONS: Administration of exogenous PCHE equivalent to activity present in 25 ml/kg of human plasma (in a 65-kg patient, this dose is equivalent to PCHE activity of 1,625 ml of adult human plasma) resulted in reliable antagonism of mivacurium-induced neuromuscular blockade. Nevertheless, because of the prohibitive cost of this compound, this reversal modality is unlikely to have a routine practical application at this time.

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).

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.

Mivacurium chloride (Mivacron) is a new benzylisoquinolinium choline-like diester neuromuscular blocking drug with an onset of action at equipotent doses that is comparable to atracurium and vecuronium but slower than succinylcholine. Its clinical duration (injection-25% recovery and injection-95% recovery) is twice that of succinylcholine but one-half to one-third that of atracurium and vecuronium. Mivacurium is easy to use as a continuous infusion and when used this way its recovery characteristics are unchanged. It is readily antagonized by anticholinesterase drugs. The ED95 in adults under narcotic-based anesthesia is 0.07-0.08 mg/kg. At twice the ED95 (0.15 mg/kg) onset time is about 2 to 3 minutes, duration to 25% recovery is 15 to 20 minutes, and 5-95% recovery time about 14 minutes. The mean infusion rate in adults is 6 micrograms/kg/min (range 2-15) with a 5-95% recovery time of 14 minutes. Enflurane and isoflurane require a 20-30% decrease in dosage; halothane, enflurane, and isoflurane prolong the duration of mivacurium 25-30%. The ED95 in children 2 to 12 years of age is slightly higher (0.09-0.11 mg/kg) with a faster onset and shorter duration. In these young patients, a dose of 0.2 mg/kg has an onset comparable to succinylcholine. Being chemically related to atracurium, mivacurium may cause histamine release. When administered rapidly at doses of 0.2 mg/kg or greater in adults, histamine release and transient hypotension have been observed. Doses of 0.2 mg/kg or higher are not recommended by the manufacturer. Mivacurium is metabolized by plasma cholinesterase. In vitro, the rate is about 70% that of succinylcholine. In patients with normal or slightly less than normal plasma cholinesterase activity, no prolonged durations of action have been observed. In patients heterozygous for the atypical gene and at a dose of 0.2 mg/kg, 50% prolongation has been shown. Those individuals homozygous for the atypical gene are exquisitely sensitive to mivacurium and have a markedly prolonged blockade that is readily reversible. In these patients and those with acquired deficiencies, mivacurium should not be used. The duration of action in elderly patients is comparable to that in the young, while in prerenal transplant patients, its duration is prolonged by about 50%, and in prehepatic transplant patients, duration of block is increased threefold. Mivacurium possesses the advantages of short duration, unchanged recovery characteristics following infusions (without phase II block or tachyphylaxis), and precise control.

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.