Interactions between suxamethonium and mivacurium or atracurium

We have compared the dose-response relationships of suxamethonium, mivacurium and atracurium and examined the interactions of suxamethonium with mivacurium or atracurium in humans by isobolographic analysis. We studied 100 adult patients during fentanyl and thiopentone anaesthesia. Neuromuscular function was monitored using a Myograph 2000 (Biometer Co., Odense, Denmark). The dose-response curves were determined by probit analysis. Isobolographic and fractional analyses were used to assess quantitatively the combined effect of equipotent doses of suxamethonium, mivacurium and atracurium and to define the type of interaction between suxamethonium and mivacurium or atracurium. The ED50 values for suxamethonium, mivacurium and atracurium were 198.8 (95% confidence interval 190.7-206.9), 48.6 (45.4-51.8) and 202.1 (197.9-206.2) mg kg-1, respectively. Isobolographic and fractional analyses of the suxamethonium-mivacurium and suxamethonium-atracurium combinations demonstrated antagonistic interactions.      

Mivacurium chloride—a comparative profile

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 μg/kg. Thus, mivacurium is 0.8 times and four times as potent as vecuronium and atracurium, respectively. With 2–3×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.     

COMPARISON OF THE NEUROMUSCULAR BLOCK INDUCED BY MIVACURIUM, SUXAMETHONIUM OR ATRACURIUM DURING NITROUS OXIDE-FENTANYL ANAESTHESIA

We compared the neuromuscular and cardiovascular changes followingadministration of mivacurium 0.15, 0.20 and 0.25 mg kg^–1,suxamethonium 1.0 mg kg^–1 or atracurium 0.5 mg kg^–1i.v. in 41 (ASA physical status I or II) patients during nitrousoxide—fentanyl anaesthesia. Mean onset times for totalablation of twitch response for mivacurium 0.15, 0.20 and 0.25mg kg^–1, were 2.5, 2.4 and 2.7 min, respectively, similarto that for atracurium (2.5 min), but longer than for suxamethonium(1.1 min) (P < 0.05). Mean times from administration of druguntil twitch response recovered to 10% of control were shorterfor each dose of mivacurium (15.6, 18.0 and 20.6 min, respectively)than for atracurium (40.0 min) and longer than for suxamethonium(7.7 min) (P < 0.05). Mean infusion rate required to maintaintwitch response at 5±4% control was 6.7 µg kg^–1min^–1 for mivacurium and 6.3 µg kg^–1 min^–1for atracurium. Following neostigmine 0.045 mg kg^–1, meantimes for twitch tension to recover from 10% to 90% of controlwere similar for mivacurium (9.7 min) and atracurium (10.5 min).Transient decreases in mean arterial pressure (> 20%) wereobserved in seven of 15 patients who received the two higherdoses of mivacurium. Presented in part at the Annual Scientific Meeting of the AmericanSociety of Anesthesiologists, San Francisco, October 1988.     

Pharmacokinetics and pharmacodynamics of the benzylisoquinolinium muscle relaxants

The benzylisoquinolinium class of drugs comprises atracurium, 51W89, doxacurium, and mivacurium. Atracurium can be used as a pharmacokinetic benchmark; it has at least two distinct metabolic pathways, of which Hofmann elimination and ester hydrolysis are the most significant. The relative importance of each of these two routes is still a matter of speculation, and this, coupled with the fact that atracurium is a mixture of 10 isomers, has led to the development of many innovative pharmacokinetic modelling concepts. 51W89 is a cis-cis -isomer of atracurium and probably has a pharmacokinetic profile very similar to that of atracurium. Doxacurium, a long-acting benzylisoquinolinium, has a small apparent volume of distribution and an elimination half-time similar to that of pancuronium, and is excreted by the kidneys. Mivacurium is a short-acting benzylisoquinolinium that is rapidly hydrolysed by plasma cholinesterases. Two isomers of mivacurium are very similar, whereas the third isomer differs greatly in both pharmacological activity and elimination half-time, so that analysis requires complex pharmacokinetic methods.     

Prolonged paralysis following mivacurium administration

Mivacurium is a benzylisoquinolone, choline-like, non-depolarizing muscle relaxant. Its onset of action is similar to that of atracurium but its duration of action is shorter (approximately 10-15 minutes). Mivacurium is metabolized by plasma cholinesterases at approximately 70% of the rate of metabolism of suxamethonium. Deficiency or abnormality of plasma cholinesterase may cause the duration of action of both suxamethonium and mivacurium to be greatly prolonged. We describe a case of prolonged mivacurium paralysis after day surgery. Laboratory investigations showed a genetic tendency toward abnormal cholinesterase levels, but markedly depressed cholinesterase activity was suggestive of additional acquired causes. This patient had a history of liver disease, malnutrition and anticholinesterase use, which we believe were the most significant factors involved.     

The clinical and basic pharmacology of mivacurium: a short-acting nondepolarizing benzylisoquinolinium diester neuromuscular blocking drug

Mivacurium is a benzylisoquinolinium diester. The drug is a nondepolarizing relaxant which is hydrolysed by plasma cholinesterase at 70–88% of the rate of suxamethonium. Enzymatic hydrolysis gives the drug its short duration of action. The length of paralysis is about 2-2.5 times that of suxamethonium and one-half to one-third that of the intermediate-acting nondepolarizers. The development of mivacurium represents a collaboration between industrial pharmacologists and chemists at Burroughs Wellcome Co. (USA) and investigators at the Massachusetts General Hospital, Boston, MA, USA.     

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.     

Muskelrelaxanzien Neue Substanzen und neuromuskuläres Monitoring

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 breakdown 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.     

Skin Reactions to Intradermal Neuromuscular Blocking Agent Injections: A Randomized Multicenter Trial in Healthy Volunteers

Background: Numerous reports confirm the performance of intradermal tests for the diagnosis of anaphylaxis during anesthesia; however, there is controversy over their diagnostic value regarding the newer neuromuscular blocking agents (NMBAs).

Methods: One hundred eleven healthy volunteers were randomly assigned to receive intradermal injections of two NMBAs, at five increasing concentrations. A concentration was considered as a reactive concentration when it led to a positive reaction in more than 5% of the subjects. These concentrations were compared with the maximal concentration recommended for the diagnosis of sensitization to NMBAs.

Results: The maximal nonreactive concentrations were 10-3 m for suxamethonium; 10-4 m for pancuronium, vecuronium, rocuronium, and cisatracurium; and 10-5 m for atracurium and mivacurium. Except for mivacurium, these nonreactive concentrations were close to the maximal concentrations used for the diagnosis of sensitization against NMBAs. For mivacurium, the nonreactive concentrations were higher than the maximal concentration currently recommended in clinical practice.     

The effect of mivacurium pretreatment on intra-ocular pressure changes induced by suxamethonium

Forty patients without eye disease, undergoing elective nonophthalmic surgery, were studied in a double-blind, randomised, placebo-controlled study evaluating the efficacy of mivacurium pretreatment in attenuating the rise in intra-ocular pressure in response to suxamethonium administration, laryngoscopy and intubation. The patients were randomly allocated to receive either mivacurium 0.02 mg.kg⁻¹ or normal saline as pretreatment 3 min before a rapid sequence induction technique using alfentanil, propofol and suxamethonium. Suxamethonium induced a significant increase in intra-ocular pressure in the control group but not in the mivacurium pretreatment group (mean (SEM) increase = 3.5 (1.2) mmHg vs. 0.4 (0.8) mmHg, p < 0.05). There was a decrease in intra-ocular pressure in both groups after laryngoscopy and intubation with no significant difference between the two groups. These results show that mivacurium pretreatment is effective in preventing the increase in intra-ocular pressure after suxamethonium administration.     

Histamine release from the administration of suxamethonium and atracurium in adolescents

Cutaneous reactions and plasma histamine levels were evaluated in 30 adolescents subsequent to the administration of suxamethonium 1.5 mg kg⁻¹ or atracurium 0.6 mg kg⁻¹. Plasma histamine levels were measured by the radio-enzymatic assay using histamine N -methyl transferase. In the atracurium group, the change in plasma histamine level was significant at the 2 min mark, but was not significant in the suxamethonium group. About 60% of the patients in each group developed a cutaneous reaction. Erythematous cutaneous reactions following atracurium were frequently associated with a mild increase in plasma histamine levels, whereas the rashes induced by suxamethonium in adolescents were not associated with changes in plasma histamine.     

Skin reactions to intradermal neuromuscular blocking agent injections: a randomized multicenter trial in healthy volunteers

BACKGROUND: Numerous reports confirm the performance of intradermal tests for the diagnosis of anaphylaxis during anesthesia; however, there is controversy over their diagnostic value regarding the newer neuromuscular blocking agents (NMBAs). METHODS: One hundred eleven healthy volunteers were randomly assigned to receive intradermal injections of two NMBAs, at five increasing concentrations. A concentration was considered as a reactive concentration when it led to a positive reaction in more than 5% of the subjects. These concentrations were compared with the maximal concentration recommended for the diagnosis of sensitization to NMBAs. RESULTS: The maximal nonreactive concentrations were 10 m for suxamethonium; 10 m for pancuronium, vecuronium, rocuronium, and cisatracurium; and 10 m for atracurium and mivacurium. Except for mivacurium, these nonreactive concentrations were close to the maximal concentrations used for the diagnosis of sensitization against NMBAs. For mivacurium, the nonreactive concentrations were higher than the maximal concentration currently recommended in clinical practice. CONCLUSION: The aminosteroidal NMBAs pancuronium, vecuronium, and rocuronium and the benzylisoquinoline cisatracurium have a similar potency to induce a nonspecific skin reactivity. If the criteria for positivity and the maximal concentrations of the commercially available compounds recommended by French practice guidelines are used, the risk of false-positive results is limited, and only minor modifications of these recommendations could be suggested. A slight reduction in the maximal concentration used for rocuronium from 1:100 to 1:200 and an increase from 1:1,000 to 1:200 for mivacurium can be proposed.     

Comparison of suxamethonium and different combinations of rocuronium and mivacurium for rapid tracheal intubation in children

The use of suxamethonium in children is associated with undesirable side effects. The synergistic effect of a rocuronium-mivacurium combination can be considered as an acceptable alternative to suxamethonium in clinical practice. The calculated ED50 of the rocuronium-mivacurium mixture was only 62% of the predicted value assuming a purely additive interaction. The use of this combination has not been evaluated in children. In this two-part study, we assessed the intubating conditions and pharmacodynamics of suxamethonium, rocuronium, mivacurium or a rocuronium-mivacurium combinations in children. We studied 120 ASA I children of both sexes, aged 3-10 yr. Children were premedicated with trimeprazine 2 mg kg-1 orally, and received fentanyl 2 micrograms kg-1 and propofol 2 mg kg-1 for induction of anaesthesia. They were allocated randomly to receive one of the following drugs or drug combinations: suxamethonium 1.0 mg kg-1, mivacurium 0.2 mg kg-1, rocuronium 0.6 or 0.9 mg kg-1, mivacurium 0.1 mg kg-1 with rocuronium 0.3 mg kg-1 or mivacurium 0.15 mg kg-1 with rocuronium 0.45 mg kg-1. In part 1, 60 s after administration of the neuromuscular blocking drug or drug combination, tracheal intubation was performed in 60 children by mimicking rapid sequence induction, and intubating conditions were evaluated by a blinded investigator according to a standard score. In part 2, neuromuscular monitoring was established before administration of neuromuscular blocking agent(s) and the time from injection of drug or drug combination until complete ablation of T1 (onset) and recovery of T1 to 25% (duration) were recorded in another 60 children. The frequency of distribution of excellent or good intubating conditions in the higher dose of rocuronium and the combination groups were similar to those in the suxamethonium group, but significantly different (P < 0.05) from those in the mivacurium group. Mean onset time was faster in the suxamethonium (55.1 (SD 11.4) s), rocuronium 0.9 mg kg-1 (70.5 (37.7) s), mivacurium 0.1 mg kg-1 with rocuronium 0.3 mg kg-1 (67 (35.9) s) and mivacurium 0.15 mg kg-1 with rocuronium 0.45 mg kg-1 (55 (26.7) s) groups compared with the mivacurium 0.2 mg kg-1 (116 (26.8) s) and rocuronium 0.6 mg kg-1 (97.9 (29) s) groups. This study demonstrated that the combination of rocuronium 0.45 mg kg-1 and mivacurium 0.15 mg kg-1 could possibly be considered as an acceptable alternative to suxamethonium when rapid sequence induction of anaesthesia is indicated in children because it provides uniform excellent intubating conditions and complete neuromuscular block in < 60 s.      

CLINICAL PHARMACOLOGY OF MIVACURIUM CHLORIDE (BW B1090U) INFUSION: COMPARISON WITH VECURONIUM AND ATRACURIUM

Mivacurium chloride (BWB1090U) is a new, short-acting non-depolarizingneuromuscular blocking agent. It is a synthetic bis-benzylisoquinoliniumdiester, which is hydrolysed rapidly by plasma cholinesterase.This study compares mivacurium, atracurium and vecuronium bycontinuous i.v. infusion. The duration of mivacurium infusionranged from 29.5 to 286 min. The steady state infusion ratesnecessary to maintain 95 (SEM 4)% twitch suppression were: mivacurium8.3 (0.7) µg kg^–1 min^–1; atracurium 7.9 (0.4)µg kg^–1 min^–1; vecuronium 1.2 (0.3) µgkg^–1 min^–1. Following infusions of mivacurium, variousrecovery 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 significantlyfrom those following single bolus doses. Recovery times followingcessation of mivacarium infusions were approximately 50% ofthose 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 were13.8 (0.9) and 32.0 (1.2) min, respectively. Comparative recoverytimes for mivacurium were 40–50% of those for vecuronium.There was a significant correlation between the infusion rateof mivacurium required to maintain 95% twitch depression andthe plasma cholinesterase activity of individual subjects. Presented in part in Abstract form at the Annual Meeting, AmericanSociety of Anesthesiologist, Las Vegas, Nevada, 1986.     

Dose-response studies of the interaction between mivacurium and suxamethonium

We have determined the effect of pretreatment with mivacuriumon the potency of suxamethonium and the effect of prior administrationof suxamethonium on the potency of mivacurium. We studied 100ASA I or II patients during thiopentone-fentanyl-nitrous oxide-isofluraneanaesthesia. Neuro-muscular block was recorded as the evokedthenar mechanomyographic response to train-of-four stimulationof the ulnar nerve (2 Hz at 12-s intervals). Single dose-responsecurves were determined by probit analysis. Pretreatment withmivacurium had a marked antagonistic effect on the developmentof subsequent depolarizing block produced by suxamethonium.The dose-response curves for suxamethonium alone and after pretreatmentwith mivacurium did not deviate from parallelism, but thoseconstructed after mivacurium were shifted significantly to theright (P < 0.0001). The calculated doses producing 50% depressionof T1 (ED₅₀) were 86 (95% confidence intervals 83–88)and 217 (208–225) µg kg^–1 for suxamethoniumalone and after mivacurium, respectively. This study also demonstratedthat prior administration of suxamethonium did not appear toinfluence either the slope of the regression lines or the potencyof mivacurium. Combining the results of this study with a previousstudy (mivacurium ED₅₀ = 20.8 (20.3–21.3) µg kg^–1during isoflurane-nitrous oxide anaesthesia), we suggest thatthe potency of mivacurium did not differ from that observedafter suxamethonium (17.4 (16.9–17.9) µg kg^–1).(Br.J. Anaesth. 1995; 74: 26–30) ^*Present address: Department of Anaesthesia, King Faisal University,Saudi Arabia     

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.     

Die klinische Pharmakologie neuer Benzylisochinolin-Diester-Verbindungen Unter besonderer Berücksichtigung von Cisatracurium und Mivacurium

The benzylisochinoline muscle relaxants have a highly selective affinity to the motor endplate which is associated with an absence of autonomic side effects such as ganglionic and vagus block. The requirement of only low clinical doses also reduces histamine liberation. Muscle relaxants with high neuromuscular blocking potency have a slow onset. Both atracurium and cisatracurium undergo Hofmann-Elimination in the plasma whereas mivacurium is hydrolyzed by pseudocholinesterase. The difference in kinetics between these pathways render atracurium and cisatracurium muscle relaxants of intermediate duration of action while mivacurium is short acting. Cisatracurium, one of the ten stereoisomeres of atracurium, is 3 to 4 times as potent as atracurium, does not release histamine, has no cardiovascular side effects and, due to the small clinical doses resulting from its high neuromuscular blocking potency, produces only negligible quantities of laudanosine. Its ED₉₅ is 0.05 mg/kg. Good intubation conditions can be expected within 1.5 to 2 min following 3- to 4-times the ED₉₅. Thereafter is takes about 65 min for T1 to recover to 25% of control. Maintenance doses of 0.02 to 0.04 mg/kg have a duration of action of 15 to 20 min. An infusion of cisatracurium of 1.0 to 2.0 mcg/kg/min, is adequate to maintain a 90 to 95% neuromuscular block. The time of recovery is largely independent on the total dose of cisatracurium administered by either repeated injection or infusion. – Mivacurium is a racemate of 3 stereoisomeres of which the trans-trans- and the cis-trans-compound account for 95% of the neuromuscular blocking effect. In adults the ED₉₅ is 0.08 mg/kg. The ensuing recovery of T1 to 25% of control is about 15 min. Rapid injection of 3×ED₉₅ may transiently lower the arterial blood pressure and may produce skin flushing in an incidence of 30 to 40%. Larger doses should be injected slowly with 30 to 60 s. The onset of mivacurium neuromuscular block following 3×ED₉₅ is relatively slow (2 min). Maintenance doses of 0.05 to 0.1 mg/kg have a duration of action of 5 to 10 min. A 95% neuromuscular block may be maintained by an infusion of 3 to 12 μg/kg/min. The time of recovery does not depend on the total cumulative dose given by either repeated injection or by infusion. The duration of mivacurium neuromuscular block may be drastically prolonged in the presence of low or atypical plasmacholinesterase. Both neostigmine and edrophonium are suitable reversal agents. ? None of the presently available benzylisochinoline muscle relaxants has the potential to completely replace succinylcholine.     

Response to atracurium and mivacurium in a patient with Charcot-Marie-Tooth disease

Purpose

We studied the neuromuscular effects of both atracurium and mivacurium in a patient with Charcot-Marie-Tooth disease (CMTD) during nitrous oxide-oxygen-alfentanil-propofol anaesthesia. Neuromuscular blockade was monitored electromyographically. Train-of-four stimulation (2Hz @ 20 sec intervals) was delivered to the ulnar nerve throughout the period of observation.

Clinical features

A 17-yr-old man with the diagnosis of CMTD was presented twice for two different orthopaedic surgical procedures. The CMTD had been diagnosed since childhood. Neurological examination revealed distal wasting of the upper and lower limbs, generalised absence of reflexes and decreased sensation in a stocking distribution. In both anaesthetics, induction was carried out with alfentanil and propofol, and anaesthesia was maintained with nitrous oxide in oxygen, alfentanil and propofol infusion. The patient demonstrated a normal response to both atracurium and mivacurium. Onset time and the maximum block attained after atracurium and mivacurium were 240 and 210 sec, and 97% and 99% inhibition of T1 (the first twitch of TOF stimulation), respectively. Recovery of T1 to 10% of the control value occurred 30 and 11.5 min after the administration of atracurium and mivacurium, respectively. The patient made uneventful recoveries after both anaesthetics.

Conclusion

There was no evidence of prolonged response to atracurium and mivacurium in our patient with CMTD.     

COMPARISON OF MIVACURIUM AND SUXAMETHONIUM ADMINISTERED BY BOLUS AND INFUSION

Mivacurium chloride is a new, short-acting non-depolarizingneuromuscular blocking agent presently undergoing clinical evaluation.The neuromuscular effects of mivacurium and suxamethonium givenby bolus and infusion were compared in adult patients duringnitrous oxide-oxygen-oploid anaesthesia. Neuromuscular blockwas monitored by recording the compound electromyogram of theadductor pollicis muscle resulting from supramaximal train-of-fourstimuli applied to the ulnar nerve. Time to onset of completeblock and recovery to T₅ were significantly shorter for suxamethoniumthan for mivacurium (1.0 (0.1) v. 2.5 (0.3) min and 6.4 (0.7)v. 17.5 (1.8) min; mean (SEM)). Conditions for tracheal intubationwere similar in the two groups although intubation was performed0.75–1.3 min later following mivacurium. The infusionrate required to maintain neuromuscular block was 88.6 (10.4)µg kg^–1 min^–1 for suxamethonium and 7.8 (1.2)µg kg^–1 min^–1 for mivacurium. There was asignificant negative correlation between recovery to T₅ andinfusion rate for mivacurium and for suxamethonium. It was equallyeasy to titrate the in fusion rate to the desired degree ofblock in each group. The recovery index (T₂₅–T₇₅) afterthe infusion stopped was similar in patients who received mivacuriumand those who received suxamethonium.     

Interactions between mivacurium and atracurium

We have studied the interaction between atracurium and mivacurium.The dose—response relationships of atracurium, mivacuriumand their combination were studied in 96 ASA I or II patientsduring thiopentone—fentanyl—nitrous oxide—isoflurane(1.2% end-tidal) anaesthesia. Neuromuscular block was recordedas the evoked thenar mechanomyographic response to train-of-fourstimulation of the ulnar nerve (2 Hz at 12-s intervals). Thedose—response curves were determined by probit analysis.Isobolographic and algebraic (fractional) analyses were usedto assess quantitatively the combined effect of equipotent dosesof atracurium and mivacurium and to define the type of interactionbetween these drugs. Isobolograms were constructed by plottingsingle drug ED₅₀ points on the dose co-ordinates and a combinedED₅₀ point in the dose field. The calculated doses producing50% depression (ED₅₀) of the first twitch height were 50.5 (95%confidence intervals 48.9–52.1) and 20.8 (20.3–21.3) µg kg^–1 for the atracurium and mivacurium groups,respectively. Isobolographic and fractional analyses of theatracurium-mivacurium combination demonstrated zero interaction(additivism). An additional 26 patients anaesthetized with thiopentone-fentanyl-nitrousoxide—isoflurane were allocated randomly to receive eitheratracurium 0.5 mg kg^–1 (n = 13) or mivacurium 0.15 mgkg^–1 (n = 13). Additional maintenance doses of mivacurium0.1 mg kg^–1 were administered to patients in both groups,whenever the first twitch recovered to 10% of control. The durationof the first maintenance dose of mivacurium to 10% recoveryof the first twitch was greater (P < 0.0005) after atracurium(25 (21.8–28.5) min) than after mivacurium (14.2 (11.9–16.6)min). However, the duration of the second maintenance dose ofmivacurium after atracurium (18.3 (12.6–24) min) was similarto that of mivacurium after mivacurium (14.6 (10.6–18.6)min). We conclude that the combination of atracurium and mivacuriumis additive and that the use of mivacurium after atracurium-inducedneuromuscular block results in increased duration of the first(but not the subsequent) maintenance dose of mivacurium.