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.      

Duration of the pharmacodynamic interaction between pancuronium and mivacurium

The aim of this study was to determine for how long the duration of action of increments of mivacurium can be influenced by previous pancuronium administration. Fifteen patients, ASA I or II, undergoing general anaesthesia for major abdominal surgery were investigated. The post-tetanic count (PTC) was measured at the adductor pollicis muscle. Pancuronium 0.1 mg kg-1 was injected first. At recovery of the 10th response of the PTC (PTC10), a second dose of pancuronium was injected (0.02 mg kg-1). On recovery to PTC10, a bolus of mivacurium (0.04 mg kg- 1) was given and regularly repeated at recovery of PTC10 until the end of surgery. The mean duration of the second dose of pancuronium was 53 min (SD 13 min) and of the first dose of mivacurium, 66 min (SD 14 min) (P < 0.01). The duration of action of further mivacurium boluses decreased significantly until the fifth dose. It took 222 minutes (95% confidence interval 190, 253 min) after the second pancuronium dose before the duration of action of mivacurium returned to normal values and became constant and predictable.      

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.     

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.     

Dose-response relationship for mivacurium inpatients with phenotypically abnormal plasma cholinesterase activity

During thiopentone-fentanyl-nitrous oxide anaesthesia and using a cumulative design, we studied the dose-response relationship of mivacurium in 8 patients: 7 patients phenotypically homozygous for the atypical plasma cholinesterase gene and 1 patient homozygous for the silent gene. The estimated mean ED₅₀ and ED₉₅ were 15 and 20 μg. kg. bw^-1 in patients homozygous for the atypical gene, and 13 and 16 μg. kg. bw^-1 in the patient homozygous for the silent gene, respectively. The results indicate that mivacurium is 4-5 times more potent in patients homozygous for the atypical or the silent gene than in patients with normal plasma cholinesterase activity and phenotype.     

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.      

Interactions between mivacurium and pancuronium

We have compared the dose-response relationships of mivacurium, pancuronium and their combination, and examined the interactions by isobolographic and fractional analyses. We studied 70 adult patients during nitrous oxide-fentanyl-propofol anaesthesia. The dose-response curves were determined by probit analysis. The ED95 and ED50 values for mivacurium were 84.2 (95% confidence interval 80.2-88.1) micrograms kg- 1 and 46.2 (40.2-52.1) micrograms kg-1, respectively. Corresponding values for pancuronium were 68.5 (63.7-73.2) micrograms kg-1 and 40.7 (35.5-45.9) micrograms kg-1, respectively. Isobolographic and fractional analyses of the mivacurium-pancuronium combination demonstrated a synergistic interaction. An additional 30 patients were allocated randomly to receive either mivacurium 84.2 micrograms kg-1 (n = 15) or pancuronium 68.5 micrograms kg-1 (n = 15). When the first twitch (T1) of TOF recovered to 25%, each patient received mivacurium 46.2 micrograms kg-1. The times after administration of mivacurium until T1 25% in the mivacurium-pancuronium group were 6.4 (3.5-9.4) min and 49.8 (44.7-54.9) min, respectively (P < 0.0001). We conclude that the combination of mivacurium and pancuronium was synergistic and after pancuronium-induced neuromuscular block, mivacurium became a longer acting agent than the shorter agent.      

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.     

Neuromuscular interaction between cisatracurium and mivacurium, atracurium, vecuronium or rocuronium administered in combination

We compared the dose–response relationships of cisatracurium, mivacurium, atracurium, vecuronium and rocuronium and examined the interactions of cisatracurium with mivacurium, atracurium, vecuronium and rocuronium in humans by isobolographic and fractional analyses. We studied 180 adult patients during nitrous oxide–fentanyl–propofol anaesthesia. Neuromuscular block was monitored using mechanomyography to detect the twitch response of the ulnar nerve at the wrist. The dose–response curves were determined by probit analysis. The calculated ED₅₀ values and their 95% confidence intervals were 40.9 (38.1–43.7), 49.8 (47.0–52.6), 187.2 (175.1–199.3), 36.6 (34.7–38.5) and 136.4 (129.2–143.6) μg.kg⁻¹ for cisatracurium, mivacurium, atracurium, vecuronium and rocuronium, respectively. Corresponding ED₉₅ values were 57.6 (53.5–61.7), 91.8 (88.1–95.5), 253.1 (238.9–267.3), 52.9 (49.1–56.7) and 288.7 (276.2–301.2) μg.kg⁻¹, respectively. The interaction between cisatracurium and mivacurium, vecuronium or rocuronium was found to be synergistic, but the interaction between cisatracurium and atracurium was found to be additive. Synergy between cisatracurium and vecuronium or rocuronium was greater than between cisatracurium and mivacurium.     

Synergism between mivacurium and pancuronium in adults

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

Neuromuscular interactions between mivacurium and esmolol in rabbits

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) μgkg⁻¹ with placebo to 61 (9.8) μgkg⁻¹ during esmolol 100 μgkg⁻¹.min⁻¹, 49 (8.2) μgkg⁻¹ during esmolol 300 μgkg⁻¹.min⁻¹ and 54 (7.3) μgkg⁻¹ during esmolol 500 μgkg⁻¹.min⁻¹, respectively (p < 0.001). The duration of neuromuscular block with mivacurium 0.16 mgkg⁻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.     

Interactions between suxamethonium and non-depolarizing neuromuscular blocking drugs

In anaesthetized cats, we have confirmed that previously injectedsuxamethonium potentiates non-depolarizing neuromuscular blockingdrugs whereas, when injected during the block, suxamethoniumantagonizes the paralysis. We have attempted to explain theseinteractions by studying the effects of suxamethonium on extracellularlyrecorded nerve ending waveforms that correspond to the ioniccurrents in the mouse triangularis sterni isolated nerve-musclepreparation. The preparations were paralysed with µ-conotoxin(obtained from the cone snail), which is believed to act byselectively blocking sodium channels in muscle, and which thereforeshould not interfere with currents at the nerve endings. Suxamethonium,in concentrations of 0.5-300 µmol litre^–1, produceda concentration-dependent increase in the amplitude of the waveformcorresponding to the inward calcium current evoked by a nerveimpulse. This effect did not occur in the presence of tubocurarine,suggesting that suxamethonium, which is a nicotinic agonist,may have been acting on a nicotinic receptor on the nerve endingsthat is coupled to the voltage-operated calcium channels. Theinward calcium current is believed to be responsible for neurotransmitter(acetylcholine) release. It is concluded, therefore, that itsenhancement by suxamethonium contributes to the ability of thisdrug to reverse non-depolarizing block. Suxamethonium also exertedcomplex effects on the waveform corresponding to the outwardflowing calcium-activating potassium current at the nerve endings,but no effect was observed in this isolated nerve-muscle preparationthat could obviously explain the ability of suxamethonium topotentiate subsequently injected non-depolarizing blocking drugs.     

Neuromuscular interactions between suxamethonium and magnesium sulphate in the cat

In order to study the neuromuscular interactions between suxamethoniumand magnesium sulphate (MgSO₄), we have determined the dose-responserelationship of suxamethonium and the neuromuscular actionsof 1.25xED₅₀ dose of suxamethonium, both before and after pretreatmentwith MgSO₄. We have also compared the effect of 1.25xED₅₀ doseof suxamethonium in the absence and in the presence of 50%neuromuscularblock, established previously by infusion of MgSO₄. Twenty-onecats were anaesthetized with urethane. Train-of-four stimulationwas applied every 12s to the sciatic nerve and the force ofcontraction of the tibialis anterior muscle was measured. Thepotency of suxamethonium decreased in each instance with pretreatmentwith MgSO₄. The ED₅₀ of suxamethonium increased significantlyfrom mean 21.0 (SEM 1.9) µg kg^–1 before MgSO₄ to25.6 (2.3) µg kg^–1 after MgSO₄ 60 mg kg^–1and to 26.6 (2.2) µg kg^–1 after MgSO₄ 90 mg kg^–1(P<0.05). Twitch depression produced by 1.25xED₅₀ dose ofsuxamethonium decreased significantly with MgSO₄ pretreatment,from 76.7 (2.6)% before MgSO₄ to 61.7 (6.4)% after MgSO₄ 60mg kg^–1 and 48.7 (7.5)% after MgSO₄ 90 mg kg^–1 (P<0.05).With stable 50% neuromuscular block, established previouslyby infusion of MgSO₄ the 1.25xED₅₀ dose of suxamethonium producedmore twitch augmentation (133 (6.3)%vs 108.3 (1.3)%; P<0.05)and less twitch depression (31.6 (9.6)% vs 74.1 (0.6)%, P<0.05)than in the absence of MgSO₄. The results of all three methodsdemonstrated that the pharmacological interaction between suxamethoniumand magnesium was antagonistic.     

Assessment of the interaction between atracurium and suxamethonium at 50% neuromuscular block using closed-loop feedback control of infusion of atracurium

We have studied the effect of prior administration of suxamethoniumon the infusion requirements of atracurium at 50% neuromuscularblock in patients undergoing elective general surgery. Anaesthesiawas maintained with nitrous oxide in oxygen, propofol and fentanyl.Of 20 patients given atracurium, only 10 were given prior administrationof suxamethonium 1 mg kg^–1. At the beginning of the infusion,atracurium 0.3 mg kg^–1 was given by bolus administration.Interaction between the two drugs was assessed by determiningthe steady state rate of infusion necessary to produce a constant50% neuromuscular block. This was accomplished by applying non-linearcurve fitting to data on the cumulative dose requirements duringanaesthesia. The neuromuscular blocking effect was found tobe similar with or without prior administration of suxamethonium.The mean steady-state rate of infusion for atracurium was 0.19(SD 0.03) mg kg^–1 h^–1 for patients given suxamethoniumand 0.18 (0.09) mg kg^–1 h^–1 for those who were notgiven suxamethonium. Thus prior administration of suxamethoniumdid not affect the infusion requirements of atracurium at 50%neuromuscular block, unlike the situation at constant 90% neuromuscularblock.