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.      

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.      

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.     

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 the haemodynamic effects of mivacurium and atracurium during fentanyl anaesthesia

We have measured the haemodynamic effects of mivacurium 0.15and 0.2 mg kg^–1, and atracurium 0.5 mg kg^–1 administeredover 10–15 s in patients undergoing coronary artery bypasssurgery under fentanyl anaesthesia. There were no significanthaemodynamic changes in the atracurium group, other than a transientdecrease in pulmonary arterial wedge pressure. Changes in heartrate were small in all three groups. Mivacurium 0.15 mg kg^–1produced changes of only small magnitude (12% decrease in meanarterial pressure and 16% decrease in systemic vascular resistanceindex) however, mivacurium 0.2 mg kg^–1 produced a 25%reduction in mean arterial pressure, a 14% increase in cardiacindex and a 35% decrease in systemic vascular resistance index.Erythema developed in two, three and seven patients after atracurium,mivacurium 0.15mgkg^–1 and mivacurium 0.2 mg kg^–1,respectively. One patient exhibited a 54% decrease in mean arterialpressure, generalized erythema and bronchospasm after mivacurium0.2mg kg^–1. The haemodynamic changes with mivacurium suggestedhistamine release. (Br. J. Anaesth. 1995; 74: 330–332)     

Interactions between atracurium and vecuronium on indirectly elicited muscle twitch in vitro

In vitro experiments using the indirectly stimulated rat phrenic-nerve diaphragm preparation have demonstrated simple summation of the inhibitory actions of vecuronium and atracurium.     

Histamine-release haemodynamic changes produced by rocuronium, vecuronium, mivacurium, atracurium and tubocurarine

We have examined the effects of different benzyl-isoquinolinium and steroidal neuromuscular blocking compounds on plasma concentrations of histamine, heart rate and arterial pressure in surgical patients. A single, rapid (5-s) bolus of mivacurium 0.2 mg kg-1, atracurium 0.6 mg kg-1, tubocurarine 0.5 mg kg-1, vecuronium 0.1 mg kg-1 or rocuronium 0.6 mg kg-1 was administered to 75 patients (n = 15 in each group). Anaesthesia was induced with thiopentone 6 mg kg-1 i.v. and maintained with isoflurane and 70% nitrous oxide in oxygen. Venous blood samples were obtained before induction, 1 min after thiopentone and 1, 3 and 5 min after administration of the neuromuscular blocking drug. Mivacurium, atracurium and tubocurarine caused 370%, 234% and 252% increases in plasma histamine concentrations at 1 min, respectively. Corresponding values at 3 min were 223%, 148% and 157%, respectively. These changes were significant (P < 0.01) at 1 and 3 min. In contrast, the rocuronium and vecuronium groups had no significant changes in either plasma histamine concentrations or haemodynamic variables.      

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.     

Interactions of vecuronium and atracurium in an in vitro nerve-muscle preparation

Atracurium and vecuronium were compared when given alone and in combination in the in vitro rat phrenic nerve-hemidiaphragm preparation stimulated via the phrenic nerve. The slopes of the log dose response curves of atracurium and vecuronium were parallel; their ED50s were 1.12 +/- 0.0035.10(-5)M and 5.89 +/- 0.16.10(-6)M, respectively. The combination's log dose response curves were significantly shifted to the left when compared with those of either relaxant alone; an increased potency is displayed by the combination. These observations indicate nondepolarizing muscle relaxant synergy for the combination of equal proportions of vecuronium and atracurium. The synergistic interaction of vecuronium and atracurium in this in vitro-model is not dependent on pharmacokinetic factors such as uptake, distribution, and biodegradation as are present in the in vivo animal models and in humans. Synergy of vecuronium and atracurium in vitro is a new finding and is consistent with hypotheses of multiple receptor sites and different modes of action of the "competitive" neuromuscular blocking agents. This degree of synergy, seen in the in vitro animal data, if extrapolatable to humans, is probably of little clinical significance.     

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.     

The influence of atracurium, cisatracurium, and mivacurium on the proliferation of two human cell lines in vitro

We tested the influence of atracurium and cisatracurium (final concentrations: 0, 0.96, 3.2, 9.6, 32, and 96 microM) on proliferation of human cells (hepatoma HepG2 cells and human umbilical vein endothelial cells) in vitro. In additional experiments, glutathione, N-acetylcysteine, or carboxyl esterase was added before the addition of either relaxant. The number of cells counted after 72 h of incubation was expressed as a percentage of the mean cell number in wells incubated without additives. Atracurium and cisatracurium progressively decreased cell proliferation in a concentration-dependent pattern. With human umbilical vein endothelial cells, atracurium or cisatracurium (3.2 microM) decreased the cell count to 67.7 % (SD, 14.8%) and 50% (SD, 8.6%), respectively. Cell proliferation was not inhibited by mivacurium. The results were similar to those with HepG2 cells. Glutathione, N-acetylcysteine, and carboxyl esterase partially reversed the effects of atracurium and cisatracurium. When incubated in a buffer with glutathione, atracurium decreased the number of glutathione-sulfhydryl groups. The findings that atracurium and cisatracurium inhibit proliferation of human cell lines in vitro, but that mivacurium does not, and that this effect is alleviated by glutathione and N-acetylcysteine, as well as by the carboxyl esterase, indicate that the inhibition may be caused by the reactive acrylate metabolites.     

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.      

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     

Quantitation of the interaction between atracurium and succinylcholine using closed-loop feedback control of infusion of atracurium

The authors used closed-loop feedback control of infusion of atracurium to study the effect of prior administration of succinylcholine on neuromuscular blockade induced by atracurium in patients undergoing otolaryngologic surgery. Anesthesia was maintained with nitrous oxide in oxygen, flunitrazepam, and fentanyl. Of 14 patients given atracurium, seven were given prior administration of succinylcholine and seven were not. Interaction between the two drugs was quantified by determining the asymptotic steady-state rate of infusion necessary to produce a constant 90% neuromuscular blockade. This was accomplished by applying nonlinear curve-fitting to data on the cumulative dose requirement during anesthesia. The neuromuscular blocking effect of atracurium was found to be greater after prior administration of succinylcholine. The asymptotic steady-state rate of infusion (+/- SD) for atracurium was 0.27 +/- 0.06 mg.kg-1.h-1 for patients given succinylcholine and 0.38 +/- 0.10 mg.kg-1.h-1 for those not given succinylcholine. The clinical implication of this study is that the clinician should be aware of the fact that an induction dose of 1 mg/kg of succinylcholine does reduce atracurium requirement for 90% neuromuscular blockade by approximately 30%.     

A comparison between vecuronium and atracurium in myasthenia gravis

We evaluated the effect of vecuronium bromide and atracurium besylate on the train–of–four response in the management of muscle relaxation in 20 patients with myasthenia gravis (MG) who were undergoing thymectomy. We confirmed the safe use of these two non–depolarizing muscle relaxants in MG patients. Vecuronium (0.04 mg–kg^-1) demonstrated a lesser clinical duration than did atracurium (0.2 mg–kg^-1) (38± 19 vs 50 ± 21 min, mean ± s.e.mean). The recovery time for vecuronium patients was shorter than that for atracurium patients (22 ± 18 vs 38± 18 min), but the time until onset of neuromuscular blockade was longer with vecuronium (246 ±105 vs 107 ± 103 s). During spontaneous recovery from neuromuscular relaxation, at Tl/C of 25% and 100%, the train–of–four fade with vecuronium was significantly greater than that with atracurium (0.04 ± 0.02, 0.16 ± 0.03 vs 0.17 ±0.01, 0.83 ± 0.03), suggesting that vecuronium had a greater prejunctional effect than did atracurium.