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Discussion

This study reveals that pretreatment of MgSO₄ significantly hastens the onset time of cisatracurium without significantly prolonging the recovery characteristics and does not influence the mean arterial pressure and heart rate. Furthermore, although the concentration of the blood ionized magnesium is significantly increased after the administration of MgSO₄, there was no adverse effect in any of the patients.

After pre-treatment with MgSO₄, the hastened onset time and prolonged recovery characteristics of NMBAs were observed [3,4]. Fuchs-Buder et al. [3] reported that MgSO₄ 40 mg/kg as an infusion over 15 minutes significantly accelerated the onset time and prolonged the recovery index of vecuronium. Pretreatment with MgSO₄ 30 mg/kg within 5 minutes also increased the speed of onset and prolonged the recovery index of atracurium [4]. Telci et al. [13] found that the clinical duration and time of TOF > 0.7 of vecuronium was significantly longer after 30 mg/kg of MgSO₄ followed by 10 mg/kg/h continuous infusion. Different doses of MgSO₄ as an infusion markedly reduced NMBA consumption, which resulted from the reduced ED₅₀ and ED₉₀ of the NMBAs [3,14]. Schulz-Stubner et al. [14] concluded that mivacurium consumption was markedly reduced from 0.01 to 0.008 mg/kg/min in patients receiving MgSO₄ infusion. In contrast to these results, Gupta et al. [15] reported that the onset time of rocuronium was unaffected by a 30 mg/kg bolus of MgSO₄ following infusion before induction of anesthesia, but the clinical duration was significantly longer in the MgSO₄ group. Kussman et al. [5] reported that MgSO₄ 60 mg/kg, injected 1 minute before rocuronium, significantly prolonged the clinical duration of the neuromuscular block but curiously had no influence on the onset time.

In this study, pretreatment with MgSO₄ showed conflicting results on the onset time and recovery characteristics, in contrast to previous reports [3,5,13,15]. The reasons for this differential effect remain obscure. Our results for the onset time were similar to previously reported results [3,4], except for Kussman's report [5]. Kussman et al. [5] speculated that the differences in the effect of magnesium pretreatment on the onset time reflected differences in the pharmacodynamic properties; the shorter the baseline onset time of the NMBA, such as rocuronium, the less effect MgSO₄ pre-treatment would have on its reduction. However, they ignored the fact that the effect of MgSO₄ on the neuromuscular endplate was both concentration- and time-dependent and that at least 4-6 minutes were necessary to reach the motor nerve terminal in a concentration high enough to interfere with the NMBAs [12,16]. In other words, after a rapid bolus injection immediately before rocuronium, the magnesium ions have no opportunity to reach the motor nerve terminal in a concentration that is high enough to interfere with rocuronium. Consequently, an MgSO₄ infusion with enough time to interfere with NMBAs, rather than a bolus injection immediately before the rocuronium, should impact on the NMBAs. MgSO₄ may accelerate the transportation of NMBAs to the motor nerve terminal by increasing peripheral blood flow because of its vasodilatation effect [12]. MAP usually decreased after MgSO₄ administration; however, the cardiac output and cardiac index were significantly increased due to the consequence of the increase in HR as well as the reduced ventricular afterload [17,18]. In our study, we detected that the MAP and HR were increased immediately after MgSO₄ administration and we assumed that this effect influenced the onset time of cisatracurium resulting from the increasing cardiac output. Our results on the recovery characteristics were not anticipated because the majority of previous studies reported that MgSO₄ pre-treatment prolonged the recovery [3-5,8,12,13,19]. One explanation for the differences between previous reports and our study may be the differences in the dose responses of MgSO₄. Some authors used the infusion of MgSO₄ from 40 to 60 mg/kg, for over 15 min [3,12], others used the single bolus dosed from 30 to 70 mg/kg and continuous infusion during the operation [8,15]. Fuchs-Buder et al. [3] reported that the ionized concentration after the end of 40 mg/kg MgSO₄ infusion was 1.08 mmol/L and that MgSO₄ increased the neuromuscular potency of rocuronium. Pinard et al. [8] reported that the ionized magnesium concentration after the end of 70 mg/kg MgSO₄ infusion was 1.28 mmol/L and that the ionized magnesium concentration on arrival at the intensive care unit was 1.11 mmol/L, resulting from the continuous infusion of MgSO₄ during the operation. Their plasma concentration might be higher than the ionized concentration. Plasma concentrations of magnesium more than 2.5 mmol/L produce a neuromuscular blockade [1]. In our study, the ionized concentrations were 1.51 and 1.40 mg/dl (0.6-0.62 mmol/L) after the end of infusion and 120 min after operation. We assumed that the concentration of ionized magnesium did not last long enough to prolong the recovery characteristics, because we used a smaller dose of MgSO₄ (30 mg/kg) without continuous infusion.

In terms of safety, Fuchs-Buder et al. [3] reported that this was clinically safe as no symptoms of muscle weakness were observed. Telci et al. [13] and Schulz-Stubner et al. [14] also demonstrated that magnesium infusion was well tolerated, with no signs of muscle weakness. Although our results on the concentration of ionized magnesium after the administration of MgSO₄ 30 mg/kg were higher than those of the control group, they were in the normal ranges at the all time points of study without adverse effects such as heat or burning sensations, an acceleration of the heart rate and arrhythmia.

The dose of MgSO₄ and the timing of administration were chosen arbitrarily. The timing and duration of administration were taken from a previously published MgSO₄-vecuronium interaction study [3]. Many authors have used from 30 to 70 mg/kg of MgSO₄ and most authors reported that these doses were effective to reduce the onset time and prolong the recovery index without any significant side effects [3-5,8,12,13,19]. Therefore we decided to use 30 mg/kg MgSO₄ to evaluate the effect on the onset time and recovery characteristics and to avoid clinical adverse effects even if all doses were safe.

As an alternative to succinylcholine, high doses of NMBAs have been used for rapid sequence intubation. 1.5 mg/kg of cisatracurium (3 × ED₉₅) provided intubation conditions within 90 seconds and its mean onset time was 3.4 minute, which was not sufficient as an alternative to succinylcholine [20]. Even if an excessively high dose of NMBA prolongs the duration of the neuromuscular block in a dose-dependent manner, which may not be acceptable in every surgical setting, it is not considered for cisatracurium because it is dose-independent in terms of recovery. In our MgSO₄-cisatracurium interaction study, the mean onset time was 1.8 minutes, which was significantly hastened compared with 1.5 mg/kg of cisatracurium. We assumed that the MgSO₄-cisatracurium combination could provide intubation conditions within 60 seconds and was sufficient as an alternative for succinylcholine. However, the limitation of our study is that we did not measure the intubation conditions to determine whether MgSO₄-cisatracurium combination can alternate for succinylcholine.

In conclusion, MgSO₄ shortens the onset time of cisatracurium without significant prolongation of the recovery characteristics of cisatracurium. In addition, we suggest that further investigation is required on different doses of MgSO₄-cisatracurium combination to determine whether they can serve as an alternative to succinylcholine for rapid sequence intubation.