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Materials and Methods

This prospective randomized placebo-controlled trial was approved by the institutional Ethics Committee. Written informed consent was obtained from all patients. We recruited American Society of Anesthesiologists (ASA) physical status I or II patients, aged 18-65 years, scheduled for an elective surgery lasting at least 120 min. The study protocol adhered to published guidelines on pharmacodynamic studies of NMBA [9]. Patients with an allergy to cisatracurium and MgSO₄, neuromuscular disease, with expected difficult mask ventilation or intubation, receiving medications known to influence neuromuscular function (for instance, calcium channel blockers, aminoglycosides or phenytoine), with electrolyte abnormalities, with hepatic or renal insufficiency, with a body mass index of < 19 or > 28, and who were pregnant or breastfeeding were excluded from the study.

All patients were pre-medicated with intramuscular midazolam (0.05 mg/kg) 30 minutes before anesthesia. Standard monitoring included an ECG, non-invasive blood pressure, endtidal partial pressure of carbon dioxide, and peripheral pulse oximetry. Study medications were produced and randomized (using a random number table) by the non-investigating nurse in indistinguishable, numbered syringes.

Patients were allocated to one of two groups. In the MgSO₄ group (group M), patients received MgSO₄30 mg/kg in 0.9% normal saline (total volume 100 ml) intravenously. In the control group (group C), patients received the same volume of 0.9% normal saline alone. The study drugs were given using a volumetric infusion pump for 15 min before induction of anesthesia. At the end of study drug administration, the intravenous line was flushed, and anesthesia was induced with remifentanil and propofol based on a Minto pharmacokinetic model using a TCI device (Orchestra® Base Primea, Fresenius-Vial, France) [10]. The targeted effect-site concentrations of propofol and remifentanil for induction were 4 µg/ml and 3 ng/ml, respectively. For the maintenance of anesthesia, a propofol effect-site concentration of 3 ± 2 µg/ml and a remifentanil effect-site concentration of 3 ± 0.5 ng/ml with a 50% oxygen-air mixture were used.

Neuromuscular function was assessed by electromyography of the adductor pollicis, on the side opposite the blood pressure cuff and intravenous line, with train-of-four using the neuromuscular transmission module and was displayed on an anesthetic monitoring system (Anesthetic Monitoring System S/5™, Datex-Ohmeda Inc., Helsinki, Finland). Surface electrodes were placed on cleaned skin over the ulnar nerve on the volar side of the wrist. The arm was kept in the same position during the entire study procedure. After injection of remifentanil 2 µg/kg, for over 30 seconds, the stimulus current needed to achieve the maximal response of the adductor pollicis muscle was automatically determined in each patient. The search began with a 10 mA stimulus and the response was measured. The current was increased in steps of 5 mA until the increase in the current no longer increased the response. This maximal current was then automatically increased by 15%, resulting in a supramaximal current. If the supramaximal current was not found or the response was too weak, the current was set at 70 mA. Each patient's supramaximal stimulation was applied with 0.2 ms duration square waves and a 1 second cycle time. After the supramaximal current was obtained and the induction of anesthesia was completed, a bolus dose of cisatracurium 1.5 mg/kg was administered intravenously. We measured and recorded the onset and recovery characteristics defined as follows: (1) the time in seconds from the start of cisatracurium injection until the first change of T1 response (lag time; LT); (2) the time in seconds from the start of cisatracurium injection until 95% depression of T1 response (onset time, OT); (3) the time in minutes from the start of cisatracurium injection until T1 of the TOF had recovered to 25% of the control T1 value (clinical duration, CD); (4) the time in minutes between 25% and 75% recovery of the control T1 value (recovery index, RI); (5) the time in minutes between 25% recovery of the control T1 value and a TOF ratio of 0.9 (recovery time, RT); and (6) the time from the start of cisatracurium injection until a TOF ratio of 0.9 (total recovery time, TRT) [11,12]. The mean arterial blood pressure (MAP) and heart rate (HR) were measured at the following time points: before and after study agent's administration, and at 30, 60, 90, 120 min after operation start. Blood samples for ionized magnesium (normal range 1.1-1.7 mg/dl) were obtained before and after the study agent's administration, at 120 min after the start of operation and 24 h after operation.

Based on studies that reported a 36% decrease in the onset time of vecuronium with 60 mg/kg MgSO₄pre-treatment [12], we assumed that a 20% reduction of onset time with cisatracurium 1.5 mg/kg with 30 mg/kg of MgSO₄ pre-treatment, corresponding to approximately 31 seconds, could be considered clinically significant. With an estimated standard deviation (SD) of 37 seconds, we calculated the necessary sample size using the level of statistical significance as α = 0.05 and β = 0.2. Twenty-four patients were needed in each group to test our hypothesis.

SPSS (Windows ver. 19.0, SPSS Inc., Chicago, IL) was used for statistical analysis. All measured values were denoted as mean ± SD, number of patients, or medians (ranges). Age, body weight index, and supramaximal current were analyzed by the Mann-Whitney U test. Height, weight, and lean body weight were analyzed by unpaired two-tailed Student's t-tests. Gender was analyzed by the x² test. LT, OT, CD, RI, RT, and TRT were analyzed by the Mann-Whitney U test for non-parametric test. Mean arterial pressure, heart rate, and the concentration of ionized magnesium were analyzed by repeated measures of ANOVA, and when a significant intergroup difference was found, the Mann-Whitney U test was used to compare the groups at individual time points. P values < 0.05 were considered statistically significant.