Magnesium, the fourth most common cation in the body and the second most common intracellular cation after potassium, has numerous physiological effects including activation of many enzymes involved in energy metabolism and protein synthesis . Magnesium also has antinociceptive effects in animal and human models [2,3]. These effects of magnesium are primarily based on antagonism of both calcium and the N-methyl-D-aspartate (NMDA) receptor [3,4].
Schulz-Stubner and colleagues  reported that magnesium administration led to a significant reduction in remifentanil consumption during surgery with lower pain scores and analgesic requirement in the postoperative period. A 60% reduction in minimum alveolar concentration of halothane was also demonstrated in magnesium-treated rats . Recently, Telci and colleagues  reported that magnesium 30 mg kg−1 administration before anaesthesia induction and 10 mg kg−1 continuous intravenous (i.v.) infusion during anaesthesia have a significant reduction in i.v. anaesthetic consumption during total i.v. anaesthesia.
Parenteral magnesium administration decreases the systemic vascular resistance. Magnesium has been used to attenuate adverse cardiovascular effects during laryngoscopy and intubation . The mechanism of action appears to be a significant reduction in the increase of norepinephrine concentrations , inhibition of catecholamine release from the adrenal medulla , and the calcium antagonistic effects of magnesium ions at the level of vascular smooth muscle cells .
Although enthusiasm has been aroused about using magnesium sulphate before induction and during anaesthesia, there is limited information regarding its effects on the minimum alveolar anaesthetic concentration for endotracheal intubation (MACEI) and surgical incision (MAC) of volatile anaesthetics. The purpose of this prospective, randomized, placebo-controlled study was to evaluate whether the dosage of i.v. magnesium sulphate administered before anaesthesia induction and during anaesthesia reduces sevoflurane MACEI and MAC, and attenuates haemodynamic responses to endotracheal intubation and surgical incision.
After obtaining approval from our Ethics Committee and written informed consent from each patient, we studied 120 ASA I-II patients aged 14-55 yr scheduled for elective surgery. Exclusion criteria were a history of hypertension, asthma, drug or alcohol abuse, coronary artery disease, hepatic and renal dysfunction, a history of oesophageal reflux or hiatus hernia; significant obesity; predicted difficulty in intubation or airway maintenance, patients taking centrally acting medication or medication with autonomic action and predicted skin incision <5 cm.
Patients were not premedicated before induction of anaesthesia. All patients were fasted for a minimum of 8 h, and drinking alcohol was prohibited for 24 h before the induction of anaesthesia. MACEI and MAC were determined in two subgroups of study.
Sixty patients were included in this subgroup of the study. All patients were given saline 0.9% 5 mL kg−1 before the induction of anaesthesia and were randomly designated to receive either i.v. saline 0.9% (Group I, n = 20) and magnesium sulphate 30 mg kg−1 + 10 mg kg−1 h−1 by continuous infusion (Group II, n = 20) or 50 mg kg−1 bolus + 10 mg kg−1 h−1 by continuous infusion (Group III, n = 20). Anaesthesia was induced with 7% sevoflurane in oxygen (6L min−1) during spontaneous ventilation without any i.v. anaesthetics and neuromuscular relaxants. For determination of MACEI, 2.2%, 2.4%, 2.6%, 2.8%, 3.0% and 3.2% sevoflurane concentrations in oxygen were used. The end-tidal sevoflurane concentration was maintained at a predetermined concentration for at least 15 min. A single anaesthesiologist performed all endotracheal intubations and judged the responses. Patients with gross purposeful movement during laryngoscopy or after endotracheal intubation were given 7% sevoflurane and 0.1 mg kg−1 vecuronium immediately.
Sixty patients were included in this subgroup of the study. All patients were given saline 0.9% 5 mL kg−1 before the induction of anaesthesia and were randomly designated to receive either i.v. saline 0.9% (Group I, n = 20) and magnesium sulphate 30 mg kg−1 + 10 mg kg−1 h−1 by continuous infusion (Group II, n = 20) or 50 mg kg−1 bolus + 10 mg kg−1 h−1 continuous infusion (Group III, n = 20). Patients were intubated after anaesthesia induction with 7% sevoflurane without any i.v. anaesthetics and muscle relaxant. For determination of the MAC, 1.8%, 2.0%, 2.2%, 2.4%, 2.6% and 2.8% sevoflurane concentrations in oxygen were used. The end-tidal sevoflurane concentration was maintained at the predetermined concentration for at least 15 min before skin incision. Patients were observed for 1 min for gross purposeful muscular movements after skin incision (5 cm for all patients). No local anaesthetics were used before all data were collected. Patients who showed purposeful muscular movements after skin incision were given 7% sevoflurane and 0.1 mg kg−1 vecuronium immediately.
Patients were randomized by means of individually prepared envelopes in either MACEI or MAC studies. Saline 0.9% or magnesium sulphate solutions were prepared by an independent anaesthetist. Therefore, all anaesthesia personnel were blinded to the infused solution. Bolus doses were given to the patients 15 min before induction of anaesthesia and 10 mg kg−1 h−1 continuous i.v. magnesium sulphate infusion was started in Groups II and III or i.v. saline 0.9% at the same infusion rate as in Group I. Problems at the injection site and side-effects of magnesium administration were evaluated. Agitation was defined as physical excitement and restlessness associated with magnesium administration.
The patients were monitored with an electrocardiogram, a pulse oximeter and by measuring indirect arterial pressure. The inspired and end-tidal concentrations of agents were measured throughout the study with a gas monitor (Dräger®; Cato Edition, Lübeck, Germany) that had been calibrated before study. A catheter was inserted at the elbow of the breathing circuit and the end-tidal concentrations of sevoflurane were measured at the nares before endotracheal intubation. After intubation, end-tidal concentrations of sevoflurane were measured from the distal end of the tracheal tube through a catheter that had been inserted into it.
Dixon’s up-down method  was used to determination of MACEI and MAC with 0.20% step size. If purposeful movement was observed the next target concentration was 0.20% higher, and if purposeful movement was negative, 0.20% lower. Coughing and bucking were considered purposeful. Magnesium doses which were adequate to keep serum magnesium concentration 150% or 200% of baseline level, and the initial end-tidal sevoflurane concentrations and intervals used in MACEI and MAC determination were chosen from our pilot study. Return of the end-tidal CO2 to zero and good wave formation with a plateau were obtained throughout the study period. Assisted or controlled ventilation were performed to maintain end-tidal CO2 concentration between 30-40 mmHg. Rectal temperature was maintained at 36-37°C throughout the study period. Adequate depth of anaesthesia was maintained with controlling disappearance of eyelash and corneal reflexes in all patients.
Mean arterial pressure (MAP) and heart rate (HR) were recorded as baseline which was the mean of three resting measurements in the operating room before any instrumentation and 1, 3, 5, 10 min after the anaesthesia induction and after intubation in MACEI study group, and after skin incision in MAC study group.
The MAC of sevoflurane was estimated by logistic regression analysis. Parametric data were analysed with one-way analysis of variance. Differences in haemodynamic data among groups were analysed with two-way analysis of variance. Differences from baseline within groups were assessed using paired-sample t-test. P < 0.05 was considered as significant.
There were no significant differences in patient characteristics data, i.e. age, height, weight, ASA physical status among the three groups in MACEI study (Table 1). Median and 95% confidence limits for sevoflurane MACEI were 2.68 (2.48-2.85), 2.88 (2.70-3.06) and 2.96 (2.70-3.16) in Groups I, II and III, respectively. There was no statistically significant difference among three groups regarding sevoflurane MACEI.
The baseline values of MAP and HR were comparable between groups. After tracheal intubation, MAP and HR did not increase in comparison with the level of baseline values in Groups II and III (Figs 1 and 2).
There were no significant differences in patient characteristics data, i.e. age, height, weight, ASA physical status among the three groups in MAC study (Table 2). Median and 95% confidence limits for sevoflurane MAC were 2.08 (1.76-2.40), 2.26 (2.08-2.47) and 2.40 (2.19-2.68) in Groups I, II and III, respectively. The MAC measured in Group III was significantly higher than Group I (P < 0.05).
The baseline values of MAP and HR were comparable between groups. After skin incision, MAP and HR did not increase in comparison with the level of baseline value in Groups II and III (Figs 1 and 2).
No patients needed treatments for haemodynamic abnormalities defined as hypertension (MAP > 120 mmHg) and hypotension (MAP < 60 mmHg), or tachycardia (HR > 120 bpm) and bradycardia (HR < 40 bpm) lasting for at least 1 min. Other side-effects and problems at injection site that were seen during magnesium administration are shown in Table 3.
The present study showed the effects of administration of magnesium sulphate before induction of anaesthesia on sevoflurane MACEI, MAC and haemodynamic responses to tracheal intubation and surgical incision. Regarding sevoflurane MACEI and MAC, the administration of magnesium sulphate prior to anaesthetic induction and during anaesthesia increased sevoflurane MACEI and MAC approximately 7% and 11%, respectively, at the dose of 30 mg kg−1 and 10% and 15%, respectively, at the dose of 50 mg kg−1 compared to placebo group.
Magnesium acts as an antagonist at the NMDA receptor and its associated ion channels [12,13]. Therefore, theoretically, magnesium could modulate pain by preventing nociception-associated central sensitization via blockade of the NMDA receptor calcium ionophore. Patients given preoperative bolus and postoperative magnesium sulphate infusion have lower intra- [5,14] and postoperative [3,14-16] analgesic requirements than control patients. Recent studies demonstrated a significant reduction in i.v. anaesthetic and analgesic consumption in patients, who received i.v. magnesium sulphate pre- and intraoperatively. In a study by Telci and colleagues , it was shown that 30 mg kg−1 magnesium sulphate as a bolus before induction of anaesthesia and 10 mg kg−1 h−1 by continuous i.v. infusion during the operation period significantly reduces the propofol, remifentanil and vecuronium requirements during total i.v. anaesthesia. Time for induction of anaesthesia (BIS = 60) was shorter (55.4 ± 10.6 s) in the magnesium group compared to the control group (81.2 ± 13.6 s) (P < 0.0001). Sedative effect of magnesium sulphate is the proposed mechanism for rapid induction of anaesthesia and reduction of propofol consumption according to this study. In another study by Schulz-Stubner and colleagues  administration of a single dose 50 mg kg−1 magnesium sulphate after induction of anaesthesia with 1-2 mg kg−1 propofol caused a significant reduction in remifentanil consumption whereas propofol consumption remained unchanged. In this study magnesium sulphate was recommended as a safe and cost-effective supplement to a general anaesthetic regimen with propofol, remifentanil and mivacurium. A significant reduction in fentanyl consumption was also shown in a study by Koinig and colleagues . Although the exact mechanism of the interaction between opioid analgesia and NMDA receptor complex has not been elucidated, magnesium potentiated the analgesic effect of opioids .
There is little information regarding effects of magnesium on inhalational anaesthetics. In a study by Thompson and colleagues , a reduced halothane MAC with increased plasma magnesium levels has been reported. In that study halothane MAC began to decrease when plasma magnesium levels were over 7 mg dL−1. After administration of 50 mg kg−1 magnesium sulphate, serum magnesium concentrations increased from a mean baseline level of 0.79- 1.62 mg dL−1 in a study by Schulz-Stubner and colleagues  and from 1.65 to 3.51 mg dL−1 in a study by Ko and colleagues . In another experimental study  expressed in Xenopus oocytes 20% MAC reduction of volatile anaesthetics by magnesium has been reported.
In our study, MACEI and MAC determined in magnesium-treated groups were not statistically different from the control group, except Group III in MAC study. Although we administered bolus doses of magnesium over 15 min, more than half of patients had unwanted side-effects or problems at injection site compared to the control groups. Very few of these side-effects were serious but most of them were unpleasant and many patients experienced multiple side-effects. These side-effects seem to be stress factor and patients’ discomfort, and main cause of increased MAC levels in patients administered magnesium.
Magnesium is regarded as a central nervous system depressant because of its anticonvulsant properties in pre-eclamptic patients. When ventilation is maintained in these patients, even very high levels of serum magnesium do not produce central nervous system depression . Transport of magnesium across the blood-brain barrier is limited in normal human beings and its concentration in cerebrospinal fluid is well controlled . The i.v. magnesium sulphate fails to induce sleep in healthy volunteers even when administered at magnesium serum concentrations 10 times higher than normal . According to a study by Ko and colleagues  perioperative i.v. administration of magnesium sulphate 50 mg kg−1 bolus and 15 mg kg−1 h−1 continuous infusion did not increase cerebrospinal fluid magnesium concentration and had no effects on postoperative pain. There was an inverse relation between cumulative postoperative analgesic consumption and cerebrospinal fluid magnesium concentration. These results suggest that the cerebrospinal fluid magnesium concentration affects postoperative pain, but perioperative i.v. magnesium administration had no analgesic effects.
Laryngoscopy and tracheal intubation are often associated with tachycardia, hypertension and dysrhythmias . A reflex sympathetic discharge caused by stimulation of the upper airway is discussed as the underlying mechanism. Haemodynamic responses to tracheal intubation are associated with an increase in plasma catecholamine concentrations [9,23,24] and are attenuated by administration of β-adrenergic blockers .
Magnesium sulphate given before anaesthesia induction significantly attenuated the increase in MAP and HR after tracheal intubation. After surgical skin incision, it was markedly attenuated in both groups given magnesium. Magnesium sulphate has been shown to obtund the hypertensive response to intubation in patients with pre-eclampsia . The mechanism of action appears to be inhibition of catecholamine release from the adrenal medulla  with epinephrine concentrations unchanged from baseline and a significant decrease in the increase in norepinephrine concentrations .
We did not measure serum magnesium sulphate concentration because of serum magnesium estimations may not provide representative information on the status of other stores [7,27].
In summary, our results suggest that magnesium sulphate administered before induction of anaesthesia, 50 mg kg−1 with 10 mg kg−1 h−1 continuous infusion during the operation, has increased the MAC of sevoflurane. Magnesium sulphate caused a higher rate of side-effects but attenuated the increase in HR and MAP during intubation and skin incision.
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