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Magnesium Research 2012; 25 (2): 72-8

ORIGINAL ARTICLE

The effects of magnesium sulphate on desurane requirement, early recovery and postoperative analgesia in laparascopic cholecystectomy
Bilge Olgun, Gonca Oguz, Mens ure Kaya, Serpil S avl, Hamit Erdal Eskic rak, Ihsan Gney, Nihal Kadogullar Dr A.Y. Ankara Oncology Education and Research Hospital, Department of Anesthesiology, Ankara, Turkey
Correspondence: G. Oguz, Hukukc u Dostlar Sitesi 495. Sok. No: 13, C ayyolu Yenimahalle/Ankara, Turkey <goncatuncel@hotmail.com>

Abstract. Purpose: we evaluated the effects of magnesium sulphate infusion on anesthetic requirement, early recovery and postoperative analgesia in desurane-remifentanil-based, balanced anaesthesia. Methods: 60, ASA (American Society of Anesthesiologists) group 1-2 patients who were scheduled for laparoscopic cholecystectomy were randomly divided into two groups. Before anesthesia, the magnesium-treated group (n = 30) received a 15 min infusion of 40 mg/kg of magnesium sulphate followed by 10 mg/kg/h by continuous i.v. infusion during the operation. The same volume of isotonic saline was administered to the control group (n = 30). Anesthesia was induced with propofol, remifentanil and vecuronium, and maintained with desurane 3-6%, O2 /air and remifentanil infusion. Desurane was titrated to maintain BIS (bispectral index) values of 40-60. The times from cessation of anesthesia to spontaneous breathing, eye opening, extubation, reaching BIS 70, and Aldrete scores were recorded. After surgery, patients received a patient-controlled, morphine analgesia device. Results: demographic variables were similar. During the 15 min infusion of magnesium sulphate, the BIS value was signicantly lower in the magnesium sulphate-treated group. The amounts of propofol and desurane used were less in the magnesium sulphate-treated group, by 18% and 22% respectively (p<0.05). The groups did not differ with respect to the time taken to reach BIS 70, spontaneous breathing, eye opening and extubation. Alderete and VAS (visual analogue scale) pain scores, and total morphine consumption were signicantly lower in the magnesium sulphate-treated group. There were no differences in side effects, but the rate of re-intubation was higher in the group receiving magnesium sulphate (p = 0.03). Conclusion: perioperative use of magnesium sulphate reduced propofol and desurane consumption, and the postoperative morphine requirement, while causing a delay in recovery by decreasing the Aldrete score.
Key words: anesthesia, desurane, magnesium, postoperative pain, recovery
doi:10.1684/mrh.2012.0315

There has been an interest in the use of magnesium, the second most abundant, intracellular cation, in anesthesia practice in recent years. At the beginning of the last century, magnesium sulphate was proposed as a general anesthetic

owing to its depressant effects on the central nervous system [1]. In various studies, it has been shown to potentiate anesthetic drugs and reduce anesthetic consumption during surgery [1, 2].

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Kadogullar G, Kaya M, S To cite this article: Olgun B, Oguz avl S, Eskic rak HE, Gney I, N. The effects of magnesium sulphate on desurane requirement, early recovery and postoperative analgesia in laparascopic cholecystectomy. Magnes Res 2012; 25(2): 72-8 doi:10.1684/mrh.2012.0315

Effects of magnesium on anesthetic requirement

The anesthetic effect of magnesium is thought to be related to several mechanisms, such as antagonism of NMDA receptors in the central nervous system, decrease of the stress response to surgery by reducing catecholamine release [3] and inhibition of acetylcholine release at motor nerve terminals [4]. A competitive antagonism in hippocampal presynaptic calcium channels that regulate neurotransmitter release in the central nervous system has also been suggested [5]. Perioperative analgesia, an important component of anesthesia, is an effective factor in the recovery process. The demonstration of an inverse relationship between the severity of pain and the serum magnesium concentration has led to further investigation of magnesium [6]. Inhibition of calcium inux, antagonism of NMDA receptors, and prevention of central sensitization after peripheral tissue injury or inammation by inhibition of dorsal horn NMDA receptors have been suggested as the analgesic mechanisms [7]. Also, NMDA antagonists have been shown to potentiate the analgesic effect of opioids by delaying or reducing the development of acute tolerance [8]. We hypothesized that a magnesium sulphate infusion would reduce the amount of anesthetic agents needed. The primary aim of this double-blind, randomised, placebocontrolled study was to assess the effects of a perioperatively-administered, magnesium sulphate infusion on anesthetic requirement in desurane-remifentanil-based, balanced anesthesia. Early recovery parameters and postoperative morphine use were also investigated.

Methods and materials After obtaining approval of the Institutional Ethics Committee and the patients informed consent, 60, ASA physical status 1-2 patients, aged 20-70, scheduled for laparoscopic cholecystectomy were included in this double blind, randomized, prospective study. Exclusion criteria included hepatic, neuromuscular, renal, respiratory and cardiovascular system disorders, prior treatment with calcium channel blockers, opioids or magnesium, and known allergy to the study drugs. Patients were randomly allocated into one of the groups using a computer-generated, random list

of numbers (magnesium sulphate-treated group (n = 30), control group receiving saline (n = 30)). Before surgery, all patients were informed about the use of a patient-controlled analgesia device (Abbott APM Provider pump, North Chicago, IL, USA) and the Visual Analogue Scale (VAS 0: no pain, VAS 10: most severe pain experienced). After premedication with midazolam 0.07 mg/kg i.m., monitoring of standard ECG, pulse oxymetry and non-invasive blood pressure was established on arrival at the operating room. The depth of anesthesia was monitored with a bispectral index monitor (BIS), which uses processed electroencephalogram signals to measure the depth of sedation on a unitless scale from 0 to 100. A PENLON (SIGMA ALPHA, AYBO, Eczacbas , Baxter, UK) vaporizator was used to measure desurane consumption. This automatically calculates the amount of desurane use. Fifteen minutes before the induction of anesthesia, a continuous, i.v. infusion of 40 mg/kg of magnesium sulphate, 15% in 100 mL saline, and then 10 mg/kg bwt/h was administered to the magnesium-treated group and was continued throughout the operation. The same volume of isotonic saline was administered, at the same infusion rate, to the control group. In both groups, anesthesia was induced with remifentanil 1 g/kg and propofol 1 mg/s until a BIS value of 40 was reached. Orotracheal intubation was undertaken 3 min after administration of vecuronium 0.1 mg/kg. Remifentanil infusion was started at an infusion rate of 0.25 g/kg//min after the induction of anesthesia, and reduced to 0.125 g/kg/min, 10 min after intubation. Anesthesia was maintained with desurane 3-6%, O2 /air and remifentanil infusion. Desurane was titrated to maintain BIS values between 40-60, during anesthesia. Baseline MAP (mean arterial pressure), HR (heart rate), BIS and SpO2 values were recorded initially, at 5, 10 and 15 min before induction, 1, 3 and 5 min after intubation and at 5 min intervals during the surgery. If MAP and HR exceeded 20% of baseline values while BIS was within the targeted range, a bolus of remifentanil 1 g/kg bwt was given. If the situation was not resolved 5 min later, the infusion rate was increased to 0.25 g/kg bwt/min after another 1 g/kg bwt bolus. Nitroglycerine was administered when needed. An MAP 20% lower than baseline was treated with ephedrine 5 mg, and an HR<45 beats/min with atropine 10 g/kg bwt.

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All of the anesthetics and the magnesium infusion were discontinued at the end of skin closure, and the total consumption of drugs was noted. Neuromuscular block was antagonized with intravenous neostigmine 0.04 mg/kg and atropine 0.02 mg/kg bwt. The time from cessation of anesthesia to the beginning of spontaneous breathing, eye opening, extubation and reaching a BIS value of 70 was recorded. Patients were extubated when BIS 70. Postoperative recovery was assessed using the Aldrete scoring system. Blood samples were taken from patients before infusion and 10 min after cessation of infusion of magnesium sulphate in order to measure serum magnesium concentrations. Following surgery, all patients received a patient-controlled analgesia device (PCA) adjusted to deliver a 5 mg loading dose of morphine, a bolus of 1 mg, and a 10 min lock-out period. An additional 5 mg bolus dose of morphine was given when VAS4. MAP, HR, respiratory rate and VAS pain scores were evaluated at postoperative 0, 1, 2, 4, 6, 12 and 24 h. Patient satisfaction, side-effects such as nausea-vomiting and pruritis, and the need for re-intubation were also recorded. Patient satisfaction was assessed using a 4-point scale (1 = bad, 2 = moderate, 3 = good, 4 = excellent). Nausea and vomiting were treated with ondansetron 4 mg i.v. The primary outcome of this study was to obtain a decrease in the desurane requirement. Allowing an error of 0.01 and a error of 0.10, it was estimated that a minimum of 27 patients per group would be required to show a 20% decrease in desurane requirement. Thus, 30 patients were recruited for each group in case of possible drop-outs from the study. Secondary outcome variables included propofol and morphine consumption, patient satisfaction and occurrence of side-effects.

Statistical analysis was performed using SPSS statistical software (version 15.0, SPSS, Chicago, IL, USA) and MedCalc version 11.2.0.0. The distribution of the data was analyzed using the Kolmogorov Smirnov test. The independent sample T-test was used to make between-group comparisons. Side-effects were analyzed using the 2 test. P-values below 0.05 were considered signicant. Values expressed as means are given with the standard error of the mean.

Results The demographic variables and duration of surgery were similar between the two groups. The demographic characteristics are shown in table 1. During the 15 min infusion period of the study drugs, prior to the induction of anesthesia, there were no differences between MAP and HR, however, BIS values were signicantly lower in the magnesium sulphate-treated group (table 2). The amount of propofol used for the induction of anesthesia was low in magnesium-treated patients (p = 0.016). The magnesium sulphatetreated group received 114.3 29.3 mg of propofol, while the group receiving saline received 137.7 42.2 mg. The total consumption of desurane was also found to be signicantly lower in the magnesium sulphate-treated group (p = 0.005). Propofol and desurane consumption rates are shown in table 3. MAP, HR and BIS values were similar between the groups throughout the surgery. Five patients in the magnesium sulphate-treated group and eight patients in the saline group received atropine because of bradycardia. Intraoperative use of atropine and ephedrine were similar. The groups did not differ with respect to the time taken to reach a BIS value of 70 following;

Table 1. Demographic characteristics of patients in the group receiving magnesium sulphate treatment compared to controls receiving saline.
Magnesium sulphate (n = 30) 47.7 11.4 76.0 12.7 25 / 5 (20 / 10) 64.1 20.8 Saline (n = 30) 45.4 12.4 75.9 13.0 25 / 5 (16 / 14) 70.6 16.5

Age (yr) Weight (kg) Gender (F/M) ASA (I/II) Duration of operation (min)

Mean SD; ASA: American Society of Anesthesiologists

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Table 2. BIS values before anesthesia in magnesium sulphate-treated group compared to controls receiving saline.
Magnesium sulphate (n = 30) 95 10.6 92.6 9.2 89.9 9.9 86.4 11.5 Saline (n = 30) 97.3 1.9 97 2.0 95.9 3.8 93.8 6.3 T -0.049 2.512 3.049 3.077 P 0.961 0.015* 0.003* 0.003*

BIS 0 min BIS 5 min BIS 10 min BIS 15 min

Mean SD; *P<0.05; BIS: bispectral index; T: Students t test

Table 3. Propofol, desurane and morphine consumption in magnesium sulphate-treated group compared to controls receiving saline.
Magnesium sulphate (n = 30) 114.3 29.2 46.7 13.5 25.9 11.6 Saline (n = 30) 137.6 42.1 59.9 21 33.2 16.1 T 2.491 2.896 2.024 P 0.016* 0.005* 0.048*

Propofol (mg) Desurane (mL) Morphine (mg)

Mean SD; *P<0.05; T: Students t test

cessation of the anesthetics, spontaneous breathing, eye opening and extubation. Alderete scores on leaving the operating room were lower in the magnesium sulphate-treated group (p = 0.008) (table 4). Postoperative measurements of MAP, HR and respiratory rate were found to be similar in both groups. VAS pain scores and total morphine consumption were signicantly lower in the magnesium sulphate group. VAS scores are presented in table 5 and the total morphine dose in table 3. There were no differences between the groups as regards side effects such as nausea-vomiting, urinary retention and pruritis, however, the rate of re-intubation was higher in the group treated with magnesium sulphate (p = 0.03). Four patients in the magnesium sulphate-treated group were reintubated because of respiratory depression.

The postoperative magnesium levels were increased signicantly compared to preoperative values in the magnesium sulphate-treated group, while no difference was observed in the group receiving saline (table 6). Patient satisfaction rates were similar in both groups.

Discussion In this study, we have demonstrated that perioperative use of magnesium sulphate reduced the requirement for anesthetic drugs during general anesthesia induction and maintenance, postoperative morphine consumption and VAS pain scores, but signicantly increased recovery time. Magnesium has numerous physiological effects including the regulation of many ion channels

Table 4. Time taken to reach BIS 70, spontaneous breathing, extubation, eye opening, and Aldrete scores in the magnesium sulphate-treated group compared to controls receiving saline.
Magnesium sulphate (n = 30) 5.17 2.4 6.02 2.8 6.21 2.3 6.59 2.9 8.16 1.1 Saline (n = 30) 4.97 2 5.39 2.7 5.97 2.5 6.30 2.9 9.00 1.2 T 0.346 0.869 0.379 0.399 2.741 P 0.731 0.388 0.706 0.692 0.008*

Time to reach BIS 70 (min) Spontaneous breathing (min) Extubation (min) Eye opening (min) Aldrete score

Mean SD; *P<0.05; T: Students t test; BIS: bispectral index

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Table 5. Postoperative VAS pain scores in the magnesium sulphate-treated group compared to controls receiving saline.
Magnesium sulphate (n = 30) 5.9 2.3 4.3 2.1 2.9 1.8 1.8 1.1 1.4 1.0 1.1 0.4 1.0 0.1 Saline (n = 30) 7.3 2.3 6.4 2.1 4.2 1.9 3.2 1.9 2.3 1.5 1.8 1.3 1.4 1.0 T 2.397 3.826 2.726 3.373 2.721 2.669 2.317 P 0.020* 0.000* 0.008* 0.001* 0.009* 0.010* 0.024*

0 min 1h 2h 4h 8h 12 h 24 h

Mean SD; *P<0.05; T: Students t test; VAS: visual analogue scale

Table 6. Serum magnesium concentration in the magnesium sulphate-treated group compared to controls receiving saline.
Magnesium sulphate (n = 30) Preoperative magnesium concentration (mmol.L-1 ) Postoperative magnesium concentration (mmol.L-1 ) Mean SD; *P<0.05, Students t test 1.9 0.3 3.2 0.2* Saline (n = 30) 1.9 0.2 1.9 0.3

and activation of enzymatic reactions. It has been shown to have a general anesthetic effect and to enhance the effects of local anesthetics [9, 10]. Although many studies regarding the effects of magnesium on anesthetic consumption have been reported, most of them involve total intravenous anesthesia while studies investigating inhalation anesthesia are few [11-13]. We were not able to nd any literature about the effect of magnesium on the induction doses of anesthetics. In our study, we found the induction dose of propofol needed to reach a BIS value of 40 to be 18% lower in the magnesium sulphate-treated group. In the present study, the BIS values showed a signicant decrease during preoperative infusion of magnesium sulphate. Seyhan and colleagues have shown in their study that a single bolus of 40 mg/kg magnesium achieved a 13.5% decrease in the intraoperative propofol requirement. This reduction was doubled when it was combined with a 10 mg/kg/h infusion [13]. They also reported that higher doses of magnesium sulphate did not provide any additional effect, but produced hemodynamic consequences. Although there is little information available about the effects of magnesium on inhalation anaesthetics, in rats, magnesium has been shown to reduce the MAC value of halothane by 60% [14]. Studies with similar doses of magnesium

have shown a reduction in anesthetic consumption [1,2]. The magnesium dose used in our study was found to reduce intraoperative desurane consumption by 22%. The magnesium sulphatetreated group used 46.7 13.5 mL of desurane, while consumption was 59.9 21 mL in the group receiving saline. It is also well known that magnesium sulphate inhibits acetylcholine release at motor nerve terminals, thus potentiating the effects of neuromuscular blocking agents [15, 16]. In the literature, several cases of recurarization have been reported during magnesium sulphate use [17]. We did not use neuromuscular monitoring during the study; therefore we did not investigate the effects of magnesium on neuromuscular blockers. However, four patients in the magnesium group developed respiratory depression after extubation and thus required re-intubation. After 30 min of mechanical ventilation, the patients were re-extubated. They experienced no further respiratory complications. Studies with similar doses of magnesium have shown a longer duration of the effect of neuromuscular agents and later extubation times, but re-intubation has not been a frequent issue [1, 13]. The absence of neuromuscular monitoring is a limitation of our study. We performed extubation when tidal volume was sufcient and clinical tests were available. The

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postoperative serum magnesium levels of these patients were within the therapeutic range and they did not receive any anesthetic or analgesic drugs that were outside the study protocol. Although we did not use neuromuscular monitoring, we believe that the effects of magnesium on the neuromuscular junction may be responsible for this consequence. Modied Aldrete scores on leaving the operating room were also low in the magnesium group. This result is in accordance with the other studies [13]. Magnesium is known to inhibit the release of catecholamine from peripheral adrenergic nerve terminals and adrenal gland, and produce vasodilatation by calcium antagonistic effects on blood vessel smooth muscle [18]. Several studies have been performed looking at the effects of magnesium on hemodynamics [18, 19]. Although Ryu et al. found magnesium to decrease signicantly MAP and HR during total intravenous anesthesia [20], Tramer et al. have not demonstrated any hemodynamic differences between the groups [21]. In our study, the response to intubation and surgery, and intraoperative hemodynamic parameters were similar. The discrepancies between the results from these studies might be due to differences in methodology or the dosages of magnesium and anesthetics used. It is known that the plasma magnesium concentration does not reect the magnesium content of the tissues; however, magnesium toxicity has been reported to start at serum magnesium concentrations of 2.5-5 mmol/L, resulting in cardiac arrest at 12.5 mmol/L [22]. We therefore measured the serum magnesium concentrations and showed that the concentration increased 1.5-2-fold postoperatively, without reaching toxic levels. Postoperative pain control is an important factor for recovery and perioperative morbidity. Serum magnesium concentration has been reported to decrease during anesthesia and return to baseline 1-3 days after surgery [12]. Magnesium produces a voltage-dependent blockade of NMDA receptors, and its potential effects on postoperative opioid consumption have been widely investigated [23, 24]. In one of the primary investigations involving the analgesic effects of magnesium, Tramer et al. demonstrated that perioperative magnesium reduced postoperative analgesic use, provided better sleep quality and patient comfort, without any side effects [21]. In the same study, they showed a 30%

decrease in postoperative morphine consumption in magnesium-treated group. Pickering et al. showed that magnesium alone did not improve the pain indicators in patients with neuropathic pain, but diminished the frequency of pain paroxysms and improved the emotional component when compared to the placebo group [25]. In our study, we obtained a 21% decrease in postoperative morphine consumption by adding magnesium as an adjuvant to anesthesia. VAS pain scores were also lower in the magnesium group at all time intervals measured. Although we used a patient-controlled analgesia device and administered a bolus dose of morphine when VAS 4, patients reported high pain scores in the rst two, postoperative hours. We believe that the residual effects of intraperitoneal insufation of gases during the surgery, leading to abdominal discomfort, might be responsible for these high scores. Studies report a feeling of ushing especially during rapid infusion rates [26]. We observed ushing in four patients in the magnesium sulphate-treated group. The side effect prole was similar in both groups. Although Tramer et al. have suggested that magnesium reduced nausea and vomiting by decreasing postoperative opioid consumption [21], many investigators have reported that magnesium did not offer any advantage [13]. Similarly, we did not demonstrate any difference in the incidence of nausea-vomiting that could be linked to the decrease in morphine use. Patient satisfaction rates were also similar between the two groups. With the exception of one patient, even those who were re-intubated scored their anesthesia experience as good. We think that postoperative analgesia seems to be more important for the patients. However, in addition to the fact that patients might be reluctant to share their real thoughts with their doctors, , showing close attention to the patient, and frequent questioning regarding pain and side effects might have also increased the levels of satisfaction, particularly for those who were re-entubated. In this study, the perioperative use of magnesium sulphate reduced propofol and desurane consumption and the postoperative morphine requirement, while causing a delay in recovery as shown by a decreased Aldrete score. We suggest that magnesium has a signicant analgesic and anesthetic-sparing effect, but special care must be taken as it can also lead to inadequate respiration and a delay in recovery.

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