The effect of magnesium sulfate on postoperative pain in patients undergoing major abdominal surgery under remifentanil-based anesthesia

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1 대한마취과학회지 2008; 55: 286~90 Korean J Anesthesiol Vol. 55, No. 3, September, 2008 임상연구 The effect of magnesium sulfate on postoperative pain in patients undergoing major abdominal surgery under remifentanil-based anesthesia Department of Anesthesiology and Pain Medicine, College of Medicine, Wonkwang University, Iksan; *Department of Oral and Maxillofacial Surgery, Daejeon Dental Hospital, Wonkwang University, Daejeon; Department of Anesthesiology and Pain Medicine, Sanbon Hospital, Gunpo; Department of Surgery, Wonkwang-Gusan Medical Center, Wonkwang University, Gunsan; Departments of Obstetrics and Gynecology, Surgery, College of Medicine, Wonkwang University, Iksan, Korea Cheol Lee, M.D., Mi Soon Jang, M.D., Yoon Kang Song, M.D., Seri O, M.D.*, Seo Young Moon, M.D., Dong Baek Kang, M.D., Byoung Ryun Kim, M.D., and Seung Jae Byun, M.D. Background: Opioid tolerance may involve activation of the N-methyl-D-aspartate (NMDA) system. The possible involvement of the NMDA system suggests that one of the NMDA receptor antagonists, magnesium may be a useful adjunct to opioids for the treatment of postoperative pain following remifentanil infusion. Methods: For this study, 70 patients scheduled for major abdominal surgery under remifentanil-based anesthesia were randomly allocated into groups that received either magnesium sulfate (group M) or saline (group C) intravenously. The patients in the group M received 25% magnesium sulfate at a dose of 50 mg/kg in 100 ml of saline, and those in the group C received an equal volume of saline prior to the induction of anesthesia. In addition, patients in both groups received 10 mg/kg/h infusion of either magnesium sulfate (group M) or an equal volume of saline (group C) until the end of surgery. Pain was assessed using a visual analog scale at 30 min, and 6, 12, 24, and 36 hours after operation. The time to the first use of postoperative analgesic and cumulative analgesic consumption in both groups were also evaluated. Results: The visual analog scale scores for pain and cumulative analgesic consumption were significantly lower in the group M than in the group C. The time to the first use of postoperative analgesic was significantly shorter in group C than in the group M. Conclusions: Use of the NMDA-receptor antagonist, magnesium sulfate as an adjuvant analgesic reduced postoperative pain in patients undergoing major abdominal surgery under remifentanil-based anesthesia. (Korean J Anesthesiol 2008; 55: ) Key Words: magnesium sulfate, NMDA receptor, postoperative pain, remifentanil. INTRODUCTION Received:April 18, 2008 Corresponding to:cheol Lee, Department of Anesthesiology and Pain Medicine, College of Medicine, Wonkwang University, 344-2, Sinyongdong, Iksan , Korea. Tel: , Fax: ironyii@wonkwang.ac.kr This study was supported by Wonkwang University in Remifentanil a short-acting opioid with predictable and rapid recovery that is relatively independent of the dose. 1) A corollary of short action is that patients may experience considerable surgical pain in the immediate postoperative period. 2) Supplemental opioids are thus often given prophylactically to the patients who are likely to experience postoperative pain. 1) Despite this precaution, postoperative analgesic requirement in patients given intraoperative remifentanil is often surprisingly great. 3) This observation suggests that remifentanil may be associated with acute opioid tolerance. Magnesium, first known for its efficacy in the treatment of arrhythmia and preeclmpsia, has recently been shown to have analgesic and anesthetic efficacy, prompting studies in which magnesium sulfate is used as an adjuvant in anesthesia administration. 4,5) It has been suggested that magnesium has the potential to treat and prevent pain by acting as an antagonist of N-methyl-D-aspartate (NMDA) receptors. 6) The development of hypomagnesemia has been reported in 60 70% of postoperative patients. 7,8) Also reduced serum magnesium concentration is related with perioperative morbidity. 9,10) We performed a study to characterize response in serum 286

2 Cheol Lee, et al:magnesium and postoperative pain magnesium concentration in patients undergoing elective major abdominal surgery under remifentanil-based anesthesia. We also tested the hypothesis that magnesium infusion decreases postoperative pain and opioid requirement in patients undergoing major abdominal surgery under remifentanil-based anesthesia. MATERIALS AND METHODS After obtaining approval from the Institutional Review Board and written informed consent, 70 ASA I II patients undergoing elective major abdominal surgery were enrolled in the study. Patients were excluded if they had major hepatic, renal and cardiovascular disease or asthma, chronic obstructive pulmonary disease, as well as known allergy to magnesium sulfate or other drugs, and treatment with calcium channel blocker, opioids and anticoagulant. The patients were assigned randomly to one of two groups. The magnesium group (group M) received 25% magnesium sulfate and the control group (group C) received 0.9% normal saline in a double blind fashion. The solutions were prepared by the coordinator of the study, and the anesthesiologist in charge of the patients during the operation was unaware of the study medication. Group M patients received magnesium sulfate in 100 ml of isotonic saline 50 mg/kg, administered as a slow intravenous (i.v.) bolus over 15minutes period before the induction of anesthesia, and 10 mg/kg/h by continuous i.v. infusion during the operation. The same volume of isotonic saline was administered to group C patients. The patients were not premedicated before the induction of anesthesia and were placed routine monitors. All patients underwent arterial catheter and urinary catheter placement as part of their routine management, and received lactated Ringer solution for crystalloid. To determine the pre and postoperative serum magnesium, albumin, and hematocrit level, 4 ml of arterial blood samples withdrawn from patients after induction of general anesthesia and at the end of surgery, and analyzed immediately after collection in an adjacent laboratory. Induction of anesthesia was commenced with a slow (30 60 s) i.v. bolus dose of remifentanil 1μg/kg and followed by propofol 2 mg/kg and tracheal intubation was facilitated with rocurounium 0.9 mg/kg. After intubation of trachea, end-tidal sevoflurane concentration was maintained at 0.8 minimum alveolar concentration, adjust to age. A remifentanil infusion was started at a rate of 0.25μg/kg/min and subsequently increased stepwise by 0.05μg/kg/min increments if insufficient anesthesia was suspected. Our criteria for possibly insufficient anesthesia were a heart rate that exceeded preinduction values by 15% and/or a systolic arterial blood pressure that exceeded baseline values by 20% at least 1 min. The anesthesia level was monitored using the bispectral index (BIS) method. The BIS electrodes were placed on the forehead and connected to BIS monitoring system (BIS XP, A-2000, Aspect Medical Systems, USA). The concentration of sevoflurane was titrated to maintain a BIS in the range 40 to 60. Muscle relaxation was monitored with peripheral nerve stimulator (TOF Watch R Organon, Ireland). Train of four (TOF) stimulation was measured every 10 min. Rocuronium 0.2 mg/kg was administered when the TOF count was 2 or more. If the mean arterial pressure decreased during the operation by more than 20% of that recorded before induction of anesthesia, the patients received 10 mg i.v. bolus doses of ephedrine. If the heart rate decreased to less than 50 beats/min, 0.5 mg i.v. atropine bolus was administered. Thirty minutes before the end of surgery, 100μg bolus dose of fentanyl was administered intravenously. At the end of surgery, neuromuscular blockade was reversed with neostigmine 0.05 mg/kg and atropine 0.02 mg/kg when the TOF ratio had returned to 25%. When BIS values reached 80 and spontaneous breathing was achieved, extubation was performed. Remifentanil and magnesium sulfate infusion were discontinued when the last surgical stitch was placed. At the end of surgery, every patients were administered analgesics by patient-controlled analgesia (PCA) pump (Accufusor R WooYoung medical, Korea) containing morphine 40 mg, ketorolac 180 mg, and ondansetron 16 mg in normal saline in a total volume of 100 ml. This device was set to deliver basal infusion 2 ml/hr, bolus dose 0.5 ml with a 15 min lockout time. Pain scores at movement were documented using the 10-point linear visual analog scale which is a straight line with the left end of the line representing no pain and the right end of the line representing the worst pain. Patients are asked to mark on the line where they think their pain is. Pain severity and postoperative PCA analgesic solution consumption at 30 min, 6, 12, 24, and 36 hour after operation were recorded. A trained anesthesiologist who was not involved in the study assessed pain, and analgesic consumption. An i.v. dose of fentanyl 50μg if patients reported VAS 5 or i.v. dose of ketorolac 30 mg if VAS < 5 were administered during recovery. The time to first postoperative analgesic requirement 287

3 Korean J Anesthesiol:Vol. 55. No. 3, 2008 and side effects, such as hypotension, bradycardia, nausea, and shivering were also recorded. All patients were monitored in the postoperative recovery room for the first 24 hours. Postoperative monitoring included noninvasive blood pressure, heart rate, and pulse oximetry. Nausea was treated with i.v. metoclopromide 10 mg, and postoperative shivering was treated by forced air warming blanket. The results are presented as mean ± standard deviation, Table 1. Demographic Data, Anesthetic Characteristics and Postoperative Events Group C Group M (n = 35) (n = 35) Age (yr) 61.4 ± ± 3.8 Weight (kg) 61.8 ± ± 2.4 Gender (M/F) 18/17 16/19 Procedure Whipple's operation PPPD 9 8 Colectomy with colorectal anastomosis 8 9 Colectomy with coloanal anastomosis 7 8 Duration of anesthesia (min) ± ± 32.1 Administered crystalloid (ml) 3,239.7 ± ,304.6 ± Time weighted mean remifentanil dose (μg/kg/min) 0.30 ± ± 0.21* Total rocuronium consumption (mg/kg/h) 0.66 ± ± 0.06* The time to first postoperatvie analgesic requirement (min) 55.1 ± ± 5.1* Hypotension 8 6 Bradycardia 10 6 Nausea 3 9 Shivering 16 7* Dysrhythmia 2 0 Values are mean ± SD or number of patients. *: P < 0.05 compared with group C. PPPD: pylorus preserving pancreaticoduodenectomy. median (range), or the number of patients. Changes in variable affecting preoperative to postoperative values were analyzed with paired t-test. Comparisons of age, body weight, the time to first postoperative analgesic requirement, and administered crystalloid between groups were conducted using Student s t test. Chi-square test was used to analyze nonparametric data such as gender, and frequencies of shivering, hypotension, bradycardia, and nausea. VAS scores for pain were analyzed using Mann-Whitney U test. P < 0.05 was considered the minimum level of statistical significance. RESULTS The two groups were comparable with respect to age, weight, gender distribution, procedure, duration of anesthesia, administered crystalloid and dysrhythmia. Remifentanil consumption was statistically greater in group C than in group M. The time to first postoperative analgesic requirement was significantly longer in group M than in group C. Patients in group M significantly received less total rocuronium consumption than in group C. Hypotension, bradycardia, and nausea were statistically similar in both groups. Shivering was significantly lower in group M than in group C (Table 1). The patients in both groups had significantly lower serum albumin, and hematocrit concentrations postoperatively than preoperatively. Whereas serum total magnesium in group C was significantly decreased, total magnesium in group M was significantly increased in the postoperative concentration than on preoperative concentration (Table 2). VAS scores for pain were significantly lower in group M than in group C for postoperative 12 hours after surgery (Table 3). Cumulative analgesic consumption through PCA device was significantly lower in group M than in group C at 6, 12, 24, and 36 hours (Table 4). Table 2. Preoperative and Postoperative Laboratory Data Preoperative Postoperative Preoperative Postoperative Total Magnesium (mg/l) 1.80 ± ± 0.55* 1.81 ± ± 0.47* Albumine (g/dl) 4.13 ± ± 0.22* 4.12 ± ± 0.23* Hematocrit (%) ± ± 1.95* ± ± 1.88* Values are mean ± SD. *: P < 0.05 compared with preoperative concentration, : P < 0.05 compared with postoperative concentration of group C. 288

4 Cheol Lee, et al:magnesium and postoperative pain Table 3. Visual Analog Scale Scores for Pain 30 min after operation 7 (6 9) 7 (5 8)* 6 h after operation 7 (6 8) 6 (5 8)* 12 h after operation 6 (4 7) 5 (4 7)* 24 h after operation 5 (3 6) 4 (3 6) 36 h after operation 3 (3 4) 3 (2 3) Values are median (range). *: P < 0.05 compared with group C. Table 4. Postoperative Cumulative Injected Volume through PCA Pump (ml) 30 min after operation 2.91 ± ± h after operation ± ± 2.53* 12 h after operation ± ± 1.85* 24 h after operation ± ± 1.80* 36 h after operation ± ± 2.65* Values are mean ± SD or number of patients. PCA: patients controlled analgesia. *: P < 0.05 compared with group C. DISCUSSION We confirmed our hypothesis that magnesium infusion decreases postoperative pain and opioid requirement in patients undergoing major abdominal surgery under remifentanil-based anesthesia. Consequently, patients in the control group required analgesics earlier and required greater doses to achieve satisfactory analgesia. Interestingly, this increased morphine consumption. Hypomagnesemia has been proposed as the most underdiagnosed electrolyte deficiency, and routine monitoring has been recommended for patient populations with or at high risk of developing cardiac dysrhythmias. 11) The development of hypomagnesemia has been reported in postoperative and critically ill patients. 12,13) The detailed mechanism of postoperative hypomagnesemia, to date, has not been determined. However, the decrease in total serum magnesium concentrations correlated with the degree of hypoalbuminemia, indicating a reduction in the protein bound fraction of magnesium. Serum total protein and albumin concentrations decreased during surgery: total protein and albumin concentrations decreased significantly in correlation with fluid administration, with an average decrease of almost 40% for albumin. In this study, the volume of administered crystalloid was correlated significantly with the reduction in total magnesium. We determined that serum magnesium levels were lower postoperatively in group C. Although this decrease was significant, we believe that it is not important clinically. Indeed, no clinical symptoms of hypomagnesemia were observed in our patients. However, there is evidence that the response of the NMDA receptors is greatly enhanced by reducing the extracellular magnesium concentration below the physiological level. 14) It has been shown that magnesium sulfate has analgesic efficacy and reduces the need for postoperative analgesics because it acts as a NMDA antagonist and blocks calcium channels. 4,5,15,16) However some investigators have suggested that magnesium sulfate infusion has no effect on postoperative analgesia, basing their reasoning on the fact that only a small proportion of the i.v administered magnesium sulfate crosses the blood-brain barrier. 17,18) Clinical reports of reduced postoperative analgesic requirements with i.v infusion of magnesium sulfate, support our finding of potentiated opioid analgesia by magnesium, although this effect has not always been seen clinically. 19) The mechanism of potentiation seen in some clinical studies is probably a different mechanism than that seen with intrathecal drug administration, because even at large plasma concentrations, only a small amount of the magnesium ion crosses the blood-brain barrier. McCarthy et al. 20) reported that conversely, plasma concentrations, even after continuous intrathecal infusion, are not increased in rats. Therefore, it is likely that magnesium can potentiate opioid analgesic effects by both central and peripheral mechanisms. Conflicting results have been published concerning the effect of the volatile anesthetics at very low concentrations (i.e., minimum alveolar concentrations) on pain. some studies have demonstrated an increase in pain threshold 21,22) However, other studies found no hypoalgesic or hyperalgesic effect of subanesthetic concentrations of inhalation anesthetics. 23,24) Our data demonstrated a significant reduction in rocuronium consumption during general anesthesia with continuous magnesium sulfate infusion. The effect on rocuronium consumption is not surprising as the effect of magnesium ions at the neuromuscular junction are well known. Not unexpectedly, magnesium was shown to decrease the risk of postoperative shivering. In healthy volunteers, magnesium sulfate (80 mg/kg bolus followed by an infusion at 2 g/hr) was shown to reduce the shivering threshold. 25) In clinical practice, magnesium's beneficial effect on shivering is of minor 289

5 Korean J Anesthesiol:Vol. 55. No. 3, 2008 importance compared with, for the efficacy that was reported with meperidine or clonidine. 26) In conclusion, Intraoperative magnesium supplementation has favorable effect on neuromuscular blockade, shivering, postoperative pain intensity and analgesic requirement without impairing hemodynamic parameters. Therefore, it may be worthwhile to further study the role of magnesium as supplements to intraoperative anesthetics and postoperative analgesia, since this molecule is inexpensive, relatively harmless, and the biological basis for its potential antinociceptive effect is promising. REFERENCES 1. Thompson JP, Rowbotham DJ: Remifentanil: An opioid for the 21st century. Br J Anaesth 1996; 76: Dershwitz M, Randel GI, Rosow CE, Fragen RJ, Connors PM, Librojo ES, et al: Initial clinical experience with remifentanil, a new opioid metabolized by esterases. 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