- Email: [email protected]
I.V. infusion of magnesium sulphate during spinal anaesthesia improves postoperative analgesia
British Journal of Anaesthesia 104 (1): 89–93 (2010)
doi:10.1093/bja/aep334
Advance Access publication November 19, 2009
I.V. infusion of magnesium sulphate during spinal anaesthesia improves postoperative analgesia J.-Y. Hwang1, H.-S. Na1, Y.-T. Jeon1, Y.-J. Ro2, C.-S. Kim2 and S.-H. Do1* 1
Department of Anaesthesiology and Pain Medicine, Seoul National University Bundang Hospital, 166 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Republic of Korea. 2Department of Anaesthesiology and Pain Medicine, Seoul National University Boramae Medical Center, Republic of Korea *Corresponding author. E-mail: [email protected]
Methods. Forty patients undergoing total hip replacement arthroplasty under spinal anaesthesia were included. After the induction of spinal anaesthesia, the magnesium group (Group M) received magnesium sulphate 50 mg kg21 for 15 min and then 15 mg kg21 h21 by continuous i.v. infusion until the end of surgery. The saline group (Group S) received the same volume of isotonic saline over the same period. After surgery, a patient-controlled analgesia (PCA) device containing morphine and ketorolac was provided for the patients. Postoperative pain scores, PCA consumption, and the incidences of shivering, postoperative nausea, and vomiting were evaluated immediately after surgery, and at 30 min, 4, 24, and 48 h after surgery. Serum magnesium concentrations were checked before the induction of anaesthesia, immediately after surgery, and at 1 and 24 h after surgery. Results. Postoperative pain scores were significantly lower in Group M at 4, 24, and 48 h after surgery (P,0.05). Cumulative postoperative PCA consumptions were also significantly lower in Group M at 4, 24, and 48 h after surgery (P,0.05). Postoperative magnesium concentrations were higher in Group M (P,0.05 at 4, 24, and 48 h after surgery), but no side-effects associated with hypermagnesemia were observed. Haemodynamic variables and the incidences of shivering, nausea, and vomiting were similar in the two groups. Conclusions. I.V. magnesium sulphate administration during spinal anaesthesia improves postoperative analgesia. Br J Anaesth 2010; 104: 89–93 Keywords: anaesthetic techniques, subarachnoid; analgesia, patient controlled; analgesia, postoperative; ions, magnesium; pain, postoperative Accepted for publication: August 28, 2009
Total hip replacement arthroplasty is accompanied by moderate to severe pain after surgery and adequate postoperative pain management is important for early rehabilitation and functional recovery.1 2 Magnesium (Mg) has antinociceptive effects due to its antagonistic effect of N-methyl-D-aspartate (NMDA) receptor. Numerous clinical investigations have demonstrated that Mg infusion during general anaesthesia reduced anaesthetic requirement and postoperative analgesic consumption,3 – 6 whereas other studies suggested that perioperative Mg administration had little effect on postoperative pain.7 8
Relatively few studies have been conducted on the effects of magnesium sulphate administration during regional anaesthesia. A previous study demonstrated that magnesium sulphate infusion started immediately after the induction of spinal anaesthesia and extended for 24 h reduced analgesic consumption without any effect on spinal block.9 However, patients included in this study underwent minor surgical procedures not associated with moderate to severe pain, and postoperative pain scores were similar between the groups other than at 12 h after surgery. Thus, the effects of systemic Mg during spinal
# The Author [2009]. Published by Oxford University Press on behalf of The Board of Directors of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://bja.oxfordjournals.org/ at Kainan University on April 12, 2015
Background. In a randomized, double-blind, prospective study, we have evaluated the effect of i.v. infusion of magnesium sulphate during spinal anaesthesia on postoperative analgesia and postoperative analgesic requirements.
Hwang et al.
anaesthesia on postoperative analgesia and analgesic consumption have not been fully determined yet. Accordingly, the aim of this study was to evaluate the effect of an i.v. infusion of magnesium sulphate during spinal anaesthesia on postoperative pain and analgesic consumption.
Methods
Age Sex (M/F) Height (cm) Weight (kg) ASA (I/II) Anaesthetic time (min)
Group M (n520)
Group S (n520)
47.0 (31 –65) 9/11 164.5 (9.7) 63.4 (1.7) 15/5 195 (41)
49.9 (27 –68) 13/7 165.9 (11.9) 66.1 (10.7) 16/4 192 (38)
period. After surgery, patients were transferred to the postanaesthetic room. Postoperative PCA consumption and pain scores were recorded immediately after surgery, at 30 min, and 4, 24, and 48 h after surgery. If necessary, ketorolac 30 mg was i.v. administered as rescue analgesia during the postoperative period. Pain scores were evaluated using a 0 – 100 mm VAS (0, no pain, to 100, worst pain imaginable). The incidences of shivering and postoperative nausea and vomiting (PONV) were recorded at 30 min, and 4, 24, and 48 h after surgery. Blood samples for serum Mg concentration were obtained immediately after surgery, and 1 and 24 h after surgery (normal range at our centre 0.75 – 1.0 mmol litre21). Patients’ overall satisfaction levels were assessed using a five-point scale (1, very unsatisfactory; 5, excellent). The primary outcome of this study was postoperative PCA drug consumption. On the basis of pilot data, 20 patients per group were required to detect a significant difference in the postoperative PCA consumption at a significance level of 95% with a power of 80%. Power Analysis and Sample Size software (2005, NCSS, USA) was used for this calculation. Values were expressed as mean (SD) or median (inter-quartile ranges). The SPSS software (version 12.0; SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The Mann – Whitney test was used to analyse quantitative data (weight, height, age, VAS pain scores, PCA consumptions, and satisfaction score), and the x2 test was used for qualitative data (gender). Repeated-measures ANOVA was used to analyse haemodynamic variables over time between two groups. Statistical significance was accepted for a P-value of ,0.05.
Results No significant difference was found between the two groups in terms of age, weight, height, gender, or anaesthetic time (Table 1). No technical failure related to spinal anaesthesia occurred and all surgery proceeded without difficulty. The two groups were similar in terms of height of spinal block, mean time to first pain, and administered dose of bupivacaine (Table 2).
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This study was approved by the Institutional Ethics Committee and written informed consent was obtained from all patients. Forty ASA I and II patients undergoing total hip replacement arthroplasty were enrolled in this study. Exclusion criteria were cardiovascular, hepatic, or renal dysfunction, neuromuscular diseases, opioid or analgesic abuse, and prior treatment with calcium channel blockers. Patients were informed of the study purpose and protocol, and were instructed how to use the visual analogue scale (VAS) and the patient-controlled analgesia (PCA) device during a preoperative visit. After premedication with i.v. midazolam 0.03 mg kg21, patients were transferred to the operating theatre. Ringer’s solution 500 ml was given over 15 min, and intraoperative monitoring included non-invasive arterial pressure, ECG, and pulse oximetry. Spinal anaesthesia was performed through the L3 – 4 or L4 –5 interspace in the lateral decubitus position with the surgical side down. After dural puncture with a 25 G Quincke needle, hyperbaric bupivacaine 0.5% solution (Heavy Marcaine Spinal 0.5%w, AstraZeneca AB, Sweden) with fentanyl 20 mg was injected intrathecally. Bupivacaine dose was determined based on height (height ,155 cm¼12 mg; 155 – 170 cm¼13 mg; 170– 180 cm¼14 mg; 180 cm¼15 mg). Patients were randomly assigned to two groups using closed envelopes chosen by patients before the study. Patients in the magnesium group (Group M, n¼20) received magnesium sulphate 50 mg kg21 for 15 min after spinal anaesthesia and then 15 mg kg21 h21 by continuous i.v. infusion until the end of surgery. Patients in the saline group (Group S, n¼20) received the same volume of isotonic saline over the same period. Infusions were prepared in pharmacy and they were administered using the infusion machines identical in appearance. Study data were recorded by an observer unaware of group assignments. The height of spinal block was evaluated for cold sensation 15 min after intrathecal administration of bupivacaine. If the systolic arterial pressure decreased to below 90 mm Hg or if mean arterial pressure decreased .20% from baseline, ephedrine 5 mg was given i.v. If heart rate decreased to ,45 beats min21, i.v. atropine 0.5 mg was administered. In each case, a PCA device containing morphine 70 mg and ketorolac 150 mg in normal saline in a total volume of 100 ml was connected i.v. at the end of surgery. This was set to deliver a 1 ml bolus dose with a 10 min lockout
Table 1 Patient characteristics and anaesthetic time. Values shown are mean (range) for age, mean (SD), or patient numbers (n). Group M, Mg group; Group S, saline group. No significant differences between the two groups
Magnesium sulphate during spinal anaesthesia
Height of spinal block Time to first pain (min) Dose of bupivacaine (mg)
Group M (n520)
Group S (n520)
T5 (T3 –6) 249 (41) 13.1 (0.8)
T6 (T4 –8) 224 (38) 13.4 (0.9)
Mean arterial pressure (mm Hg)
Table 2 Characteristics of spinal block. Values are presented as means (range) for height of spinal block or means (SD). Group M, Mg group; Group S, saline group. No significant differences between the two groups
Table 3 Perioperative serum magnesium concentrations. Values are presented as means (SD). Units are mmol litre21. Group M, Mg group; Group S, saline group. *P,0.05 compared with Group S
0.82 1.31 1.10 0.93
0.87 (0.06) 0.82 (0.20) 0.80 (0.14) 0.78 (0.09)
(0.10) (0.13)* (0.09)* (0.07)*
100 90 80 70 60 50 40
Pr e Po ind st uct in io du n ct io 5 n m 10 in m 1 5 in m 3 0 in m 6 0 in m 9 0 in 12 min 0 m Po in st op PA .3 R Po 0 s m Po top in st . 4 Po op. h st 24 op h .4 8 h
Group S (n520)
Group M Group S
Time course Fig 1 Perioperative mean arterial pressure. Group M, Mg group; Group S, saline group. Values are presented as means (SD). Group M patients had a lower mean arterial pressure except immediately after the induction of spinal anaesthesia. No significant difference was observed between the two groups during the perioperative period.
Postoperative serum Mg concentrations in Group M were significantly higher than those in Group S (P,0.001 immediately after surgery, and at 1 and 24 h after surgery, Table 3). However, all patients in Group M had a serum Mg concentration in the normal range 24 h after surgery. There was no significant difference in haemodynamic variables (mean arterial pressure and heart rate) during the intra- or postoperative period (Figs 1 and 2). Six patients in Group M and three patients in Group S developed hypotension, and two patients in Group M and one patient in Group S experienced bradycardia during surgery. In accordance with the study protocol, ephedrine 5 mg and atropine 0.5 mg were administered in each event, and in all cases, arterial pressure and heart rate were normalized. Postoperative VAS scores were markedly lower in Group M at 4, 24, and 48 h after surgery (all P,0.001, Table 4). Furthermore, cumulative postoperative PCA consumptions were markedly lower in Group M (P,0.001 at 4, 24, and 48 h after surgery, Fig. 3), and fewer patients in Group M required additional rescue analgesia during the postoperative period (2 vs 6 patients), but this was not statistically significant (P¼0.079). The incidences of PONV and shivering after surgery were similar in the two groups. However, global satisfaction scores were significantly higher in Group M [3.4 (0.6) vs 2.6 (0.5), P,0.05].
Heart rate (beats min–1)
110
Group M Group S
100 90 80 70 60 50
Pr e Po ind st uct in io du n ct io 5 n m 10 in m 15 in m 30 in m 60 in m 90 in 12 min 0 m Po in st op PA . R Po 30 st min Po op st . 4 Po op. h st 24 op h .4 8 h
40
Time course Fig 2 Perioperative heart rate. Group M, Mg group; Group S, saline group. Values are presented as means (SD). Group M patients had a lower heart rate except before the induction of spinal anaesthesia. No significant difference was observed between the two groups during the perioperative period.
Table 4 Average VAS pain scores. Values are presented as medians and inter-quartile ranges. Group M, Mg group; Group S, saline group. *P,0.05 compared with Group S
Immediately postoperative Postoperative 30 min Postoperative 4 h Postoperative 24 h Postoperative 48 h
Discussion This study showed that i.v. magnesium sulphate infusion during surgery under spinal anaesthesia reduced postoperative pain and analgesic consumption without any notable complications. Total hip replacement arthroplasty is usually associated with moderate to severe postoperative pain, which disturbs early rehabilitation and functional recovery.1 Accordingly, a number of strategies for pain
Group M (n520)
Group S (n520)
0 (0 –3) 0 (0 –10) 30 (20 – 40)* 20 (10 – 30)* 12 (5 –15)*
0 15 50 38 29
(0– 13) (0– 35) (45 –64) (32 –45) (22 –35)
management have been introduced during the postoperative period. Regional anaesthesia is preferred to general anaesthesia during the perioperative period and patient-
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Preoperative Immediately postoperative Postoperative 1 h Postoperative 1 day
Group M (n520)
110
Hwang et al.
60
PCA vol (ml)
50
Group M Group S *
40 30
*
20 * 10 0
Immediate 30 min 4h 24 h Time after surgery
48 h
controlled epidural analgesia or nerve blocks have also been used in some patients. Improvements in understanding the mechanism of pain have resulted in the administration of analgesics before exposure to pain stimuli to prevent the central sensitization and the amplification of postoperative pain.1 2 Magnesium sulphate has been used in obstetric and cardiac patients. Its use as an adjuvant for perioperative analgesia is based on the properties of NMDA receptor antagonist and calcium channel blocker. However, although the basic mechanism of analgesic effect of Mg is unclear, it is presumed that its antagonism of NMDA receptor prevents the induction of central sensitization due to peripheral nociceptive stimulation and abolishes hypersensitivity. In addition, calcium channel blockers have shown antinociceptive effects in animals and morphine potentiation in patients with chronic pain.10 Our findings are partly in line with those in a previous study,9 where, immediately after spinal block, patients received a 5 mg kg21 bolus of magnesium sulphate followed by a 500 mg h21 infusion or saline in the same volumes for 24 h, and postoperative analgesic consumption was significantly lower in the Mg group. However, VAS scores in the two groups during the first 24 h after surgery were similar except at 12 h after surgery, and thus, it is assumed that the dosage of magnesium sulphate used was insufficient for postoperative analgesia. Adequate bolus and infusion doses of magnesium sulphate are important for effective analgesia. In a comparison of the effects of three different dose regimens of Mg on postoperative morphine consumption,11 a single bolus injection at 40 mg kg21 was found to reduce postoperative morphine consumption, and when this was followed by a maintenance infusion of 10 mg kg21 h21, the effect was enhanced. Moreover, increasing the maintenance infusion to 20 mg kg21 h21 provided no additional advantage and induced unwarranted haemodynamic effects. Pre- and intraoperative administration of magnesium sulphate
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Fig 3 The total amount of PCA drug. The concentrations of morphine and ketorolac are 0.7 and 1.5 mg ml21, respectively. Group M, Mg group; Group S, saline group. Values are presented as means (SD). The error bars indicate 1 SD.*P,0.05 compared with Group S.
(50 mg kg21 bolus and maintenance 15 mg kg21 h21 of magnesium sulphate) in gynaecology patients receiving total i.v. anaesthesia reduced rocuronium requirement and improved the quality of postoperative analgesia without any significant side-effects.5 8 Accordingly, in the present study, we administered a 50 mg kg21 bolus and a maintenance dose of 15 mg kg21 h21. Postoperative VAS scores and cumulative PCA consumption were both markedly lower in Group M at 4, 24, and 48 h. There was no significant difference of postoperative pain and analgesic use immediately and 30 min after surgery, which we attribute to the residual effect of spinal anaesthesia. Theoretically, two groups of patients using PCA in the present study should have titrated to much the same pain scores irrespective of an adjuvant drug. However, previous studies of the effect of Mg on postoperative analgesia also showed different VAS scores between the control and the Mg groups, even though the patients used PCA in the postoperative period.4 5 9 11 Possible explanations include: PCA use can reduce postoperative pain but cannot make it zero, and PCAs use opioids with or without ketorolac, which have dose-related side-effects, such as nausea and vomiting, and these side-effects stop unlimited use of the PCA. In addition, PCA settings include a lockout time to prevent overdose and patients may not, at times, get as much analgesic as they want. Adjuvant drugs such as magnesium sulphate can further reduce pain and analgesic consumptions in postoperative patients using PCA. After surgery, patients in Group M had higher serum Mg concentrations than those in Group S, but there was no side-effect associated with hypermagnesemia. Theoretically, minor side-effects of parenteral Mg such as flushing, nausea, and headache are expected at the serum Mg level above 2 mmol litre21, and potentially life-threatening complications, primarily involved in the cardiovascular and neuromuscular systems, occur when serum Mg concentrations exceed 5 mmol litre21.12 In the present study, the average serum Mg concentration after surgery in Group M was 1.31 (0.13) mmol litre21, which is below the level of minor side-effects. Serum Mg concentrations decreased to 1.10 (0.13) mmol litre21 at 1 h after surgery and normalized at 24 h after surgery [0.93 (0.07) mmol litre21]. Conversely, hypomagnesemia frequently occurs during the perioperative period and Group S in our study showed low normal serum Mg concentrations in the postoperative period.10 13 Magnesium causes a dose-dependent negative inotropic effect, and in humans, haemodynamic studies have shown that it has a peripheral ( predominantly arteriolar) vasodilatory effect.14 – 16 After rapid infusion of 3 or 4 g of magnesium sulphate, systolic arterial pressure decreased in relation to decreased systemic vascular resistance.10 In the present study, considering the negative intropic effect of Mg, prehydration with 500 ml of lactated Ringer’s solution was performed and the Mg bolus dose was infused over 15 min, which is probably why no significant hypotension
Magnesium sulphate during spinal anaesthesia
3 Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative analgesia. Anesthesiology 1996; 84: 340 – 7 4 Koinig H, Wallner T, Marhofer P, Andel H, Horauf K, Mayer N. Magnesium sulfate reduces intra- and postoperative analgesic requirements. Anesth Analg 1998; 87: 206 – 10 5 Ryu JH, Kang MH, Park KS, Do SH. Effects of magnesium sulphate on intraoperative anaesthetic requirements and postoperative analgesia in gynaecology patients receiving total intravenous anaesthesia. Br J Anaesth 2008; 100: 397 – 403 6 Ozcan PE, Tugrul S, Senturk NM, et al. Role of magnesium sulfate in postoperative pain management for patients undergoing thoracotomy. J Cardiothorac Vasc Anesth 2007; 21: 827 – 31 7 Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS. Magnesium sulfate does not reduce postoperative analgesic requirements. Anesthesiology 2001; 95: 640– 6 8 Bhatia A, Kashyap L, Pawar DK, Trikha A. Effect of intraoperative magnesium infusion on perioperative analgesia in open cholecystectomy. J Clin Anesth 2004; 16: 262 – 5 9 Apan A, Buyukkocak U, Ozcan S, Sari E, Basar H. Postoperative magnesium sulphate infusion reduces analgesic requirements in spinal anaesthesia. Eur J Anaesthesiol 2004; 21: 766– 9 10 Dube L, Granry JC. The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review. Can J Anaesth 2003; 50: 732 – 46 11 Seyhan TO, Tugrul M, Sungur MO, et al. Effects of three different dose regimens of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery. Br J Anaesth 2006; 96: 247 – 52 12 Vissers RJ, Purssell R. Iatrogenic magnesium overdose: two case reports. J Emerg Med 1996; 14: 187 – 91 13 Place HM, Enzenauer RJ, Muff BJ, Ziporin PJ, Brown CW. Hypomagnesemia in postoperative spine fusion patients. Spine 1996; 21: 2268– 72 14 James MFM. Magnesium: an emerging drug in anaesthesia. Br J Anaesth 2009; 103: 465 – 7 15 Jee D-L, Lee D-H, Yun S-S, Lee C-H. Magnesium sulphate attenuates arterial pressure increase during laparoscopic cholecystectomy under pneumoperitoneum. Br J Anaesth 2009; 103: 484 – 9 16 Ryu J-H, Sohn I-S, Do SH. Controlled hypotension for middle ear surgery: a comparison between remifentanil and magnesium sulphate. Br J Anaesth 2009; 103: 490 – 5 17 Ghoneim MM, Long JP. The interaction between magnesium and other neuromuscular blocking agents. Anesthesiology 1970; 32: 23 – 7
References 1 Maheshwari AV, Blum YC, Shekhar L, Ranawat AS, Ranawat CS. Multimodal pain management after total hip and knee arthroplasty at the Ranawat Orthopaedic Center. Clin Orthop Relat Res 2009; 467: 1418– 23 2 Fischer HB, Simanski CJ. A procedure-specific systematic review and consensus recommendations for analgesia after total hip replacement. Anaesthesia 2005; 60: 1189 – 202
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was encountered after administering the Mg bolus dose and no significant inter-group haemodynamic differences were observed during the surgery. In the present study, time to first pain sensation and spinal block height were similar in the two groups, which is in accord with the findings of a previous study.9 There was no significant difference between the Mg and the control groups in terms of spinal block height or the duration of motor block.9 It should be noted that we did not assess the duration of motor block during the present study, because the protocol at our institute after total hip replacement arthroplasty is that patients should not move their legs during the early postoperative period. Magnesium sulphate administration may have another benefit, namely, as it has been suggested that it potentiates neuromuscular block during general anaesthesia.5 11 It has been shown that the basic mechanisms involve a reduction of the amount of acetylcholine released from motor nerve terminals and a decrease in the depolarizing action of acetylcholine at the endplate, or a depression of muscle fibre membrane excitability.17 Accordingly, i.v. Mg administration during spinal anaesthesia may facilitate muscle relaxation and surgical procedures that require extensive joint rotation, such as total hip replacement arthroplasty. However, further study is required to validate this hypothesis. In summary, we found that magnesium sulphate given i.v. during spinal anaesthesia reduced postoperative pain and analgesic consumption without complications.
doi:10.1093/bja/aep334
Advance Access publication November 19, 2009
I.V. infusion of magnesium sulphate during spinal anaesthesia improves postoperative analgesia J.-Y. Hwang1, H.-S. Na1, Y.-T. Jeon1, Y.-J. Ro2, C.-S. Kim2 and S.-H. Do1* 1
Department of Anaesthesiology and Pain Medicine, Seoul National University Bundang Hospital, 166 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Republic of Korea. 2Department of Anaesthesiology and Pain Medicine, Seoul National University Boramae Medical Center, Republic of Korea *Corresponding author. E-mail: [email protected]
Methods. Forty patients undergoing total hip replacement arthroplasty under spinal anaesthesia were included. After the induction of spinal anaesthesia, the magnesium group (Group M) received magnesium sulphate 50 mg kg21 for 15 min and then 15 mg kg21 h21 by continuous i.v. infusion until the end of surgery. The saline group (Group S) received the same volume of isotonic saline over the same period. After surgery, a patient-controlled analgesia (PCA) device containing morphine and ketorolac was provided for the patients. Postoperative pain scores, PCA consumption, and the incidences of shivering, postoperative nausea, and vomiting were evaluated immediately after surgery, and at 30 min, 4, 24, and 48 h after surgery. Serum magnesium concentrations were checked before the induction of anaesthesia, immediately after surgery, and at 1 and 24 h after surgery. Results. Postoperative pain scores were significantly lower in Group M at 4, 24, and 48 h after surgery (P,0.05). Cumulative postoperative PCA consumptions were also significantly lower in Group M at 4, 24, and 48 h after surgery (P,0.05). Postoperative magnesium concentrations were higher in Group M (P,0.05 at 4, 24, and 48 h after surgery), but no side-effects associated with hypermagnesemia were observed. Haemodynamic variables and the incidences of shivering, nausea, and vomiting were similar in the two groups. Conclusions. I.V. magnesium sulphate administration during spinal anaesthesia improves postoperative analgesia. Br J Anaesth 2010; 104: 89–93 Keywords: anaesthetic techniques, subarachnoid; analgesia, patient controlled; analgesia, postoperative; ions, magnesium; pain, postoperative Accepted for publication: August 28, 2009
Total hip replacement arthroplasty is accompanied by moderate to severe pain after surgery and adequate postoperative pain management is important for early rehabilitation and functional recovery.1 2 Magnesium (Mg) has antinociceptive effects due to its antagonistic effect of N-methyl-D-aspartate (NMDA) receptor. Numerous clinical investigations have demonstrated that Mg infusion during general anaesthesia reduced anaesthetic requirement and postoperative analgesic consumption,3 – 6 whereas other studies suggested that perioperative Mg administration had little effect on postoperative pain.7 8
Relatively few studies have been conducted on the effects of magnesium sulphate administration during regional anaesthesia. A previous study demonstrated that magnesium sulphate infusion started immediately after the induction of spinal anaesthesia and extended for 24 h reduced analgesic consumption without any effect on spinal block.9 However, patients included in this study underwent minor surgical procedures not associated with moderate to severe pain, and postoperative pain scores were similar between the groups other than at 12 h after surgery. Thus, the effects of systemic Mg during spinal
# The Author [2009]. Published by Oxford University Press on behalf of The Board of Directors of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://bja.oxfordjournals.org/ at Kainan University on April 12, 2015
Background. In a randomized, double-blind, prospective study, we have evaluated the effect of i.v. infusion of magnesium sulphate during spinal anaesthesia on postoperative analgesia and postoperative analgesic requirements.
Hwang et al.
anaesthesia on postoperative analgesia and analgesic consumption have not been fully determined yet. Accordingly, the aim of this study was to evaluate the effect of an i.v. infusion of magnesium sulphate during spinal anaesthesia on postoperative pain and analgesic consumption.
Methods
Age Sex (M/F) Height (cm) Weight (kg) ASA (I/II) Anaesthetic time (min)
Group M (n520)
Group S (n520)
47.0 (31 –65) 9/11 164.5 (9.7) 63.4 (1.7) 15/5 195 (41)
49.9 (27 –68) 13/7 165.9 (11.9) 66.1 (10.7) 16/4 192 (38)
period. After surgery, patients were transferred to the postanaesthetic room. Postoperative PCA consumption and pain scores were recorded immediately after surgery, at 30 min, and 4, 24, and 48 h after surgery. If necessary, ketorolac 30 mg was i.v. administered as rescue analgesia during the postoperative period. Pain scores were evaluated using a 0 – 100 mm VAS (0, no pain, to 100, worst pain imaginable). The incidences of shivering and postoperative nausea and vomiting (PONV) were recorded at 30 min, and 4, 24, and 48 h after surgery. Blood samples for serum Mg concentration were obtained immediately after surgery, and 1 and 24 h after surgery (normal range at our centre 0.75 – 1.0 mmol litre21). Patients’ overall satisfaction levels were assessed using a five-point scale (1, very unsatisfactory; 5, excellent). The primary outcome of this study was postoperative PCA drug consumption. On the basis of pilot data, 20 patients per group were required to detect a significant difference in the postoperative PCA consumption at a significance level of 95% with a power of 80%. Power Analysis and Sample Size software (2005, NCSS, USA) was used for this calculation. Values were expressed as mean (SD) or median (inter-quartile ranges). The SPSS software (version 12.0; SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The Mann – Whitney test was used to analyse quantitative data (weight, height, age, VAS pain scores, PCA consumptions, and satisfaction score), and the x2 test was used for qualitative data (gender). Repeated-measures ANOVA was used to analyse haemodynamic variables over time between two groups. Statistical significance was accepted for a P-value of ,0.05.
Results No significant difference was found between the two groups in terms of age, weight, height, gender, or anaesthetic time (Table 1). No technical failure related to spinal anaesthesia occurred and all surgery proceeded without difficulty. The two groups were similar in terms of height of spinal block, mean time to first pain, and administered dose of bupivacaine (Table 2).
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This study was approved by the Institutional Ethics Committee and written informed consent was obtained from all patients. Forty ASA I and II patients undergoing total hip replacement arthroplasty were enrolled in this study. Exclusion criteria were cardiovascular, hepatic, or renal dysfunction, neuromuscular diseases, opioid or analgesic abuse, and prior treatment with calcium channel blockers. Patients were informed of the study purpose and protocol, and were instructed how to use the visual analogue scale (VAS) and the patient-controlled analgesia (PCA) device during a preoperative visit. After premedication with i.v. midazolam 0.03 mg kg21, patients were transferred to the operating theatre. Ringer’s solution 500 ml was given over 15 min, and intraoperative monitoring included non-invasive arterial pressure, ECG, and pulse oximetry. Spinal anaesthesia was performed through the L3 – 4 or L4 –5 interspace in the lateral decubitus position with the surgical side down. After dural puncture with a 25 G Quincke needle, hyperbaric bupivacaine 0.5% solution (Heavy Marcaine Spinal 0.5%w, AstraZeneca AB, Sweden) with fentanyl 20 mg was injected intrathecally. Bupivacaine dose was determined based on height (height ,155 cm¼12 mg; 155 – 170 cm¼13 mg; 170– 180 cm¼14 mg; 180 cm¼15 mg). Patients were randomly assigned to two groups using closed envelopes chosen by patients before the study. Patients in the magnesium group (Group M, n¼20) received magnesium sulphate 50 mg kg21 for 15 min after spinal anaesthesia and then 15 mg kg21 h21 by continuous i.v. infusion until the end of surgery. Patients in the saline group (Group S, n¼20) received the same volume of isotonic saline over the same period. Infusions were prepared in pharmacy and they were administered using the infusion machines identical in appearance. Study data were recorded by an observer unaware of group assignments. The height of spinal block was evaluated for cold sensation 15 min after intrathecal administration of bupivacaine. If the systolic arterial pressure decreased to below 90 mm Hg or if mean arterial pressure decreased .20% from baseline, ephedrine 5 mg was given i.v. If heart rate decreased to ,45 beats min21, i.v. atropine 0.5 mg was administered. In each case, a PCA device containing morphine 70 mg and ketorolac 150 mg in normal saline in a total volume of 100 ml was connected i.v. at the end of surgery. This was set to deliver a 1 ml bolus dose with a 10 min lockout
Table 1 Patient characteristics and anaesthetic time. Values shown are mean (range) for age, mean (SD), or patient numbers (n). Group M, Mg group; Group S, saline group. No significant differences between the two groups
Magnesium sulphate during spinal anaesthesia
Height of spinal block Time to first pain (min) Dose of bupivacaine (mg)
Group M (n520)
Group S (n520)
T5 (T3 –6) 249 (41) 13.1 (0.8)
T6 (T4 –8) 224 (38) 13.4 (0.9)
Mean arterial pressure (mm Hg)
Table 2 Characteristics of spinal block. Values are presented as means (range) for height of spinal block or means (SD). Group M, Mg group; Group S, saline group. No significant differences between the two groups
Table 3 Perioperative serum magnesium concentrations. Values are presented as means (SD). Units are mmol litre21. Group M, Mg group; Group S, saline group. *P,0.05 compared with Group S
0.82 1.31 1.10 0.93
0.87 (0.06) 0.82 (0.20) 0.80 (0.14) 0.78 (0.09)
(0.10) (0.13)* (0.09)* (0.07)*
100 90 80 70 60 50 40
Pr e Po ind st uct in io du n ct io 5 n m 10 in m 1 5 in m 3 0 in m 6 0 in m 9 0 in 12 min 0 m Po in st op PA .3 R Po 0 s m Po top in st . 4 Po op. h st 24 op h .4 8 h
Group S (n520)
Group M Group S
Time course Fig 1 Perioperative mean arterial pressure. Group M, Mg group; Group S, saline group. Values are presented as means (SD). Group M patients had a lower mean arterial pressure except immediately after the induction of spinal anaesthesia. No significant difference was observed between the two groups during the perioperative period.
Postoperative serum Mg concentrations in Group M were significantly higher than those in Group S (P,0.001 immediately after surgery, and at 1 and 24 h after surgery, Table 3). However, all patients in Group M had a serum Mg concentration in the normal range 24 h after surgery. There was no significant difference in haemodynamic variables (mean arterial pressure and heart rate) during the intra- or postoperative period (Figs 1 and 2). Six patients in Group M and three patients in Group S developed hypotension, and two patients in Group M and one patient in Group S experienced bradycardia during surgery. In accordance with the study protocol, ephedrine 5 mg and atropine 0.5 mg were administered in each event, and in all cases, arterial pressure and heart rate were normalized. Postoperative VAS scores were markedly lower in Group M at 4, 24, and 48 h after surgery (all P,0.001, Table 4). Furthermore, cumulative postoperative PCA consumptions were markedly lower in Group M (P,0.001 at 4, 24, and 48 h after surgery, Fig. 3), and fewer patients in Group M required additional rescue analgesia during the postoperative period (2 vs 6 patients), but this was not statistically significant (P¼0.079). The incidences of PONV and shivering after surgery were similar in the two groups. However, global satisfaction scores were significantly higher in Group M [3.4 (0.6) vs 2.6 (0.5), P,0.05].
Heart rate (beats min–1)
110
Group M Group S
100 90 80 70 60 50
Pr e Po ind st uct in io du n ct io 5 n m 10 in m 15 in m 30 in m 60 in m 90 in 12 min 0 m Po in st op PA . R Po 30 st min Po op st . 4 Po op. h st 24 op h .4 8 h
40
Time course Fig 2 Perioperative heart rate. Group M, Mg group; Group S, saline group. Values are presented as means (SD). Group M patients had a lower heart rate except before the induction of spinal anaesthesia. No significant difference was observed between the two groups during the perioperative period.
Table 4 Average VAS pain scores. Values are presented as medians and inter-quartile ranges. Group M, Mg group; Group S, saline group. *P,0.05 compared with Group S
Immediately postoperative Postoperative 30 min Postoperative 4 h Postoperative 24 h Postoperative 48 h
Discussion This study showed that i.v. magnesium sulphate infusion during surgery under spinal anaesthesia reduced postoperative pain and analgesic consumption without any notable complications. Total hip replacement arthroplasty is usually associated with moderate to severe postoperative pain, which disturbs early rehabilitation and functional recovery.1 Accordingly, a number of strategies for pain
Group M (n520)
Group S (n520)
0 (0 –3) 0 (0 –10) 30 (20 – 40)* 20 (10 – 30)* 12 (5 –15)*
0 15 50 38 29
(0– 13) (0– 35) (45 –64) (32 –45) (22 –35)
management have been introduced during the postoperative period. Regional anaesthesia is preferred to general anaesthesia during the perioperative period and patient-
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Preoperative Immediately postoperative Postoperative 1 h Postoperative 1 day
Group M (n520)
110
Hwang et al.
60
PCA vol (ml)
50
Group M Group S *
40 30
*
20 * 10 0
Immediate 30 min 4h 24 h Time after surgery
48 h
controlled epidural analgesia or nerve blocks have also been used in some patients. Improvements in understanding the mechanism of pain have resulted in the administration of analgesics before exposure to pain stimuli to prevent the central sensitization and the amplification of postoperative pain.1 2 Magnesium sulphate has been used in obstetric and cardiac patients. Its use as an adjuvant for perioperative analgesia is based on the properties of NMDA receptor antagonist and calcium channel blocker. However, although the basic mechanism of analgesic effect of Mg is unclear, it is presumed that its antagonism of NMDA receptor prevents the induction of central sensitization due to peripheral nociceptive stimulation and abolishes hypersensitivity. In addition, calcium channel blockers have shown antinociceptive effects in animals and morphine potentiation in patients with chronic pain.10 Our findings are partly in line with those in a previous study,9 where, immediately after spinal block, patients received a 5 mg kg21 bolus of magnesium sulphate followed by a 500 mg h21 infusion or saline in the same volumes for 24 h, and postoperative analgesic consumption was significantly lower in the Mg group. However, VAS scores in the two groups during the first 24 h after surgery were similar except at 12 h after surgery, and thus, it is assumed that the dosage of magnesium sulphate used was insufficient for postoperative analgesia. Adequate bolus and infusion doses of magnesium sulphate are important for effective analgesia. In a comparison of the effects of three different dose regimens of Mg on postoperative morphine consumption,11 a single bolus injection at 40 mg kg21 was found to reduce postoperative morphine consumption, and when this was followed by a maintenance infusion of 10 mg kg21 h21, the effect was enhanced. Moreover, increasing the maintenance infusion to 20 mg kg21 h21 provided no additional advantage and induced unwarranted haemodynamic effects. Pre- and intraoperative administration of magnesium sulphate
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Fig 3 The total amount of PCA drug. The concentrations of morphine and ketorolac are 0.7 and 1.5 mg ml21, respectively. Group M, Mg group; Group S, saline group. Values are presented as means (SD). The error bars indicate 1 SD.*P,0.05 compared with Group S.
(50 mg kg21 bolus and maintenance 15 mg kg21 h21 of magnesium sulphate) in gynaecology patients receiving total i.v. anaesthesia reduced rocuronium requirement and improved the quality of postoperative analgesia without any significant side-effects.5 8 Accordingly, in the present study, we administered a 50 mg kg21 bolus and a maintenance dose of 15 mg kg21 h21. Postoperative VAS scores and cumulative PCA consumption were both markedly lower in Group M at 4, 24, and 48 h. There was no significant difference of postoperative pain and analgesic use immediately and 30 min after surgery, which we attribute to the residual effect of spinal anaesthesia. Theoretically, two groups of patients using PCA in the present study should have titrated to much the same pain scores irrespective of an adjuvant drug. However, previous studies of the effect of Mg on postoperative analgesia also showed different VAS scores between the control and the Mg groups, even though the patients used PCA in the postoperative period.4 5 9 11 Possible explanations include: PCA use can reduce postoperative pain but cannot make it zero, and PCAs use opioids with or without ketorolac, which have dose-related side-effects, such as nausea and vomiting, and these side-effects stop unlimited use of the PCA. In addition, PCA settings include a lockout time to prevent overdose and patients may not, at times, get as much analgesic as they want. Adjuvant drugs such as magnesium sulphate can further reduce pain and analgesic consumptions in postoperative patients using PCA. After surgery, patients in Group M had higher serum Mg concentrations than those in Group S, but there was no side-effect associated with hypermagnesemia. Theoretically, minor side-effects of parenteral Mg such as flushing, nausea, and headache are expected at the serum Mg level above 2 mmol litre21, and potentially life-threatening complications, primarily involved in the cardiovascular and neuromuscular systems, occur when serum Mg concentrations exceed 5 mmol litre21.12 In the present study, the average serum Mg concentration after surgery in Group M was 1.31 (0.13) mmol litre21, which is below the level of minor side-effects. Serum Mg concentrations decreased to 1.10 (0.13) mmol litre21 at 1 h after surgery and normalized at 24 h after surgery [0.93 (0.07) mmol litre21]. Conversely, hypomagnesemia frequently occurs during the perioperative period and Group S in our study showed low normal serum Mg concentrations in the postoperative period.10 13 Magnesium causes a dose-dependent negative inotropic effect, and in humans, haemodynamic studies have shown that it has a peripheral ( predominantly arteriolar) vasodilatory effect.14 – 16 After rapid infusion of 3 or 4 g of magnesium sulphate, systolic arterial pressure decreased in relation to decreased systemic vascular resistance.10 In the present study, considering the negative intropic effect of Mg, prehydration with 500 ml of lactated Ringer’s solution was performed and the Mg bolus dose was infused over 15 min, which is probably why no significant hypotension
Magnesium sulphate during spinal anaesthesia
3 Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative analgesia. Anesthesiology 1996; 84: 340 – 7 4 Koinig H, Wallner T, Marhofer P, Andel H, Horauf K, Mayer N. Magnesium sulfate reduces intra- and postoperative analgesic requirements. Anesth Analg 1998; 87: 206 – 10 5 Ryu JH, Kang MH, Park KS, Do SH. Effects of magnesium sulphate on intraoperative anaesthetic requirements and postoperative analgesia in gynaecology patients receiving total intravenous anaesthesia. Br J Anaesth 2008; 100: 397 – 403 6 Ozcan PE, Tugrul S, Senturk NM, et al. Role of magnesium sulfate in postoperative pain management for patients undergoing thoracotomy. J Cardiothorac Vasc Anesth 2007; 21: 827 – 31 7 Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS. Magnesium sulfate does not reduce postoperative analgesic requirements. Anesthesiology 2001; 95: 640– 6 8 Bhatia A, Kashyap L, Pawar DK, Trikha A. Effect of intraoperative magnesium infusion on perioperative analgesia in open cholecystectomy. J Clin Anesth 2004; 16: 262 – 5 9 Apan A, Buyukkocak U, Ozcan S, Sari E, Basar H. Postoperative magnesium sulphate infusion reduces analgesic requirements in spinal anaesthesia. Eur J Anaesthesiol 2004; 21: 766– 9 10 Dube L, Granry JC. The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review. Can J Anaesth 2003; 50: 732 – 46 11 Seyhan TO, Tugrul M, Sungur MO, et al. Effects of three different dose regimens of magnesium on propofol requirements, haemodynamic variables and postoperative pain relief in gynaecological surgery. Br J Anaesth 2006; 96: 247 – 52 12 Vissers RJ, Purssell R. Iatrogenic magnesium overdose: two case reports. J Emerg Med 1996; 14: 187 – 91 13 Place HM, Enzenauer RJ, Muff BJ, Ziporin PJ, Brown CW. Hypomagnesemia in postoperative spine fusion patients. Spine 1996; 21: 2268– 72 14 James MFM. Magnesium: an emerging drug in anaesthesia. Br J Anaesth 2009; 103: 465 – 7 15 Jee D-L, Lee D-H, Yun S-S, Lee C-H. Magnesium sulphate attenuates arterial pressure increase during laparoscopic cholecystectomy under pneumoperitoneum. Br J Anaesth 2009; 103: 484 – 9 16 Ryu J-H, Sohn I-S, Do SH. Controlled hypotension for middle ear surgery: a comparison between remifentanil and magnesium sulphate. Br J Anaesth 2009; 103: 490 – 5 17 Ghoneim MM, Long JP. The interaction between magnesium and other neuromuscular blocking agents. Anesthesiology 1970; 32: 23 – 7
References 1 Maheshwari AV, Blum YC, Shekhar L, Ranawat AS, Ranawat CS. Multimodal pain management after total hip and knee arthroplasty at the Ranawat Orthopaedic Center. Clin Orthop Relat Res 2009; 467: 1418– 23 2 Fischer HB, Simanski CJ. A procedure-specific systematic review and consensus recommendations for analgesia after total hip replacement. Anaesthesia 2005; 60: 1189 – 202
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was encountered after administering the Mg bolus dose and no significant inter-group haemodynamic differences were observed during the surgery. In the present study, time to first pain sensation and spinal block height were similar in the two groups, which is in accord with the findings of a previous study.9 There was no significant difference between the Mg and the control groups in terms of spinal block height or the duration of motor block.9 It should be noted that we did not assess the duration of motor block during the present study, because the protocol at our institute after total hip replacement arthroplasty is that patients should not move their legs during the early postoperative period. Magnesium sulphate administration may have another benefit, namely, as it has been suggested that it potentiates neuromuscular block during general anaesthesia.5 11 It has been shown that the basic mechanisms involve a reduction of the amount of acetylcholine released from motor nerve terminals and a decrease in the depolarizing action of acetylcholine at the endplate, or a depression of muscle fibre membrane excitability.17 Accordingly, i.v. Mg administration during spinal anaesthesia may facilitate muscle relaxation and surgical procedures that require extensive joint rotation, such as total hip replacement arthroplasty. However, further study is required to validate this hypothesis. In summary, we found that magnesium sulphate given i.v. during spinal anaesthesia reduced postoperative pain and analgesic consumption without complications.