|Year : 2015 | Volume
| Issue : 1 | Page : 70-75
Comparative study between the effect of intrathecal midazolam versus intrathecal midazolam plus magnesium sulfate on the efficacy and duration of analgesia in patients undergoing cesarean section
Maged L Boules, Josepph M Botros
Department of Anaesthesiology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
|Date of Submission||06-Jul-2014|
|Date of Acceptance||20-Oct-2014|
|Date of Web Publication||25-Mar-2015|
Maged L Boules
35 Ibrahim El Baessy Street, Ahmed Oraby Agouza, Giza
Source of Support: None, Conflict of Interest: None
Regional techniques using either epidural or intrathecal routes are currently the most popular methods of pain relief during labor and delivery.
The aim of the study was to compare efficacy and duration of analgesia produced by adding magnesium sulfate to intrathecal bupivacaine (10 mg) plus midazolam (1 mg) in patients undergoing cesarean section.
Patients and methods
In our study, 60 patients aged 18-35 years of American Society of Anesthesiologists (ASA) class I and II were scheduled for a cesarian section under an intrathecal block and divided randomly into two groups: midazolam group (group M): A total of 30 patients received 10 mg/2 ml intrathecal 0.5% hyperbaric bupivacaine, midazolam (1 mg/0.2 ml), and 0.8 ml normal saline and magnesium midazolam group (group MM): A total of 30 patients received 10 mg/2 ml intrathecal 0.5% hyperbaric bupivacaine, midazolam (1 mg/0.2 ml), magnesium sulfate (50 mg/0.5 ml), and 0.3 ml normal saline. The onset and duration of both sensory and motor block, the total dose of analgesia, and adverse effects were recorded.
The onset of sensory block was significantly delayed in the MM group compared with the M group (6.05 ± 1.1 vs. 3.5 ± 0.45 min, P = 0.024); the duration of sensory block was longer in the MM group compared with the M group (132.4 ± 7.8 vs. 115.3 ± 6.60 min, P = 0.018). In addition, the onset of motor block was delayed in the MM group (7.05 ± 1.3 min) compared with the M group (5 ± 0.65 min, P = 0.028) as well as its duration (149.9 ± 8.67 vs. 126.3 ± 5.35 min, P = 0.005).
The addition of magnesium sulfate to intrathecal bupivacaine plus midazolam led to a significant delay in the onset of both sensory and motor blockade, and also prolonged their duration without side effects.
Keywords: cesarean section, magnesium sulfate, midazolam
|How to cite this article:|
Boules ML, Botros JM. Comparative study between the effect of intrathecal midazolam versus intrathecal midazolam plus magnesium sulfate on the efficacy and duration of analgesia in patients undergoing cesarean section. Ain-Shams J Anaesthesiol 2015;8:70-5
|How to cite this URL:|
Boules ML, Botros JM. Comparative study between the effect of intrathecal midazolam versus intrathecal midazolam plus magnesium sulfate on the efficacy and duration of analgesia in patients undergoing cesarean section. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2022 Jan 22];8:70-5. Available from: http://www.asja.eg.net/text.asp?2015/8/1/70/153941
| Introduction|| |
Spinal anesthesia is commonly used for cesarean section as a means to avoid the risks of general anesthesia, allowing a parturient to remain awake and enjoy the birth experience  . The quality and duration of seand motor block and decreasing postoperative pain is important in cesarean section and for the patient's satisfaction. Opioids and other drugs such as magnesium sulfate, clonidine, and neostigmine are added to local anesthetics for this purpose  .
Midazolam, a water-soluble benzodiazepine, produces an analgesic action through the benzodiazepine/g-aminobutyric acid receptor complex in the spinal cord  .
Magnesium sulfate blocks the N-methyl-d-aspartate channels in a voltage-dependent manner to improve the quality and duration of spinal block. However, the safety profile of the use of magnesium sulfate has been documented by histopathological analysis in experimental studies  . Systemic delivery of magnesium sulfate decreases postoperative opioid requirements  .
The aim of this study was to compare the efficacy and duration of analgesia produced by adding magnesium sulfate to intrathecal bupivacaine (10 mg) plus midazolam (1 mg) in patients undergoing cesarean section.
| Patients and methods|| |
After ethical committee approval, this study was carried out at Al-Fayoum University Hospital and all patients provided full written informed consent before participation in this study.
In a double-blinded randomized-controlled trial, a total of 60 patients aged 18-35 years of American Society of Anesthesiologists (ASA) physical status class I or II were scheduled for cesarean section under an intrathecal block and divided randomly into two groups:
(1) Midazolam group (group M): Thirty patients received intrathecal 0.5% hyperbaric bupivacaine (10 mg/2 ml), preservative-free midazolam (1 mg/0.2 ml), and 0.8 ml normal saline.
(2) Magnesium/midazolam group (group MM): Thirty patients received intrathecal 0.5% hyperbaric bupivacaine (10 mg/2 ml), preservative-free magnesium sulfate (50 mg/0.5 ml), preservative-free midazolam (1 mg/0.2 ml), and 0.3 ml normal saline.
Exclusion criteria included coexisting hepatorenal or other end organ disease, bleeding tendency, patient refusal, severe mitral stenosis and severe aortic stenosis, severe spinal lesion, signs of lesion in the central nervous system, abscess or infection of skin and soft tissue in the site of needle insertion, severe anxiety, restlessness, significant mental disorders or drug abuse, hypersensitivity to any of the study drugs, and complicated pregnancy.
Routine preoperative investigations including complete blood picture, renal function tests, liver function tests, and coagulation profile were performed.
The operating theater nurse assistant used a randomization protocol (according to a computer-generated random number sequence) to assign participants to their respective groups, and an independent anesthesiologist, who did not participate in the study or data collection, prepared unlabeled syringes containing the study drugs.
All patients fasted for 8 h preoperatively and received an 18 G cannula; intravenous fluids in the form of lactated Ringer's solution were infused at a rate of 10 ml/kg as a preload before spinal anesthesia.
Standard monitoring devices including ECG, pulse oximetry, and noninvasive blood pressure (NIBP) monitor were used to measure the hemodynamic variables. Lumbar puncture was performed in the sitting position (with a 25 G Quincke's needle); the spinal needle was introduced into the subarachnoid space at the L3-L4 or the L4-L5 midline approach under complete aseptic conditions. Immediately after the subarachnoid injection, the parturient was turned supine and her head was rested on a pillow. Oxygen was administered routinely by a face mask at 4 l/min until the end of the operation.
Preoperatively, all the baseline parameters were recorded including heart rate (HR), mean arterial blood pressure (MAP), and pulse oximetry (SpO 2 ). On arrival to the operating theater, the vital signs including MAP, HR, SpO 2 , and side effects were also recorded at baseline, 5, 10, 20, 30, 45, 60, 90 min, and postoperatively.
The onset and duration of sensory block were also recorded. The onset of sensory block was defined as the time between injections of the intrathecal anesthetic until the absence of pain at T6 dermatome (xiphisternum), which was assessed using the pin-prick test.
The onset and duration of motor block were measured. Motor block was assessed using the modified Bromage score according to Jones et al.  .
Onset of motor block is defined as the time from the intrathecal injection of the drug until the modified Bromage score was reached  . The duration of motor block was defined as the time from the intrathecal injection of the drug until complete motor block recovery. Complete motor block was assumed when the modified Bromage score was 0.
Pain was assessed using a verbal numeric scale  from 0 to 10 (0 = no pain, 1, 2, 3 = mild pain; 4, 5, 6 = moderate pain; 7, 8, 9, 10 = severe pain) every 15 min after the block until the end of the surgery and 2, 4, 8, and 24 h postoperatively.
The total dose of analgesic requirement [intravenous pethidine (mg)] was calculated in the first 24 h postoperatively.
The incidence of hypotension (MAP <20% of baseline), bradycardia (HR <50 beats/min), hypoxemia, excessive sedation, shivering, nausea, and vomiting were recorded at baseline, 5, 10, 20, 30, 45, 60, 90 min, and postoperatively.
Overall patient satisfaction with anesthesia and analgesia was scored at 24 h as 1 = excellent; 2 = good; and 3 = poor  .
Power analysis was carried out on the level of duration of sensory block after surgery for independent samples using Student's t-test because it was the main outcome variable in the present study. A previous study showed that the duration of sensory block after cesarean section was 263.9, with SD 23.3  . On the basis of the assumption that a mean difference of 10% of sensory block duration was a clinically significant difference between groups, and for a power of 0.9 and an α error of 0.05, a minimum sample size of 18 patients was calculated for each group. A total of 30 patients were included in each group to compensate for possible dropouts.
Data management and analysis were carried out using the statistical package for social sciences (SPSS-17 Chicago, IL 60606-6412, USA). Numerical data were summarized using means and SDs or median and ranges. Categorical data were summarized as percentages. Comparisons between the two groups with respect to numeric variables were carried out using the Mann-Whitney test. The χ2 -test was used to compare between the groups with respect to categorical data. P-values less than 0.05 were considered significant.
| Results|| |
Maternal demographic data are shown in [Table 1]. There was no statistically significant difference between the study groups in the maternal demographic data and duration of surgery.
In terms of the HR, there was no statistically significant difference between both groups before, during, and after the end of surgery (P > 0.05).
Similarly, there was no statistically significant difference between the study groups in the MAP before, during, and after the end of surgery (P > 0.05).
Moreover, there was no statistically significant difference between both study groups in the peripheral oxygen saturation (SpO 2 %) before, during, and after the end of surgery (P > 0.05).
In terms of the onset of sensory block, there was a statistically significant difference between both groups, where it was found to be delayed in the MM group in comparison with the M group (P = 0.024) as shown in [Table 2]. In addition, there was a significant prolongation in the duration of sensory block when magnesium sulfate was added to midazolam (P = 0.018) ([Figure 1]).
|Figure 1: Comparison between groups M and MM in the duration of sensory block. M, midazolam; MM, magnesium plus midazolam.|
Click here to view
Comparison of the highest level of sensory block at 15 min between both groups showed no statistically significant difference (P = 0.247) ([Table 3]).
The onset of motor block was significantly delayed in the MM group compared with the M group (7.05 ± 1.3 min in the MM group vs. 5 ± 0.65 min in the M group, P = 0.028).
|Table 3 Comparison of the highest level of sensory block at 15 min between the studied groups|
Click here to view
There was a statistically significant difference between the study groups in the duration of motor block. The duration was significantly longer in the MM group (149.9 ± 8.67 min) compared with the M group (126.3 ± 5.35 min, P = 0.005).
In terms of the total dose of pethidine (mg) taken postoperatively, the MM group consumed less pethidine (60.5 ± 8.09 mg) compared with the M group (81.5 ± 9.19 mg, P = 0.016).
Moreover, the highest percentage of patient satisfaction was found in the MM group compared with the M group (P = 0.003) as shown in [Table 4].
No significant difference in the side effects including bradycardia, hypotension, itching, nausea, vomiting, and sedation was observed among both groups (P > 0.05) ([Table 5]).
| Discussion|| |
The results of our study showed that the addition of magnesium sulfate to intrathecal bupivacaine and midazolam causes a significant increase in the duration of both sensory and motor blockade without side effects.
In this study, 60 patients were divided randomly into two groups: the M group (bupivacaine and 1 mg midazolam) and the MM group (bupivacaine, midazolam, and 50 mg magnesium sulfate).
The hemodynamic variables were comparable in the study groups throughout the study, with no statistically significant difference (P > 0.05).
Previous studies concluded that sympathetic nervous system function remains intact after intrathecal midazolam  .
Three possible mechanisms are suggested for the antinociceptive action of midazolam: first, through benzodiazepine/g-aminobutyric acid-A receptor complex-mediated analgesia as they are abundantly present in lamina II of the dorsal horn of the spinal cord  . It also induces the release of endogenous opioid acting at spinal delta receptors, such as naltrinadole; a delta receptor opioid antagonist suppresses its analgesic effect  . Third, it inhibits adenosine uptake or enhances adenosine release  .
Intrathecal midazolam has been shown to be free of neurotoxicity or other adverse effects up to 2 mg  .
Tucker et al.  reported that among women in labor, a combination of intrathecal midazolam and fentanyl provided significant pain relief and did not increase the incidence of any maternal adverse event; this is also in agreement with our study.
A comparable result was reported by Shah et al.  , who carried out a prospective, randomized, and observer-blinded study that involved 60 patients undergoing minor and intermediate lower abdominal surgery. They concluded that the quality of postoperative pain relief improved in the experimental group, who received buprenorphine and bupivacaine supplemented with intrathecal midazolam (2 mg). Others also observed that intrathecal midazolam produced postoperative pain relief for patients with chronic lumbar pain and for women undergoing cesarean section delivery while also having an antiemetic effect  .
The safety of administration of intrathecal magnesium sulfate has been evaluated in animal and human studies; a recent human study found no deleterious effects of intrathecal magnesium on spinal opioid analgesia in laboring parturients  . Thus, intrathecal magnesium seems to have a good safety profile. This is comparable with our study, where there were no side effects related to the drug used.
In addition, we found a delay in the onset of sensory block with the addition of intrathecal magnesium sulfate to intrathecal midazolam. This was in agreement with the study carried out by Nath et al.  , who reported that the intrathecal magnesium sulfate (100 mg) added to fentanyl (0.5 ml) and hyperbaric bupivacaine (2.5 ml) led to a delay in the onset of sensory block.
In our study, the duration of sensory block was significantly prolonged in the MM group compared with the M group, which was statistically significant (P = 0.018). Khalili et al.  reported that the addition of 100 mg magnesium sulfate to spinal anesthesia led to a significant increase in the duration of the sensory block, which was in agreement with our study. Previous data are inconsistent on the effects of prolongation of the sensory block by magnesium sulfate, with some studies reporting an increase in the duration of the sensory block  and others reporting a decrease  . The mechanisms by which magnesium sulfate exerts a positive or a negative effect on the duration of sensory block are not clear. We are currently unable to explain this increase in the duration of the sensory block in spinal anesthesia with the addition of magnesium sulfate as an adjunct to bupivacaine, and this should be addressed in further studies.
In terms of the onset of motor block, we found a delay in the onset of motor block with the addition of intrathecal magnesium sulfate to intrathecal midazolam. This was in agreement with the study carried out by Rathmell et al.  , who added 2.5 ml (12.5 mg) of hyperbaric bupivacaine+0.5 ml (25 μg) of fentanyl+0.5 ml (100 mg) of 20% magnesium sulfate and observed a significant delay in the onset of motor block.
The delayed onset could be because of the solution of magnesium sulfate having a different pH, which might explain our findings. Also, an increase in the metabolism of bupivacaine because of the activation of cytochrome P450 by magnesium sulfate may be responsible for the delayed onset  .
In terms of the duration of motor block (Bromage = 0, no motor loss), it was found that the duration of motor block was significantly prolonged in the MM group compared with the M group. However, Khalili et al.  reported that the addition of 100 mg magnesium sulfate to spinal anesthesia did not affect the time to complete motor recovery.
In our study, the total dose of analgesic requirement on the operative day was significantly decreased in the MM group compared with the M group (P = 0.016). Similar observations were made by Khalili et al.  , who found that the addition of 100 mg magnesium sulfate to spinal anesthesia reduced the postoperative analgesic requirement without additional side effects.
Magnesium-induced augmentation of analgesia when supplemented with bupivacaine and fentanyl has been reported in other studies; use of intrathecal magnesium reduces postoperative epidural analgesic requirement  . Studies in which 50 mg magnesium sulfate was administered intrathecally in patients undergoing total knee replacement and knee arthroscopy showed that the verbal rating scores at 120 min, first analgesic requirement, and 36 h morphine requirement were significantly lower after an intrathecal injection of magnesium sulfate, respectively, compared with the control group (P < 0.05)  .
In parturients with mild preeclampsia undergoing cesarean delivery, the addition of magnesium sulfate 50 mg to the intrathecal combination of bupivacaine and fentanyl prolongs the duration of analgesia and reduces the postoperative analgesic requirements without additional side effects  .
Intrathecal magnesium has been used for labor analgesia at a dose of 50 mg in addition to fentanyl, and the authors observed that there was significant prolongation in the median duration of analgesia (75 min) in the magnesium plus fentanyl group compared with the fentanyl-alone group (60 min)  .
Our results are in contrast to the study of Unlugenc et al.  , who reported a decrease in the duration of analgesia with the addition of intrathecal magnesium sulfate.
The optimal dose of intrathecal magnesium sulfate has not been reported. Earlier studies with 50 and 100 mg yielded satisfactory analgesia without significant added adverse effects  . The increased dose may carry the risk of respiratory depression, but none of our patients had any episode of respiratory depression  . Use of intrathecal magnesium sulfate did not lead to any signs of systemic toxicity, such as arterial hypotension, cardiac arrhythmias, somnolence, double vision, slurred speech, or weakness either intraoperatively or during the postoperative course in patients treated with magnesium sulfate who underwent major orthopedic surgery  . We also did not encounter any of the above-mentioned complications during the intraoperative or postoperative periods.
| Conclusion|| |
The addition of 50 mg magnesium sulfate to intrathecal bupivacaine (10 mg) plus 1 mg midazolam led to a significant delay in the onset of both sensory and motor blockade, and also prolonged their duration without side effects. In addition, it seemed that these drugs were enough to provide effective anesthesia and analgesia.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yousef AA, Amr YM. The effect of adding magnesium sulphate to epidural bupivacaine and fentanyl in elective caesarean section using combined spinal-epidural anaesthesia: a prospective double blind randomised study. Int J Obstet Anesth 2010; 19:401-404.
Ashburn MA, Love G, Pace NL. Respiratory-related critical events with intravenous patient-controlled analgesia. Clin J Pain 1994; 10:52-56.
Ho KM, Ismail H Use of intrathecal midazolam to improve perioperative analgesia: a meta-analysis. Anaesth Intensive Care 2008; 36:365-373.
Xiao WH, Bennett GJ. Magnesium suppresses neuropathic pain responses in rats via a spinal site of action. Brain Res 1994; 666:168-172.
Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative analgesia. Anesthesiology 1996; 84:340-347.
Jones KR, Vojir CP, Hutt E, Fink R. Determining mild, moderate, and severe pain equivalency across pain-intensity tools in nursing home residents. J Rehabil Res Dev 2007; 44:305-314.
Riham H, Wael E, Mohamed K. The value of epidural magnesium sulfate as an adjuvant to bupivacaine and fentanyl for labor anesthesia. Egypt J Anaesth 2013; 29:219-224.
Faiz SH, Rahimzadeh P, Imani F, Bakhtiari A. Intrathecal injection of magnesium sulfate: shivering prevention during cesarean section: a randomized, double-blinded, controlled study. Korean J Anesthesiol 2013; 65:293-298.
Yaksh TL, Allen JW. The use of intrathecal midazolam in humans: a case study of process. Anesth Analg 2004; 98:1536-1545.
Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology 1990; 73:273-277.
Goodchild CS, Guo Z, Musgreave A, Gent JP. Antinociception by intrathecal midazolam involves endogenous neurotransmitters acting at spinal cord delta opioid receptors. Br J Anaesth 1996; 77:758-763.
Nishiyama T, Matsukawa T, Hanaoka K. Acute phase histopathological study of spinally administered midazolam in cats. Anesth Analg 1999; 89:717-720.
Tucker AP, Lai C, Nadeson R, Goodchild CS. Intrathecal midazolam I: a cohort study investigating safety. Anesth Analg 2004; 98: 1512-1520.
Shah FR, Halbe AR, Panchal ID, Goodchild CS. Improvement in postoperative pain relief by the addition of midazolam to an intrathecal injection of buprenorphine and bupivacaine. Eur J Anaesthesiol 2003; 20:904-910.
Rathmell JP, Lair TR, Nauman B. The role of intrathecal drugs in the treatment of acute pain. Anesth Analg 2005; 101:S30-S43.
Lee JW, Kim MK, Shin YS, Mestiri T, Merghli A, Mebazaa MS, et al.
The analgesic effect of single dose of intrathecal magnesium sulfate. Korean J Anesthesiol 2007; 52:72-76.
Nath MP, Garg R, Talukdar T, Choudhary D, Chakrabarty A. To evaluate the efficacy of intrathecal magnesium sulphate for hysterectomy under subarachnoid block with bupivacaine and fentanyl: a prospective randomized double blind clinical trial. Saudi J Anaesth 2012; 6:254-258.
Khalili G, Janghorbani M, Sajedi P, Ahmadi G Effects of adjunct intrathecal magnesium sulfate to bupivacaine for spinal anesthesia: a randomized, double-blind trial in patients undergoing lower extremity surgery. J Anesth 2011; 25:892-897.
Ozalevli M, Cetin TO, Unlugenc H, Guler T, Isik G. The effect of adding intrathecal magnesium sulphate to bupivacaine-fentanyl spinal anaesthesia. Acta Anaesthesiol Scand 2005; 49:1514-1519.
Dayioðlu H, Baykara ZN, Salbes A, Solak M, Toker K Effects of adding magnesium to bupivacaine and fentanyl for spinal anesthesia in knee arthroscopy. J Anesth 2009; 23:19-25.
Biswas BN, Rudra A, Bose BK, Nath S, Solak M, Toker K. Intrathecal fentanyl with hyperbaric bupivacaine improves analgesia during caesarean delivery and in early postoperative period. Indian J Anaesth 2002; 66:469-472.
Malleeswaran S, Panda N, Mathew P, Bagga R A randomised study of magnesium sulphate as an adjuvant to intrathecal bupivacaine in patients with mild preeclampsia undergoing caesarean section. Int J Obstet Anesth 2010; 19:161-166.
Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg 2002; 95:661-666.
Unlugenc H, Ozalevli M, Gunduz M, Gunasti S, Urunsak IF, Guler T, Isik G. Comparison of intrathecal magnesium, fentanyl, or placebo combined with bupivacaine 0.5% for parturients undergoing elective cesarean delivery. Acta Anaesthesiol Scand 2009; 53:346-353.
Witlin AG, Sibai BM. Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol 1998; 92:883-889.
Arcioni R, Palmisani S, Tigano S, Santorsola C, Sauli V, Romanò S, et al.
Combined intrathecal and epidural magnesium sulfate supplementation of spinal anesthesia to reduce post-operative analgesic requirements: a prospective, randomized, double-blind, controlled trial in patients undergoing major orthopedic surgery. Acta Anaesthesiol Scand 2007; 51:482-489.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
|This article has been cited by|
||Our article after ten years: Intrathecal midazolam as supplementary analgesia for chronic lumbar pain - 15 yearsćexperience
| ||J Procházka,A Hejcl,L Procházková |
| ||Anesteziologie a intenzivní medicína. 2021; 32(2): 94 |
|[Pubmed] | [DOI]|
||Comparing the Effect of Adding Fentanyl, Sufentanil, and Placebo with Intrathecal Bupivacaine on Duration of Analgesia and Complications of Spinal Anesthesia in Patients Undergoing Cesarean Section
| ||Farnoush Farzi,Ali Mirmansouri,Bahram Naderi Nabi,Zahra Atrkar Roushan,Samaneh Ghazanfar Tehran,Mona Nematollahi Sani,Soodabe Makhlooghi Azad,Maryam Nemati |
| ||Anesthesiology and Pain Medicine. 2017; In Press(In Press) |
|[Pubmed] | [DOI]|