|Year : 2013 | Volume
| Issue : 3 | Page : 175-181
Clinical effects of intrathecal midazolam versus intrathecal magnesium sulfate as adjunctsto hyperbaric bupivacaine: A comparative study
Sapna Shashni, Abhijit S Nair, T V S Gopal
Department of Anesthesiology, Axon Anesthesia Associates, Care Hospitals, Banjara Hills, Hyderabad, Andhra Pradesh, India
|Date of Web Publication||7-Jan-2014|
Abhijit S Nair
Department of Anesthesiology, Axon Anesthesia Associates, Care Hospitals, Road Number 1, Banjara Hills, Hyderabad - 500 034, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Adjuvants are added to intrathecal local anesthetics to improve quality and duration of subarachnoid block. The present study was designed to compare the analgesic efficacy and quality of anesthesia produced by midazolam (1 mg) versus magnesium sulfate (50 mg) when given as adjuncts to hyperbaric bupivacaine intrathecally. In our study, we compared 1 mg midazolam and 50 mg magnesium sulfate as an additive to bupivacaine intrathecally. Materials and Methods: We conducted our study on 124 patients with(ASA) I and II physical status undergoing elective lower abdominal and orthopedic surgeries after approval from Institutional Ethics Committee. There were two groups; group MZ which received 3 ml of 0.5% heavy bupivacaine with 1 mg of preservative free midazolam and group MG which received 3 ml of 0.5% heavy bupivacaine with 50 mg magnesium sulfate intrathecally. The onset and duration of sensory block, onset and duration of motor block, and duration of analgesia were recorded. Results: The onset and duration of sensory block was longer in MG group as compared to the MZ group. The onset and duration of motor block was longer in MG group as compared to MZ group. Also, the total duration of analgesia was more in MG group as compared to MZ group. Conclusion: We concluded that 50 mg of intrathecal magnesium sulfate prolonged the duration of sensory and motor block and also the duration of postoperative analgesia with low pain scores as compared to midazolam group. However, it delayed the onset of sensory andmotor block. On the other hand 1 mg of intrathecal midazolam produced an early onset of sensory and motor block but the duration of analgesia was less as compared to the magnesium group.
Keywords: Bupivacaine, midazolam, magnesium sulfate, spinal anesthesia
|How to cite this article:|
Shashni S, Nair AS, Gopal T. Clinical effects of intrathecal midazolam versus intrathecal magnesium sulfate as adjunctsto hyperbaric bupivacaine: A comparative study. Indian J Pain 2013;27:175-81
|How to cite this URL:|
Shashni S, Nair AS, Gopal T. Clinical effects of intrathecal midazolam versus intrathecal magnesium sulfate as adjunctsto hyperbaric bupivacaine: A comparative study. Indian J Pain [serial online] 2013 [cited 2020 Feb 21];27:175-81. Available from: http://www.indianjpain.org/text.asp?2013/27/3/175/124604
| Introduction|| |
To improve the quality of central neuraxial block or spinal anesthesia, adjuvant drugs are used with local anesthetics. These drugs enhance or potentiate the actions of local anesthetics in order to improve the latency of the block, duration, and quality of analgesia.  Opioids that are added intrathecally prolong the duration of anesthesia, but are associated with a number of undesirable side effects like delayed respiratory depression, urinary retention, pruritis, nausea, and vomiting. Other drugs that potentiate spinal antinociception like clonidine and neostigmine also exhibit adverse effects like respiratory depression, pruritus, and excessive nausea or vomiting.  Drugs like dexmedetomidine, dexamethasone have also been used successfully as an adjunct in spinal anesthesia along with local anesthetic. ,
Magnesium sulfate exerts its analgesic action as a noncompetitive N-Methyl-D-aspartate (NMDA) receptor antagonist, blocking ion channels in a voltage dependent manner when used intrathecally. The addition of magnesium reduces the activation of C-fibers by inhibiting the slow excitatory postsynaptic currents produced by NMDA receptor activation.  NMDA receptor antagonists abolish calcium and sodium influx into cells leading to central sensitization and windup attributed to peripheral nociceptive stimulation. They abolish hypersensitization by blocking NMDA receptor activation in the dorsal horn by excitatory amino acid transmitters, notably glutamate, and aspartate.  Magnesium is also known as nature's physiological calcium channel blocker. On the other hand intrathecal midazolam has been shown to have analgesic properties and potentiate the effects of intrathecal local anesthetic. The mechanism by which midazolam provides analgesia has been explored in several recent studies, it acts through gamma-aminobutyric acid (GABA) receptors present in the dorsal horn of the spinal cord with the highest density of these receptors found within the lamina II of the dorsal horn ganglia, a region that plays a prominent role in processing nociceptive and thermoceptive stimulation. It may also have central antinociceptive effect via the activation of spinal δ opioid receptors. [7 ],,,
Our study shows a longer duration of analgesia with the use of intrathecal magnesium sulfate as compared to midazolam. There are several studies which have demonstrated the analgesic effects of magnesium sulfate when added intrathecally with hyperbaric bupivacaine in an attempt to prolong the duration of analgesia.
Review of Literature
Intrathecal midazolam and magnesium along with local anesthetic have been studied by using various doses. But the optimum dose of either adjunct has not been described. If the dose is exceeded, there are adverse effects seen or a delay in recovery from spinal anesthesia. When underdosed, it offers no advantage as an intrathecal adjuvant. Jabalameliand Pakzadmoghadam investigated the effect of addition of different doses of magnesium sulfate to bupivacaine intrathecally for cesarean section. They used 50, 75 and 100 mg with bupivacaine and realized that it caused a delay in onset of sensory and motor block. Duration of sensory and motor block was longer in patients who received 75 and 100 mg than 50 mg. Recovery time was shorter in patients who received 50 mg magnesium intrathecally.  Khalili et al., conducted a double blind randomized controlled trial involving 79 ASA I and II patients scheduled for lower extremity orthopedic surgery. Patients received 15 mg bupivacaine with 100 mg magnesium in one group and 15 mg bupivacaine with 0.2 cc normal saline intrathecally in other group. They observed that the onset of sensory block was slow in magnesium group but duration of sensory block was significantly longer. Although mean duration of spinal anesthesia was not significantly different, total analgesic requirement for 24 h following surgery was lower in magnesium group.  Pascual-Ramírez et al., performed a meta-analysis of available literature and included 12 studies with 817 patients. They concluded that onset of motor block was slow when magnesium was added intrathecally, but found no difference in time to full motor recovery, incidence of pruritus, postoperative nausea and vomiting, bradycardia, hypotension, and urinary retention. 
Shadangi et al., conducted a prospective, randomized, double blind study with 100 patients for elective lower abdominal, lower limb, and gynecological procedures and divided them into two groups. First group received 15 mg bupivacaine with 0.4 ml normal saline intrathecally and second group received 15 mg bupivacaine with 2 mg midazolam intrathecally. They concluded from the results that onset of sensory and motor block was comparable, but duration of sensory block was prolonged. Also, duration of effective analgesia was significantly longer in the midazolam group.  Wu et al., divided 60 patients scheduled for diabetic foot debridement into two groups. First group received 7.5 mg hyperbaric bupivacaine and second group received 5 mg hyperbaric bupivacaine with 2 mg midazolam intrathecally. They concluded from the results that requirement of analgesia was significantly low for 24 h in patients who received midazolam intrathecally. There was also early recovery of motor function in midazolam group which could be due to less dose of bupivacaine used. 
| Materials and Methods|| |
This prospective, randomized controlled, double blind study was carried out in the Department of Anesthesia, Care Hospital, Banjara Hills, Hyderabad after approval by the institutional ethical committee. The study was conducted on 124 patients of ASA I and II in the age group of 18-60 years undergoing various elective lower abdominal and orthopedic procedures. Exclusion criteria were any contraindications to regional anesthesia, patients with uncontrollable hypertension, patients with known allergy to the study drug, andpatient unable to communicate making postoperative assessment difficult.
After a detailed preanesthetic checkup and investigations, an informed consent was taken from patients before their participation in the study. Patients were randomized to one of the two groups using computer generated random number sequence and sealed opaque envelopes.
Group MZ: Three milliliter (15 mg) 0.5% hyperbaric bupivacaine + 1 mg of midazolam (preservative free).
Group MG: Three milliliter (15 mg) 0.5% hyperbaric bupivacaine + 50 mg of magnesium sulfate (preservative free).
The equipments used were 18G intravenous cannula, 27 G spinal needle (Whitacre), and 0.5% hyperbaric bupivacaine, study drug. We monitored oxygen saturation with pulse oximeter, blood pressure with noninvasive blood pressure (BP) cuff, heart rate with lead II and V5 electrocardiography. Under due asepsis and after local infiltration with 2% lignocaine, lumbar puncture was done in L4-5 space with 27 G spinal needle and bupivacaine with the study drug was injected and time was noted.
All recorded physiological variables were entered in a case record form. The observations were made by the anesthesiologist who was unaware of group allocation and was blinded to the study. The parameters such as heart rate and blood pressure were recorded at 5 min intervals intraoperatively till the end of the procedure. Electrocardiogram (ECG) and SpO 2 were monitored continuously till the end of the procedure. Hypotension was defined as blood pressure lower than 20% of baseline value and was treated with i.v. fluids and inj. phenylephrine 100 μg. Bradycardia was defined as heart rate < 50/min and was treated with 0.5 mg of inj. atropine intravenously. The level of sensory block was checked using pinprick method and the motor block was assessed by the Bromage scale. Motor block was assessed by the modified Bromage score (0: No motor block, 1: Inability to flex the hip, 2: Inability to flex the knee, and 3: Inability to flex ankle).
The onset of sensory block was defined as the time to reach T6 dermatome level, by pinprick method. The duration of sensory block was defined as the mean time for regression of the level of sensory anesthesia below T12 dermatome. The onset of motor block was determined by the time taken to reach a Bromage scale of 3. The duration of motor block was defined as the time of intrathecal injection of drug to the time till Bromage scale reaches zero. The total duration of analgesia was the time from the intrathecal injection of the drug to the time when patient first requests analgesia.
The data collected by the comparative study of both groups was analyzed by suitable statistical method. Data was analyzed using two factor analysis of variance (ANOVA) technique.
ANOVA, t-test, Mann-Whitney test, and variance ratio test were the statistical hypothesis tests used to assess significance of difference in patient characteristics, success rate of each method, and the duration of analgesia provided. Age, weight, sex, ASA grade, onset, and duration of sensory and motor blockade, sedation score, visual analog scale (VAS) score between the two groups, and duration of analgesia were analyzed by ANOVA. Repeated measurements of systolic and diastolic blood pressure, heart rate, SpO 2 were compared with ANOVA. Probability (P) value of ≤0.05 was considered to be significant.
Observation and Results
The following table shows the distribution of sedation score within the two groups at regular time intervals. The P value for the sedation score at 15, 30 , 45, and 60 min were <0.05 which is statistically significant. The sedation score was higher in the midazolam group than in the magnesium group [Figure 1] and [Table 1].
Onset of sensory block
The following table displays the variation in the onset of the sensory blockade between the two groups [Figure 2] and [Table 2].
Sensory block (duration)
The following table shows the variation in the duration of the sensory blockade [Figure 3] and [Table 3].
Motor block (onset)
The following table illustrates the variation in the onset of motor blockade between the two groups[Figure 4] and [Table 4].
Duration of motor block
The following table demonstrates the variation in the duration of motor blockade between the two groups [Figure 5] and [Table 5].
The following table shows the incidence of side effects between the two groups [Figure 6] and [Table 6].
Duration of analgesia
The table shows the variation in the duration of analgesia between the two groups [Figure 7] and [Table 7].
|Figure 7: Frequency distribution for total duration of analgesia in minutes|
Click here to view
| Results|| |
The onset of sensory block was longer with the magnesium sulfate group (5.96 ± 0.958 min) as compared to midazolam group (3.629 ± 0.773 min). This difference was statistically significant. The duration of sensory was found to be 153.548 ± 19.761 min in the magnesium sulfate group which was longer than the midazolam group (138.871 ± 12.559 min). This difference was found to be statistically significant. The mean duration of onset of motor block in the magnesium sulfate group was 8.323 ± 1.388 min and in the midazolam group was 7.952 ± 0.818 min and this difference was statistically significant.
The duration of motor block was longer in the magnesium sulfate group (133.065 ± 14.210 min) as compared to the midazolam group (127.339 ± 10.391 min). The total duration of analgesia which is the time from the intrathecal injection of the drug to the time when patient first requests analgesia was found to be longer in the magnesium sulfate group (206.452 ± 26.246 min) as compared to the midazolam group (185.323 ± 12.895 min) with P < 0.05 which is statistically significant.
The incidence of hypotension (defined as blood pressure lower than 20% of baseline value) was equal among the two groups and was not statistically significant. Bradycardia (defined as a heart rate < 50/min) was not seen in any of the patients in our study. In our study we found two patients in the midazolam group and three patients in magnesium sulfate group who experienced shivering. In the midazolam group two patients experienced nausea and one patient had vomiting; whereas, in the magnesium sulfate group four patients had nausea and two patients experienced vomiting. Other adverse effects like pruritis and urinary retention were not seen in any of the study groups. In our study, though we found no significant hemodynamic side effects with intrathecal midazolam or magnesium sulfate, we did observe higher sedation scores in the midazolam group as compared to the magnesium sulfate group with a P value < 0.05, which was statistically significant.
| Conclusion|| |
In our study we compared the clinical effects of intrathecal midazolam (1 mg preservative free) with intrathecal magnesium sulfate (50 mg preservative free) when used as adjuncts to hyperbaric bupivacaine in patients undergoing lower abdominal and orthopedic surgery.
- The two study groups were comparable with respect to age, gender, weight, height, and ASA physical status.
- We found that the onset of sensory block was prolonged with magnesium group (5.96 ± 0.958 min) as compared to the midazolam group (3.629 ± 0.773 min) and this difference was statistically significant.
- The duration of sensory block was 153.548 ± 19.761 min in the magnesium sulfate group, which was longer than the midazolam group (138.871 ± 12.559 min) and hence statistically significant.
- The onset of motor block in the magnesium group was 8.323 ± 1.388 min, which was longer than the midazolam group (7.952 ± 0.818 min).
- We observed a longer duration of motor block in the magnesium group (133.065 ± 14.210 min) as compared to the midazolam group (127.339 ± 10.391 min) and this difference was statistically significant.
- Our study shows that 50 mg magnesium sulfate when added to hyperbaric bupivacaine intrathecally resulted in a prolonged duration of postoperative analgesia as compared to 1 mg of intrathecal midazolam (206.452 ± 26.246 vs 185.323 ± 12.895 min) and this difference was statistically significant.
- We observed that the incidence of hypotension and other adverse effects such as nausea, vomiting, and shivering was comparable between the two groups and not statistically significant.
- The sedation scores were found to be higher in the midazolam group as compared to the magnesium sulfate group.
- The VAS score at the time when patient first requests for analgesia was higher in the midazolam group as compared to the magnesium sulfate group.
Our study confirms the analgesic efficacy of both intrathecal magnesium sulfate (50 mg) and midazolam (1 mg) when added to hyperbaric bupivacaine for spinal anesthesia. We conclude that 50 mg of intrathecal magnesium sulfate prolongs the duration of sensory and motor block and also the duration of postoperative analgesia with low pain scores as compared to midazolam group. However, it delayed the onset of sensory and motor block. On the other hand, 1 mg of intrathecal midazolam produced an early onset of sensory and motor block, but the duration of analgesia was less as compared to the magnesium group.
| References|| |
|1.||Schug SA, Saunders D, Kurowski I, Paech MJ. Neuraxial drug administration: A review of treatment options for anaesthesia and analgesia. CNS Drugs. 2006;20:917-33. |
|2.||Staikou C, Paraskeva A. The effects of intrathecal and systemic adjuvants on subarachnoid block. Minerva Anestesiol. 2013 July 9. ( Epub Ahead of print ). |
|3.||Kim JE, Kim NY, Lee HS, Kil HK. Effects of intrathecal dexmedetomidine on low-dose bupivacaine spinal anesthesia in elderly patients undergoing transurethral prostatectomy. Biol Pharm Bull 2013;36:959-65. |
|4.||Bani-Hashem N, Hassan-Nasab B, Pour EA, Maleh PA, Nabavi A, Jabbari A. Addition of intrathecal Dexamethasone to Bupivacaine for spinal anesthesia in orthopedic surgery. Saudi J Anaesth 2011;5:382-6. |
|5.||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. |
|6.||Ozalevli M, Cetin TO, Unlugence H. The effect of adding intrathecal magnesium sulphate to bupivacaine - fentanyl spinal anesthesia. Acta Anaesthesiol Scand 2005;49:1514-9. |
|7.||Bharti N, Madan R, Mohanty PR, Kaul HL. Intrathecal midazolam added to bupivacaine improves the duration and quality of spinal anaesthesia. Acta Anaesthesiol Scand 2003;47:1101-5. |
|8.||Ho KM, Ismail H. Use of intrathecal midazolam to improve perioperative analgesia: A metaanalysis. Anaesth Intensive Care 2008;36:365-73. |
|9.||Tucker AP, Lai C, Nadeson R, Goodchild CS. Intrathecal midazolam I: A cohort study investigating safety. Anesth Analg 2004;98:1512-20. |
|10.||Joshi SA, Khadke VV, Subhedar RD, Patil AW, Motghare VM. Comparative evaluation of intrathecal midazolam and low dose clonidine: Efficacy, safety and duration of analgesia. A randomized, double blind, prospective clinical trial. Indian J Pharmacol 2012;44:357-61. |
|11.||Jabalameli M, Pakzadmoghadam SH. Adding different doses of intrathecal magnesium sulfate for spinal anesthesia in the cesarean section: A prospective double blind randomized trial. Adv Biomed Res 2012;1:7. |
|12.||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;25:892-7. |
|13.||Pascual-Ramírez J, Gil-Trujillo S, Alcantarilla C. Intrathecal magnesium as analgesic adjuvant for spinal anesthesia: A meta-analysis of randomized trials. Minerva Anestesiol 2013;79:667-78. |
|14.||Shadangi BK, Garg R, Pandey R, Das T. Effects of intrathecal midazolam in spinal anaesthesia: A prospective randomised case control study. Singapore Med J 2011;52:432-5. |
|15.||Wu YW, Shiau JM, Hong CC, Hung CP, Lu HF, Tseng CC. Intrathecal midazolam combined with low-dose bupivacaine improves postoperative recovery in diabetic mellitus patients undergoing foot debridement. Acta Anaesthesiol Taiwan 2005;43:129-34. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]