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ORIGINAL ARTICLE
Year : 2023 | Volume
: 13
| Issue : 1 | Page : 51-57
Comparison of two different doses of magnesium sulfate as an adjuvant to intrathecal bupivacaine in patients with pre-eclampsia undergoing elective cesarean section: A prospective double-blind randomized study
Swapnil Tuteja1, Apoorva Gupta2, Savita Choudhary3, Roshni Panwar3, Rajeshwar Zala3, Ravina Bhokan3
1 Department of Anesthesia, American International Institute of Medical Sciences, Udaipur, Rajasthan, India
2 Department of Anesthesia, The Oxford Medical College Hospital and Research Center, Bangaluru, Karnataka, India
3 Department of Anesthesiology and Critical Care, Geetanjali Medical College, Udaipur, Rajasthan, India
Correspondence Address:
Dr. Savita Choudhary
Professor, Department of Anesthesiology and Critical Care, Geetanjali Medical College, Udaipur, Rajasthan
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/JOACC.JOACC_35_22
Background: Intrathecal magnesium sulfate is now emerging as a safe and effective adjuvant for spinal anesthesia (SA). The aim of the present study was to compare the efficacy of two doses of intrathecal magnesium in parturients with pre-eclampsia. Methods: This prospective randomized double-blind study was conducted on 105 parturients undergoing elective cesarean section (CS) who were randomized into three groups of 35 each: Group C, M50, and M75. Group M50 and group M75 received 50 mg of 50% (0.1 ml) and 75 mg of 50% (0.15 ml) magnesium sulfate, respectively. All of the groups received 10 mg of 0.5% heavy bupivacaine with normal saline accordingly to make a total volume of 2.2 ml. The sensory and motor block characteristics, visual analogue scale (VAS) score, post-operative analgesic requirements, hemodynamic parameters, and adverse effects were compared. Results: The sensory and motor block characteristics were significantly delayed in group M75 compared to group M50 and the control group (P < 0.05). VAS scores were significantly high in the control group up to 6 h as compared to group M50 and group M75 (P < 0.05). The time to first rescue analgesia was significantly extended in group M75 (222.86 ± 12.502 min) as compared to group M50 (221.14 ± 13.671 min) and the control group (127.43 ± 11.464 min) (P < 0.05). Conclusion: Intrathecal magnesium sulfate at doses of 50 mg and 75 mg in pre-eclamptic parturients undergoing elective CS results in prolonged duration of analgesia, decreased VAS scores and also delays the first rescue analgesic requirement with a favorable adverse effect profile in terms of decreased incidence of nausea and shivering.
Keywords: Cesarean section, intrathecal adjuncts, magnesium sulfate, parturients, pre-eclampsia
Several intrathecal adjuncts such as opioids, clonidine, dexmedetomidine, and neostigmine have been used for prolonging analgesia, reducing the dose of intrathecal local anesthetic, and also to intensify the effects of subarachnoid blocks. However, significant undesirable effects such as pruritus, urinary retention, respiratory depression, sedation, hemodynamic instability, nausea, and vomiting may limit their use.[1],[2],[3],[4] Intrathecal magnesium has been found to be safe and effective as an adjuvant to bupivacaine for spinal anesthesia (SA).[5],[6],[7],[8],[9]
Central sensitization, an activity-dependent increase in the excitability of spinal neurons, is considered as one of the mechanisms involved in persistent post-operative pain,[6] and it depends on the activation of dorsal horn N-methyl D-aspartate (NMDA) receptors by excitatory amino acid transmitters such as aspartate and glutamate. Magnesium sulfate is known as "nature's physiological calcium channel blocker" and it non-competitively antagonizes NMDA receptors in a voltage-dependent fashion.[10],[11] Anti-nociceptive activity of magnesium is probably due to the regulation of calcium influx into the cells in the central nervous system and antagonism of NMDA receptors.[12] The analgesic effect of magnesium is due to negative modulation on NMDA receptors, along with coupling with ion channels such as K+ and Ca2+.
Due to physiologic changes in pregnancy and pre-eclampsia, the dose requirement of intrathecal MgSO4 may vary. Intrathecal magnesium sulfate has been used usually in doses of 50 mg and 100 mg in the previous studies only fewer side effects were reported with these doses.[7],[13] Few studies have demonstrated that the addition of magnesium sulfate to intrathecal local anesthetics with or without opioids could prolong the duration of analgesia, reduce post-operative analgesic requirements, and perioperative shivering without significant side effects.[6],[8],[13],[14],[15],[16] The present study was planned to evaluate the effect of adding two different doses of magnesium sulfate (50 mg vs 75 mg) to 0.5% hyperbaric bupivacaine intrathecally in parturients with pre-eclampsia scheduled for elective cesarean section (CS).
Material and MethodsThis prospective, randomized, double-blinded controlled study was conducted at a tertiary-care teaching center from February 2019 to June 2020 after obtaining approval from the Institutional Research Review Board and Human Research Ethics Committee (approval number GU/HREC/EC/2019/1573 dated February 1, 2019). All pre-eclamptic parturients aged 18–40 years, ASA grade II with singleton pregnancy, undergoing elective cesarean delivery, and not on MgSO4 prophylaxis were included. Written informed consent was obtained from each participant. Parturients with coexisting hepato-renal or other end-organ disease, uncontrolled hypertension, morbid obesity, twin or complicated pregnancy, contraindication or refusal to subarachnoid block, known allergy to any of the study drugs, history of opium addiction, or consuming drugs that modify pain perception were excluded.
A routine pre-anesthetic evaluation of each case was carried out a day before surgery. Maternal demographic data including age, weight (kg), gestation week (weeks), parity, and number of previous CS were noted. Patients were kept nil orally for 6 h before surgery, and peripheral 18-gauge intravenous (i.v.) cannula was inserted in the non-dominant upper limb. All parturients were premedicated with i.v. injection of ranitidine (1 mg/kg), injection of metoclopramide (1–2 mg/kg), and cohydration with lactated Ringer's solution. Before entering the operating room, all patients were familiarized with the procedure, including the visual analogue scale (VAS) score for pain assessment (0= no pain and 10= maximum imaginable pain). On arrival at the operation theater, the baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), mean arterial pressure (MAP), electrocardiogram (ECG), and oxygen saturation (SpO2) were recorded in the supine position. Randomization was performed using a computer-generated random table, and the parturients were assigned to three groups. The patient and the anesthesiologist who monitored the patients were blinded to group allocation. The study drug was prepared by an anesthesiologist who was not involved in the study. All of the groups received 10 mg of 0.5% heavy bupivacaine with normal saline to make a total volume of 2.2 ml in all groups with additional magnesium sulfate, 50 and 75 mg in the groups M50 and M75, respectively. Subarachnoid block (SAB) was performed with strict aseptic precautions in the L3-L4 or L4-L5 intervertebral space using a 25G Quincke spinal needle with the patient in the sitting position. The study drug was injected as per group allocation and the patient was repositioned immediately following the block in the supine position with a wedge under the right buttock. The hemodynamic variables such as HR, SBP, DBP, MAP, and SpO2 were recorded at the time of spinal drug administration, then every 2 min for the next 20 min, and thereafter every 5 min until the completion of surgery. Hypotension was defined as a fall in SBP below 20% of baseline and was treated with 6 mg of intravenous ephedrine incrementally. Any decrease in HR below 50/min was regarded as bradycardia and was treated with 0.6 mg of intravenous atropine.
The sensory block was assessed by the pinprick method every 1 min until the maximum height of sensory block was achieved. The onset of sensory block was defined as the time to reach the T6 dermatome. The duration of sensory block was defined as the time of regression of two segments from the maximal block height. Post-operatively, sensory block monitoring was carried out every 5 min until 30 min. The motor blockade was assessed according to the Bromage scale. Complete motor block was defined as score 3 and complete motor block recovery as score 0. This was assessed every 1 min until Bromage 3 was achieved and reassessed after the completion of surgery at regular intervals until Bromage 0 was achieved.
The VAS score was noted at different time intervals until 24 h post-operatively. The duration of SA was defined as the time from intrathecal injection to demand for the first dose of rescue analgesia in the post-operative period. An injection of tramadol (2 mg/kg) i.v. was given as a rescue analgesic when VAS ≥3 and supplemented with an injection of diclofenac 75 mg i.v. if required. The total number of doses and the total dose of analgesic required in 24 h post-operatively were recorded.
Adverse effects such as nausea, vomiting (treated with ondansetron i.v. 0.15 mg/kg), pruritus, bradycardia, and shivering were recorded along with neonatal Apgar scores.
The primary outcome was to compare the efficacy of two different doses of magnesium sulfate on the basis of characteristics of sensory and motor block. The secondary outcomes were to compare post-operative analgesic requirements, requirement of ephedrine, hemodynamic variables, neonatal outcome, and adverse effects.
The sample size was calculated using software Epi info™ 7 with the assumption of an alpha error of 5% (confidence level 95%) and a beta error of 20% (power of study 80%); a minimum of 22 participants were required in each group. Using Cochrane's formula, samples of 35 patients were taken for each group.
Statistical analysis: Data was presented as mean, standard deviation (SD), median (interquartile range), or number as appropriate. Statistical analysis was performed using IBM SPSS statistics software version 21. Numerical data were compared among all the three groups against baseline values using analysis of variance (ANOVA). The categorical data were analyzed by chi-square test. The results were expressed as the mean ± SD. P values less than 0.05 were considered significant.
ResultsThe study included 105 patients who were randomly allocated into three equal groups [Figure 1]. Demographic data, obstetric data, and neonatal outcomes in all three groups were found comparable and non-significant (P > 0.05) [Table 1]. Hemodynamic parameters (HR, SBP, DBP, MAP, and SpO2) in all of the three groups at different time intervals intra-operatively and post-operatively were found comparable (P > 0.05).
Table 1: Comparison of demographic, obstetric data, and neonatal outcomes in the three groupsThe onset of sensory block, as well as the time to reach the maximum level of sensory block, was earliest in the control group (4.57 ± 0.884 min) and (6.51 ± 1.04 min), respectively, followed by M50 (6.20 ± 0.901 min; 8.34 ± 0.684 min) and M75 (6.34 ± 0.765 min; 8.54 ± 0.657 min), respectively, which was statistically significant (P < 0.001). Time to two-segment sensory regression, that is, the duration of sensory block was earliest for control (106.29 ± 11.137 min) than M50 (166.86 ± 7.96 min) and M75 (167.71 ± 7.702 min), which was statistically significant (P < 0.001), although on comparing these sensory block characteristics between groups M75 and M50, the difference was statistically non-significant (P > 0.05) [Figure 2].
A faster onset of motor block was observed in the control group (2.14 ± 0.692 min), as compared to M50 (2.34 ± 0.0684 min) and M75 (2.71 ± 0.0825 min), which was statistically significant (P < 0.05). The time to reach Bromage 3, that is, complete motor block was significantly earlier in the control group (6.74 ± 1.039 min), followed by M50 (6.83 ± 0.747 min) and M75 (7.51 ± 0.742 min) (P < 0.001). Complete motor recovery, that is, the time to reach Bromage 0 was earliest for control (92.57 ± 11.464 min) than for M50 (108.57 ± 7.724 min) and M75 (120.0 ± 8.044 min), which was statistically significant (P < 0.001) [Figure 3].
The VAS score in three groups at different time intervals was found to be significant from 30 min to 6 h among three groups (P < 0.05). However, beyond 8 h, up to 24 h, there was no statistically significant difference in the VAS score between the three groups (P > 0.05)[Figure 4].
Figure 4: Comparison of the VAS in all three groups at different time intervalsThe time to first rescue analgesia was significantly extended in group M75 (222.86 ± 12.502) than in group M50 (221.14 ± 13.671 min) and the control group (127.43 ± 11.464 min), which was found to be significant (P < 0.001) [Figure 5]. The total number of doses and the total dose of rescue analgesic was highest in the control group than in group M75 and group M50 but was found to be statistically non-significant (P > 0.05).
Figure 5: Comparison of time to first rescue analgesic dose in all three groupsThe incidence of nausea was 34.28% in the control group, whereas it was 11.42% in both M50 and M75 groups, which was statistically significant (P < 0.05). The incidence of shivering in groups C, M50, and M75 was 31.42%, 5.71%, and 5.71%, respectively (P < 0.05)[Table 2].
DiscussionThe results of the present study showed a non-significant change in the sensory block characteristics after intrathecal administration of 75 mg and 50 mg doses of magnesium sulfate as an adjuvant to bupivacaine in SA. However, the onset of sensory blockade was significantly prolonged in group M75 followed by group M50 and the control group. This might be a consequence of the addition of magnesium to bupivacaine; the pH and baricity of the solution differed and hence the delayed onset of sensory blockade.[5],[17] Pascual-Ramirez et al.[16] have also suggested that the delay in onset with the addition of magnesium could also indicate the modulation of the neuronal electrical conduction blockade. Rana et al.[18] found a significant difference in the mean onset time of sensory block with adjuvant magnesium than fentanyl and fentanyl–magnesium combination. The earlier onset with fentanyl could be attributed to its lipophilic nature. In the present study, there was a statistically significant difference between the three groups in terms of time to reach the maximum level of sensory block. It was delayed in group M75 and group M50 than in group C. Previously studies[9],[19],[20] have shown that the time to attain the maximum sensory block was longer in the magnesium group than fentanyl added intrathecally. Elie Hamawy et al.[21] compared intrathecal magnesium 10 mg and dexmedetomidine 10 μg with the control group and found that the duration of sensory block was significantly extended in group M vs group D and group C. Similarly in our study, the duration of sensory block was prolonged in group M75 and M50 than in group C. Magnesium sulfate is a potent intrathecal adjuvant and has analgesic and anti-nociceptive properties owing to its non-competitive NMDA receptor antagonism action, which prevents the induction of intrathecal central sensitization attributed to peripheral nociceptive stimulation and thereby results in enhanced analgesia.[11]
The onset of motor block was statistically significant in the groups with study drugs as compared to the control group. The delayed onset could be a result of the change in the pharmacokinetics of bupivacaine due to the activation of cytochrome p450 and other cytochromes by magnesium.[14],[22] The time to attain complete motor block and duration of motor block was significantly prolonged in groups M75 and M50. Similarly, other studies have also shown that magnesium sulfate delays the onset of both sensory and motor blocks.[9],[15],[16],[23]
Our control group patients experienced more post-operative pain with higher VAS scores at various time intervals as compared to group M50 and group M75. Prolonged sensory blockade in the magnesium group could be the reason for lower VAS scores in the early post-operative period, which could further lend credence to the anti-nociceptive action of MgSO4 as supported by other studies.[20],[24] Magnesium sulfate as an adjuvant might improve patient comfort by increasing the pain threshold during peritoneal handling.
The duration of analgesia was significantly decreased in group C as compared to group M50 and group M75; however, there was no significant difference between M50 and M75, which was further corroborated by Kathuria et al.[24] On analyzing the analgesic consumption in these patients over 24 h, although we observed higher VAS scores and higher analgesic consumption in the control group, there was no statistical significance, as compared to the magnesium groups.
Similar to the previous study,[25] the incidence of nausea in the present study was higher in the control group (34.28%) as compared to group M50 (11.42%) and group M75 (11.42%), which was found to be statistically significant (P < 0.05). Similarly, the incidence of shivering was found to be 31.42% in the control group as compared to 5.71% in both M50 and M75 groups, which was statistically significant (P < 0.05). Magnesium sulfate reduces the incidence of shivering after neuraxial blockade when given via the intrathecal or i.v. route.[8] Magnesium sulfate may reduce post-operative shivering due to its antagonizing property on the NMDA receptor which modulates thermoregulation at multiple levels such as pre-optic anterior hypothalamus, locus coeruleus, and the dorsal horn of the spinal cord.[26],[27] Sarma et al.[20] found that the incidence of shivering was 10% in the fentanyl group, whereas no patient in the magnesium group had shivering.
The incidence of hypotension was highest in the control group (17.4%) than in the M50 (2.85%) and M75 groups (2.85%) but was statistically non-significant in the present study. Other studies had also reported similar results. This may be attributed to the absence of the systemic effect of intrathecal magnesium.[28],[29] Moreover, patients with pre-eclampsia experience less hypotension during SA due to increased production of circulating factors with a potent vasopressor effect, decreased synthesis of vasodilators such as nitric oxide, prostacyclin because of endothelial and vascular smooth muscle dysfunction, and increased sensitivity to vasopressor drugs.[29]
This study had some limitations. The total fluid requirement, oxytocin used, and blood loss during the study period were not recorded. Placental transfer and exposure of neonates to the study drug should also be studied in the future.
Determining the optimum bolus dose by sequential analysis and evaluating the safety of the drug in high-risk obstetric patients in a larger study population during emergency cesarean delivery can further enhance our knowledge of the safety of intrathecal magnesium. Long-term follow-up of these patients to assess signs of neurotoxicity, neurologic deficits, or severity of chronic pain that may reveal the action of magnesium sulfate in modulating wind-up and synaptic plasticity can be areas of further research.
ConclusionMagnesium sulfate in both doses (50 mg and 75 mg) as an adjuvant to hyperbaric bupivacaine for SA in pre-eclamptic parturients undergoing elective CS results in prolonged duration of analgesia, decreased VAS scores, and delay in the first rescue analgesic requirement with a favorable adverse effect profile in terms of decreased incidence of nausea and shivering.
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Conflicts of interest
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References
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