|Year : 2017 | Volume
| Issue : 1 | Page : 20-25
Efficacy of magnesium sulphate and/or fentanyl as adjuvants to intrathecal low-dose bupivacaine in parturients undergoing elective caesarean section
Shelly Rana, Dheeraj Singha, Sudarshan Kumar, Yuvraj Singh, Jai Singh, RK Verma
Department of Anaesthesia, DRPGMC, Kangra, Himachal Pradesh, India
|Date of Web Publication||1-Jun-2017|
Department of Anaesthesia, DRPGMC, Kangra, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
Background and Aim: Recent developments in the field of intrathecal adjuvants have led to accelerated functional recovery with adequate postoperative analgesia following caesarean section. Encouraging results have been obtained with the use of intrathecal magnesium with or without fentanyl in parturients. This study was conceived to evaluate the effects of adding magnesium sulphate and/or fentanyl to low-dose intrathecal bupivacaine in parturients undergoing caesarean section under subarachnoid block (SAB). Materials and Methods: Ninety, American Society of Anesthesiologists I or II, parturients for the elective caesarean section were enrolled in this prospective randomized, double-blind study. The parturients were randomly assigned to three groups. In Group M, parturients received 8.5 mg (1.7 mL) hyperbaric bupivacaine 0.5% with 50 mg (0.1 mL) magnesium sulphate and 0.4 mL normal saline. Group F received 8.5 mg hyperbaric bupivacaine 0.5% with 20 μg (0.4 mL) fentanyl and 0.1 mL of normal saline and Group MF parturients received 8.5 mg hyperbaric bupivacaine 0.5% with 20 μg fentanyl added to 50 mg magnesium sulphate. Results: Parturients in the group MF were pain free for longest period (273.70 ± 49.30 min) as compared to group M (252.67 ± 40.76 min) and group F (239.80 ± 38.45 mins) [gp MF vs F and, gp M vs F (P = 0.00)]. The total doses of rescue analgesics were least in group MF (2.43 ± 0.56) and maximum in group F (3.30 ± 0.63), with comparable neonatal outcomes in three groups. Conclusion: Our data supports synergistic action of intrathecal magnesium sulphate to fentanyl, and it is concluded that on addition of intrathecal magnesium sulphate and fentanyl to low-dose bupivacaine as adjuvant in subarachnoid block, results in prolonged duration of postoperative analgesia with lesser pain scores and lesser dose of rescue analgesia with better haemodynamic stability.
Keywords: Adjuvants, anaesthesia, analgesia, pain, postoperative, magnesium sulphate
|How to cite this article:|
Rana S, Singha D, Kumar S, Singh Y, Singh J, Verma R K. Efficacy of magnesium sulphate and/or fentanyl as adjuvants to intrathecal low-dose bupivacaine in parturients undergoing elective caesarean section. J Obstet Anaesth Crit Care 2017;7:20-5
|How to cite this URL:|
Rana S, Singha D, Kumar S, Singh Y, Singh J, Verma R K. Efficacy of magnesium sulphate and/or fentanyl as adjuvants to intrathecal low-dose bupivacaine in parturients undergoing elective caesarean section. J Obstet Anaesth Crit Care [serial online] 2017 [cited 2017 Aug 22];7:20-5. Available from: http://www.joacc.com/text.asp?2017/7/1/20/207391
| Introduction|| |
Changing patterns of obstetric management and an increase in maternal requests have contributed to the increasing rate of caesarean delivery, the incidence ranging between 20–40%. Post-caesarean delivery pain relief is important as adequate analgesia tends to enhance the mother's ability to optimally care for her infant in the immediate postpartum period. Pain relief must be safe, effective and should not interfere with the mother's ability to care for her infant, with no adverse neonatal effects  in breast-feeding women.
Neuraxial anaesthesia for caesarean delivery  is preferred to general anaesthesia, because it minimizes the risk of failed intubation, ventilation and aspiration. Neuraxial anaesthesia has the benefit of an awake mother at delivery and no anaesthetic exposure to the neonate. Addition of opioids to intrathecally and/or epidurally administered local anaesthetic provides an easy and effective means to maintain prolonged postoperative analgesia. The combination allows for a reduction in doses of both classes of drugs, thus reducing the likelihood of side effects attributable to each.
Recent studies suggested , that magnesium sulphate can also play a beneficial role in spinal anaesthesia when administered via intrathecal route. Intrathecal magnesium sulphate has been shown to increase the potency of lipophilic opioids with or without local anaesthetics in caesarean sections, by virtue of it being voltage-gated N-methyl-D-aspartate (NMDA)-receptor antagonist.
The present study compared the synergistic effect of magnesium sulphate and/or fentanyl added to low-dose intrathecal bupivicaine 0.5% (hyperbaric), in parturients undergoing caesarean section under subarachnoid block (SAB).
| Material and Methods|| |
After approval by Hospital Institutional Ethics Committee, this prospective, randomized, double-blind, controlled clinical trial was conducted from May 2014 to December 2015. This study was carried out on 90American Society of Anesthesiologists (ASA) I-II parturients, undergoing elective caesarean section under SAB. Parturients refusal for block, presence of bleeding disorders, thrombocytopenia, local infection at the site of intrathecal injection, any history of allergy to study drugs, parturients having pregnancy-induced hypertension were excluded from study. Parturient in whom the block effect was partial and required supplementary anaesthesia, parturients on magnesium therapy and foetal distress were also excluded from the study.
All parturients were explained about the procedure, advantages and risks of the procedure during the preoperative assessment done one day prior to surgery and then informed consent was obtained from the patient. Pain was assessed using a verbal numeric scale (VNS) from 0 to 10 (0 = no pain; 10 = maximum imaginable pain). The parturients were randomized into three groups using computer generated random number table.
In Group M, parturients received 8.5 mg (1.7 mL) hyperbaric bupivacaine 0.5% with 50 mg (0.1 mL) magnesium sulphate and 0.4 mL normal saline. Group F received 8.5 mg hyperbaric bupivacaine 0.5% with 20 μg (0.4 mL) fentanyl and 0.1 mL of normal saline and Group MF parturients received 8.5 mg hyperbaric bupivacaine 0.5% with 20 μg fentanyl added to 50 mg magnesium sulphate.
Random group assigned was enclosed in a sealed opaque envelope to ensure concealment of allocation sequence. After shifting the patient inside operation theatre, sealed envelope was opened by anaesthesiologist not involved in the study to prepare the drug solution according to randomization. The observer who collected the peri-operative data as well as the parturients were blinded to the drug solution administered.
All patients were kept nil orally for eight hours for solid food and clear fluid was allowed, till two hour before the procedure. They were given premedication in the form of injection ranitidine 50 mg and injection metoclopramide 10 mg intravenously half an hour prior to surgery. On arrival to operation theatre, standard monitoring including pulse oximeter, automated blood pressure and five lead electro-cardiogram was commenced and baseline parameters, i.e., heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), peripheral oxygen saturation (Spo2) were recorded. Parturients were given intravenous preload of 10 ml/kg Ringer's lactate solution before surgery.
Lumbar puncture was performed in the left lateral position using a 26-gauge quincke needle at L3-4 interspace using a midline approach. After free flow of cerebrospinal fluid, the premixed solution (2.2 mL) was injected over 10 seconds with the needle orifice directed cephalad. The parturients were immediately placed in supine position. Oxygen was supplemented at the rate of 4 liters/min to the parturients with oxygen mask.
HR, SBP, DBP and mean arterial pressure were noted at baseline, immediately after block insertion and then every 2 min for the first 30 min and every 5 min until the end of the surgery. Hypotension was defined as a fall in systolic pressure >20% below baseline and injection phenylephrine 25 μg bolus was given. Bradycardia (heart rate <50/min) was treated with intravenous atropine sulphate 0.02 mg/kg. Sensory block was assessed every minute by pinprick in the dermatomes T-10, T-8 and T-6, until a stable level of block was achieved and surgery was permitted after T6 sensory block.
The duration of sensory block was defined as the time from intrathecal injection to regression of the sensory block to L1. Motor block was assessed using a modified bromage score [0 = no motor loss; 1 = inability to flex hip; 2 = inability to flex hip and knee; 3 = inability to flex hip, knee and ankle] with motor recovery assumed, when the score was zero.
The duration of analgesia was defined as the period from spinal injection to the time of administration of first rescue analgesic for pain in the postoperative period. Pain was assessed using a VNS from 0 to 10 (0 = no pain; 10 = maximum imaginable pain) every 15 min after the block until the end of the surgery and 2, 4, 8, 12, 24 h postoperatively. Postoperatively, intramuscular diclofenac 75 mg was given for rescue analgesia, whenever the pain score was >3 and second rescue analgesic in the form of tramadol (1 mg/kg), slow intravenously, if no relief was achieved within 30 min of the diclofenac injection.
The incidence of side effects such as sedation, pruritus, nausea and vomiting was noted every 15 min during surgery and 2, 4, 8, 12 and 24 h postoperatively. Neonatal outcome was assessed by Apgar score at 1 and 5 min and the need for neonatal mask ventilation and tracheal intubation by a paediatrician, unaware of the study medication.
The primary outcome included block characteristics and duration of analgesia. The secondary outcomes were VNS score over a period of 24 h, number of rescue analgesics, haemodynamic stability and neonatal outcomes.
Data was collected and entered in MS Excel 2010. Statistical analysis was performed using SPSS software 17 (SPSS, Inc., Chicago, IL). Normal distribution of the collected data was first verified with the Kolmogorov-Smirnov test. Continuous variables were analyzed with analysis of variance or the Kruskal-Wallis test on the basis of data distribution. Post hoc comparisons were performed with the unpaired Student's t-test or the Mann–Whitney U-test with Bonferroni's correction, as indicated. Categorical variables were analyzed with the contingency table analysis and the Fisher's exact test. P ≤ 0.05 was considered significant. Continuous variables are presented as mean ± SD or median (range) according to data distribution, whereas categorical variables are presented as number (percentage).
Duration of analgesia was taken as the outcome measure for the purpose of sample size calculation. It was estimated that 24 subjects would be required per group in order to detect a difference of 45 min in this parameter between the groups, with 80% power and 5% probability of Type 1 error. This calculation assumed a pooled standard deviation of 45 min for the duration of analgesia. To account for probable drop outs and block failure we included 30 patients in each group.
| Results|| |
Ninety-eight parturients with singleton pregnancy, scheduled for elective caesarean section under SAB enrolled in the study; of these eight parturients were excluded for not meeting the inclusion criteria. Thereby, remaining 90 parturients were randomly divided into three groups. All patients had successful spinal anaesthesia, so no patient was excluded from the study and thirty in each group completed the study successfully. All the parturients were comparable to each other with respect to maternal age, gestational age, gravida status and body mass index, duration of surgery and ASA status [Table 1].
The median value for peak level of sensory block was T4(T4-T6), T4(T4-T6) and T4(T3-T6) in groups M, MF and F, respectively (P > 0.05). Sensory block at T10 level was achieved in minutes (mean ± SD: 1.51 ± 0.39, 2.15 ± 0.74 and 1.61 ± 0.46; gp M and F, gp F and MF: P = 0.000), respectively, in groups F, MF and M. Mean time taken to achieve adequate motor block (bromage score 3) was (mean ± SD) 2.39 ± 0.51, 5.28 ± 1.76 and 3.46 ± 0.64 min in groups F, MF and M, respectively (P = 0.001) [Figure 1]. Total duration of sensory block (regression to T10) was maximum in group MF (211 ± 59.67 min) and minimum in group F (177.13 ± 62.42 min) and in group M, the duration was 192 ± 50.67 min. (P = 0.102) [Figure 2].
|Figure 1: Block characteristics in three groups. Values expressed as mean ± SD. *: gp M and F (P < 0.05), † : gp F and MF (P < 0.05), ‡: gp M and MF (P < 0.05)|
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|Figure 2: Block characteristics in three groups, values expressed as mean ± SD. *: gp M and F (P < 0.05), † : gp F and MF (P < 0.05), ‡: gp M and MF (P < 0.05)|
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Mean duration of motor block (time taken to achieve bromage 0) was minimum in group MF (108.33 ± 29.12 min) and maximum in group M (155.10 ± 59.79 min). In group F, this time was 148.37 ± 60.12 min (P < 0.001; gp M and MF, F and MF: P =0.000, 0.002) [Figure 2]. First rescue analgesia was provided when the VNS score of the patient was >3 at any time in the postoperative period. Mean time till requirement of first post-operative analgesic dose was minimum in group F (239.80 ± 38.45 min) and maximum in group MF (273.70 ± 49.30 min). Mean time till requirement of first post-operative analgesic dose was 252.67 ± 40.76 min in group M (gp MF vs F; gp M and gp F: P =0.001) [Figure 2].
No parturient in any group complained of pain during intraoperative period. In the postoperative period, pain scores were significantly lower at 4 h in the magnesium plus fentanyl group as compared to magnesium and fentanyl group (mean ± SD) 0.5 ± 0.33; 2.50 ± 1.33 and 3.50 ± 1.70 vs. 0.5 ± 0.33, respectively (gp MF and F: P = 0.003 and MF and M: P = 0.023). Though the pain scores at 8, 12 and 24 h were not significant, cumulative VNS scores in the first 24 h were lower in magnesium plus fentanyl groups than in magnesium and fentanyl groups [Figure 3]. Mean dose of rescue analgesics required was minimum in group MF (2.0 ± 0.56) and maximum in group F (2.80 ± 0.63), while mean rescue analgesic requirement was 2.50 ± 0.79 in group M (gp F vs MF: P = 0.04).
|Figure 3: Graphical presentation of verbal numeric score (VNS) over a period of 24 h postoperatively. Data expressed as mean ± SD. *: gp M and F (P < 0.05), † : gp F and MF (P < 0.05), ‡: gp M and MF (P < 0.05)|
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Parturients were haemodynamically stable in the perioperative period; however, the requirement of phenylephrine was maximum in group F (43.3%) and minimum in group M (13.3%). Total phenylephrine requirement in group MF was (30%: gp F vs M: P = 0.02) [Figure 4].
|Figure 4: Phenylephrine requirement in three groups expressed as numbers. *: gp M and F (P < 0.05), † : gp F and MF (P < 0.05), ‡: gp M and MF (P < 0.05)|
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Neonatal outcome was comparable in the three groups, and no baby required mask ventilation or tracheal intubation at birth. Apgar score of newborn's at birth, 1 min and 5 min after birth was >7 in all the study groups (P = 0.43) [Figure 5].
|Figure 5: Neonatal Apgar score at 1 and 5 minute expressed as median. P > 0.05 in all three groups|
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| Discussion|| |
Addition of opioids to intrathecally and/or epidurally administered local anaesthetic solutions increases the duration of postoperative pain relief. However, the beneficial effect of opioids is dose dependent and increased does are associated with significant side effects.
The use of intrathecal magnesium sulphate in studies, have proved its synergistic effect on lipophilic opioids at lower doses especially in prolonging the duration of analgesia in the postoperative period, by virtue of NMDA receptor antagonist properties.
The present study intended to compare the synergistic effect of magnesium sulphate, and/or fentanyl added to low-dose intrathecal bupivicaine (8.5 mg) 0.5% in parturients undergoing caesarean section under SAB.
Caesarean delivery requires traction of peritoneum and handling of intra-peritoneal organs, resulting in intra-operative visceral pain as observed by Pedersen et al. Thirty-six parturients undergoing elective caesarean section were given intrathecal 7.5 mg–10 mg bupivacaine in group A and 10–12.5 mg of bupivacaine in group B on the basis of height. The moderate to severe pain, in association with peritoneal traction, occurred in 12 patients in group A (70.5%), but only in 6 patients in group B (31.6%). With higher doses of hyperbaric bupivacaine, incidence of intra-operative visceral pain associated is reduced, but with adverse effects like hypotension, bradycardia and nausea.
Bupivacaine sparing effect of intrathecal fentanyl was studied by Choi and colleagues  in spinal anaesthesia for caesarean section, and the authors concluded that the optimal dose of hyperbaric bupivacaine to produce surgical anaesthesia was 12 mg, which was accompanied by high sensory block. With the addition of 10 μg of fentanyl, the dose of bupivacaine could be reduced to 8 mg in spinal anaesthesia for caesarean delivery.
Therefore, the addition of fentanyl in cesarean section has become more popular, with the aim of providing haemodynamic stability with lesser doses of bupivacaine, and quality analgesia in the perioperative period. The results of study by Sabin Gauchan  indicated that 20 μg of intrathecal fentanyl added to hyperbaric bupivacaine (2 ml) for spinal anaesthesia increases the duration of postoperative analgesia, without any adverse effect on foetus and mother. Therefore, a dose of 20 μg (0.4 mL) fentanyl as adjuvant to low-dose 1.7 ml (8.5 mg) intrathecal bupivacaine was chosen for this study.
The dose of magnesium used in the present study was based on data from Buvendraan et al., where 50 mg of spinal magnesium sulphate potentiated fentanyl anti-nociception.
In the present study, the onset of both sensory and motor block was shorter (mean ± SD: 1.51 ± 0.39; 2.39 ± 0.51 min, respectively,) in parturients, who received fentanyl and bupivacaine, than those who received bupivacaine and magnesium (1.61 ± 0.46; 3.46 ± 0.64 min) and fentanyl + magnesium with bupivacaine (2.15 ± 0.74; 5.28 ± 1.76 min). There was significant difference in sensory onset time between [gp F vs MF and gp F vs M: P value = 0.00] group and in motor onset time the significant difference was observed within all three groups (P value = 0.04).
The earlier onset with fentanyl can be attributed to its lipophilic properties. The lipophilic opioids rapidly traverse the dura mater, where they are sequestered in the epidural fat and enter the systemic circulation; they also rapidly penetrate the spinal cord where they binds opioid receptors within the white matter as well as dorsal horn receptors and eventually enter the systemic circulation as they are cleared from the spinal cord. It may also exert a supraspinal action by intrathecal cephalic spread.
However, magnesium had delayed effect on the onset of sensory and motor block with or without fentanyl suggesting that MgSO4 acted only at the spinal level. The combination of fentanyl and magnesium sulphate might result in change of pH, baricity of the injectate solution and contribute to delay in onset, when two drugs are given intrathecally.,
The results of the present study shows that addition of intrathecal magnesium to fentanyl and bupivacaine decreases the duration of motor block as compared to fentanyl group; however, the duration was increased when magnesium was added to bupivacaine. The results can be explained by the lipophilic nature of fentanyl, leading to rapid decline in cerebrospinal fluid levels of the drug as compared to magnesium. These findings correlate well with the study  wherein the duration of motor block was more in magnesium group as compared to fentanyl group.
However, when magnesium is given along with fentanyl and bupivacaine, the resulting change in baricity or pH might have impact on duration of motor block. Other factors that might contribute are obstetric or non-obstetric patients and premixing or sequential administration of the drugs intrathecally.
Increased duration of sensory block was observed in MF and M group and can be explained due to a synergistic interaction between NMDA antagonists and local anaesthetics. Intrathecal magnesium sulphate has been shown to increase the potency of lipophilic opioids with or without local anaesthetics. Potentiation of opioid antinociception occurs by blocking the spinally mediated facilitatory component evoked by repetitive C-fibre stimulation.
The duration of analgesia was increased with addition of magnesium to fentanyl and local anaesthetic and is in accordance to study by Dayioglu et al. In the present study, VNS score at 4 h and cumulative score over a period of 24-h postoperative was significantly less in the MF group. Sometimes, adnexal handling and peritoneal stretch results in parturient discomfort undergoing caesarean section under spinal anaesthesia, leading to pain and nausea. Intrathecal magnesium might increase the threshold of pain due to peritoneal handling and provide greater patient comfort, more so in combination with lipophilic opioid.
In the present study, requirement of phenylephrine was maximum in group F 13 (43.3%) and minimum in group M 4 (13.3%). Total phenylephrine requirement in group MF was 9 (30%), [gp F vs M: P = 0.02]. Similar results were shown in the study done by Sarika K et al., the incidence of hypotension was more in fentanyl group as compared to magnesium group. This may be attributable to supraspinal action  or by intrathecal cephalic spread.
Neonatal outcome as assessed by Apgar score at 1 and 5 minutes in three groups was comparable. Similarly, no adverse foetal outcome of intrathecal fentanyl and magnesium was observed by Malleeswaran et al.
The incidence of nausea and vomiting was comparable in three groups with 26.6% in fentanyl group, as compared to 23.3% and 20% in groups M and MF, respectively (P = 0.102), throughout the study period and this may be related to absence of significant hypotension among groups. The 20 μg of intrathecal fentanyl was also found to be free of significant side effects as observed by Sabin G et al.
In conclusion, the addition of both intrathecal magnesium and fentanyl to low-dose bupivacaine for spinal anaesthesia, in partureints undergoing caesarean section, results in prolonged duration of analgesia with lower pain scores, better haemodynamic Stability and satisfactory neonatal outcomes.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]