|Year : 2015 | Volume
| Issue : 1 | Page : 9-15
Comparison of intrathecal magnesium and fentanyl as adjuvants to hyperbaric bupivacaine in preeclamptic parturients undergoing elective cesarean sections
Bharat Arora1, Deba Gopal Pathak1, Abhijit Tarat1, Deepannita Sutradhar1, Rupankar Nath1, Babita Sheokand2
1 Department of Anaesthesiology and Critical Care, Silchar Medical College and Hospital, Cachar, Assam, India
2 Department of Obstetrics and Gynecology, Silchar Medical College and Hospital, Cachar, Assam, India
|Date of Web Publication||15-Apr-2015|
Dr. Bharat Arora
Room No. 2, New Doctor's Hostel, Silchar Medical Colleege and Hospital, Cachar, Assam - 788 014
Source of Support: None, Conflict of Interest: None
Aims: The aim of this study was to evaluate the onset, duration of sensory and motor block, hemodynamic effects (if any), duration and quality of postoperative analgesia, and adverse effects of magnesium or fentanyl given intrathecally with hyperbaric 0.5% bupivacaine in patients with mild preeclampsia undergoing elective caesarean sections.
Materials and Methods: A total of 60 women with mild preeclampsia undergoing elective cesarean section were included in a prospective, double-blind, controlled trial. Patients were randomly assigned to receive spinal anesthesia with 2 mL 0.5% hyperbaric bupivacaine with 12.5 μg fentanyl (Group F) or 0.1 mL of 50% magnesium sulfate (50 mg) (Group M) with 0.15 ml preservative free distilled water. Onset, duration and recovery of sensory and motor block, time to maximum sensory block, duration of spinal anesthesia and postoperative analgesia requirements were studied. Statistical comparison was carried out using the Chi-square or Fisher's exact tests and independent Student's t-test where appropriate.
Results: The onset of both sensory and motor block was slower in the magnesium group. The duration of spinal anesthesia (246 min ± 11 min vs. 284 min ± 15 min; P < 0.001) and motor block (186.3 ± 12 min vs. 210 ± 10 min; P < 0.001) were significantly longer in the magnesium group. Total analgesic dose requirement was less in Group M. Hemodynamic parameters were comparable in the two groups. Intrathecal magnesium caused minimal side effects.
Conclusions: The addition of magnesium sulfate 50 mg to bupivacaine for sub-arachnoid block in patients with mild preeclampsia undergoing elective cesarean section prolongs the duration of analgesia and reduces postoperative analgesic requirements without additional side effects and adverse neonatal outcomes
Keywords: Analgesia, magnesium, preeclampsia, spinal anesthesia
|How to cite this article:|
Arora B, Pathak DG, Tarat A, Sutradhar D, Nath R, Sheokand B. Comparison of intrathecal magnesium and fentanyl as adjuvants to hyperbaric bupivacaine in preeclamptic parturients undergoing elective cesarean sections. J Obstet Anaesth Crit Care 2015;5:9-15
|How to cite this URL:|
Arora B, Pathak DG, Tarat A, Sutradhar D, Nath R, Sheokand B. Comparison of intrathecal magnesium and fentanyl as adjuvants to hyperbaric bupivacaine in preeclamptic parturients undergoing elective cesarean sections. J Obstet Anaesth Crit Care [serial online] 2015 [cited 2019 Sep 16];5:9-15. Available from: http://www.joacc.com/text.asp?2015/5/1/9/155193
| Introduction|| |
The safety and efficacy of regional anesthesia for preeclamptic patients undergoing caesarean section is well established, ,, but one limitation with spinal anesthesia is, it's relatively short duration of postoperative analgesia. Here lies the role of adding adjuvants to intrathecal local anesthetics. Local anesthetics plus opioids administered together intrathecally have been shown to have a synergistic analgesic effect. ,, Intrathecal opioids increase the quality of analgesia and reduces local anesthetic requirements, with some studies showing favorable effects on hemodynamics stability, ,,, though with side-effects such as pruritus, nausea and vomiting.
Postoperative pain is associated with neuroendocrine responses, catecholamine release and increased morbidity.  Noxious stimulus leads to a release of glutamate and aspartate neurotransmitters. Activation of N-methyl-D-aspartate (NMDA) or AMPA receptors through this mechanism may lead to central sensitization of pain, which may be important in determining the duration and intensity of postoperative pain. , This may be detrimental especially in preeclamptic patients.  In addition, effective pain relief facilitates early ambulation of the mother and help in strengthening the maternal-child bonding earlier. Adequate analgesia following caesarean section decreases morbidity improves patient outcome and facilitates care of the newborn Intrathecal magnesium, an NMDA antagonist, has been shown to prolong analgesia without significant side effects in healthy parturients.
Clinical trials in obstetric , and nonobstetric ,,, populations have shown that intrathecal magnesium increases the duration of analgesia without increasing side effects. Intrathecal magnesium has been found to be safe and effective as an adjuvant to bupivacaine in normal parturients for labor analgesia.  The present study therefore compared the effect of adding intrathecal magnesium sulfate to bupivacaine in spinal anesthesia in women with mild preeclampsia undergoing elective caesarean section, with bupivacaine-fentanyl spinal anesthesia.
Animal studies have shown that intrathecal magnesium produces antinociception and potentiation of opioid activity, presumably by its action as a voltage-gated NMDA-receptor antagonist. , (mediate neuronal signaling and play a critical role in pain processing). It is the fourth most common cation in the body. Normal magnesium level in cerebrospinal fluid (CSF) amounts to 2.2 ± 0.9 mEq. Its neuroprotective role is still under evaluation.
| Materials and Methods|| |
After approval of the Institutional Ethical Committee and written informed consent, 60 pregnant women with singleton pregnancies diagnosed with mild preeclampsia , (systolic pressure 140-160 mmHg, diastolic pressure 90-110 mmHg) put-up for elective cesarean section were enrolled in a prospective, randomized controlled study. Exclusion criteria were American Society of Anesthesiologists Grade III and IV, thrombocytopenia, HELLP syndrome, parturient receiving magnesium therapy, fetal distress, contraindications to spinal anesthesia and patient's refusal for regional anesthesia.
Patients were randomly assigned to two groups using computer-generated random numbers; the assignment was sealed in opaque envelopes. Group F received a solution of 0.5% hyperbaric bupivacaine 2 mL, and fentanyl 12.5 μg (0.25 mL). Group M received a solution of 0.5% hyperbaric bupivacaine 2 mL and preservative-free 50% magnesium sulfate 0.1 mL and preservative free saline 0.15 mL. An insulin syringe was used to measure volumes <1 mL. The total volume of injectate was 2.25 mL in both the groups.
All patients received a 500-mL intravenous (i.v.) preload of normal saline before spinal anesthesia. Lumbar puncture was performed in the left lateral position using a 25-gauge Quincke needle at L2-L3 or L3-L4 intervertebral space using a midline approach. After free flow of CSF, the premixed solution was injected over 10 s with the needle orifice directed cephalad. The patient was immediately turned supine with left uterine displacement using a wedge under the right hip. Sensory block was assessed every minute by pinprick in the midclavicular line until a stable level of block was achieved. The duration of sensory block was defined as the time from intrathecal injection to regression of the sensory block to T12. 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 spinal anesthesia was defined as the period from the spinal injection to the time of administration of first rescue analgesic for pain in the postoperative period.
Heart rate (HR), systolic and diastolic pressure and mean arterial pressure (MAP) were noted at baseline, immediately after block insertion and then every 3 min for the first 20 min and every 10 min until the end of the surgery. Hypotension was defined as a fall in systolic pressure >20% below baseline and was treated by increasing the normal saline infusion rate and by 6-mg boluses of mephentermine. Bradycardia (HR <50 beats/min) was treated with i.v. atropine sulfate (0.6 mg). The total doses of mephentermine and atropine required in both the groups were noted. The incidence of side effects such as sedation, pruritus, nausea and vomiting were noted every 15 min during surgery and 2, 4, 8, 12 and 24 h, postoperatively. Pruritus was graded as 0 = none; 1 = mild; and 2 = severe.  Sedation was measured using the modified Ramsey Sedation Score. 1 = cooperative, oriented, tranquil, 2 = responds to commands only, 3 = brisk response to light glabellar tap or loud noise, 4 = sluggish response to light glabellar tap or loud noise, 5 = no response.
Nausea and vomiting were graded as 0 = no nausea or vomiting; 1 = nausea no vomiting; 2 = both nausea and vomiting present; and 3 = more than 2 episodes of vomiting in 30 min. I.v. ondansetron 4 mg was given as rescue medication for vomiting and severe pruritus. Neonatal outcome was assessed by Apgar score at 1 and 5 min, and the need for neonatal mask ventilation and tracheal intubation by a pediatrician who was unaware of the study medication.
Pain was assessed using a visual analogue scale (VAS) 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. If pain scores were more than 3 even after two doses of diclofenac, then i.v. paracetamol 10 mg/kg was added. Overall patient satisfaction with anesthesia and analgesia was scored at 24 h as 1 = excellent; 2 = good and 3 = bad.
Sample size analysis determined that n = 30/group was required to detect a 25 min difference in the duration of analgesia (primary outcome variable) between groups, with a power of 90% and a significance level of 5%. Statistical analysis was performed with SPSS for windows version 15.0 (SPSS 15, SPSS Inc, Chicago, Il, USA). Statistical comparison was carried out using the Chi-square or Fisher's exact tests and Independent Student's t-test where appropriate. A value of P < 0.05 was considered statistically significant. The results were expressed as mean (standard deviation).
| Results and Observation|| |
A total of 60 patients were enrolled, 30 in each group. The two groups were comparable with respect to age, weight, height, gestational age and preoperative drug intake. The duration of surgery was also similar [Table 1].
Characteristics of spinal anesthesia are presented in [Table 2]. The highest sensory level achieved was similar in both the groups. The time to reach maximum block height (5.3 ± 0.5 min vs. 8.7 ± 0.5 min) and the onset of motor block (5 ± 1 min vs. 6 ± 1 min) were significantly slower in Group M than in the Group F. Sensory block regressed to T12 more slowly in the magnesium than in the fentanyl group (200 ± 12 min vs. 244 ± 12 min; P < 0.001). The total pain-free period and duration of motor block were significantly longer in the magnesium groups (246 ± 11 min vs. 284 ± 15 min; P < 0.001).
Preoperative hemodynamic variables (HR, systolic pressure, diastolic pressure and MAP) were similar in the two groups and all decreased 5-15 min after spinal anesthesia, with no difference between them [Figure 1], [Figure 2], [Figure 3]. The incidence of hypotension seen with Group F was comparable to Group M. There were no episodes of bradycardia in Group M, and none of the patients needed atropine sulfate. However, 2 patients experienced bradycardia in Group F and were treated with 0.6 mg atropine sulfate. Mean systolic pressure were comparable through-out the operation, with no patient recording systolic blood pressure >110 mmHg after the completion of the operation [Figure 1]. Total intra-operative consumption of mephentermine was less in Group M (10 ± 0.5 mg) in comparison to Group F (15 ± 0.5 mg). None of the patients required vasopressors postoperatively.
|Figure 1: Hemodynamic variation n in systolic blood pressure in Group F and Group M|
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|Figure 3: Hemodynamic variation in diastolic blood pressure in Group F and Group M|
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The percentage of patients with effective analgesia 3 h after spinal anesthesia was higher in the Group M than in Group F (30 vs. 18 patients; P < 0.001). No patient in any group complained of pain during surgery. In the postoperative period, pain scores (median [interquartile range]) were significantly lower at 4 h in the magnesium group (1 [1-2] vs. 2 [2-2]; P < 0.001), though the pain scores at 2, 8, 12 and 24 h were similar. Cumulative VAS scores in the first 24 h were significantly lower in Group M (9 [8-10]; P = 0.035) than in the fentanyl (10 [8-11]). Mean diclofenac consumption over a 24 h study period was significantly lower in Group M (100.5 mg vs. 125.5 mg; P < 0.001). Patients were observed for the efficacy of rescue analgesic and followed-up with i.v. paracetamol 10 mg/kg if VAS scores >3 after 2 doses of diclofenac.
The incidence of side effects in Group M was less as compared to Group F throughout the study period [Table 3]. Intra-operatively 19 patients (32% of the patients) had mild sedation with lethargic response to name spoken in normal tone (Ramsay Sedation Score 2); the incidence being more in Group F (56.7% vs. 6.6%). Fifteen patients (25%) complained of nausea intra-operatively, with no significant difference between the groups. No patient vomited intra-operatively. There was no nausea or vomiting in the postoperative period in either group. None of the patients complained of intra-operative or postoperative pruritus. None of the patients complained of shivering postoperatively in Group M. No patient complained of postdural puncture headache or radiculopathy or lower limb weakness in the postoperative period. 6 patients had a nauseating response to adnexal stimuli or peritoneal handling in Group F as compared to only 1 patient in Group M (P < 0.05). Overall patient satisfaction was better in the magnesium group (P = 0.001).
Neonatal outcome was also similar in the two 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 >9 in all the patients in the study group.
| Discussion|| |
The current study demonstrates that the addition of magnesium as an adjuvant with bupivacaine for the sub-arachnoid block, significantly improves the duration of postoperative analgesia by reducing the postoperative analgesic consumption in patients with mild preeclampsia undergoing elective caesarean section
In the present study, the cumulative VAS score and 24-h postoperative analgesic consumption were significantly less in the magnesium group. Similar reductions in analgesic requirements have been reported by Marzouk et al. who studied the effect of three different doses of intrathecal magnesium.  Since the pain may lead to either high VAS scores or high analgesic consumption, intrathecal magnesium reduces the analgesic consumption in patients observed over a 24 h period. Sometimes, adnexal handling and peritoneal stretch prove to be discomforting for patients undergoing caesarean section under spinal anesthesia, leading to pain and nausea. Intrathecal magnesium seems to increase the thresh-hold of pain arousing due to peritoneal handling and provide greater patient comfort intra-operatively as compared to fentanyl. 
Our findings reinforce the role of magnesium sulfate, an NMDA antagonist, as an effective spinal adjuvant. NMDA receptor channels are ligand-gated ion channels that generate slow excitatory postsynaptic currents at glutamatergic synapses. Evidence suggests that sustained NMDA receptor activation promotes intracellular signaling that culminates in long-term synaptic plasticity, wind-up phenomenon and central sensitization. , These events appear to be relevant as they determine, in part, duration and intensity of postoperative pain.  NMDA receptor antagonists are thought to prevent the induction of central sensitization attributed to peripheral nociceptive stimulation. Even large systemic doses of magnesium sulfate may fail to achieve effective CSF concentrations because of insufficient blood-brain barrier penetration. Ko et al. gave a magnesium 50-mg/kg i.v. bolus followed by a 15 mg/kg/h infusion and found that CSF magnesium concentrations were similar between the intrathecal and i.v. magnesium groups.  They also demonstrated an inverse relationship between CSF magnesium concentration and postoperative analgesic requirement. Hence, intrathecal magnesium can potentiate spinal analgesia without risking the side effects of the large i.v. doses of magnesium required to achieve effective CSF concentrations.  Analgesic action of magnesium occurs through spinal pathway on central receptors, so effective CSF concentrations are necessary to have therapeutic benefits, which could not be achieved by i.v. dosing.
The onset and resolution of motor blockade and the time to attain maximum sensory level in the present study were longer in the magnesium group. Though hyperbaric bupivacaine was used in our study, Ozalevli et al. observed a similar delay in onset of spinal anesthesia when adding intrathecal magnesium to isobaric bupivacaine.  These authors suggested that the difference in pH and baricity of the solution containing magnesium contributed to the delayed onset, which may also be the case in our study, although this delay of approximately 1 min, in both the studies is probably insignificant. In our study, the time to complete motor recovery was prolonged in the magnesium group (186.3 ± 12 min vs. 210 ± 10 min; P < 0.001); Malleeswaran  observed that addition of intrathecal magnesium sulfate to bupivacaine-fentanyl anesthesia prolonged the duration of analgesia, which was found to be significant. Arcioni et al. also observed that intrathecal and epidural magnesium sulfate potentiated and prolonged motor block. ,,
Though i.v. magnesium is known to cause hypotension when used to treat eclampsia,  the present study found no significant hemodynamic effect following the addition magnesium to our spinal solution. This may be attributed to the absence of systemic vasodilator effects of spinal magnesium. , Although an increased incidence of drowsiness and confusion was reported in eclamptic parturients treated with i.v. magnesium,  our study did not find an increase in sedation following intrathecal magnesium. An increased risk of respiratory depression in laboring parturients has also been reported with i.v. magnesium.  It is likely that intrathecal magnesium sulfate potentiates spinal anesthesia by a localized action on spinal nociceptive pathways, which may explain the absence of central side effects seen following systemic administration of large doses of magnesium. 
Nausea and vomiting during caesarean delivery performed with regional anesthesia may be associated with hypotension and visceral pain. In our study, the incidence of nausea was 25% with no difference between the groups, which can be explained by the groups' similar hemodynamics. The incidence of pruritus in our study was nil with both the groups. None of the patients in the present study complained of itching or pruritus may be because of the low dose of fentanyl used in our study. Gόrkan et al. showed incidence of pruritus (43.3%) when fentanyl 25 μg was added to bupivacaine 7-10 mg. 
The safety of intrathecal magnesium has been extensively evaluated in animals. ,, Studies in which intrathecal magnesium was given to various different groups of patients found that none had symptoms suggestive of neurotoxicity, ,,,,, nor did they exhibit signs of systemic toxicity such as hypotension, arrhythmias, somnolence or weakness, during the study. The dose of magnesium used in this study was based on data from Buvanendran et al. who found that 50 mg of intrathecal magnesium potentiated fentanyl antinociception;  this represented 10% of a dose shown to be nontoxic in dogs.  In various other clinical studies, intrathecal magnesium 50 mg was found to be safe and effective. ,,
Nath et al.  studied magnesium as an intrathecal adjuvant to bupivacaine-fentanyl anesthesia for postoperative analgesia and found similar delay in onset time, duration of anesthesia and similar side effect profile though the dose of both magnesium and fentanyl used in that study was double of that used in our study.  The addition of magnesium may even reduce intrathecal dose requirement of local anesthetic agents, for which studies need to be extensively carried out. The results and observation from the two groups studied shows that magnesium alone can even replace fentanyl, thereby avoiding opioid side effects such as sedation, pruritus and respiratory depression. Thus, Magnesium, a nonopioid drug, and having no restrictions like other scheduled drugs, can be used as an adjuvant with bupivacaine intrathecally to increase the duration of postoperative analgesia, in mild pregnancy-induced hypertension patients posted for elective caesarian section with no additional side effects.
| Conclusion|| |
From the present study, it can be concluded that the addition of magnesium sulfate 50 mg to bupivacaine for sub-arachnoid block in patients with mild preeclampsia undergoing elective cesarean section prolongs the duration of analgesia and reduces postoperative analgesic requirements without additional side effects and adverse neonatal outcomes and has efficacy similar to fentanyl in managing the intra-operative and postoperative hemodynamics. Though the onset of motor blockade is delayed, there is intense motor and sensory blockade similar to that achieved when fentanyl is used as an adjuvant.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]