Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 8  |  Issue : 2  |  Page : 230-235

Comparison of intrathecal magnesium, dexmedetomidine, or placebo combined with bupivacaine 0.5% for patients with mild pre-eclampsia undergoing cesarean section


Department of Anesthesiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission29-Sep-2014
Date of Acceptance28-Jan-2015
Date of Web Publication8-May-2015

Correspondence Address:
Tamer Y Elie Hamawy
Department of Anesthesiology, Faculty of Medicine, Ain Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.156696

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  Abstract 

Background
Neuraxial anesthesia for pre-eclamptic patients undergoing cesarean section is a well-established safe and effective anesthetic technique. Several agents had been studied as adjuvants to commonly used intrathecal drugs.
Aim
The aim of this prospective, randomized, double-blinded placebo-controlled study is to compare intrathecal magnesium versus dexmedetomidine (DXM) combined with bupivacaine 0.5% for parturients with mild pre-eclampsia undergoing cesarean section in terms of duration of spinal block as a primary outcome and postoperative analgesia and incidence of intraoperative side effects as secondary outcomes.
Patients and methods
Ninety pregnant women with singleton pregnancies, scheduled for elective cesarean section and diagnosed with mild pre-eclampsia, were enrolled in this prospective, randomized-controlled double-blind study. Lumbar puncture was performed and then patients were allocated to three groups: group D [0.5% hyperbaric bupivacaine 2.5 ml and 0.1 ml (10 μg) preservative-free DXM]; group M [0.5% hyperbaric bupivacaine 2.5 ml and 0.1 ml preservative-free 10% magnesium sulfate (10 mg)]; and group C (0.5% hyperbaric bupivacaine 2.5 ml and preservative-free saline 0.1 ml as a control). Duration of sensory block, motor block, maximal level of sensory block, and duration of spinal anesthesia were recorded. The incidences of hypotension, sedation, nausea, and vomiting were noted every 15 min during surgery. Pain was assessed using a verbal numeric scale from 0 to 10 at 2, 4, 8, 12, 18, and 24 h postoperatively. Intramuscular diclofenac 75 mg was administered for rescue analgesia whenever the pain score was greater than 3. Overall patient satisfaction with anesthesia and analgesia was recorded at 24 h as 1 = excellent; 2 = good; and 3 = poor.
Results
The three groups were comparable with respect to patients' demographics, gestational age, and duration of surgery. The duration of sensory block, motor block, and spinal anesthesia were prolonged in group M (175.2 ± 19.4, 216.3 ± 12.6, and 200.3 ± 6.4 min) compared with group D (153 ± 4.78, 181.7 ± 7.8, and 160.4 ± 7 min) and group C (150.37 ± 8.8, 171 ± 8.1, and 165 ± 5.83 min), P < 0.001. There was less ephedrine consumption in group M (7.87 ± 0.98 mg) compared with group D (12.4 ± 1.1 mg) and group C (12.3 ± 1.3 mg), P < 0.001. The cumulative requirement of diclofenac over 24 h was significantly less in group M (135.8 ± 27.7 mg) than in group D (183.3 ± 26.7 mg) and group C (187 ± 22.6 mg), P < 0.001. Verbal numeric scale scores in the first 24 h were significantly higher in the control group (group C) than the other two groups.
Conclusion
The addition of intrathecal magnesium sulfate (10 mg) to bupivacaine in patients with mild pre-eclampsia undergoing cesarean section prolongs the duration of analgesia and reduces postoperative analgesic requirements without additional side effects compared with intrathecal DXM (10 μg).

Keywords: dexmedetomidine, intrathecal, magnesium, pre-eclampsia


How to cite this article:
Elie Hamawy TY, Mohamed MH. Comparison of intrathecal magnesium, dexmedetomidine, or placebo combined with bupivacaine 0.5% for patients with mild pre-eclampsia undergoing cesarean section. Ain-Shams J Anaesthesiol 2015;8:230-5

How to cite this URL:
Elie Hamawy TY, Mohamed MH. Comparison of intrathecal magnesium, dexmedetomidine, or placebo combined with bupivacaine 0.5% for patients with mild pre-eclampsia undergoing cesarean section. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2021 Oct 26];8:230-5. Available from: http://www.asja.eg.net/text.asp?2015/8/2/230/156696


  Introduction Top


Neuraxial anesthesia for pre-eclamptic patients undergoing cesarean section is a well-established safe and effective anesthetic technique [1] . Spinal block is the preferred technique because of its rapid onset, superior blockade, lower failure rates, and cost-effectiveness, but has the drawbacks of a shorter duration of block and lack of postoperative analgesia [2] . This may be detrimental especially in pre-eclamptic patients as postoperative pain is associated with neuroendocrine responses, catecholamine release, and increased morbidity. In addition, effective pain relief for the new mother facilitates early ambulation and care of the newborn [3] . Recently, the use of intrathecal adjuvants has gained popularity with the aim of prolonging block duration, higher success rates, patient satisfaction, and decreased resource utilization [4] . Effective postoperative pain management is essential for rehabilitation and acceleration of functional recovery, enabling patients to return to their normal activity more quickly [3] .

Magnesium ion inhibits calcium entry into the cells by noncompetitive blockade of the dorsal horn N-methyl-d-aspartate (NMDA) receptor, which modulates or prevents central pain sensitization [5] . Therefore, there is a theoretical role for exogenously administered magnesium sulfate to act as an analgesic adjuvant. Intravenous use has shown limited analgesic capacity, which may be explained by the fact that magnesium does not cross the blood-brain barrier and, therefore, exerts no action on NMDA receptors. Accordingly, direct intrathecal administration could improve its performance as an analgesic adjuvant [6] . Clinical trials in obstetric [7] and nonobstetric populations [8] 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 [9] .

Dexmedetomidine (DXM) is a highly selective α2 agonist. It is used as an intravenous sedative and adjuvant analgesic drug. Side effects include bradycardia and hypotension [10] . Animal studies for intrathecal DXM have shown its antinociceptive effect [11],[12] . DXM (3 μg) or clonidine (30 μg), when added to intrathecal bupivacaine, reduced the onset time and prolonged the duration of sensory and motor block with preserved hemodynamic stability and lack of sedation in patients undergoing urology procedures [13] .

We compared the effects of adding intrathecal magnesium and DXM to bupivacaine for parturients undergoing elective cesarean section in terms of block characteristics and postoperative analgesia.


  Patients and methods Top


Following Ethics Committee approval and informed parturient consent, 90 pregnant women with singleton pregnancies, scheduled for elective cesarean section and diagnosed with mild pre-eclampsia (systolic pressure 140-160 mmHg, diastolic pressure 90-110 mmHg measured on two occasions separated by a 4-6 h period and a proteinuria with a urine dipstick of a ≥+1 or ≥300 mg/24 h) after 20 weeks of gestation in a previously normotensive parturient [14] were enrolled in this prospective, randomized-controlled double-blind study carried out in Ain Shams University Maternity Hospital during the time period between December 2013 and March 2014. Exclusion criteria included ASA grade greater than II, patients with severe pre-eclampsia (systolic pressure ≥160 mmHg, diastolic pressure ≥110 mmHg, and a proteinuria ≥5 g/24 h), renal or hepatic impairment, thrombocytopenia, HELLP syndrome, magnesium therapy, fetal distress, or any contraindication to spinal anesthesia.

Patients were fasted for 6 h preoperatively. No premedications were administered. Intraoperative monitoring included pulse oximetry, automated blood pressure cuff, and five-lead ECG. An observer blinded to the study groups performed all preblock assessments.

Following an infusion of 10 ml/kg lactated Ringer's solution and with parturients in the sitting position, lumbar puncture was performed at the L2-L3 or L3-L4 level through a midline approach using a 25 G Quincke spinal needle (Spinocan; B Braun Medical, Melsungen, Germany). Using computer-generated random numbers, patients were allocated to three groups.

  1. Group D received a premixed solution of 0.5% hyperbaric bupivacaine 2.5 ml and 0.1 ml (10 μg) preservative-free DXM.
  2. Group M received a premixed solution of 0.5% hyperbaric bupivacaine 2.5 ml and 0.1 ml preservative-free 10% magnesium sulfate (10 mg).
  3. Group C received a premixed solution of 0.5% hyperbaric bupivacaine 2.5 ml and preservative-free saline 0.1 ml as a control.
Volumes less than 1 ml were measured using an insulin syringe. The total volume of injectate was 2.6 ml in all groups, and it was prepared by a nurse not involved in the outcome measurement. Patients and the anesthesiologist collecting data were all blinded to group allocation. After an intrathecal injection, the parturients were placed in a supine position at a 15°-20° left tilt for comfort. Oxygen 2-4 l/min was delivered routinely through a face mask until the end of surgery.

Sensory block was evaluated by a pinprick test in the midclavicular line. The onset of sensory block was defined as the time between the end of injection of the intrathecal anesthetic mixture and the absence of pain at the T10 dermatome; the duration of sensory block was defined as the time for regression of two segments from the maximum block height evaluated by pinprick. The maximal level of sensory block was assessed by pinprick every 5 min for 25 min after the completion of an intrathecal injection. Motor block was assessed using the modified Bromage score [15] (0, no motor loss; 1, inability to flex the hip; 2, inability to flex the knee; and 3, inability to flex the ankle); the onset of motor block was defined as the time from the intrathecal injection to Bromage 1 score, whereas the duration of motor block was considered when the modified Bromage score was zero. The duration of spinal anesthesia was defined as the time period from spinal drug injection to the time of first rescue analgesic drug administration in the postoperative period. The regression time for sensory and motor blocks was recorded. All durations were calculated considering the time of spinal injection as time zero.

Heart rate and mean arterial pressure were noted at baseline, immediately after block insertion, and then every 5 min for the first 20 min and every 10 min until the end of the surgery. Hypotension was defined as a decrease in mean arterial pressure greater than or equal to 20% below the baseline and was treated by 5 mg boluses of ephedrine. The incidences of nausea and vomiting were noted every 15 min during surgery. Intravenous ondansetron 4 mg was administered as rescue medication for vomiting. Sedation was assessed using a five-point scale, with 0 = alert and 5 = deep sleep. Postoperatively, pain was assessed using a verbal numeric scale (VNS) [16] from 0 to 10 (0 = no pain; 10 = maximum imaginable pain) at the end of surgery and at 4, 8, 12 14, 18, and 24 h postoperatively. Intramuscular diclofenac 75 mg was administered for rescue analgesia whenever the pain score was greater than 3. Overall patient satisfaction with anesthesia and analgesia was scored at 24 h as 1 = excellent; 2 = good; and 3 = poor.

Sample size calculation showed that 25 patients per study group achieves 81% power to detect a 20 min difference between the mean duration of sensory block using an F-test with a 0.05 significance level. The size of the variation in the means is represented by their SD, which is 11.79. The common SD within a group is assumed to be 32. Thirty patients per group were included to replace any dropouts.

Data obtained were tabulated and analyzed using the statistical package for social science standard SPSS (SPSS) software package version 17 (Chicago, IL). Data were expressed as means ± SD, median IQR, or numbers and percentages. The χ2 -test was used to compare categorical covariates. For parametric data, analysis of variance was used to compare continuous covariates and the Kruskal-Wallis test for nonparametric data. If the P-value was significant, Tukey's post hoc was used to determine the significance between each pair of groups, with a P-value less than0.05 considered statistically significant.


  Results Top


Ninety patients were enrolled, 30 in each group. No patients were excluded. The three groups were comparable with respect to age, BMI, gestational age, and duration of surgery ([Table 1]).
Table 1 Patients' demographics

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The onset of sensory and motor blocks was rapid in group D (2.5 ± 0.4 and 4.2 ± 0.4 min) compared with group M (6.2 ± 0.8 and 7.2 ± 0.7 min) and group C (5.4 ± 0.66 and 5 ± 1.1 min), P < 0.001, whereas the durations of sensory block, motor block, and spinal anesthesia were prolonged in group M (175.2 ± 19.4, 216.3 ± 12.6, and 200.3 ± 6.4 min) compared with group D (153 ± 4.78, 181.7 ± 7.8, and 160.4 ± 7 min) and group C (150.37 ± 8.8, 171 ± 8.1, and 165 ± 5.83 min), P < 0.001 ([Table 2]). There was less ephedrine consumption in group M (7.87 ± 0.98 mg) compared with group D (12.4 ± 1.1 mg) and group C (12.3 ± 1.3 mg), P < 0.001 ([Table 3]). The cumulative requirement of diclofenac over 24 h was significantly less in group M (135.8 ± 27.7 mg) than in group D (183.3 ± 26.7 mg) and group C (187 ± 22.6 mg), P < 0.001 ([Table 3]).
Table 2 Characteristics of spinal anesthesia

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Table 3 Total dose of intraoperative ephedrine and postoperative diclofenac

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There were no significant differences between the groups in intraoperative sedation and vomiting ([Table 4]).Overall patient satisfaction was significantly better in group M than in the other two groups ([Table 4]). Neonatal outcome was similar in the three groups and no baby required mask ventilation or tracheal intubation ([Table 4]).
Table 4 Sedation score, incidence of vomiting, patient satisfaction, and APGAR score

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VNS scores in the first 24 h were significantly higher in the control group (group C) than in the other two groups ([Table 5]).
Table 5 Verbal numeric scale

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  Discussion Top


In this prospective, randomized, double-blind, placebo-controlled trial, we provide evidence that the addition of intrathecal magnesium sulfate (10 mg) to bupivacaine for spinal anesthesia significantly prolongs the duration of spinal block as a primary outcome and reduces postoperative analgesic consumption in patients with mild pre-eclampsia compared with intrathecal DXM as a secondary outcome (10 μg). Also, we found that the addition of intrathecal DXM to bupivacaine significantly reduces the onset time of spinal block compared with the addition of magnesium or bupivacaine alone.

Noxious stimulation activates the release of many neurotransmitters, which bind to different subtypes of excitatory amino acid receptors, including NMDA receptors. Activation of these receptors leads to calcium influx into the cell and initiates a series of central sensitizations such as wind-up and long-term potentiation in the spinal cord in response to the prolonged stimulation [15] . Central sensitization is considered to play an important role in pain perception and is believed to be one of the mechanisms involved in the persistence of postoperative pain [16] . Therefore, NMDA receptor signaling plays an important role in determining the duration of acute pain, and accordingly, NMDA receptor antagonists play a role in the prevention and treatment of postinjury pain. NMDA receptor channels are ligand-gated ion channels that generate slow excitatory postsynaptic currents at glutamatergic synapses. The Mg 2 ion blocks NMDA receptor-associated channels in a voltage-dependent manner [17] . Evidence suggests that sustained NMDA receptor activation promotes intracellular signaling that results in long-term synaptic plasticity, wind-up phenomenon, and central sensitization. These events appear to be effective as they determine, in part, the duration and intensity of postoperative pain; therefore, NMDA receptor antagonists are considered to prevent the induction of central sensitization attributed to peripheral nociceptive stimulation [18] .

In the magnesium group, it was found that the time of onset of sensory and motor blockade were longer. In a study by Ozalevli et al. [19] , a similar delay in onset of spinal anesthesia was observed on adding intrathecal magnesium to fentanyl and isobaric bupivacaine (we used hyperbaric bupivacaine in our study), which was attributed to the difference in pH and baricity of the solution containing magnesium [20] .

The effect of adding magnesium to intrathecal bupivacaine has been studied in earlier clinical trials and they reported an increase in the duration of analgesia with intrathecal magnesium of 18-48 min in various obstetric [17] and nonobstetric populations [19],[21] . Our results emphasize the role of magnesium sulfate (being an NMDA antagonist) as an effective intrathecal adjuvant. Although the decrease in pain scores at various times during the first 24 h after surgery was not statistically significant in group M than group D, the 24 h postoperative analgesic consumption was significantly less in the magnesium group. The comparable pain scores in our study may be explained by an efficient regimen used for rescue analgesia. We found that the addition of magnesium to intrathecal bupivacaine did not affect the patients' hemodynamics compared with the control group, despite the fact that intravenous magnesium leads to hypotension [22] , which may be attributed to the absence of the systemic vasodilator effect of intrathecal magnesium. Also, there was no significant sedative effect of intrathecal magnesium in our study, despite the fact that intravenous magnesium increases the incidence of confusion and drowsiness in eclamptic patients [23] . The absence of central side effects observed following systemic administration of magnesium in our study may be explained by the fact that magnesium augments spinal block by a localized action on spinal nociceptive pathways.

Intravenous DXM reduces opioid and inhalational anesthetic requirements during anesthesia [24] . The use of α2 adrenoreceptor agonists as an adjuvant to local anesthetics in spinal anesthesia has been studied. Kanazi and colleagues found that DXM (3 μg) or clonidine (30 μg), when added to intrathecal bupivacaine for patients undergoing transurethral resection of prostate or bladder tumor under spinal anesthesia, produces a similar prolongation in the duration of the motor and sensory block and shorter onset of both motor and sensory block with preserved hemodynamic stability and lack of sedation [25] . In our study, DXM produced a shorter onset of motor and sensory blocks, but it did not increase the duration of any of the blocks, although we used a higher dose (10 μg).


  Conclusion Top


The addition of intrathecal magnesium sulfate (50 mg) to bupivacaine in patients with mild pre-eclampsia undergoing cesarean section prolongs the duration of analgesia and reduces postoperative analgesic requirements without additional side effects compared with intrathecal DXM (10 μg).[26]


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

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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.  Back to cited text no. 19
    
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23.
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.  Back to cited text no. 23
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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