Abstract

Background

Magnesium has been proven to have antinociceptive effects in animal and human models of pain. Its effect is primarily based on the regulation of calcium influx into the cell, which is natural physiological calcium antagonism and N-methyl-d-aspartate (NMDA) receptor antagonism.

Methods

One hundred and eight patients undergoing surgery with spinal anesthesia received either 250 mg of intravenous magnesium sulfate followed by an infusion of 500 mg magnesium sulfate (25 mg/mL) at the rate of 20 mL/hour; or the same volume of normal saline (control group) as bolus and infusion. The primary end-points in the study were to evaluate the analgesic effect and duration of sensory and motor blockade. The secondary end-points included assessment of hemodynamic effects of intravenous magnesium sulfate and rescue analgesia requirement.

Results

Sensory and motor blockade, respectively, were 25 minutes and 34 minutes shorter in the control group. Less patients in the magnesium group (33% vs. 53.7%) than in control group required rescue analgesia in the postoperative period. The control group required rescue analgesia nearly 3 hours earlier than the magnesium group. Only one patient in the control group experienced bradycardia. There was no event of intraoperative hypotension in either of the groups.

Conclusion

Intravenous magnesium sulfate when given as a bolus, followed by an infusion, delayed and decreased the need of rescue analgesics after spinal anesthesia.

Keywords

anesthesia ; analgesia ; bupivacaine ; magnesium sulfate ; postoperative ; spinal;

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1. Introduction

Postoperative pain should be effectively treated because it represents an important component of postoperative recovery. Effective treatment serves to blunt autonomic, somatic and endocrine reflexes with a resultant potential decrease in perioperative morbidity. The most common treatment practice is a poly-pharmacological approach.¹Noxious stimulation leads to the release of glutamate and aspartate neurotransmitters, which bind to various subclasses of excitatory amino acid receptors, including the N-methyl D-aspartate (NMDA) receptor. Activation of NMDA receptors leads to calcium and sodium influx into the cell, with an efflux of potassium and initiation of central sensitization and wind-up. Magnesium blocks NMDA channels in a voltage-dependent way, and its addition produces a reduction of NMDA-induced currents.²

Studies related to magnesium sulfate administration reveal that the anesthetic and analgesia quality may improve.³ The true site of action of magnesium is probably at the spinal cord NMDA receptors. Hence, it has been used as an adjunct to analgesics and anesthetic agents for intraoperative and postoperative analgesia.³ Several recent reports have described the efficacy of magnesium infusions in moderate dosage both during surgery and in the postoperative period for decreasing postoperative analgesic requirements.3, 4

2. Methods

The study was approved by the Ethics Committee for Research on Human Subjects, Seth G.S. Medical College & KEM Hospital, Parel, Mumbai 400012. Vide EC/219/2012 and Dr Kamal Hazari as chairperson on 21 January, 2013.

After written informed consent, 108 patients, posted for lower abdominal and lower limb surgeries under spinal anesthesia, were studied in this prospective and randomized double-blinded study. In accordance with a previous study carried out by Apan et al,⁵ the visual analog scale (VAS) score was considered as the primary end-point. Standard deviation was 24 in the control group and 16 in the magnesium group. To find a difference in both the groups regarding VAS, with the power of the study at 80% and keeping alpha error at 5%, 54 patients were needed per group. The randomization was computer based, and patients were either assigned to the magnesium group or the control group. The primary end-points in the study were to evaluate the analgesic effect and duration of sensory and motor blockade. The secondary end-points included assessment of hemodynamic effects of intravenous magnesium sulfate and rescue analgesia requirement.

American Society of Anesthesiologists physical status I and II patients undergoing surgery under spinal blockade, within the age group of 18–65 years and height within 150–180cm were included. Patients with severe or controlled systemic diseases, neurological, cardiovascular, respiratory disease, bleeding disorders, renal dysfunction or congenital disorders; those receiving calcium channel blockers or previous administration or allergy of magnesium sulfate were excluded. Pregnant females, lactating mothers and patients allergic to bupivacaine were also excluded.

An injection of 15 mg (3 mL) of 0.5% hyperbaric bupivacaine was given intrathecally in the L3–L4 space. The patient was made supine, then 0.5 mL (250 mg) of magnesium sulfate was given intravenously, followed by an infusion of 500 mg magnesium sulfate (25mg/mL) at the rate of 20 mL/hour in the magnesium group; or the same volume of normal saline (control group) as bolus and infusion was given. This was injected through another vascular access used exclusively for this purpose. The anesthesiologist evaluating the patient was not aware of which group the patient was in.

Duration of sensory block was defined as the time between injection of intrathecal bupivacaine and regression to L1 dermatome level. Duration of motor block was defined as the time between injection of intrathecal bupivacaine and recovery of knee flexion and ability to lift the knee at least 10 cm from bed surface. Heart rate and mean blood pressure (MAP) was measured every 4 hours. Bradycardia [heart rate < 55 beats per minute (bpm)] or hypotension (mean blood pressure < 70% of base line) were monitored and appropriately managed.

Postoperatively, the VAS score (scale in millimeters on a 10-cm line with numbers from 0 to 10; 0 = no pain and 10 = worst pain imaginable) was used to assess analgesia every 4 hours for 24 hours. Rescue analgesia (intravenous tramadol 50 mg) was given when VAS score exceeded 3. Sedation was evaluated according to a four-point rating scale. 1, Patient fully awake; 2, patient somnolent but responds to verbal commands; 3, patient somnolent but responds to tactile stimuli; 4, patient asleep but responds to pain. Patients were monitored and appropriately treated for other side effects such as a burning or heat sensation at the site of injection, or pruritus.

Descriptive statistics was used for categorical data. Data was analyzed using professional statistics package EpiInfo 7.0 (Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, USA) version for windows. Descriptive data was represented as mean ± standard deviation for numeric variables, and percentages and proportions for categorical variables. Appropriate tests of significance like the independent t-test and Chi-square test were used depending on the nature and distribution of variables. Values of p < 0.05 were considered statistically significant.

3. Results

Demographic data with respect to age, weight, height, gender, and American Society of Anesthesiologists grade was comparable and is depicted in Table 1.

The types of surgeries included lower limb orthopedic and lower abdominal surgeries and were comparable in both groups (Table 2). The duration of the surgery was about 71 minutes in both groups.

The postoperative VAS score, as shown in Figure 1 and Table 3, was analyzed by dividing the score into ranges of 0–3, 4–6 and 7–10. In the immediate postoperative period, no patient had a VAS score more than 6. One patient in the magnesium group and seven in the control group had a VAS score of 4–6, which was statistically significant (p = 0.006). Whereas at the 4-hour interval, seven patients in the magnesium group and 17 patients in the control group, had a VAS score of 4–6, which was also statistically significant (p = 0.001).

The duration of sensory blockade in the magnesium group was 128.04 ± 14.97 minutes and in the control group was 103.89 ± 12.27 minutes; a difference of about 25 minutes was observed which was statistically significant (p = 0.001). The duration of motor blockade in the magnesium and control groups was 154.89 ± 18.73 minutes and 120.52 ± 11.12 minutes, respectively, amounting to a difference of about 34 minutes between the two groups; this difference was also significant statistically (p = 0.001). A total of 18 patients in the magnesium group required rescue analgesia, amounting to 33.3% of the group. In the control group, 29 patients required rescue analgesia, amounting to 53.7% of the group (Table 4). The lower number of patients in the magnesium group requiring rescue analgesia was also a statistically significant difference (p = 0.033). The control group required rescue analgesia earlier than the magnesium group. The magnesium group required rescue analgesia at 7.89 ± 4.31 hours, whereas the control group required it earlier at 4.59 ± 4.01 hours in the postoperative period (p = 0.009).

There was no significant difference in MAP found between the magnesium group and the control group. Only one patient in the control group experienced bradycardia, which was treated with intravenous atropine 0.6 mg. None of the patients in the magnesium group experienced bradycardia. There was no event of intraoperative hypotension in either of the groups.

There was no statistical difference in the sedation score in both the magnesium and control groups. Three patients experienced flushing in the magnesium group.

4. Discussion

Perioperative intravenous magnesium has been studied and considered as an efficacious modality of postoperative analgesia in various studies.⁶ The main finding of this study suggests that intravenous magnesium sulfate given as a bolus of 250 mg, followed by an infusion of 500 mg/hour, improved postoperative analgesia by delaying as well as decreasing the need of postoperative analgesics. The VAS scores in the immediate postoperative period were significantly less in the magnesium group. The analgesic properties of magnesium are due to the NMDA glutamate receptor blocking action, which hampers calcium entry into the cell and the initiation of central sensitization process. Two earlier clinical studies showed that VAS scores were significantly lower in patients receiving perioperative magnesium.7, 8

In our study, the duration of sensory blockade as well as motor blockade in the magnesium group was significantly more than that in the control group. However, studies carried out by Apan et al and Kumar et al did not show any significant difference among the two groups in this regard.5, 8

We observed that magnesium decreased the requirement for postoperative rescue analgesia as well as delaying its requirement. The mean analgesic consumption or the total dose of analgesics required in patients who received perioperative intravenous magnesium infusion was lower compared to the control group in previous studies.5, 6, 7. A study which used patient controlled analgesia showed that analgesia consumption and additional rescue analgesia required were lower in the magnesium group.⁹ Ko et al¹⁰ included patients for abdominal hysterectomy under general anesthesia with epidural, and patient controlled analgesia. They found that the perioperative use of intravenous magnesium did not have any effect on postoperative pain, attributing this finding to the lack of increase in magnesium levels in cerebrospinal fluid following its intravenous administration. The limitations of our study are that reduced pain scores and reduced requirements for postoperative analgesia in the magnesium group could be a result of the longer block, rather than a reduction in nociception. The study did not allow a separation of the longer spinal blockade versus the potential analgesic effect of magnesium.

5. Conclusion

The observations of this study suggest that intravenous magnesium sulfate given as a bolus of 250 mg, followed by an infusion of 500 mg/hour improved postoperative analgesia by delaying as well as decreasing the need of postoperative analgesics. It also prolonged the duration of sensory and motor blockade of spinal anesthesia. There was no significant difference in hemodynamic variables and sedation in both groups.