Pain after caesarean section is the most common and important complain of mothers at most of the medical centers^[1]. Postpartum pain is the worst fear of mothers which would stop them from getting back into shape for taking care of and breastfeeding their neonate. Therefore anesthesiologists should try their best to get mothers to their desirable condition as fast as possible^[1,2]. Pain intensity after caesarean section depends on many different factors including type and duration of the surgery, the method of anesthesia, the type of consumed anesthetic and patient’s psychological and mental condition^[1,3-5].

  Different methods for controlling pain after caesarean section have been studied; non-steroidal and opioid anti-inflammatory drugs is the traditional and most common used method. The side effects of these drugs include digestive problems, nausea and vomiting, respiratory distress, constipation and drowsiness^[1,2]. The more modern methods like constant infusion of epidural or patient controlled analgesia (PCA), besides requiring trained personnel and special facilities, are expensive methods that sometimes are associated with various side effects^[1,2].

  Magnesium sulfate has a widespread application in the field of obstetrics and gynecology. It is used for preventing and treating convulsions in preeclampsia and eclampsia. Magnesium sulfate is an N-Methyl-D-Aspartate and its related channels’ receptor antagonist^[6-8] and also has a calcium channel blocker effect which in patients with chronic pain works like opioid drugs^[4,8-10]. Magnesium sulfate would prevent the secretion of catecholamine from adrenal medulla and peripheral nerves terminals and would also block catecholamine receptors directly^[1,11]. Therefore magnesium would cause sympathetic block and would indirectly lead to vasodilatation and consequently decrease blood pressure^[5,12-14].

  From 1990, the effect of magnesium and opioid consumption on postoperative pain has been evaluated in gynecologicandocular surgeries, arthroscopic surgical procedures and surgical treatment of lumbar spine^{[3,9,13,15-17]}. In this study the effect of intravenous infusion of magnesium sulfate during surgery on reduction of pain intensity, the need for painkillers and postoperative side effects after caesarean section with spinal anesthesia has been evaluated.

Methods

  This study was a randomized controlled double-blind clinical trial which was conducted after taking approval from ethics committee of the research council of Isfahan University of Medical sciences from winter 2015 to autumn 2015 at Shahid Beheshti teaching medical center.

  ASA I, II pregnant women who were candidates for caesarean and had no history of liver dysfunction, renal dysfunction (GFR < 60 mL/min/1.73 m²) and cardiovascular problems, especially AV blockage, any heart problems or EF < 40%, any type of heart block, cardiac arrhythmia, diagnosed hypertension or pregnancy hypertension, diabetes, neurologic problems or addiction, diagnosed allergy to magnesium sulfate, myopathy and calcium channel blocker consumption were enrolled in the study. Any changes in the type of anesthesia or surgery which led to hysterectomy or urology interventions, severe hemorrhage and need for massive blood transfusion and lingered surgery more than 2 hours caused exclusion from the study.

  Patients were allocated into two groups of magnesium sulfate receivers and normal saline receivers by random block method. The intervention group received 40 mg/kg of magnesium sulfate in 100 cc of normal saline 10 minutes before spinal anesthesia and then infusion of 15 mg/kg/h of magnesium sulfate during the surgery. The control group received similar dosage of normal saline.

  The routine monitoring of electrocardiogram, pulse oximetry and non-invasive blood pressure was contacted to patients before spinal anesthesia. After receiving 500 cc of Ringer, spinal anesthesia was conducted by the anesthesiologist using a 25 gauge quincke needle at L3 - L4 level with 0.5 cc of Sufentanyl and 0.2 cc of 0.5% hyper-thin Marcaine.

  Patients’ vital signs including systolic, diastolic and the mean of blood pressure, heart rate, oxygen saturation and respiratory rate were measured and recorded before the spinal anesthesia, right after the spinal anesthesia, 3, 5, 10 and 15 minutes after anesthesia and then every half an hour until the end of the surgery and every 15 minutes in the recovery. The maximum level of sensory block was checked and recorded 10 minutes after anesthesia using two-sided Pin Prick at the mid-axillary line. Patients’ pain was measured and recorded with numerical rating scale (NRS) from the time motor block started to wear off at the baseline, 30 minutes and 4, 12 and 24 hours after the surgery using modified Bromage scale grade V*. The rating of pain intensity was as “no pain = 0”, “mild pain = 1 - 4”, “moderate pain = 5 - 7”, and “severe pain = 8 - 10” which pains with score of 4 or more required intervention.

* Modified Bromage scale: 1 = complete motor blockade; 2 = almost complete motor blockade: The patient is able to only move the feet; 3 = partial motor blockade: The patient is able to move the knees; 4 = detectable weakness of hip flexion: The patient is able to raise the leg but is unable to keep it raised; 5 = no detectable weakness of hip flexion: The patient is able to keep the leg raised for at least 10 seconds; 6 = no weakness at all: The patient is able to perform partial knee bend while supine).

  In case of an NRS ≥ 4, Diclofenac 100 mg suppository was prescribed for the patients and if the pain continued, 50 mg of Pethidinewas injected intramuscularly. After transferring to the ward, patients who received standard treatment with Diclofenac and Pethidine, based on their request and NRS ≥ 4, again received Diclofenac 100 mg suppository and if needed, 50 mg of intramuscular Pethidine. The first request for painkillers at the recovery and the ward and also the additional consumed dosage of Diclofenac and Pethidine were recorded. The serum level of magnesium in all patients was checked and recorded before starting the infusion and right after the end of the infusion. For all the patients the first time to tolerate oral liquids was recorded and compared between them.

  Considering a confidence interval of 95%, power test of 0.84 and accuracy of 0.5, the sample size for each group was calculated to be 20. Statistical analysis was conducted using SPSS 21 (Chicago, Illinois, USA). P value less than 0.05 was considered statistically significant. Qualitative variables were analyzed using t test and Chi-square test. Categorical variables were analyzed using Mann-Whitney test. Variance analysis with repeated measures, Newman-Keuls and post hoc student tests were used for hemodynamic variables at different time in both groups.

Results

  Forty pregnant women were enrolled in the study and 1 from each group was excluded due inadequate numbness to undergo general anesthesia. Demographic characteristics and the mean duration of surgery and recovery are respectively shown in (table 1 and 2).

Table 1: Frequency distribution and dispersion of demographic characteristics of the participants (for each group separately).

A p value of less than 0.05 indicated statistical significance.

Table 2: Comparing the mean duration of surgery and recovery between both groups.

P value of less than 0.05 indicated statistical significance.

  A significant difference was observed between both groups regarding the mean of systolic blood pressure right after and 3 minutes after spinal anesthesia (p < 0.05) (Diagram 1). There was a significant difference between the mean of diastolic blood pressure of both groups 3 and 5 minutes after spinal anesthesia and 15 minutes into recovery (p < 0.05) (Diagram 2).

  The difference between the mean of heart rate of both groups was only significant right before spinal anesthesia (p = 0.044 < 0.05); meaning that the mean of heart rate in the magnesium receiving group was lower than the placebo group (Diagram 3).

  The difference between the mean of changes in oxygen saturation of both groups was not significant at any of the measured times (p > 0.05) (Diagram 4). There was a significant difference between the mean of changes in the mean arterial pressure of both groups 3 and 5 minutes after spinal anesthesia and 15 minutes into recovery (p < 0.05) (Diagram 5). Regarding the mean of respiratory rate, no significant difference was observed between both groups at any of the measured times (p > 0.05) (Diagram 6).

Table 1: Measurement times for diagrams 1 to 6

Diagram 1:

Diagram 2:

Diagram 3:

Diagram 4:

Diagram 5:

Diagram 6:

  The mean of pain intensity 30 minutes and 4, 12 and 24 hours after motor block wear off had a significant difference between both groups (p < 0.05) (Table 3); in a way that pain intensity in the magnesium receiving group was significantly lower than the placebo group at all the mentioned times. There was no significant difference between the pain intensity of both groups at the time motor block started to wear off (p > 0.05) (Diagram 7).

Table 3: Determining and comparing pain intensity in both groups at different time intervals after surgery according to NRS.

Diagram 7:

  In the magnesium receiving group, from the time motor block started to wear off, most of the patients experienced pain with mild intensity and as time passed by, a few percent experienced moderate pain and a fewer percent experienced severe pain. In the placebo group most of the patients experienced mild and moderate pain and, as it can be observed, from the time motor block started to wear off, experiencing pain with severe intensity have increased among the patients of this group. Eventually, 24 hours after motor block wears off, 77.8% of the patients in magnesium group reported mild pain and 66.7% of patients in the placebo group reported moderate pain (Table 4).

Table 4: Determining and comparing pain intensity in both groups.

  The difference between the consumed Diclofenac suppositories in both groups during the first 24 hours after motor block wear off was significant (p < 0.05). Regarding the injection of Pethidine, the difference between both groups was only significant during the first 4 hours. It must be noted that in the magnesium receiving group, the highest consumption of Diclofenac and Pethidine happened 12 hours after motor block wear off. Comparison between the frequencies of painkiller consumption in both groups is shown in table 5.

Table 5: Comparing the frequency of painkiller (Diclofenac and Pethidine) consumption in both groups.

*A p value of less than 0.05 indicated statistical significance.</p >

  The frequency of occurrence of side effects had no significant difference between both groups (p > 0.05) (Table 6). 44% of the patients of the placebo group (8 patients) experienced no side effects and the most common side effect in this group was shivering, nausea and vomiting (22%). In the magnesium group 38.9% of patients (7 patients) experienced no side effects; hypotension with the prevalence of 22.2% (4 patients) and then flushing and shivering with the prevalence of 11.1% (2 patients) were the most common side effects.

Table 6: Determining and comparing the frequency of occurrence of side effects after surgery in the both studied groups.

*A p value of less than 0.05 indicated statistical significance.

  Considering a significance level of 5%, Pearson Chi-square test showed no significant difference between the motor block level of both groups (p > 0.05) (Table 7).

Table 7: Determining and comparing the frequency of the level of motor block between both studied groups.

*A p value of less than 0.05 indicated statistical significance.

  The mean serum level of magnesium before infusion in both groups was similar and no significant relation between the studied group and the serum level of magnesium was observed (p > 0.05) (Table 8). On the other hand the mean serum level of magnesium after infusion in the magnesium receiving group was higher than the placebo group; the relation between the serum level of magnesium and the magnesium receiving group after infusion was significant (p = 0.000 < 0.05). The serum level after infusion still was in the normal range (Table 8).

Table 8: Determining and comparing the mean serum level of magnesium in both groups.

*A p value of less than 0.05 indicated statistical significance.
Data are presented as mean ± SD

  There was a significant difference between the mean time of oral administration in both groups (p = 0.015 < 0.05); in a way that the mean time interval before tolerating oral liquids in the magnesium receiving group was 10 hours and 53 minutes and in the placebo group was 12 hours and 6 minutes (Table 9).

Table 9: Determining and comparing the mean of the first time to tolerate oral liquids in both groups.

*A p value of less than 0.05 indicated statistical significance.

  The mean of Apgar score of neonates 1 and 5 minutes after delivery had no significant difference between both groups (Table 10) (p > 0.05).

Table 10: Determining and comparing the mean of Apgar score of neonates in both groups.

*A p value of less than 0.05 indicated statistical significance.

Discussion

  Pain control after surgery and reducing its related morbidity, would decrease the duration of patients’ hospitalization and treatment expenses, which, especially in developing countries, is of great importance^[5]. The main result of this study was that prescribing magnesium sulfate during caesarean section with spinal anesthesia, along with hemodynamic stability of patient during surgery, could significantly decrease patient’s pain and consumption of non-steroidal anti-inflammatory drugs and opioid, in addition could also decrease the period of ileus after caesarean section; this could have an important in fast discharge of the patient from the hospital. Faster return of the mother to the family has an especial importance in the mental health and hygiene of the family and the society. Considering a meta-analysis that was conducted in 2013, the palliative effect of magnesium sulfate has been approved by a few studies and further studies are required in this field^[10].

  The definite lingered analgesic effect of magnesium sulfate could be caused by inhibiting the receptors of N-Methyl-D-Aspartate (NMDA)^[6,10]. Prescribing intravenous magnesium sulfate with bolus dose in back surgery has decreased the consumption of painkillers after surgery and has also led to better sleeping and more satisfaction during the first 24 hours after surgery in patients^[1]. The present study also revealed decreased consumption of painkillers and increased satisfaction in patients which a suggested mechanism for this matter is magnesium sulfate’s effect as “the physiologic blocker of calcium channel”^[18]. This analgesic effect in knee arthroscopy for patients who received bolus and infusion of magnesium sulfate significantly decreased the consumption of fentanyl during and after surgery for 4 hours after surgery^[1]. Consuming Lidocaine and magnesium sulfate for laparoscopic cholecystectomy has also decreased the need for opioids and painkillers during and after the surgery; also the magnesium receiving group experienced better sleep^[1,2]. Also the effect of magnesium sulfate has been studied in patients undergoing women’s specialized surgeries and it was revealed that the magnesium receiving group required less chromium during hysterectomy. Also patients’ pain intensity was lower after the surgery and they required fewer painkillers and experienced a better quality sleep^[1,3]. This matter was also approved in the present study. The effectiveness of magnesium sulfate which delayed the first request for painkiller has been approved previously and this matter was also confirmed for pregnant women in the present study^[9,19]. Some studies revealed no significant effect of magnesium sulfate on pain reduction after surgery^[15,16] but since they used general anesthesia, their results could not be compared with the results of the present study. On the other hand, in the present study, besides pain reduction, the interval before tolerating oral liquids was decreased too which is one of the benefits of magnesium sulfate especially in caesarean section; this has been approved in previous studies too. Also the serum level of magnesium was not in the toxic range in the present study. Since the stress of surgery would increase the sympathetic activities, it would inhibit bowel movements^[17]. Magnesium sulfate with its lysissympathoeffect could be effective on reduction of ileus after surgery^[14] and the results of the present also approved this matter.

  By and large, our study is comparable with other studies^[20,21] which determine perioperative intravenous magnesium sulfate (bolus or infusion) reduce analgesic consumption and pain score in the first 24 hours postoperative without any serious side effects.

  In a recent study^[22] the analgesic effect of magnesium sulfate was compared with ketorolac in laparascopic surgery. The results emphasized that intravenous magnesium sulfate reduced morphine consumption and pain intensity similar to ketorolac. As the safety of magnesium sulfate usage is a priority of this drug in comparison of other painkillers with serious side effects, this study can recommend usage of this drug to reduce pain and also ileus time after cesarean surgery in parturient.

  One of the limitations of the present study was not measuring the magnesium level of cerebrospinal fluid (CSF) and it is suggested to consider it in further studies. Another limitation in this study was the problems the patients had with the loading dose infusion, which means they had nausea and vomiting and complained for flushing. So we had to slow the infusion rate more than 10 minutes.

Conclusion

  The present study resulted that intravenous infusion of magnesium sulfate ((loading dose 40 mg/kg and continuing with 15 mg/kg/h) during surgery, with the least side effects, could be used in caesarean sections with spinal anesthesia and would definitely decrease pain intensity and duration of ileus after surgery and would also increase the analgesic period and the time of requesting painkillers by the mothers. Also prescription of this drug had no adverse effect on Apgar score of the neonates.

Acknowledge:
  The authors wish to sincerely thank the support of all the colleagues in Baheshti Hospital Medical Center affiliated to Isfahan University of Medical Sciences in Isfahan, Iran. Furthermore, our special thanks go to the patients, who wholeheartedly and actively assisted us to carry out this research. No conflict of interest existed. This prospective randomized observational study was approved by the Ethics Committee of our university, (Anesthesiology and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran) and all patients gave written, informed consent.

Conflict of interest: Authors have no conflict of interests.

Financial Disclosure: Anesthesiology and Critical Care Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.

References