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Postoperative analgesic effects of magnesium sulphate versus placebo in pre eclmpsic patients with cesarean section

Usually the anesthetists becomes involved with a pre-eclamptic patient when asked to initiate anesthesia during managing of preeclampsia. Anaesthetists can and should take an active role in the monitoring and management of pre-eclamptic patients in addition to providing analgesia for labour and anesthesia for operative delivery. (1)

Anaesthesia for operative delivery raises further considerations. The choice in this situation lies between regional anaesthesia (i.e., epidural or spinal) and general anaesthesia. Caesarean section is often required because of the worsening fetal status and delivery of the infant is the only way to end pre-eclampsia .If time permits and there are no contra-indications (i.e., coagulopathy or non-acceptance by the patient) then epidural anaesthesia is the best choice for Caesarean section.(2)

Therefore, anesthesiologists and surgeons are increasingly turning to non-opioid analgesic techniques as adjuvants for managing pain during the perioperative period to minimize the adverse effects of analgesic medications. Multimodal or "balanced" analgesic techniques involving the use of smaller doses of opioids in combination with non-opioid analgesic drugs [e.g., local anesthetics, ketamine, acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs)] are becoming increasingly popular approaches to preventing pain after surgery. (3) (4)

MgSO4 is increasingly used as an adjuvant to general anaesthesia, mainly for haemodynamic control and nociception modulation(5).ALSO, the use of low concentrations of volatile anaesthetics with avoidance of opioids may induce intraoperative awareness and adverse haemodynamic responses during Caesarean section. Magnesium is well known to reduce anaesthetic requirements and to block noxious stimuli. So,intravenous magnesium sulphate can modulates anaesthetic depth and analgesic efficacy during Caesarean section.(6)

Magnesium has postsynaptic N-methyl D-aspartate (NMDA) calcium channel blocker properties, and has been used successfully to potentiate opioid analgesia and to treat neuropathic pain in animals. (7) (8) Tramer and colleagues (9)conducted the first clinical trial showing that perioperative administration of magnesium sulphate was associated with lower analgesic requirements in the postoperative period.

Patients and methods

With the approval of Ethics and Research Committee of the Department of Anesthesia in Tanta University Hospital and with informed written consent the study was done in the Obstetric and Gynecology Department. We planned an elective section at 37 weeks of gestation to avoid the stress of labour and vaginal delivery. Patients were randomly divided into two equal groups. patients undergoing emergency surgery or allergic to any of the drugs during anaesthesia were excluded from the study. Befor operation,all patients were taught to use PCA device and visual analogue pain score(VAPS).

On arrival in the operating room, two peripheral venous canulae were placed in all patients before induction of anaesthesia and isotonic saline infusion was started at a rate of 8-12 ml kg-1 h-1 in one of them, Routine monitoring of ECG, pulse oximetry and non-invasive blood pressure was established before induction of anaesthesia and continued throughout the operations.

In the magnesium group a bolus of 6g infusion of magnesium sulphate in a total of 100 ml normal saline was given 30 min before induction of anaesthesia, followed by infusion of 2g per hour for 24 hours(Sibai regime). In the control group, infusion of 100 ml normal saline was given 30 min before induction of anaesthesia. After preoxygenation with 10 l/minute for at least 2 min, anaesthesia was induced by intavenous propofol 2 mg kg-1 followed by 2mg/kg suxamethonium .Cricoid pressure was applied as consciousness is lost and maintained until the trachea is intubated, the cuff inflated and found to be leak free. The lungs were ventilated with 50% nitrous oxide: 50% oxygen is given with 0.75% isoflurane which continued to the end of procedure.

Muscle relaxation was achieved with 0.5 mg kg-1 atracurium once the suxamethonium weaned off and peripheral nerve stimulator was used to assess neuromuscular blockad. Following delivery of the baby, Deepen anaesthesia with a 0.1 mg morphine i.v and reducing the inspired oxygen concentration to 40%. For both groups following delivery of the baby a slow oxytocin drip (20 units in 500ml normal saline at 100 ml/hr) was started. Any residual neuromuscular block was reversed by neostigmine 0.08mg\kg and atropine 0.02mg\kg, administered 100% oxygen, the patient was extubated and awake after thorough suction of the pharynx and the risk of aspiration was reduced by emptying the stomach before extubation.

The time from cessation of anaesthetics to beginning of spontaneous movements, response to verbal commands and time to extubation were recorded. patients were moved to the recovery area where pain score was assessed 1\2 an hour after surgery,using visual analogue score(VAS)(0=no pain;10=most sever pain).On arrival to the post-anaesthesia care unit(PACU) pain relief was achieved by patient controlled analgesia pump. The PCAP solution contained morphine 1mg\ml.The initial incremental dose was 1.5ml with a lockout interval of 8minutes and a 4-hour limit was increased to 40ml if analgesia was inadequate after one hour. If analgesia remained inadequate after an additional hour,the incremental dose was further increased to2.5ml.All patients received intravenous PCA morphine.The patients were randomly assigned to one of two equal treatment groups:

Group I :received magnesium sulphate 6g loading dose infusion over 20-30 minutes, then 2g magnesium sulphate per hour for 24 hours.

Group II :received an i.v infusion of (placebo), 100 ml normal saline was given 30 min. before induction of anaesthesia then every hour. Patients were asked to quantify their pain on visual analogue scale (VAPS) between 0 and 10, with 0 representing no pain and 10 representing the worest imaginable pain. Pain assessment and morphine use were recorded 4, 8, 12, 16, 20,24hours after surgery.

Statistical analysis:

Data were expressed as mean (SD).Between-group differences were analyzed using one-way analysis of variance (ANOVA).Intragroup differences were analyzed using repeated measures ANOVA. post-hoc analysis(Newman-Keul ̓s test) was performed if significance was detected. A P value of<0.05 was considered statistically significant.

Results:

There were no significant differences among the treatment groups with the respect to age, height, or weight (Table1.).

The total dose of morphine and cumulative doses for each of the six time periods were significantly less in group I than in the group II (Table 2).

The pain scores were significantly lower in group I than group II in evaluation fifth and sixth only (Table 3).

Table1.Demographic data of patients in the two groups of study. Values are means (SD).

Magnesium

sulphate

(n=15)

Placebo

( n=15)

Age(years)

42(6)

41(7)

Height(cm)

170(4)

172(3)

Weight(kg)

85(9)

90(3)

Table 2.Morphine consumption (mg) at each interval of the study and total morphine dose (mg\24hours) in the two groups. Values are means (SD).

Time interval

Magnesium

sulphate

(n=15)

Placebo

(n=15)

0-4hours

7.1(1.4)*

12.3(4.5)

4-8hours

7.6(2.2)*

10.4(3.4)

8-12hours

6.9(3.1)*

10.3(2.5)

12-16hours

5.9(2.3)*

9.5(3.1)

16-20hours

5.1(1.5)*

8.1(2.4)

20-24 hours

4.2(1.3)*

7.4(2.2)

Total morphine

(mg\24h)

35.2(8.3)*

55.1(6.2)

*Statistically significant (P<0.001)compared to Placebo group in same time interval.

Estimates were performed every 4 hours postoperatively and data were obtained at the end of the time period.

Table 3.pain scores for the two groups of the study at different time intervals. Values are means (SD).

Time interval

Magnesium

sulphate

( n=15)

Placebo

(n=15)

1 (4hours)

3.0(7.0)

4.2(1.0)

2 (8hours)

3.1(1.1)

3.8(0.7)

3 (12hours)

2.8(0.6)

3.4(0.8)

4 (16hours)

2.1(0.6)

3.1(1.0)

5 (20hours)

1.5(0.4)*

2.9(0.9)

6 (24 hours)

1.3(0.5)*

2.3(0.5)

*Statistically significant (P<0.001)compared to Placebo group in same evaluation time.

Discussion

Pain is the one of the main intra and postoperative adverse outcomes. Single analgesics, either opoids or NSAID are not able to provide effective pain relieve without side effects, such as nausea, vomiting, sedation or bleeding. Multimodal analgesic approach is recommended for management of perioperative pain. (10)

Magnesium is the fourth most common mineral salt in human body and the second intracellular cation.Magnesium plays an important role in the structure and function of human body. It is important for most biological processes including supply with cellular energy and synthesis of nuclear acids and proteins, maintenance of electrical stability and cellular integrity preservation. Magnesium also, contributes to muscle contraction, conduction of neuronal and pain impulses, and vascular tone regulation. Magnesium action as ca channel blocker and NMDA receptor antagonist could play an important role in postoperative pain, sensitization processes and hyperalgesia throughout the early postoperative period. (11) (12)

However, there are two possible mechanisms of the magnesium adjuvant analgesic effect. The first theory includes activation of NMDA receptors. NMDA receptor is an amino acid receptor responsible for excitatory synaptic transmission with binding sites positive for excitatory amino acid glutamate and negative for ketaminc or magnesium. The activation of pain pathways is explained by stimulation of NMDA receptors of dorsal horn with excitatory neurotransmitters, initiating the process of central sensitization(13)(14).

In the present study, we administered a dose of magnesium that was most likely to achieve the effect without any adverse reaction. We assumed the dose of magnesium administered in our study to be responsible for the rise in its cerebrospinal fluid concentration, therefore depressing the electro physiologic effect of NMDA receptors. The second theory includes the action of magnesium as a calcium channel antagonist. The analgesic effect of calcium channel antagonists could be mediated by a rise in the nociceptive threshold because of calcium influx into the cell. This calcium influx is responsible for the release of neurotransmitters connected with nociception and inflammatory response.(15)

Our study demonstrated an analgesic effect for magnesium suphate which was superior to placebo. Their analgesic efficacy was demonstrated by a significant opioid sparing effect in comparison to placebo, when used in conjunction with PCA morphine for postoperative pain control. We also, able to demonstrate a similar decrease in pain scores for magnesium suphate in comparison to placebo.

Many studies confirmed the efficacy of opoid sparing effect in patients given magnesium sulphate perioperatively.In their study in patients undergoing vitrectomy,Schulz-stubner et al.(16) recommended the use of magnesium sulfate as a safe analgesic adjuvant.magnesium is well known for its action as a physiologic calcium blocking agent while also inhibiting the neurotransmitter and katechollamine release.Based on the evidence, Schulz-stubner et al. conclude that one the mechanisms described is responsible for lower intraoperative opoid consumption. (16)

On the other hand,in avery recent investigation,Ryu et al.showed that the infusion of the magnesium sulphate during TIVA with propofol infusion and ramifentanil did not reduce propofol infusion while ramifentanil consumption was not changed significantly.(17) Seyhan etal.compared the effects of magnesium sulphate on intra operative fentanyl consumption in patients undergoing gynecologic procedure and found no difference between group.(18)

In all these studies magnesium was used as an adjuvant to other intravenously administered analgesic drugs and despite the promising initial work,further clinical studies did not report consistent results on magnesium action as adjuvant in perioperative analgesia.(19)(20)

Conclusion

This prospective, randomized study was designed to assess the effect of magnesium sulfate on postoperative morphine consumption and analgesia in pre eclamptic patients undergoing cesarean section. Results of our study showed the cumulative dose of morphine to be statistically lower in the magnesium treated group as compared to control group. Thus we recommend decreasing the dose of opioid used in cesarean section with pre eclamptic patients under treatment of magnesium sulphate.

References

1- Lindheimer MD, Katz AL Medical intelligence. Current concepts, Hypertension in pregnancy. N Eagl J Med 1985; 11: 675-80.

2- Hodgkinson R, Husain FJ. Hayashi RH. Systemic and pulmonary blood pressure during Caesarean section in parturients with gestational hypertension. Can Anaesth Sac I 1980; 27: 389-93.

3- Eriksson H, Tenhunen A, Korttila K. Balanced analgesia improves recovery and outcome after outpatient tubal ligation. Acta Anaesthesiol Scand 1996; 40:151-5.

4- Pavlin DJ, Horvath KD, Pavlin EG, Sima K. Preincisional treatment to prevent pain after ambulatory hernia surgery. Anesth Analg 2003; 97:1627-32.

5- Tramer M.R., Schneider J., Marti R. and Rifat K.:"Role of magnesium sulphate in postoperative analgesia". Anesthesiology, 84 (2): 340-347, 1996.

6-D. H. Lee and I. C. Kwon.Magnesium sulphate has beneficial effects as an adjuvant during general anaesthesia for Caesarean section.British Journal of Anaesthesia 2009 103(6):861-866.

7-Begon S, Pickering G, Eschalier A, Dubray C. Magnesium increases morphine analgesic effect in different experimental models of pain. Anesthesiology 2002; 96: 627-32

8-Takano Y, Sato E, Kaneko T, Sato I. Antihyperalgesic effects of intrathecally administered magnesium sulfate in rats. Pain 2000; 84: 175-9.

9- Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative analgesia. Anesthesiology 1996; 84: 340-7.

10-Kehlet H, Dahl JB: The value of ̏multimodal̋ or ̏balanced analgesia̋ in postoperative pain treatment. Anesth Analg 1993; 77:1048-1056.

11- Ferrante FM,Chan VWS,Arthur GR,Rocco AG. Interpleural analgesia after thoracotomy.Anesth Analg1991;72:105-9.

12- Birch NJ,editor.Magnesium and cell. London-Boston: Academic Press,1993;289.

13-ISERI LT, FRENCH JH. Magnesium: nature's physiological calcium blocker. Am Heart J 1984;108:188-94.

14-CODERRE TJ, MELZACK R. The role of NMDA receptor-operated calcium channels in persistent nociception after formalin induced tissue injury. J Neurosci 199Z;1Z:3671-5.

15-ISERI LT, FRENCH JH. Magnesium: nature's physiological calcium blocker. Am Heart J 1984;108:188-94.

16-Schulz-stubner S,Wettmann G,Reyle-Hahn SM,Rossaint R.Magnesium as a part of balanced general anaesthesia with propofol,remifentanil and mivacurium:adouble blind,randomized , prospective study in 50 patients.Eur J Anesthesiol2001;18:723-9.

17-Ryu JH,kANG MH,Park KS, DO SH.Effects of magnesium suphate on intraoperative anaesthetic requirements and postoperative analgesia in gynaecology patients receiving total intravenous anaesthesia.Br J Anesth 2006;96:247-52.

18-Seyhan To,Tugrul M,Sungur MO, KAYACAN S,TELCI L, PENBECI K, AKPIR K. Effects of three different dose regimens of magnesium on propofol requirements,hemodynamic variables and postoperative pain relief in gynecological surgery. Br J Anesth Z006;96:Z47-5Z.

19-Ferrante FM,Chan VWS,Arthur GR,Rocco AG.Interpleural analgesia after thoracotomy.Anesth Analg1991;72:105-9.

20- Birch NJ,editor.Magnesium and cell. London-Boston: Academic Press,1993;289.