A dose-finding randomised controlled trial of magnesium sulphate as an adjuvant in ultrasound-guided supraclavicular brachial plexus block.

BACKGROUND AND AIM: Magnesium sulphate (MgSO4) has been used as an adjuvant in brachial plexus block with encouraging results; however, there is no consensus regarding its optimal dose. Thereby, we compared the efficacy of two doses of MgSO4 as an adjuvant in ultrasound (USG) guided supraclavicular brachial plexus block.
METHODS: Ninety patients, aged 20-60 years, belonging to American Society of Anesthesiologists physical status 1 or 2, were given USG-guided supraclavicular block. Group B (n = 30) received 20 ml of 0.5%bupivacaine + 5 ml normal saline (NS), Group BM0.5(n = 30) received 20 ml of 0.5%bupivacaine + 3.75 ml NS and 125 mg MgSO4 (1.25 ml) and Group BM1(n = 30) received 20 ml of 0.5%bupivacaine + 2.5 ml NS and 250 mg MgSO4 (2.5 ml). The primary outcome of study was the duration of post-operative analgesia. The normally distributed data were analysed using analysis of variance and categorical data analysed using Chi-square test.
RESULTS: Duration of post-operative analgesia was prolonged in Groups BM1 and BM0.5 (665.13 ± 97.874, 475.10 ± 53.294) min respectively as compared to Group B (272.03 ± 40.404 min: P = 0.00). The onset times of sensory and motor block were shorter in Group BM1 (5.17 ± 2.2 min) as compared to Groups BM0.5 and B (8.9 ± 2.3 and 17.7 ± 5.1 min: P = 0.00) respectively. Sensory and motor block durations were prolonged in Group BM1 as compared to BM0.5 and B (P = 0.00).
CONCLUSIONS: MgSO4 as adjuvant in brachial plexus block increases the duration of post-operative analgesia. MgSO4 in the dose of 250mg has greater efficacy as compared to 125 mg.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Supraclavicular brachial plexus block is a safe and inexpensive technique with the advantages of providing ideal operating conditions and effective post-operative analgesia. Ultrasound (USG)-guided supraclavicular brachial plexus block allows better visualisation of underlying structures, movement of needle and direct spread of local anaesthetic and thereby making procedure safe and effective as compared to nerve stimulator-guided technique.[1]

Local anaesthetic drugs are widely used throughout anaesthetic practice, but the limited duration of action of various local anaesthetics continues to be a matter of concern for anaesthetists. A variety of perineural adjuvants[2345] have been tried to hasten the time of onset and prolong the duration of analgesia of nerve blocks with varying degrees of success. Better knowledge of pain mechanisms has highlighted the role of central sensitisation and N-methyl-D-aspartate (NMDA) receptors in post-surgical pain.[6] Magnesium sulphate (MgSO4) by virtue of NMDA receptors antagonist property[7] has been evaluated as an adjuvant to local anaesthetics in the neuraxial blocks, peripheral nerve blocks[8] and transverses abdominis block.[9]

However, the review of literature on the use of MgSO4 as an adjuvant to supraclavicular brachial plexus block reveals studies with conflicting results. The optimal dose of MgSO4 in brachial plexus block has not been ascertained. We, therefore studied the efficacy of MgSO4 in two doses (125 mg and 250 mg) as an adjuvant to bupivacaine in USG-guided supraclavicular brachial plexus block.

METHODS

After approval by the Institutional Ethics Committee and informed written consent from the patients, this prospective study (CTRI/2015/07/005979) was carried out over a period of 12 months in 90 American Society of Anesthesiologists'physical status 1 or 2 patients of either gender, age 20–60 years, having fractures of forearm bones for open reduction and internal fixation, scheduled under supraclavicular brachial plexus block.

Exclusion criteria included history of cardiac, hepatic or renal disease, chronic treatment with calcium channel blocker, contraindications to supraclavicular brachial plexus block (bleeding disorders, local or systemic infection) and inability to comprehend the visual analogue scale (VAS) for pain assessment. If the patient required supplementary anaesthesia in the intraoperative period, the block was considered a failed block.

Randomisation was achieved by a computer-generated random number table. Random group assigned was enclosed in a sealed opaque envelope to ensure concealment of allocation sequence. After shifting the patient inside the operation theatre, the sealed envelope was opened by an anaesthesiologist not involved in the study, to prepare the drug solution according to randomisation, in a sterile bowl. The observer who collected the perioperative data as well as the patients were blinded to the drug solution administered.

All patients were explained about the procedure, advantages and the risks of the procedure, during the pre-operative assessment 1 day before surgery, and then, written informed consent was obtained from the patients. Patients were educated about the VAS during the pre-operative assessment. All the patients were kept nil orally for solid food for 8h and clear fluids for 2h before surgery. The patients were premedicated with tablet alprazolam 0.5 mg the night before and 2h before surgery. In the operation theatre after securing 18-gauge intravenous cannula (IV) in the non-operated arm, maintenance fluid was started with normal saline (NS). Heart rate, non-invasive arterial blood pressure, peripheral oxygen saturation and respiratory rate were monitored, and baseline values were recorded. The patients were positioned supine with the arm placed by the side. The head was positioned, without headrest, facing 45°to the contralateral side to be blocked. The area was cleaned with chlorhexidine (0.5%) and draped. The block was performed using USG with linear high-frequency probe (6-13MHz), which was covered with sterile plastic sheath, and sterile gel was applied. The probe was placed in the supraclavicular fossa in coronal oblique plane to visualise the plexus. The pulsating, hypoechoic subclavian artery was identified, lying above the hyperechoic first rib. The hypoechoic nerve structures (trunks or divisions) were visualised posterolateral to the artery with a characteristic 'honey comb' appearance.

A sterile 50 mm 22-gauge insulated needle was advanced using an in-plane technique. When the needle was seen well, the tip was directed towards the nerve bundle. Three or four separate injections at various sites, in the bundle, were given, tending to start deep, in the'corner pocket'close to the artery, and moving more superficially.

Group B received 20 ml of 0.5% bupivacaine +5 ml of NS, Group BM0.5 received 20 ml of 0.5% bupivacaine +3.75 ml of NS along with 125 mg (1.25 ml) MgSO4 and Group BM1 was given 20 ml of 0.5% bupivacaine +2.5 ml of NS and 2.5 ml MgSO4 (250 mg) to total volume of 25 ml and final concentration of bupivacaine 0.4% in each group.

In this study, duration of analgesia was primary outcome, whereas, block characteristics and total rescue analgesic requirement were taken as secondary outcomes. Sensory loss assessment[10] was done using the pinprick test with a three-point scale: 0 = Sharp pain, 1 = Analgesia (loss of sensation to pinprick) and 2 = Loss of touch. The motor block[11] was assessed by asking the patient to flex and extend the wrist and fingers using a three-point scale: 0 = Total movement of fingers and wrist, 1 = Reduced movement of fingers and wrist and 2 = Inability to move fingers. Block was evaluated every 3 min upto 30 min after the injection of local anaesthetic. Further block assessment was done at hourly intervals in the post-operative period, to assess the duration of motor and sensory block. The onset of sensory blockade was defined as the time interval between the end of injection and loss of sensation to pinprick or a score 1 on pinprick response. The onset of motor blockade was the time interval between the end of injection and complete motor paralysis of the wrist and hand. The duration of sensory blockade was the time interval between sensory blockade and reappearance of the pinprick response. The duration of motor blockade was defined as the time interval between maximum motor blockade and complete movement of the wrist and fingers.

Pain assessment was done using VAS, obtained by asking the patient to rate the intensity of pain perceived and express it on a 10 cm horizontal scale ranging from no pain at one end (corresponding to zero) to the worst possible pain at the other end (corresponding to 10). The duration of analgesia was taken from the time of completion of block to the demand of first rescue analgesic in the post-operative period. Rescue analgesia in the form of injection diclofenac 1.5 mg/kg intramuscularly was given to patients with VAS >4. If the pain was not relieved within 30 min, injection tramadol 2 mg/kg was given intravenously. All the patients were monitored in the perioperative period for haemodynamic stability and side effects i.e., nausea, vomiting, sedation and respiratory depression.

For statistical analysis, data were collected and entered in MS Excel 2010. Statistical analysis was performed using SPSS software 18 (SPSS, Inc., Chicago, IL, USA). The one-sample Kolmogorov–Smirnov Test was employed to determine whether datasets differed from a normal distribution. Normally distributed data were analysed using analysis of variance, and categorical data were analysed using Chi-square test. Bonferroni correction was used to correct for multiple testing at different time points. A value of P < 0.05 was considered significant, and P < 0.00 was taken as highly significant.

For estimating sample size, a pilot study was done in 12 patients randomised in three groups. The duration of analgesia was 450 ± 50 and 517 ± 125.01 min (mean ± standard deviation) in 125 mg and 250 mg magnesium group, respectively, as compared to bupivacaine group (399 ± 97 min). The standardised effective size 'Cohen's d' was calculated utilising control and 250 mg magnesium groups. Twenty-three patients per group were required to detect a statistically significant difference at α = 0.05 and 80% power. Therefore, to account for probable block failures and dropouts, thirty patients were recruited in each group.

RESULTS

Total number of patients enrolled during the study period were 106 and six patients were excluded for not meeting the inclusion criteria [Figure 1]. Ten patients did not give written consent to participate in the study. Therefore, a total of ninety patients completed the study successfully, with thirty patients in each group. There was no block failure in any of the three groups. The patients in three groups were comparable to each other with respect to age, gender, weight and duration of surgery [Table 1].

Figure 1

Flow chart of patients recruited and analysed in three groups

Table 1

Demographic data of patients in three groups

It was observed that the sensory onset time was faster in Group BM1 (5.17 ± 2.2 min) than in Groups BM0.5 and B (8.9 ± 2.3, P = 0.00; 17.7 ± 5.1, P = 0.00) [Figure 2]. Similarly, the onset of motor block in Groups B, BM0.5 and BM1 was (28.47 ± 7.0, 16.30 ± 5.6 and 11.13 ± 4.6 min; P = 0.00), respectively [Figure 2]. The mean duration of motor block was (222.13 ± 32.67, 401.73 ± 56.116 and 569.00 ± 100.833 min; P = 0.00) in Groups B, BM0.5 and BM1, respectively. The mean duration of sensory block was maximum in Group BM1 (641.87 ± 100.152) followed by Group BM0.5 (451.47 ± 51.632) and minimum in Group B (252.50 ± 42.275 min), (P = 0.00) [Figure 3].

Figure 2

Comparison of onset of sensory and motor block (minutes) in three groups expressed as mean ± standard deviation. Onset of sensory and motor block was earlier in magnesium groups in dose-dependent manner (P = 0.00)

Figure 3

Comparison of duration of sensory, motor block along with duration of analgesia in three groups. Values expressed as mean ± standard deviation. Mean duration of sensory, motor block and analgesic duration was significantly increased in Group BM1as compared to BM0.5 and B (P = 0.00)

The mean duration of analgesia was (665.13 ± 97.874 min) in Group BM1 followed by Groups BM0.5 and B (475.10 ± 53.294 and 272.03 ± 40.404 min, P = 0.00), respectively [Figure 3]. Group B received maximum doses of rescue analgesics (3.20 ± 0.407) followed by Groups BM0.5 and BM1 (1.93 ± 0.25 and 1 ± 0.00, P = 0.00), respectively, over a period of 24 h in the post-operative period [Figure 4].

Figure 4

Comparative evaluation of total doses of rescue analgesic in three groups expressed as mean ± standard deviation. Group BM1 required least doses of rescue analgesic as compared to Groups B and BM0.5 (P = 0.00)

Patients remained haemodynamically stable throughout perioperative period. There was no episode of nausea, vomiting, sedation and respiratory depression in the perioperative period.

DISCUSSION

The major findings of our study were that the addition of MgSO4 in two doses to bupivacaine in USG-guided supraclavicular brachial plexus block, significantly prolongs the duration of analgesia, hastens the onset of sensory and motor blockade, and decreases the number of analgesic requirement in a dose responsive manner, without causing side effects.

Since the introduction of MgSO4 as NMDA receptors antagonist, its role has been evaluated for the analgesic properties in anaesthesia practice. The NMDA receptors play an important role in central nociceptive transmission, modulation and sensitisation of acute pain states. In addition to central location, NMDA receptors are found in the muscle and skin,[12] knee joint,[13] and play a role in sensory transmission of noxious signal.[14]

The primary hypothesis of our study, regarding the dose-dependent effect of MgSO4 as an adjuvant, on peripheral nerves is based on the surface charge theory as explained by Akutagawa et al.[15] The authors suggested that modulation of the external magnesium concentration resulted in the synergistic effect on nerve blockade due to local anaesthetics. Mert et al.[16] also observed that a high concentration of divalent ions (Mg2+ and Ca2+) attracted by the negative charge of the outer membrane surface affected Na+ channel gating and could cause hyperpolarization resulting in nerve conduction block. The above mentioned studies support our hypothesis that the higher concentration of magnesium (250 mg) provided a more pronounced prolongation of block.

The doses of MgSO4 (125 mg and 250 mg) used in our study were in accordance with the study by Goyal et al.[17] To achieve effective concentration of MgSO4 (0.5% and 1%) in 25 ml of drug solution, the doses of 125 mg and 250 mg of MgSO4 were used in Groups BM0.5 and BM1, respectively. In other studies, Mukherjee et al.[18] used 150 mg of MgSO4 in supraclavicular brachial plexus block, whereas Bansal et al.[19] used 1.5 g of MgSO4 in intravenous regional anaesthesia (IVRA), without any reported side effect and neurotoxicity.

The onset of sensory and motor block was faster in the magnesium groups in a dose-dependent manner than in the bupivacaine group. The findings of our study were in accordance with a study by Bansal et al.[19] In another study,[18] no statistical significance was observed in the onset time of sensory and motor block with magnesium (150 mg) used as an adjuvant to ropivacaine. This could be because the larger volume of local anaesthetic (30 ml) used in the study lead to a reduced effective concentration of magnesium.

In the study by Lee et al.,[20] the authors used 0.5% bupivacaine 20 ml with epinephrine (1:200,000) plus 10% MgSO4 2 ml or NS 2 ml in patients, who received an interscalene brachial plexus block for arthroscopic shoulder cuff repair. The onset times and durations of sensory and motor blocks were comparable between the two groups. The addition of epinephrine might be the contributing factor as compared to the present study. However, the mean duration of analgesia was increased in magnesium group, and is consistent with the present study. With regard to total doses of rescue analgesic, Group B received maximum doses of rescue analgesics followed by Groups BM0.5 and BM1 and is in accordance to study.[18] However, these findings were not consistent with the findings in the study by Choi et al.,[21] and various factors might have contributed to this discrepancy in the results, such as lesser concentration of ropivacaine (0.2%), lesser volume of drug (20 ml) used in axillary block and blind technique of block administration.

There are few limitation of this study. A lower volume of local anaesthetic could have been used, especially under USG guidance. Second, systemic absorption of magnesium may have contributed to the beneficial effects. Therefore, further studies are required in this regard.

CONCLUSIONS

Our data support the hypothesis that the action of MgSO4 (125 mg and 250 mg) added as an adjuvant to bupivacaine is dose dependent and prolongs the duration of analgesia and helps in reducing the demand for rescue analgesic requirements in the post-operative period without any side effects. The higher dose (250 mg) of MgSO4 was more effective as compared to 125 mg.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.