Dose–Response of Perineural Magnesium Sulphate in Ultrasound-guided Infraclavicular Brachial Plexus Block: A Randomised Double-blind Study

Introduction

Ultrasound-guided brachial plexus blocks are a cornerstone of regional anaesthesia for upper-limb surgeries, offering effective surgical anaesthesia, superior postoperative analgesia and reduced opioid consumption when compared with general anaesthesia. Among the various approaches, the infraclavicular brachial plexus block is particularly suited for procedures involving the elbow, forearm and hand, as it provides consistent blockade of the cords of the brachial plexus, a lower incidence of phrenic nerve involvement and improved catheter stability under ultrasound guidance. ¹ The infraclavicular approach has therefore gained increasing preference in contemporary regional anaesthesia practice. Appropriate local anaesthetic selection is essential for achieving effective and safe blockade. Bupivacaine is widely used for brachial plexus blockade because it is a well-established long-acting local anaesthetic that provides significantly prolonged sensory blockade and extended postoperative analgesia compared with shorter-acting combinations. ² Despite these advantages, the duration of analgesia achieved with local anaesthetics alone is often insufficient for prolonged postoperative pain control, thereby necessitating the use of adjuvants for prolonged and improved blockade.

Several pharmacological agents have been evaluated as adjuvants to local anaesthetics in brachial plexus blocks. The incorporation of alpha-2 agonists, particularly clonidine and dexmedetomidine, into local anaesthetic solutions has been found to prolong blockade duration in infraclavicular and supraclavicular approaches.^{3, 4} Similarly, corticosteroids such as dexamethasone have demonstrated a significant prolongation of analgesia when combined with ropivacaine in brachial plexus blocks. ⁵ However, the routine use of these agents is limited by concerns related to dose-dependent adverse effects, including sedation, bradycardia, hypotension and potential neurotoxicity, thereby necessitating the search for alternative adjuvants with a favourable safety profile. Magnesium sulphate (MgSO4) has emerged as a promising adjuvant in regional anaesthesia owing to its well-established anti-nociceptive properties. The analgesic effects of magnesium are primarily mediated through antagonism of N-methyl-d-aspartate (NMDA) receptors and modulation of calcium influx into neuronal cells, mechanisms that play a crucial role in preventing central sensitisation and reducing postoperative pain. ⁶ Experimental studies have demonstrated that magnesium enhances the effect of local anaesthetics on peripheral nerves, thereby potentiating nerve blockade. ⁷ In addition, magnesium has been shown to alter peripheral nerve conduction by influencing calcium-dependent synaptic transmission, further supporting its role as an effective adjunct in regional anaesthesia. ⁸

Clinical studies evaluating MgSO4 in combination with local anaesthetics for brachial plexus blocks have reported a significant prolongation of sensory block and postoperative analgesia without a corresponding increase in adverse effects.^{9, 10} Systematic reviews and meta-analyses have further reinforced these findings, concluding that MgSO4 is an effective and safe adjuvant across various regional anaesthetic techniques, including brachial plexus blocks.^{11, 12} These studies suggest that perineural MgSO4 can enhance analgesic duration while maintaining haemodynamic stability and neurological safety. Despite the growing body of evidence supporting the use of MgSO4, alongside local anaesthetics for brachial plexus blockade, uncertainty persists regarding the optimal perineural dose, particularly in ultrasound-guided infraclavicular approaches. Previous dose-finding studies have demonstrated a dose-dependent prolongation of analgesia with MgSO4; however, the balance between maximal analgesic efficacy and safety has not been clearly established. ¹³ Furthermore, limited data are available specifically evaluating higher doses of MgSO4 in infraclavicular brachial plexus blocks under ultrasound guidance.

Accordingly, the present trial investigated the influence of varying doses of perineural MgSO4 as an adjuvant to bupivacaine in ultrasound-guided infraclavicular brachial plexus block, with the objective of identifying an effective and clinically safe dose that enhances postoperative analgesia and block characteristics.

Materials and Methods

Conducted at Kasturba Hospital, this study enrolled 90 ASA I-II patients between 18 and 60 years of age scheduled for upper-limb surgery. The study design was adapted from earlier published research evaluating different doses of MgSO4 in brachial plexus blocks. ¹⁴ Participants who refused consent, weighed less than 50 kg or had absolute contraindications to brachial plexus block were excluded.

The primary outcome of the study was the duration of analgesia, while block characteristics, including onset and duration of sensory and motor block, were considered secondary outcomes, consistent with earlier dose-finding trials of MgSO4 in brachial plexus blocks. ¹³ Preoperative evaluation was performed by an anaesthesia postgraduate on the day prior to surgery, and written informed consent was obtained after explaining the procedure. During this visit, participants were educated regarding the use of the visual analogue scale (VAS). Instructions regarding nil-per-oral status, aspiration prophylaxis, continuation of chronic medications and initiation of intravenous fluids were followed as per institutional protocol. ¹³ Participants were randomised into three groups using a computer-generated randomisation sequence. Allocation concealment was ensured using sequentially numbered opaque sealed envelopes. ¹⁵ The total volume of the drug mixture was maintained at 21 mL in all groups. Preservative-free MgSO4 at a concentration of 50% (500 mg/mL) was used in the study. The study drugs consisted of 20 mL of 0.5% bupivacaine combined with varying doses of MgSO4: 125 mg in Group A, 250 mg in Group B and 500 mg in Group C, with normal saline added where necessary to maintain uniform volume, based on previously reported dose-finding protocols. ¹³

The principal investigator opened the sealed envelope once the participant reached the preoperative area, prepared the study drug according to group allocation and performed the block. He had no role in the data collection and documentation. The co-investigator, an independent anaesthesiologist, entered the block room after the block had been performed and subsequently collected and documented all study data until completion of the study. Both the participant and the outcome-assessing anaesthesiologist (co-investigator) remained blinded to group allocation throughout the study period. In the preoperative area, baseline vital parameters including heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, oxygen saturation (SpO2) and baseline VAS score were recorded 30 min before shifting the participant to the operating theatre. ¹⁵ Maintenance intravenous fluids were administered as per standard protocol.

The ultrasound-guided infraclavicular brachial plexus block was performed with the participant in the dorsal recumbent position, the arm abducted to 90°, and the head rotated approximately 45° to the contralateral side. The principal investigator stood at the head end, and the ultrasound machine was positioned on the ipsilateral side. A high-frequency linear ultrasound transducer (6–13 MHz; Sonosite SII, Bothell, USA) and a 22-gauge, 5-cm insulated needle (Stimuplex Ultra 360, B. Braun Medical, Germany) were used, following standard infraclavicular block technique. ¹ Under strict aseptic precautions, the skin was infiltrated with 2 mL of 2% lignocaine. The study drug was injected in aliquots around the cords after frequent aspiration to avoid intravascular injection. ¹³ Following injection completion, sensory and motor block characteristics were monitored at 5-min intervals for a duration of 30 min. ² Sensory block was assessed using a three-point pinprick scale in the distributions of the radial, median, ulnar and musculocutaneous nerves, while motor block was evaluated using the modified Bromage scale for the upper limb. ² Sensory block scoring was defined as 0 for sharp pain, 1 for analgesia and 2 for loss of touch. Motor block scoring was defined as 0 for complete movement of fingers and wrist, 1 for decreased movement and 2 for inability to move fingers.

Postoperative follow-up included assessments every 2 h to determine the persistence of analgesia and sensory and motor blockade. Onset of sensory and motor block was defined as the time from completion of injection to achievement of score 2. Duration of sensory block was defined as the time from score 2 to reappearance of pinprick sensation, and duration of motor block as the time from score 2 to recovery of full movement. Duration of analgesia was defined as the time from completion of injection to VAS score greater than 3 in the postoperative period. Block failure was considered when adequate sensory and motor blockade (score 2) was not achieved within 30 min following injection, in which case the participant was excluded from analysis and managed with an axillary brachial plexus block based on clinical judgement.

Adverse effects were monitored intraoperatively and postoperatively. Hypotension, defined as a reduction in mean arterial pressure of more than 20% from baseline, was treated with intravenous mephentermine 3 mg. Bradycardia, defined as a heart rate less than 50 beats per min, was treated with intravenous atropine 0.6 mg. Nausea and vomiting were treated with intravenous ondansetron 4 mg. Duration of analgesia was assessed using a 10-point VAS, where 0 represented no pain and 10 represented the worst imaginable pain. ² The time at which VAS exceeded 3 marked the end of the study period. Intravenous paracetamol was administered as rescue analgesia when VAS exceeded 3. If pain persisted after 30 min, intravenous diclofenac 75 mg was administered, followed by intravenous tramadol 1 mg/kg if pain remained uncontrolled. Intraoperative haemodynamic parameters were continuously monitored, and all adverse events were documented.

Sample size calculation was based on previously reported mean durations of analgesia of 665.13 ± 97.87, 475.10 ± 53.29 and 272.03 ± 40.40 min, with a sample size of 26 participants per group required to detect a 90-min difference with 80% power and a 95% confidence interval. ¹³ Allowing for a 10% dropout rate, 30 participants were recruited per group, resulting in a total sample size of 90. Data were entered into Microsoft Excel and analysed using SPSS version 23 (IBM Corp.). Continuous variables were expressed as mean ± standard deviation, and categorical variables as frequencies and percentages. Intergroup comparisons for continuous variables were performed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test, while categorical variables were analysed using the Chi-square test. Before performing ANOVA, the underlying statistical assumptions were evaluated. Normality of continuous variables was assessed using the Shapiro-Wilk test, and homogeneity of variances across groups was examined using Levene’s test. When these assumptions were satisfied, one-way ANOVA was used to compare group means. In addition to p values, effect sizes (η²) were calculated to quantify the magnitude of differences between groups. Where appropriate, 95% confidence intervals were reported to provide estimates of the precision of observed effects. A p value of <.05 was considered statistically significant. ¹⁶

Results

Participant flow through the study is summarised in the CONSORT diagram (Figure 1). Of the 120 patients assessed for eligibility, 90 met the inclusion criteria and were randomised equally into three groups. All randomised participants received the allocated intervention, completed follow-up and were included in the final analysis, with no losses to follow-up, protocol deviations or block failures. Ninety patients completed the study and were included in the final analysis, with 30 patients in each group. There were no protocol deviations, dropouts or block failures during the study period. The study groups did not differ significantly with respect to demographic profile, ASA classification, body measurements or operative duration (Table 1). This indicated adequate randomisation and homogeneity of baseline characteristics. The duration of postoperative analgesia differed significantly among the three groups (Table 2). Group C demonstrated the longest duration of analgesia (711 ± 38.98 min), followed by Group B (582.17 ± 29.64 min) and Group A (466.33 ± 32 min). The overall difference among groups was statistically significant (p < .001), post hoc analysis revealed statistically significant differences between all pairwise comparisons, with Group B providing longer analgesia than Group A and Group C providing significantly longer analgesia than both Groups A and B.

OPEN IN VIEWER Figure 1.

Consort Flow Diagram.

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Table 1.

Demographic and Baseline Characteristics.

Parameter	Group A (n = 30)	Group B (n = 30)	Group C (n = 30)	p Value
Age (years)	39.33 ± 10.02	40.87 ± 12.77	40.53 ± 14.53	.884
Gender (male/female)	24 (80%)/6 (20%)	21 (70%)/9 (30%)	19 (63.33%)/11 (36.67%)	.358
ASA physical status (I/II)	23 (76.67%)/7 (23.33%)	18 (60%)/12 (40%)	20 (66.67%)/10 (33.33%)	.345
Duration of surgery (min)	83.9 ± 33.09	107 ± 69.69	95.67 ± 45.9	.231
Weight (kg)	63.43 ± 10.57	64.8 ± 11.37	66.07 ± 10.86	.649
Height (cm)	163.3 ± 7.72	163.43 ± 7.99	163.6 ± 7.44	.989
Body mass index (kg/m²)	23.61 ± 3.13	24.22 ± 3.28	24.66 ± 3.38	.460

Notes: Values are expressed as mean ± SD or n (%). ASA: American Society of Anesthesiologists.

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Table 2.

Duration of Postoperative Analgesia.

Parameter	Group A (n = 30)	Group B (n = 30)	Group C (n = 30)	p Value
Duration of analgesia (min)	466.33 ± 32	582.17 ± 29.64*	711 ± 38.98**	<.001

Notes: ^*Significantly different from Group A (p < .05). ^**Significantly different from Groups A and B (p < .05). Values are expressed as mean ± SD.

A statistically significant reduction in sensory block onset time was observed in Group C compared to Groups B and A (7.07 ± 1.7 vs 10.77 ± 1.22 and 14.17 ± 1.72 min, respectively; p < .001). Similarly, sensory blockade duration increased with escalating doses of MgSO4, with the longest duration observed in Group C (641.33 ± 36.65 min), followed by Group B (521.67 ± 35.7 min) and Group A (417 ± 28.3 min) (Table 3). A comparable trend was observed for motor block characteristics. Group C had the fastest onset of motor block (11.3 ± 1.6 min) and the longest duration (565.67 ± 31.37 min), followed by Group B and Group A. Statistically significant intergroup variation was observed for both onset and duration of sensory and motor block (p < .001) (Table 3). The incidence of adverse effects, including hypotension, bradycardia, nausea and vomiting, was nil in all groups. There were no cases of block failure, and all patients achieved adequate sensory and motor blockade. (Figure 2)

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Table 3.

Sensory and Motor Block Characteristics.

Parameter	Group A (n = 30)	Group B (n = 30)	Group C (n = 30)	p Value
Sensory Block
Onset (min)	14.17 ± 1.72	10.77 ± 1.22*	7.07 ± 1.7**	<.001
Duration (min)	417 ± 28.3	521.67 ± 35.7*	641.33 ± 36.65**	<.001
Motor Block
Onset (min)	18.5 ± 1.7	14.67 ± 1.45*	11.3 ± 1.6**	<.001
Duration (min)	375.33 ± 26.23	458.5 ± 33.56*	565.67 ± 31.37**	<.001

Notes: ^*Significantly different from Group A (p < .05). ^**Significantly different from Groups A and B (p < .05). Values are expressed as mean ± SD.

OPEN IN VIEWER Figure 2.

Graphical Abstract.

Discussion

The present randomised, double-blind study demonstrates that the addition of MgSO4 to bupivacaine for ultrasound-guided infraclavicular brachial plexus block significantly prolongs the duration of postoperative analgesia in a clear dose-dependent manner. Patients receiving higher doses of MgSO4 experienced longer analgesia, faster onset and prolonged duration of both sensory and motor blockade, without an increase in adverse effects. The primary outcome of the study was the duration of postoperative analgesia following the addition of different doses of MgSO4. A statistically significant, dose-dependent prolongation of analgesia was observed, with Group C (500 mg) demonstrating the longest duration, followed by Group B (250 mg) and Group A (125 mg). These findings are consistent with the dose–response relationship reported by Verma et al., who demonstrated significantly prolonged analgesia with increasing doses of MgSO4, compared with bupivacaine alone. ¹³ In their dose-finding study, the mean duration of analgesia was 665.13 ± 97.87 min in the 250 mg group and 475.10 ± 53.29 min in the 125 mg group, closely mirroring the trend observed in the present study.

Similarly, Lee et al. reported a significant prolongation of analgesia when 200 mg of MgSO4 was added to bupivacaine with epinephrine in an interscalene brachial plexus block, with analgesia lasting approximately 664 min compared to 553 min in the control group. ¹⁰ The longer duration of analgesia observed in the present study with a 500 mg dose further supports the dose-dependent analgesic efficacy of perineural MgSO4.

The analgesic effect of MgSO4 is primarily attributed to its antagonistic action on NMDA receptors, which play a key role in central sensitisation and pain transmission. ⁶ In addition, magnesium reduces calcium influx at presynaptic nerve terminals, thereby attenuating neurotransmitter release and nociceptive transmission. Experimental evidence supporting a peripheral mechanism of action has been demonstrated by Akutagawa et al., who showed that magnesium enhances local anaesthetic-induced nerve block in isolated frog sciatic nerve preparations. ⁷ Mert et al. further demonstrated that magnesium ions decrease peripheral nerve conduction velocity, reinforcing the concept of a direct perineural effect. ⁸ These experimental findings provide a strong mechanistic foundation for the accelerated onset and prolonged duration of sensory and motor block observed in the present study.

In addition to prolonging analgesia, MgSO4 significantly accelerated the onset and prolonged the duration of both sensory and motor block in a dose-dependent fashion. Group C exhibited the fastest onset and longest duration of both sensory and motor blockade, followed by Groups B and A. These findings are in agreement with the results reported by Mukherjee et al., who observed significantly prolonged sensory and motor block durations when MgSO4 was added to local anaesthetics in brachial plexus blocks. ⁹ Similar dose-dependent improvements in block characteristics have been reported by Verma et al. ¹³ as well as in comparative studies evaluating MgSO4 as an adjuvant in different regional anaesthetic techniques. ¹¹ Furthermore, the systematic review and meta-analysis by Kandil and Mahmoud concluded that MgSO4 consistently prolongs block duration and analgesia when used as a perineural adjuvant in brachial plexus blocks, with minimal adverse effects. ¹²

The perineural doses of MgSO4 reported in the literature range from 50 to 1,000 mg.^10–12 The doses used in the present study (125, 250 and 500 mg) fall well within this established range and are consistent with those used in prior clinical studies.^{11, 13} Importantly, increasing the dose of MgSO4 in the present study did not result in any increase in adverse effects such as hypotension, bradycardia, nausea, vomiting or block failure. These findings are in line with the review by Garg et al., which concluded that MgSO4 is a safe and effective adjuvant in regional anaesthesia when used in appropriate doses. ¹¹ The absence of haemodynamic instability or neurological complications in the present study further supports the favourable safety profile of MgSO4.

Alpha-2 adrenergic agonists such as clonidine and dexmedetomidine are commonly used adjuvants to prolong block duration. However, studies by Chatrath et al. and Swami et al. have reported dose-dependent side effects, including sedation, bradycardia and hypotension, with these agents.^{3, 4} MgSO4 offers a distinct advantage by prolonging analgesia and block duration without significant haemodynamic compromise, as demonstrated in the present study. The findings of this study suggest that MgSO4, particularly at a dose of 500 mg, is an effective and safe perineural adjuvant to bupivacaine in ultrasound-guided infraclavicular brachial plexus block. The prolonged analgesia and improved block characteristics may reduce postoperative analgesic requirements and enhance patient comfort following upper-limb surgeries. This study was conducted at a single centre and did not include a control group receiving bupivacaine alone. Long-term neurological outcomes were also not assessed. Future multicentre studies with larger sample sizes and inclusion of control groups may further clarify the optimal dose and long-term safety of MgSO4, as a perineural adjuvant.

Limitations

The small sample size, single-centre design and absence of long-term neurological follow-up constitute important limitations of our study.

Conclusion

The present randomised, double-blind study demonstrates that the addition of MgSO4 to bupivacaine in ultrasound-guided infraclavicular brachial plexus block significantly prolongs postoperative analgesia in a clear dose-dependent manner. Higher doses of MgSO4 were associated with faster onset and longer duration of sensory and motor blockade, without an increase in adverse effects or block failure. Among the doses evaluated, 500 mg of MgSO4 provided the longest duration of analgesia and block characteristics, followed by 250 and 125 mg, indicating a consistent dose–response relationship. Importantly, all doses were well tolerated, with no incidence of haemodynamic instability, nausea, vomiting or neurological complications. These findings support the use of MgSO4 as an effective and safe perineural adjuvant to bupivacaine for infraclavicular brachial plexus block in upper-limb surgeries. The incorporation of MgSO4, particularly at higher doses within the studied range, may enhance postoperative pain control and reduce the need for additional analgesic interventions. Further multicentre studies are warranted to confirm these findings and to establish the optimal dose balancing maximal analgesic benefit with long-term safety.

Abbreviations

ANOVA: Analysis of variance; ASA: American Society of Anesthesiologists; cm: Centimetre; CTRI: Clinical Trials Registry of India; IBM: International Business Machines; IEC: Institutional Ethics Committee; kg: Kilogram; mg: Milligram; MgSO4: Magnesium Sulphate; MHz: Megahertz; min: Minutes; mL: Millilitre; NMDA:N-methyl-d-aspartate; SD: Standard deviation; SpO2: Peripheral oxygen saturation; SPSS: Statistical Package for the Social Sciences; VAS: Visual analogue scale.