Supraclavicular brachial plexus block: Comparison of varying doses of dexmedetomidine combined with levobupivacaine: A double-blind randomised trial.

BACKGROUND AND AIMS: The ideal dose of dexmedetomidine for brachial plexus block is a matter of debate. This study was carried out to evaluate 50 μg or 100 μg of dexmedetomidine added to 0.5% levobupivacaine, with regard to the duration of analgesia. Our study also sought to assess the onset and duration of sensorimotor blockade, haemodynamic effects, sedation and adverse effects.
METHODS: One hundred adult patients undergoing upper limb surgeries under supraclavicular brachial plexus block were randomly allocated into two groups. Group LD50 received 29 ml of 0.5% levobupivacaine plus 50 μg of dexmedetomidine diluted in 1 ml of normal saline. Group LD100 received 29 ml of 0.5% levobupivacaine plus 100 μg of dexmedetomidine diluted in 1 ml of normal saline. Duration of analgesia was the primary outcome. Onset and duration of sensorimotor blockade, haemodynamic variables, sedation score, and adverse effects were secondary outcomes. The data were analysed with Students' t-test and Chi-square test.
RESULTS: The onset of sensory block and motor block was 14.82 ± 3.8 min and 19.75 ± 6.3 min, respectively, in group LD50, while it was 11.15 ± 1.7 min and 14.3 ± 4.2 min, respectively, in group LD100. The duration of analgesia was significantly prolonged in group LD100 (1033.6 ± 141.6 vs. 776.4 ± 138.6 min; P = 0.001). The incidence of bradycardia and sedation was observed in significantly more patients in group LD100. Significantly fewer patients in group LD100 required rescue analgesia.
CONCLUSION: The 100 μg dose of dexmedetomidine in brachial plexus block hastens the onset and prolongs the duration of sensorimotor blockade and analgesia, but with higher incidence of bradycardia and sedation.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Dexmedetomidine, an α2 agonist, has been studied widely as an adjuvant to local anaesthetics in regional anaesthesia techniques to enhance the quality and duration of analgesia.[1]

Dexmedetomidine is highly selective (8 times more selective than clonidine) and a specific α2 adrenergic agonist, having analgesic, sedative, antihypertensive and anaesthetic-sparing effects when given by the systemic route.[2] Dexmedetomidine produces manageable hypotension and bradycardia, but the striking feature of this drug is the lack of opioid-related side effects such as respiratory depression, pruritus, nausea and vomiting. Addition of dexmedetomidine to local anaesthetic drugs during peripheral nerve blocks may also prove beneficial for surgical patients.

The role of dexmedetomidine as an adjuvant to local anaesthetic agents in upper limb peripheral nerve blocks has been extensively studied. Dose range of 0.5–2 μg/kg has been used in various studies.[3] A dose of 150 μg of dexmedetomidine has been associated with minimal side effects.[4] However, other studies have shown that dexmedetomidine even at 30 μg can cause significant compromise, which challenges its use in peripheral nerve blocks in day-care surgeries.[5] Besides, there is no study suggestive of any appropriate dose of dexmedetomidine as an adjuvant in supraclavicular brachial plexus block.

Hence, the present study was conducted with the primary aim of assessing the duration of analgesia of two different doses of dexmedetomidine, 50 and 100 μg added to 0.5% levobupivacaine, in patients posted for upper limb surgeries under supraclavicular brachial plexus block. The secondary outcomes measured were the onset and duration of sensorimotor blockade, haemodynamic variables and adverse effects in both the groups.

METHODS

After approval of the hospital ethical committee, patients were explained about the total procedure and only those who gave written consent were included in the study. One hundred American Society of Anesthesiologists (ASA) physical Status I and II patients, aged 18–60 years, undergoing upper limb surgeries under supraclavicular brachial plexus block, were enrolled in this prospective, randomised trial. Patients on adrenoreceptor agonist or antagonist therapy, those with known sensitivity to local anaesthetics, second or third degree heart block, renal and hepatic insufficiency, uncontrolled diabetes and hypertension, pregnant and lactating females, drug abusers and psychiatric patients were excluded from the study. The 10 cm visual analogue scale (VAS) (0, no pain and 10, worst pain imaginable) was explained during the pre-operative visit. All patients received tablet clonazepam 0.5 mg orally on the night before surgery.

One hundred patients were randomised using a computer-generated randomisation list [Figure 1]. The randomisation scheme was generated using the website Randomization.com (http://www.randomization.com). Group assignment was enclosed in a sealed envelope to ensure concealment of allocation sequence. The sealed envelope was opened by an anaesthesiologist not involved in the study who then prepared the drug solution according to randomisation. The anaesthesiologist performing the block and observing the patient was blinded to the treatment group. Data collection was done by the anaesthesiologist who was unaware of the group allocation. Patients were randomly assigned to one of the two equal groups. Patients in group LD50 received 29 ml of 0.5% levobupivacaine plus 50 μg of dexmedetomidine diluted in 1 ml of normal saline (total 30 ml). Patients in group LD100 received 29 ml of 0.5% levobupivacaine plus 100 μg of dexmedetomidine diluted in 1 ml of normal saline (total 30 ml).

Figure 1

Consort diagram showing the number of patients included and analysed

After shifting the patients to the operation theatre, non-invasive monitors such as blood pressure, oxygen saturation (SpO2) and electrocardiogram were applied, and their baseline values were recorded. Intravenous (IV) access was established using an 18-gauge cannula. Supplemental oxygen was provided through nasal cannula at 4 L/min to all patients. Sedation was provided by IV administration of midazolam 1 mg and fentanyl 30 μg before the block. Neural localisation was achieved using a nerve locator connected to a 21-gauge, 50-mm-long Stimuplex© needle. The stimulation frequency was set at 1 Hz, and the intensity of the stimulating current was initially set to deliver 1.5 mA and was then gradually decreased. The position of the needle was considered to be acceptable when an output current <0.5 mA still elicited a slight distal motor response in the forearm and hand. On negative aspiration for blood, the local anaesthetic solution was injected in incremental 5 ml boluses with intermittent aspiration.

Sensory and motor blockade were assessed for every 2 min after completion of injection till 30 min and then for every 30 min after the end of surgery till the first 12 h, thereafter hourly until the block had completely worn off. For sensory loss assessment, we used pinprick test with a 3-point scale: 0-no block, 1-analgesia (loss of sensation to pinprick) and 2 – loss of touch. Motor blockade was evaluated by the ability to flex the elbow and hand as: 0 – full flexion/extension movement in hand and arm against resistance, 1 – movement against gravity but not against resistance, 2 – flicker of movement in hand but not in arm and 3 – no movement (complete motor block).

Onset of sensory blockade was defined as the interval between the end of injection and sensory blockade evidenced by loss of sensation to pinprick or by a score of 1 on pinprick response. Onset of motor blockade was the interval between the end of injection and complete motor paralysis of wrist and hand. The duration of sensory blockade was defined as 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 wrist and fingers. Duration of analgesia was taken as the time interval between the onset of sensory blockade and the first dose of rescue analgesic given to the patient. A complete block was defined as one associated with Grade 2 sensory anaesthesia and Grade 3 motor block and only these patients were included for further study. Patients with sensory block of Grade 0, 1 and motor block of Grade 0, 1 and 2 were considered to have incomplete block and hence were excluded from further analysis and converted to general anaesthesia.

Post-operative pain was assessed using VAS (0 – no pain to 10 − worst pain) for every hour till the block lasted. Post-operative heart rate (HR), systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP) and SpO2 were recorded for every 2 h for the first 6 h and thereafter for every 4 h till the need for rescue analgesia. Rescue analgesia was provided with injection diclofenac sodium 75 mg intramuscularly when VAS ≥3 cm. The number of diclofenac injections given to each patient during the first 24 h of the post-operative period was recorded. The time between the complete sensory block and the first analgesic request was recorded as the duration of analgesia.

The incidence of side effects (bradycardia, hypotension and sedation) was also recorded. Sedation score was assessed according to the modified Ramsay Sedation scale[6] from 1 to 6 as follows: 1 = Anxious, agitated, restless; 2 = Cooperative, oriented, tranquil; 3 = Responds to commands only; 4 = Brisk response to light glabellar tap or loud noise; 5 = Sluggish response to light glabellar tap or loud noise and 6 = No response. Bradycardia was defined as a decrease in HR by 20% from the baseline value or an absolute HR <50 beats per min; which was managed by 0.5 mg IV bolus of atropine. Hypotension was defined as fall in blood pressure by 20% from the baseline or an absolute MAP <60 mmHg; which was managed by IV crystalloids (200 ml of ringer lactate/normal saline) or increments of mephentermine 3 mg IV.

Sample size calculation was done based on a pilot study of ten patients (5 in each group). The duration of analgesia in pilot study in two groups was 870.9 ± 168.2 min and 750.2 ± 221.4 min, respectively. To detect an observed difference of 2 h in the duration of analgesia between the groups, with a type 1 error of 5% and a power of 80%, the minimum sample size required was 37 in each group. We included fifty patients in each group for better validation of results. Data were checked, entered and analysed using SPSS version 19 for Windows (IBM Corp., Armonk, NY, USA). Quantitative data were represented as mean ± standard deviation, and for qualitative data, number and percentages were used. Students' t-test was used as test of significance to find an association for quantitative data. Chi-square test was used as test of significance to find the association for qualitative data. P < 0.05 was considered statistically significant.

RESULTS

Fifty patients in each group were enrolled for the study. One patient from group LD50 and one from group LD100 were excluded from the study due to incomplete/failed block. A total of 98 patients (49 in each group) were included in the study.

Both the groups were comparable with respect to age, height, weight, BMI, sex ratio, ASA physical status and the duration of surgery [Table 1]. There was no statistical significance in baseline haemodynamic parameters and type of fractures between the two groups (P > 0.05). Table 2 shows the type of fractures in the patients studied.

Table 1

Demographic data

Table 2

Type of fractures in the study patients

The sensory and motor block onset was significantly faster in group LD100 than in group LD50. The mean sensory block onset time was 12.82 ± 3.8 min in group LD50 as compared to 8.15 ± 1.7 min in group LD100 (P = 0.026). The mean motor block onset time was 17.8 ± 6.3 min in group LD50 as compared to 14.3 ± 4.2 min in group LD100 (P = 0.032) [Table 3]. The duration of sensory block was prolonged in group LD100 (997.7 ± 102.3 min) when compared to group LD50 (756.2 ± 138.5 min) (P = 0.001). The duration of motor block was also prolonged in group LD100 (902.4 ± 122.8 min) when compared to group LD50 (635.6 ± 187.6 min) (P = 0.001) [Table 3]. The duration of analgesia was significantly prolonged in group LD100 (1033.6 ± 141.6 min) when compared with group LD50 (776.4 ± 138.6 min) (P = 0.001) [Table 3]. About 16/49 patients (32.65%) in Group LD50 required diclofenac sodium injection as rescue analgesia, whereas 7 out of 49 patients (14.28%) in group LD100 required rescue analgesia in the first 24 h of post-operative period [P = 0.037; Figure 2].

Table 3

Characteristics of block in each group

Figure 2

Rescue analgesic requirement in post-operative period (P = 0.037)

The incidence of adverse effects namely sedation and bradycardia was significantly higher in group LD100 compared with group LD50 [Table 4]. However, the incidence of hypotension was statistically not significant between the groups (P = 0.056). Bradycardia required only one dose of atropine with no further recurrence in all cases. Hypotension was treated with 200 ml bolus of crystalloids (ringer lactate/normal saline) and mephentermine 3 mg IV with no further decrement. Significantly more number of patients in group LD100 had higher sedation score (>3) than those in group LD50.

Table 4

Comparison of incidence of side effects in the two groups

DISCUSSION

Results of this prospective, randomised, double-blinded study demonstrate that addition of 100 μg dexmedetomidine to 0.5% levobupivacaine produces longer duration of analgesia compared to 50 μg dexmedetomidine in supraclavicular brachial plexus block. The higher dose of dexmedetomidine also hastens the onset and prolongs the duration of sensory and motor block. Fewer patients (14.28%) in group LD100 required diclofenac sodium injection as rescue analgesic than patients (32.65%) in group LD50. The incidence of bradycardia was observed in more patients (44.9%) in LD100 group, compared to LD50 group. The higher dose of dexmedetomidine caused more sedation.

Dexmedetomidine is a potent and a highly selective α2 adrenergic agonist having sedative, sympatholytic and analgesic effects and has been described as a safe and effective additive in many anaesthetic applications and analgesic techniques.[7] It is available as a preservative-free solution and contains no stabilisers or additives. The main interest of our study was to evaluate the efficacy and safety of two doses of perineurally administered dexmedetomidine in providing adequate intraoperative anaesthesia and prolongation of the duration of analgesia in supraclavicular brachial plexus block.

Brummett et al. found that dexmedetomidine enhanced the duration of bupivacaine anaesthesia and analgesia of sciatic nerve block in rats without any evidence of histopathological damage to the nerve.[8] The action of dexmedetomidine in peripheral nerve blockade seems to be due to increase in hyperpolarisation-activated cation current that prevents the nerve from returning to its resting membrane potential. Kosugi et al. found that high concentrations of dexmedetomidine inhibit compound action potential (CAP) in frog sciatic nerves without α2 adrenoceptor activation.[9] Their result showed that dexmedetomidine reduced the peak amplitude of CAPs reversibly in a concentration-dependent manner. These findings provide the essential justification and rationale of our human studies.

In our study, the onset of sensory and motor block was earlier with the higher dose of dexmedetomidine (100 μg). In a recent study by Marhofer et al., the effect of dexmedetomidine on 0.75% ropivacaine for ulnar nerve block was studied.[10] They compared three drug regimens with ropivacaine 0.75%, interaction of ropivacaine 0.75% with systemic dexmedetomidine or perineural dexmedetomidine on ulnar nerve block. Onset of motor block was faster, and the duration of motor block was significantly prolonged by the perineural administration of dexmedetomidine.

Zhang et al. reported prolonged duration of analgesia in patients who received a higher dose of dexmedetomidine (100 μg) in 40 ml of 0.33% ropivacaine when compared to 50 μg of dexmedetomidine in axillary brachial plexus block.[11] They also found that addition of 100 μg of dexmedetomidine to ropivacaine produced prolonged duration of sensory and motor block compared to the ropivacaine alone group but concurrently increased the incidence of hypotension and bradycardia.

Esmaoglu et al. concluded that dexmedetomidine (100 μg) when used as an additive to 40 ml of 0.5% levobupivacaine prolonged axillary brachial plexus block duration.[12] They showed that dexmedetomidine shortened the sensory block onset time, motor block onset time, and prolonged the duration of the sensory block, duration of the motor block and post-operative analgesia. Swami et al. concluded that dexmedetomidine (1 μg/kg) when added to local anaesthetic (35 cc, bupivacaine 0.25%) in supraclavicular brachial plexus block enhanced the duration of sensory and motor block and also the duration of analgesia.[13] The time for rescue analgesia was prolonged in patients receiving dexmedetomidine.

Keplinger et al. assessed the dose dependency of dexmedetomidine when added to ropivacaine for peripheral nerve blockade.[14] In their study, all volunteers received an ulnar nerve block with 22.5 mg ropivacaine alone (R), or mixed with 50 (RD50), 100 (RD100) or 150μg (RD150) dexmedetomidine. There was a significant dose-dependent increase in the mean duration (SD) of analgesia with dexmedetomidine: R: 8.7 h, RD50: 16.4 h, RD100: 20.4 h and group RD150: 21.2 h. Sedation was also enhanced in a dose-dependent manner. These results are similar to the results of our study.

The analgesic effect of levobupivacaine in supraclavicular brachial plexus block was potentiated in a dose-dependent manner by adjuvant dexmedetomidine. In our study, fewer patients in LD100 group required diclofenac sodium injection as rescue analgesia (P < 0.05). This finding correlates with the studies of Kaygusuz et al.[15] Similarly, Ammar and Mahmoud also found that significantly lower IV morphine (4.9 mg vs. 13.6 mg) was given as rescue analgesic in the bupivacaine plus dexmedetomidine group while comparing with plain bupivacaine group in infraclavicular brachial plexus block.[16]

In the present study, the incidence of adverse effects namely sedation and bradycardia was significantly higher in group LD100 compared with group LD50. The incidence of hypotension was statistically not significant between the groups. However, these adverse effects can be managed easily. Sedative properties of dexmedetomidine are attributable to its lipophilic nature resulting in systemic absorption when administered perineurally. Bharti et al. reported significant sedation with the higher doses of dexmedetomidine (1.5 μg/kg) in caudal ropivacaine compared with plain ropivacaine for post-operative analgesia in paediatric day-care patients.[17] However, it did not delay the discharge of the patients.

CONCLUSION

One hundred microgram dexmedetomidine added to levobupivacaine in brachial plexus block produces a longer duration of analgesia than 50 μg. The higher dose also hastens the onset and prolongs the duration of sensorimotor blockade. Higher dose of dexmedetomidine produces higher incidence of bradycardia, which requires close monitoring.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.