|Year : 2016 | Volume
| Issue : 4 | Page : 549-557
Midazolam as an adjunct to lignocaine at two different doses in ultrasound-guided supraclavicular brachial plexus block: a randomized controlled trial
Jai Singh, Versha Verma, Priyanka Sood, Aman Thakur, Shelly Rana, Lokesh Thakur
Department of Anaesthesia, DRPGMC, Kangra at Tanda, Himachal Pradesh, India
|Date of Submission||25-Aug-2015|
|Date of Acceptance||17-May-2016|
|Date of Web Publication||12-Jan-2017|
Department of Anaesthesia, DRPGMC, Kangra at Tanda, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
Background and aims
The present study was carried out to investigate the efficacy of midazolam at two different doses as an adjunct to lignocaine with adrenaline in ultrasound-guided supraclavicular brachial plexus block. Materials and methods In this prospective controlled study, 95 consenting patients scheduled for forearm fracture surgeries were randomized into three groups. Five patients were excluded from the study for not meeting the inclusion criteria. Group L (n=30) received 20 ml of 1.5% lignocaine with adrenaline (1 : 200 000)+5 ml of normal saline (total volume=25 ml). Group M30 (n=30) received 20 ml of 1.5% lignocaine with adrenaline (1 : 200 000)+30 μg/kg midazolam+normal saline (total volume =25 ml). Group M50 (n=30) received 20 ml of 1.5% lignocaine with adrenaline (1 : 200 000)+50 μg/kg midazolam+normal saline (total volume =25 ml).
The onset of sensory and motor block was found to be earliest in group M50, followed by group M30 and group L, and the difference was statistically significant (P<0.05). The mean duration of motor block and sensory block was longest in group M50 followed by groupM30 and shortest in group L, which was also statistically significant (P<0.05). The mean duration of analgesia was longest in group M50 (254.53±34.77 min) followed by group M30 (211.03±52.69 min) and shortest in group L (181.47±20.63 min). The differences were statistically significant (P<0.05). Group L received the highest doses of rescue analgesics (2.80±0.407 doses) followed by group M30 (1.97±0.615 doses) and group M50 (1.47±0.819 doses). The difference was statistically significant (P<0.05).
Midazolam increases the duration of sensory and motor blockade and delays need for rescue analgesic. In addition, midazolam at a dose of 50 μg/kg had superior therapeutic profile compared with 30 μg/kg, and hence may be the recommended dose.
Keywords: brachial plexus, lignocaine, midazolam, postoperative analgesia, ultrasound
|How to cite this article:|
Singh J, Verma V, Sood P, Thakur A, Rana S, Thakur L. Midazolam as an adjunct to lignocaine at two different doses in ultrasound-guided supraclavicular brachial plexus block: a randomized controlled trial. Ain-Shams J Anaesthesiol 2016;9:549-57
|How to cite this URL:|
Singh J, Verma V, Sood P, Thakur A, Rana S, Thakur L. Midazolam as an adjunct to lignocaine at two different doses in ultrasound-guided supraclavicular brachial plexus block: a randomized controlled trial. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2018 Apr 19];9:549-57. Available from: http://www.asja.eg.net/text.asp?2016/9/4/549/198248
The study was presented at the 15th NZISACON 2014 at Jammu by ISA Branch Jammu on 2 November 2014.
| Introduction|| |
Brachial plexus block is a versatile and relatively safe procedure for upper limb surgeries, providing a valuable alternative to general anesthesia and a smooth transition to postoperative pain relief . There are many approaches to brachial plexus block, of which supraclavicular approach is a reliable and time-tested technique.
Supraclavicular approach for brachial plexus block was first described by Kulenkampff (1911) . It provides an effective block to the entire upper extremity and is carried out at the level of trunks of brachial plexus. The major advantage of the supraclavicular approach is that the nerves are tightly packed, and hence the onset of block is fast and the blockade achieved is dense, leading to this technique being nicknamed ‘the spinal of the arm’.
Brachial plexus block achieves ideal operating conditions by producing excellent muscular relaxation, intraoperative hemodynamic stability and the associated sympathetic block which decreases postoperative pain, vasospasm and edema . Orthopedic upper extremity surgery is reported to have a higher incidence of severe pain .
The traditional approaches for a supraclavicular block, such as eliciting sensory paresthesia or nerve-stimulated muscle contraction, often cause multiple needle attempts, which can result in pain and other complications such as neurological injury and pneumothorax. There also exists a possibility of inadvertent vascular puncture of the subclavian, suprascapular, superficial cervical, or dorsal scapular arteries with consequent local anesthetic toxicity and cardiovascular collapse ,. Ultrasound imaging has revolutionized regional anesthesia with the advantage that the anesthetist can visualize nerves and blood vessels along with the needle during its passage through the tissues . Direct visualization of subclavian artery, pleura, and first rib minimizes the risk for vascular puncture, iatrogenic pneumothorax, local anesthetic toxicity, and a failed block .
The addition of various adjuncts such as clonidine, tramadol, morphine, buprenorphine, fentanyl, sufentanyl, and pethidine has been shown to prolong postoperative analgesia . Midazolam is a water-soluble benzodiazepine that produces antinociception and enhances the effect of a local anesthetic when given intrathecally or epidurally . Midazolam produces this effect by its action on γ-aminobutyric acid-A (GABA-A) receptors ,. GABA receptors have also been found in peripheral nerves .
Midazolam as an adjunct to local anesthetics through various routes in studies conducted in the past has shown to prolong postoperative analgesia, but none of them compared two doses of midazolam in supraclavicular brachial block. Therefore, it would be justifiable to compare two different doses of midazolam to find the optimal dose of midazolam as an adjunct to lignocaine in ultrasound-guided supraclavicular brachial plexus block.
| Materials and methods|| |
After approval by the Institutional Ethics Committee, this study was carried out in 95 American Society of Anesthesiologist I/II patients of either sex, in the age group of 20–60 years, having fractures of forearm bones and scheduled for open reduction and internal fixation under supraclavicular brachial plexus block. The study was conducted in the operation theater complex, Department of Anesthesiology, Dr RPGMC (Rajendra Prasad Government Medical College, Tanda at Kangra) India, from December 2012 to December 2014.
Patient’s refusal for block, having bleeding disorders, local infections at the site where needle for block is to be inserted, and history of seizures were the exclusion criteria. Patients in whom the block effect was partial and required supplementary anesthesia were also excluded from the study.
Randomization was achieved with 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 to the operation theater, an anesthesiologist not involved in the study opened the sealed envelope and prepared the drug solution according to randomization. The observer who collected the perioperative data and all patients were blinded to the drug solution administered.
All patients were explained about the procedure, advantages, and risks of the procedure during the preoperative assessment carried out 1 day before surgery, and then informed consent was obtained from the patient. Patients were educated about the visual analogue scale (VAS) during the preoperative assessment. All patients were kept nil orally for at least 8 h before surgery, and no premedication was given. In the operation theater, after securing a 20-G intravenous cannula in the nonoperated arm, an infusion of 0.9% sodium chloride (NaCl) solution was started at the rate of 5 ml/kg/h. After standard anesthesia monitoring, baseline measurements of heart rate, noninvasive arterial blood pressure, peripheral oxygen saturation (SpO2), and respiratory rate were recorded before the block was performed.
The patients were positioned supine with the arm place by the side. The head was positioned, facing 45° to the contralateral side to be blocked without a headrest. The area was cleaned with chlorhexidine and draped. The probe was placed under sterile conditions in the supraclavicular fossa in a coronal oblique plane. Ultrasound 8–12 MHz linear probe (SonoSite Micromaxx, Bothwell, WA, USA) was used to visualize the plexus. The pulsating, hypoechoic supraclavicular artery was identified, lying above the hyperechoic first rib. The hypoechoic nerve structures (trunks or divisions) were visualized posterolateral to the artery with a characteristic ‘honeycomb’ appearance.
A sterile 50 mm, 22-G insulated needle was advanced using an in-plane technique. When the needle was seen well, the tip was directed toward the nerve bundle. Separate injections at various sites in the bundle were performed, tending to start deep, in the ‘corner pocket’ close to the artery, and then moving more superficially.
Patients were randomly allocated using a sealed envelope technique, and group L received 20 ml of 1.5% lignocaine with adrenaline (1 : 200 000)+5 ml of normal saline. Group M30 received 20 ml of 1.5% lignocaine with adrenaline (1 : 200 000)+30 μg/kg midazolam (preservative free)+normal Saline, and group M50 was administered 20 ml of 1.5% lignocaine with adrenaline (1 : 200 000)+50 μg/kg midazolam (preservative free)+normal saline (a total volume of 25 ml was given in all three groups).
We evaluated the onset, quality, and duration of sensory and motor block, along with the duration of postoperative analgesia and total analgesic requirements. Sensory loss  was assessed out using the pinprick test with a three-point scale: 0, no block; 1, analgesia (loss of sensation to pinprick); and 2, loss of touch. Motor block  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; 2, inability to move fingers. Sedation  was scored as follows: 1, awake and alert; 2, sedated and responding to verbal command; 3, sedated and responding to mild stimulus; 4, sedated and responding to moderate-to-severe physical stimulus, and 5, not arousable.
Block was evaluated every 3 min up to 30 min after the injection of local anesthetic was completed. Further block assessment was carried out at hourly intervals up to 24 h by an anesthesiologist blinded to the study.
Onset of sensory blockade was defined as the interval between the end of injection and sensory blockade and was demonstrated as loss of sensation to pinprick or by score 1 of pinprick response. Onset of motor blockade was the interval between the end of injection and complete motor paralysis of the wrist and hand. The duration of sensory block was the time interval between sensory blockade and reappearance of pinprick response. The duration of motor block was defined as the time interval between maximum motor blockade and complete movement of the wrist and fingers.
Pain was assessed using VAS, which is obtained by asking the patient to rate the intensity of pain perceived by him or her and express it on a numerical scale of 0–10 (0 represents no pain and 10 represents worst pain possible).
Duration of analgesia was taken from the time of completion of block to the demand of first rescue analgesic in the postoperative period. Rescue analgesia in the form of injection diclofenac 1.5 mg/kg intramuscularly was given to patients with VAS greater than 4.
Quality of block was assessed on the basis of two parameters:
- The number of partial/failed blocks among the three groups.
- Surgeon’s satisfaction score based on the amount of muscle relaxation and ease of performing the surgery, taken as a verbal response score ranging between 0 and 10: score 0 for full satisfaction and score 10 for complete dissatisfaction.
All patients were monitored in the perioperative period for hemodynamic stability and any side effects.
For statistical analysis, data were collected and entered in MS Excel 2007. Statistical analysis was performed using SPSS software 15 (SPSS Inc., Chicago, Illinois, USA). Analysis of variance was used to compare the three groups for quantitative data, and if there was a significant difference among the groups, a post-hoc Tukey’s test was performed. For nonparametric data, the χ2-test was applied and χ2 for trend was used for intergroup comparison of proportion of patients with different sedation scores at various timepoints. Continuous numerical data were presented as mean and SD, and categorical data were presented as percentage of patients. A P value less than 0.05 was considered statistically significant.
Assuming 90% statistical power and setting the level of significance at 5%, a sample size of 17 per group was considered adequate to discern improvement in pain scores at 24 h .
| Results|| |
Ninety-five eligible patients were enrolled in the study ([Figure 1]). Five patients were excluded from the study due to protocol violation. Remaining 90 patients were randomized into three groups of 30 in each. The study groups were comparable to each other with respect to age, sex, weight, and duration of surgery ([Table 1]).
|Figure 1: Flow chart of patients analyzed and recruited in three groups.|
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After brachial plexus block, onset of sensory block was found to be earlier in group M50 (6.37±1.45 min) than in group M30 (7.43±2.06 min) and group L (7.63±1.52 min), and it was statistically significant (P=0.010). The onset of motor block was earlier in group M50 (9.87±1.72 min) than in group M30 (11.10±2.32 min) and group L (11.27±1.85 min), which was statistically significant (P=0.004) ([Figure 2]).
|Figure 2: Comparison of onset of sensory and motor block (min) in three groups. Values expressed as mean±SD (P<0.05)*. *Difference was statistically significant.|
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The mean duration of motor block was longest in group M50 (192.50±31.85 min) followed by group M30 (153.80±55.27 min) and group L (129.50±16.94 min). The difference between the three groups was statistically significant (P=0.002). The mean duration of sensory block was longest in group M50 (221.40±31.27 min) followed by group M30 (182.60±54.27 min) and group L (153.97±18.58 min). These differences in durations were statistically significant (P=0.000). The mean duration of analgesia was longest in group M50 (254.53±34.77 min) followed by group M30 (211.03±52.69 min) and group L (181.47±20.63 min). These differences in durations were statistically significant (P<0.000) ([Figure 3]).
|Figure 3: Comparison of duration of analgesia along with duration of sensory and motor in three groups. Values are expressed as mean±SD. The mean duration of analgesia, sensory block, and motor block was significantly increased in group M50 as compared with group M30 and group L (P<0.05)*. *Difference was statistically significant.|
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Rescue analgesia in the form of diclofenac (75 mg) was administered once VAS score greater than 4 was reported. Group L received the highest doses of rescue analgesics (2.80±0.407 doses) followed by Group M30 (1.97±0.615 doses) and group M50 (1.47±0.819 dose). The difference was statistically significant (P<0.05) ([Figure 4]).
|Figure 4: Comparison of mean total number of rescue analgesic required in 24 h.Values are expressed as mean±SD. Mean total number of doses of rescue analgesic required were significantly less in group M50 as compared with group M30 and group L (P<0.05)*. *Difference was statistically significant.|
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The mean sedation score in group M50 was higher compared with group M30 at 15, 30, 45, and 60 min, and the difference was statistically significant (P<0.05). ([Figure 5]). All patients in three groups had score 1 (awake) at baseline but the proportion of patients having score 2 was 53 and 26.66% in group M30 as compared with 66.66 and 76% in group M50 at 15 and 30 min, respectively, suggesting that patients in group M50 had better sedation scores. There were no statistically significant changes in hemodynamic variables such as mean arterial pressure and heart rate. Respiratory parameters such as respiratory rate and oxygen saturation also did not show any significant change ([Figure 6]).
|Figure 5: Comparison of mean sedation score. Values are expressed as mean±SD. The mean sedation score in group M50 was higher as compared with group M30 at 15, 30, 45, and 60 min and it was found to be be statistically significant (P<0.05)*. *Difference was statistically significant.|
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|Figure 6: Comparison of respiratory rate and percentile oxygen saturation. Difference was statistically insignificant (P>0.05)*.|
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| Discussion|| |
Precise localization of peripheral nerves remains the foremost challenge of regional anesthesia with conventional modalities due to anatomical variation. Ultrasound guidance has been used to localize the peripheral nerve or plexus for accurate needle placement and confirmation of local anesthetic spread in the appropriate tissue planes . Most of the comparative studies have shown a faster onset time and longer duration of block when real-time ultrasound was used in comparison with other nerve localization techniques .
In the supraclavicular approach, a volume of 30–40 ml is generally required to produce adequate anesthesia. However, the use of ultrasound has led to a decrease in the volume of local anesthetic required for nerve blockade. According to Duggan et al. (2009) , the minimum local anesthetic volume (MLAV 50 and MLAV 95) required for ultrasound-guided supraclavicular block was 23 and 42 ml. No significant difference was observed with MLAV 50 or MLAV 95 required for the classical nerve stimulation technique. Different doses have been recommended in different studies ,. An overall volume of 20 to 25 ml of local anesthetic in combination with ultrasound guidance is commonly accepted. Thus, a volume of 25 ml was used in our study.
The studies conducted in the past have used midazolam as an adjunct to bupivacaine, which itself is a long-acting local anesthetic. Hence, by using a short-acting local anesthetic such as lignocaine, we intended to demonstrate inherent local anesthetic activity of midazolam. We chose lignocaine with adrenaline (1 : 200 000) 1.5% for our study and total volume of the drug mixture was 25 ml, so as to not exceed the maximum permissible dose of lignocaine with adrenaline (7 mg/kg) and to quantify the block better with the addition of midazolam.
Onset of sensory and motor block was faster in our study compared with the study by Biradar et al. . This can be explained on the basis that our study was ultrasound guided, which led to precise and accurate deposition of the local anesthetic around nerves under direct vision.
When compared with an ultrasound-guided study by Mirkheshti et al. , the onset of sensory and motor blockade was still faster in our study probably because in their study they used the infraclavicular approach in contrast to our study, in which we used the supraclavicular approach.
The mean duration of sensory and motor blockade as well as the mean duration of analgesia observed in our study were comparable to the studies by Mirkheshti et al.  and Biradar et al. . Our findings are consistent with the observations made by De Jong and Wagman , who explained that large fibers require a higher concentration of local anesthetic compared with small fibers. Therefore, concentration of local anesthetic to block motor fibers is greater than that for sensory fibers; motor function returns before pain perception and duration of motor block is shorter than sensory block.
Various adjuncts have been added to local anesthetics to prolong the period of analgesia ,,, but they were found to be either ineffective or produce an unacceptably high incidence of adverse effects. To date, there is no study on the effect of adding midazolam to lignocaine with adrenaline in peripheral nerve blocks. In our study, we found that the onset of sensory and motor blocks was significantly faster in patients who received the combination of midazolam and lignocaine. This could be due to a local anesthetic property of midazolam and its synergistic action with that of local anesthetics.
It was worthwhile to further compare two different doses of midazolam to find the optimal dose of midazolam as an adjunct to lignocaine in supraclavicular brachial plexus block under direct visualization by means of ultrasound. Hence, we have compared midazolam at doses of 30 and 50 μg/kg. Midazolam at a dose of 30 μg/kg has been used intrathecally  in the past and 50 μg/kg is the dose used previously in supraclavicular block ,,.
The onset of sensory block in our study was earlier in group M50 (6.37±1.45 min) in comparison with studies conducted before by Jarbo et al. , Shaikh and Veena , and El-Baradey and Elshmaa . This can be attributed to the use of bupivacaine in both these studies, which has delayed onset in comparison with lignocaine as used in our study. Moreover, the mean duration of onset of motor blockade was earlier compared with sensory blockade in their studies. However, in our study, the mean duration of onset of sensory block was earlier than the mean duration of onset of motor block. Our observation is consistent with the study by Birader et al. . Although the onset of sensory block was earlier in group M30 when compared with group L, the difference was not statistically significant.
Our study demonstrates that the patients who received midazolam had significantly increased duration of sensory blockade, motor blockade, and postoperative analgesia as compared with the control group. Duration of motor blockade was less than the duration of sensory blockade in all three groups.
Various studies in which midazolam was used in central neuraxial block found that the addition of midazolam to bupivacaine improves analgesic characteristics compared with bupivacaine alone ,. Batra et al.  used bupivacaine with midazolam intrathecally and found a significantly lower visual analogue score compared with bupivacaine alone. Midazolam produces this synergistic effect with local anesthetics by its action on the GABA-A receptor complexes present in the spinal cord . Studies in animals have revealed no neurotoxic effects of intrathecally administered midazolam . Moreover, the administration of intrathecal midazolam at a dose of 2 mg did not increase the occurrence of neurologic or urologic symptoms in humans .
More recently, Tucker et al.  demonstrated that the administration of intrathecal midazolam causes potentiation of the analgesic effect of intrathecal fentanyl in laboring patients. This could be due to local anesthetic property of midazolam and its synergistic action with that of local anesthetics.
The prolonged analgesia in groups M30 and M50 could be due to the action of midazolam on GABA-A receptors present in the brachial plexus, thus producing antinociception. Various authors have demonstrated the presence of GABA receptors in peripheral nerves. Marsh and Brown demonstrated GABA receptors in mammalian peripheral nerve trunk . Cairns and Ally observed the presence of GABA receptors within the tempromandibular joint and that its activation could decrease the transmission of nociceptive signals . The action of midazolam on GABA receptors is well established.
The mean total number of doses of rescue analgesics required in 24 h was lower in the M30 and M50 groups compared with the control group; this is consistent with the study by Aggarwal et al. .
Sedation is the inherent property of midazolam. Therefore, sedation was assessed intraoperatively and it was observed 9 min after injecting the drug until 45 min. Sedation scores were higher in group M50 compared with group M30. Partial vascular uptake of midazolam and its transport to the central nervous system where it acts and produces sedation might have accounted for this . The sedation was of limited duration, which can be explained by the fact that midazolam is highly lipophilic and diffuses faster into the blood vessels, clearance being 6–11 ml/kg/min. Moreover, it has a short half-life (102–156 min) . The mean sedation score in group M50 was higher as compared with group M30 at 15, 30, 45, and 60 min (P<0.05). The highest sedation score observed was 3 in group M50, − that is, the patient was sedated and responded to mild physical stimulus.
No patient in the study groups required additional sedation as they were comfortable with arousable sedation scores. Thus, midazolam had an added advantage as an adjunct in brachial block. There was no difference in sedation scores between groups in the postoperative period. Moreover, no patient of any of the groups experienced airway compromise or required airway assistance with any method. All patients in the control group (group L) were awake during the surgery, their sedation score being 1 (awake and alert) throughout the intraoperative period. Surgeon’s satisfaction score measured in verbal response score (0–10) in three groups was insignificant (P=0.869).
There was no significant change in the heart rate, mean arterial pressure, respiratory rate, and oxygen saturation in the intraoperative and postoperative period, and they were comparable between groups ([Figure 5]). No adverse events in the form of pneumothorax vascular puncture, etc. were encountered in any group of patients.
Limitation of our study was that we did not evaluate patient satisfaction score.
Our study supports the specific action of midazolam on peripheral nerves with the activation of GABA-A receptors, which decrease the transmission of nociceptive signals leading to improved analgesia and decreased postoperative analgesic requirement. To summarize, the addition of midazolam at a dose of 30 and 50 μg/kg to lignocaine with adrenaline in ultrasound-guided supraclavicular brachial plexus block shortened the onset and prolonged the duration of sensory and motor blockade. Augmented duration of analgesia and decreased demands for rescue analgesia were observed in our study.
| Conclusion|| |
Midazolam at a dose of 50 μg/kg is the optimal dose, as it had shorter onset of sensory and motor blockade and prolonged the duration of analgesia with a desirable sedation score without any adverse effects and hence may be the recommended dose.
CTRI No.: CTRI/2015/06/005866.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]