Comparative evaluation of 0.75% ropivacaine with clonidine and 0.5% bupivacaine with clonidine in infraclavicular brachial plexus block.

BACKGROUND: Infraclavicular brachial block with coracoids approach has gained popularity because of consistent bony landmarks and less chances of vascular puncture and pneumothorax. AIM: The aim of this study was to evaluate the effect of adding clonidine to bupivacaine or ropivacaine on the onset and duration of sensory and motor block and duration of analgesia in infraclavicular block.
MATERIALS AND METHODS: In a prospective randomized double-blind study, 60 patients of 18-65 years were randomly divided in to two groups of 30 each. Infraclavicular block was performed with 30 ml of 0.75% ropivacaine + 150 μg clonidine in group R and 30 ml of 0.5% bupivacaine + 150 μg clonidine in group B and were compared for onset and duration of sensory and motor block, postoperative analgesia, side-effects and complications.
RESULTS: Significant differences were observed in the time for onset of sensory block (5.80 ± 5.12 min in group R and 4.87 ± 1.46 min in group B, P < 0.05); onset of motor block (11.37 ± 2.66 min in group R and 9.60 ± 1.78 min in group B, P < 0.05); duration of sensory and motor block (10.07 ± 0.91 and 9.03 ± 0.89 h in group R and 12.50 ± 1.14 and 10.67 ± 1.18 h in group B respectively, P < 0.01) and duration of analgesia (15.30 ± 1.39 h in group R and 18.07 ± 1.66 h in group B). No significant difference was observed in hemodynamics, sedation, side-effects and complications. STATISTICAL ANALYSIS: Variables were compared using Chi-square test for nonparametric data and Student's t-test for parametric data.
CONCLUSION: Addition of clonidine to bupivacaine lead to early onset and prolonged duration of sensory and motor block with prolonged analgesia as compared to the addition of clonidine to ropivacaine.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Brachial plexus block (BPB) is a well-accepted technique to provide anesthesia and analgesia for upper limb orthopedic surgeries. The infraclavicular BPB with coracoids approach has gained popularity because of its consistent bony landmarks, less chances of vascular puncture, pneumothorax and adequate neural blockade.[1] Success rate of the block can be further enhanced by using electric nerve stimulator to identify the nerves and depositing the drug perineurally.[2] Variety of local anesthetics (LAs) can be used to perform ideal and complete block. Among them, bupivacaine provides a longer duration of action, but at high doses it may lead to cardiotoxicity and neurotoxicity.[3] Ropivacaine is a propyl analog of bupivacaine which combines the anesthetic potency and longer duration of action of bupivacaine with a low toxicity profile.[4] To further improve the efficacy of nerve block and postoperative analgesia, various adjuvants can be added to LAs. Clonidine, a selective α2 adrenergic agonist inhibits nocioceptive impulses by activating postjunctional α2 adrenoreceptors both at peripheral and spinal nerve endings. It improves block characteristics of LAs in peripheral nerve blocks without producing any side effects like sedation, bradycardia and hypotension as seen in spinal blocks.[5] Investigators till now compared either ropivacaine + clonidine with ropivacaine alone or bupivacaine + clonidine with bupivacaine alone. In most of these studies, these drug combinations were used in axillary[678910] or supraclavicular[1112] BPB. Very few studies are available, where these two drug combinations were compared, especially in infraclavicular BPB. Hence the present study was designed to compare the effect of adding clonidine to bupivacaine or ropivacaine, in terms of onset and duration of sensory and motor block, postoperative analgesia, side effect and complications in infraclavicular BPB.

MATERIALS AND METHODS

This prospective, randomized, double-blind study was done from September 2012 to December 2014, in which 60 patients of American Society of Anaesthesiologists grade I and II in the age group of 18–65 years of either sex, scheduled to undergo forearm or hand surgery under infraclavicular BPB were included after taking approval from the Institutional Ethical and Scientific Committee. Patients with significant neurological, psychiatric, neuromuscular, cardiovascular, pulmonary, renal or hepatic diseases, allergy to study drugs, pregnant or lactating women, morbid obesity and coagulation disorders were excluded from the study. A written informed consent was taken from all patients included in the study.

A detailed preanesthetic check-up of the patients was carried out a day before surgery. General physical examination and systemic examination was done. Routine investigations were reviewed. The interpretation of the visual analogue scale (VAS) was explained to the patients to determine the level of analgesia in the intra and postoperative period. This was carried out with a 10 cm line. The 1st end marked “0” means “no pain” and end marked “10” means “severe pain.” All patients were given tablet Alprazolam 0.25 mg orally a night prior to surgery. Patients were divided randomly into two groups of 30 each, using sealed envelope technique.

Group R (n = 30) received 30 ml of 0.75% ropivacaine hydrochloride plus 1 ml (150 μg) of clonidine.

Group B (n = 30) received 30 ml of 0.5% bupivacaine hydrochloride plus 1 ml (150 μg) of clonidine.

On the day of surgery, patients were shifted to block room where intravenous (i/v) line was secured with 18-gauge angiocath and patients were preloaded with 10 ml/kg body weight of Ringer lactate solution over 15–20 min. Multipara monitor was attached to the patients to record base line respiratory rate, pulse rate, noninvasive systolic and diastolic blood pressure, SpO2 and electrocardiogram (ECG). Premedication was given with injection glycopyrrolate 0.2 mg and injection midazolam 0.04 mg/kg i/v before performing the block. Patients were made to lie in the supine position with the head facing away from the side to be blocked. The coracoids process was located and the needle entry point, 2 cm medial and 2 cm caudal to the most prominent part of the coracoids process was marked. After appropriate skin preparation, LA was infiltrated at the needle insertion site. A 22-gauge, 100 mm insulated short beveled, Teflon-coated stimulating needle (Locoplex, Vygon, France) was introduced vertically at the specified land mark, with nerve stimulator set at a current of 2 mA and frequency of 2 Hz. As the nerve was approached, movement of the wrist or fingers were elicited and then the current was gradually reduced to 0.4 mA. When hand twitches were elicited at a current of 0.4 mA, it was taken as the end point, and the study drug was given in 5 ml incremental doses after aspiration before each dose to avoid intravascular injection. Patients in group R received 30 ml of 0.75% ropivacaine hydrochloride plus 1 ml (150 μg) clonidine and patients in group B received 30 ml of 0.5% bupivacaine hydrochloride plus 1 ml (150 μg) clonidine. The study drugs were prepared by a separate anesthesiologist in an identical syringes, and the volume of the drug was also kept constant to avoid bias. Anesthesiologist performing the block was unaware of the drug used. Same anesthesiologist also monitored all the variables throughout the study. Oxygen was routinely administered via oxygen mask at 6 L/min after performing the block. Patients were monitored for block characteristics, hemodynamic parameters and side-effects and complications. All durations were calculated considering the time of administering the block as time 0.

Sensory block

Patients were assessed for loss of sensation to pin prick over C5-T1 dermatomes using a three point's score[13] at every 2 min for the first 20 min and then every 5 min till 30 min. Score 0 was taken as a sharp pain felt, 1 as dull sensation felt (analgesia), 2 as no sensation felt (anesthesia). Time to onset of sensory block (score 1), time to complete sensory block (score 2) and total duration of sensory block (regression to score 1) was noted.

Motor block

Patients were assessed for motor block every 5 min interval for 30 min. The motor block was assessed using the modified Bromage Scale as: 0 – No movement, 1 – finger movement only, 2 – flexion of the wrist against gravity, 3 – extension of the elbow against gravity.[9] Time to onset of motor block (Bromage 2), time to complete motor block (Bromage 0) and total duration of motor block (regression to Bromage 3) was noted.

A score of 2 for sensory block and score of 0 for motor block was taken as successful block. Surgery was allowed to begin once full surgical anesthesia was established. Patients were monitored for pain using VAS score. VAS was recorded just before block, immediately after the block and then every 30 min during surgery. If patients experienced pain during surgery, that is, VAS >3, then supplementary analgesia was given as injection ketamine 0.5 mg/kg body weight and if needed it was repeated at an interval of 10 min twice, after which the patient was given general anesthesia and was excluded from the study.

Perioperatively, patients were monitored for respiratory rate, pulse rate, systolic and diastolic blood pressure, ECG, oxygen saturation and sedation every 5 min interval for first 30 min, then every 10 min interval for 60 min and then every 15 min till 180 min of giving the block. Bradycardia defined as heart rate <60 beats/min was treated by giving injection atropine sulfate 0.3 mg i/v. Hypotension defined as systolic blood pressure <100 mmHg or 30% fall from the baseline was treated with additional Ringer lactate solution and injection ephedrine hydrochloride 5 mg i/v titrated according to blood pressure.

Sedation was monitored by using four point scales.[9] Score 1 – awake; Score 2 – drowsy but responsive to verbal command; Score 3 – very drowsy but responsive to the painful stimulus; Score 4 – unresponsive.

Patients were monitored for postoperative pain every half hourly for first 1 h, then 1 hourly till 12 h and then 3 hourly till 24 h postoperatively using VAS score. Rescue analgesia in the form of injection diclofenac sodium 75 mg I/M was given when VAS score >3. Time to request for the first dose of rescue analgesia and total doses of rescue analgesia were recorded. The patients were monitored for any side effects and complications throughout intraoperative and postoperative period for 24 h, such as pneumothorax, hematoma, tinnitus, circumoral numbness, dizziness, nausea and vomiting, respiratory depression, bradycardia, hypotension and seizures. Patient satisfaction score was generated by direct questioning of the patients regarding their satisfaction about anesthesia during or after surgery. 5 – Excellent; 4 – Very Good; 3 – Good; 2 – Fair; 1 – Poor.

Statistical analysis

Duration of analgesia was taken as the outcome measure of interest for the purpose of sample size calculation. It was estimated that 28 subjects were required per group in order to detect a difference of 1 h in the duration of analgesia between the two groups. Power of the study was 90% with 5% probability of Type 1 error. The data from the present study was systematically collected, compiled and analyzed using standard statistical software SPSS 19.0 version (SPSS Inc. Chicago, IL, USA). Data was summarized as mean ± standard deviation or as number and percentages. Numerical variables were normally distributed and were compared using Chi-square test for nonparametric data and Student's t-test for parametric data. The P value was determined to finally evaluate the level of significance. P <0.05 was considered as significant at 5% significance level, P < 0.01 as significant at 1% significance level and P < 0.001 was considered as highly significant.

RESULTS

In the present study, both groups were comparable with respect to the demographic profile (P > 0.05) as shown in Table 1. After giving infraclavicular block, the mean time taken for onset of sensory block and the time to achieve complete sensory block was significantly less in group B as compared to group R. Similarly, time taken for onset of motor block and time to complete motor block was also significantly less in group B as compared to group R. In group B, mean duration of sensory block and motor block was significantly prolonged (12.50 ± 1.14 and 10.67 ± 1.18 h respectively) as compared to group R (10.07 ± 0.91 and 9.03 ± 0.89 h respectively) and the difference was highly significant in the two groups (P < 0.001). Motor and sensory block characteristics of both groups are shown in Table 2. Mean duration of surgery was comparable (group R: 71.33 ± 20.88 min and group B: 74.00 ± 25.51 min, P = 0.66) in both the groups. During surgery, supplementary analgesia was given as injection ketamine i/v, if VAS > 3. Two patients (6.7%) in group R and two patients (6.7%) in group B required supplementary analgesia and the difference among the two groups was statistically nonsignificant (P = 1.00).

Table 1

Demographic characteristic of patients in group R and group B

Table 2

Sensory and motor block characteristics in both groups

During postoperative period, patients were monitored for pain using VAS score at various time intervals. VAS scores were comparable in the two groups for first 8 h of the study. At 10th, 12th and 15th h VAS score was on the higher side in group R as compared to group B and the difference was highly significant. However at 18th h, VAS was on significantly higher side in group B than in group R (P = 0.001). Later on, VAS was again on higher side in group R as compared to group B till 24 h as shown in Figure 1. Rescue analgesia was given when patient had a VAS score >3. Total duration of analgesia (when patient demanded first dose of rescue analgesia) was prolonged in bupivacaine + clonidine group as compared to ropivacaine + clonidine group, and the difference was highly significant (P = 0.000). However, the total number of doses of rescue analgesia given in 24 h of study period was comparable in the two groups as shown in Table 2.

Figure 1

Line diagram showing mean visual analogue scale (VAS) scores in group R and group B both intra and postoperatively. The mean VAS scores at various time intervals both intra and postoperatively for 24 h. During first 8 h VAS was 0 in both the groups and then VAS started increasing and was on higher side in group R from 10th to 15th h and patient demanded first dose of rescue analgesia at 15th h. At 18th h, VAS score increased in group B and patients demanded first dose of rescue analgesia. Group R = Ropivacaine + Clonidine, Group B = Bupivacaine + Clonidine

Patients were monitored for sedation at different time intervals. Sedation score was comparable in both the groups at all measured intervals as shown in Figure 2. Baseline hemodynamic parameters were comparable. Hemodynamic parameters remained stable and comparable in the two groups at all measured intervals. Only one patient (3.33%) in group R and two patients (6.67%) in group B developed bradycardia after the block which was treated with injection atropine sulfate 0.3 mg i/v. Patients were monitored for side effects and complications for 24 h. In group R, two patients (6.67%) and in group B, one patient (3.33%) had vascular puncture at the time of giving the block. None of the patient developed pneumothorax, Horner's syndrome, hoarseness, arrhythmias, respiratory depression and neuropathy in the postoperative period. At the end of the study, patient satisfaction score was comparable (in group R: 4.63 ± 0.67 and in group B: 4.67 ± 0.66; P = 0.847) in both the groups and patients were satisfied with anesthesia and analgesia in both the groups.

Figure 2

Line diagram showing sedation in both groups at various time intervals. The comparison of mean sedation scores in group R and group B at various time intervals. Sedation was comparable in both groups. Maximum sedation score was 2 in both groups, that too at 15th min to 50th min of the study. Group R = Ropivacaine + Clonidine, Group B = Bupivacaine + Clonidine

DISCUSSION

Infraclavicular BPB offers certain advantages over supraclavicular and interscalene approaches, as the complications like pneumothorax and vascular puncture are less, and the block is more consistent.[14] The coracoids approach for infraclavicular block is still better, as the coracoid process is easy to identify, and no limb movement is required.[15] Using nerve stimulator to identify nerves, further improves the success rate of block as the drug is deposited close to the nerve sheath, and chances of vascular and neurological injuries are also less.[2] In the present study, we have used the coracoids approach for infraclavicular block using nerve stimulator. Only two patients in group R and one patient in group B had vascular puncture while performing the block. None of the patients developed pneumothorax, Horner's syndrome, hoarseness and neuropathy in the postoperative period.

Local anesthetic used alone in peripheral nerve blocks are effective in providing good operative conditions, but with shorter duration of analgesia in the postoperative period. To improve the block characteristics and to enhance the postoperative analgesia, various adjuvants are added to LAs like opioids, vasoconstrictors, alpha 2 agonists etc. Clonidine an α2 adrenergic agonist was initially used as an antihypertensive but with the discovery of α2 receptors in the central nervous system, and dorsal horn of spinal cord, the role of this drug in centrally mediated sedation and analgesia has been widely explored. It improves the conduction block of peripheral nerve plexuses by blocking the conduction of “C” and A-delta fibers and increasing the potassium conductance in isolated nerve fibers. It also causes local vasoconstriction thus reducing the vascular uptake of LAs from the peripheral nerve plexuses.[5] The results of the present study suggest that 150 μg clonidine added to bupivacaine in infraclavicular block improves the block characteristics as compared to the addition of 150 μg clonidine to ropivacaine. Previously, bupivacaine and ropivacaine alone were compared for sensory and motor block characteristics in BPB and it was found that ropivacaine provides faster onset of sensory and motor block and the duration of sensory and motor block was comparable.[16] One study even documented that the analgesic effect of ropivacaine was longer than bupivacaine in axillary BPB.[17] However, in the present study, duration of sensory and motor block and duration of analgesia was more prolonged in bupivacaine + clonidine group as compared to ropivacaine + clonidine group. Probable explanation for this difference might relate to the fact that bupivacaine itself produces vasodilatation and addition of clonidine lead to local vasoconstriction, thus delays the systemic absorption of bupivacaine and prolongs sensory and motor blockade. Ropivacaine has intrinsic vasoconstricting properties not mediated by clonidine, hence did not result in much change in sensory and motor block.[1819]

In the present study the primary outcome was faster onset of sensory and motor block, time to achieve complete sensory and motor block was less, duration of sensory and motor block and postoperative analgesia was prolonged in bupivacaine + clonidine group as compared to ropivacaine + clonidine group. El Saied et al.,[9] while using 150 μg clonidine + 40 ml of ropivacaine and comparing it with 40 ml ropivacaine alone in axillary BPB, observed that onset of sensory block was achieved in 13.6 ± 1.0–27.7 ± 2.5 min in different nerve distributions and the duration of sensory block, motor block and analgesia was 628 ± 35, 721 ± 38 and 828 ± 35 min respectively in clonidine + ropivacaine group and was prolonged as compared to plain ropivacaine group. Extended duration of sensory and motor block was explained by the synergistic mechanism of action of clonidine in combination with LAs as it enhances the sodium channel blockade action of LAs by opening the potassium channels, resulting in membrane hyperpolarisation to excitatory input.[20] Jaiswal et al.,[8] observed that addition of 150 μg clonidine to 35 ml of ropivacaine for axillary plexus block offers no advantage as it did not improve the onset time and also the prolongation of sensory and motor block was not observed. Casati et al.,[7] also demonstrated that adding clonidine 1 μg/kg to 20 ml ropivacaine has no effect on the onset time, and quality of axillary block but duration of analgesia was prolonged.

Various studies were done where clonidine was used as an adjuvant to bupivacaine and block characteristics were compared with plain bupivacaine and it was found that addition of clonidine leads to faster onset and prolonged duration of sensory and motor block with improved analgesia.[5111213] Ghoshmaulik et al.,[6] concluded that 150 μg clonidine used as an adjuvant to 30 ml of 0.5% bupivacaine resulted in prolongation of sensory block (625 ± 35 min), motor block (690 ± 38 min) and duration of analgesia (930 ± 45 min) without any significant hemodynamic variability. Erlacher et al.,[10] compared the effect of adding clonidine to different LAs like mepivacaine, bupivacaine and ropivacaine and found that clonidine has a different impact on each of the LAs in terms of onset and block prolonging action. Addition of clonidine resulted in a very impressive block prolongation in mepivacaine and bupivacaine group but failed to provide additional block prolonging effect in the ropivacaine group. It was suggested that ropivacaine itself provides long lasting nerve block without having to resort to adjuvants. It is clear from the above studies that when clonidine was added to bupivacaine it resulted in faster onset and prolonged duration of sensory and motor block with improved analgesia. However, when clonidine was added to ropivacaine, sensory and motor block and postoperative analgesia was not prolonged. The findings of the present study regarding sensory and motor block characteristics of the two groups are consistent with the above studies.

In the present study, sedation scores were comparable in both the groups. Previous studies also reported that there was no significant change in the sedation score with addition of clonidine to LAs in BPB.[7891121] Hemodynamic parameters remained stable in both groups throughout the study period which was supported by the previous studies.[578111221]

Meta-analysis of twenty randomized controlled trials was done to see the effect of clonidine as an adjuvant to the LAs for peripheral nerve and plexus block. It was observed that the relative increase in the duration of postoperative analgesia due to clonidine will largely depend upon the nature of LA used with average increase of 56% with intermediate acting LA and only 18% increase with long acting LA. Thus, the clinical relevance of adding clonidine to a long acting LA may be questioned as the relative gain will be minimal. However, the prolongation of motor block by addition of clonidine to ropivacaine was very similar to intermediate acting LA and with the addition to bupivacaine motor block was twice prolonged. Hence, it was concluded that clonidine added to LAs for single shot peripheral nerve blocks prolongs postoperative analgesia by about 2 h, which is a beneficial outcome as it provides pain free recovery. The prolongation of motor block was less with the addition of clonidine to ropivacaine as compared to bupivacaine, which allows early ambulation.[22]

Finally to conclude, clonidine, when added to bupivacaine hastens the onset of sensory and motor block in addition to prolonging the duration of sensory block, thereby providing prolonged postoperative analgesia without producing any significant side-effects as compared to ropivacaine + clonidine in infraclavicular block. However, prolongation of motor block was more in bupivacaine + clonidine group as compared to ropivacaine + clonidine group.

Further investigations are required to observe the beneficial effect of performing BPB under ultrasound guidance and to evaluate the role of other α2 agonists like dexmedetomidine in improving the block characteristics in peripheral nerve blocks.