|Ahead of print publication
Clinical evaluation of two different doses of clonidine as an adjuvant to bupivacaine in ultrasound-guided supraclavicular brachial plexus block for pediatric upper limb surgeries - A randomized trial
Rohan Sharma1, Geeta Kamal1, Shilpa Agarwal1, Anju Gupta2, Aikta Gupta1, Bhumika Kalra1
1 Department of Paediatric Anaesthesia, Chacha Nehru Bal Chikitsalya, New Delhi, India
2 Department of Anaesthesia, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||13-Apr-2022|
|Date of Decision||01-Aug-2022|
|Date of Acceptance||18-Aug-2022|
|Date of Web Publication||19-Sep-2022|
Room No. 6, 4th Floor, Porta Cabin, Teaching Block, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Clonidine as an adjuvant to local anesthetic for regional anesthesia in upper limb surgeries has been extensively studied in adults, but there is a paucity of data regarding the dose of clonidine which is effective and safe as an adjuvant in children. Aims: To find the dose of clonidine that prolongs the duration of analgesia without prolonging the side effects. Settings and Design: Prospective, randomized, double-blind study. Materials and Methods: After taking informed consent from the parents/guardian, 42 children aged 3–12 years who were scheduled to undergo unilateral upper limb surgeries below the elbow were randomized into two groups of 21 each. Group A was given 0.5 μg.kg−1 of clonidine in addition to 0.5 mL.kg−1 of 0.25% bupivacaine and Group B received 1 μg.kg−1 of clonidine added to the same volume and concentration of local anesthetic for supraclavicular brachial plexus block under general anesthesia using ultrasound guidance. The drug administration and the recording of the observations were done by an investigator blinded to the dose of clonidine. Statistical Analysis Used: Statistical testing was conducted with the Statistical Package for the Social Sciences system version SPSS 17.0. Results: The demographic parameters and baseline hemodynamic parameters were similar in the two groups. The block failed in one child in Group A. One patient in Group A required tramadol postoperatively while none of the patients in Group B required tramadol. The mean duration of analgesia (11.35 ± 1.54 h vs. 9.94 ± 1.04 h, P < 0.001) and the duration of motor block (8.86 ± 1.0 h vs. 7.77 ± 0.55 h, P < 0.001) were significantly higher in group B. Sedation scores were higher in the recovery room in Group B. Deep sedation, bradycardia, and respiratory depression were not observed in any of the cases. Conclusions: Clonidine 1 μg.kg−1 when added as an adjuvant to bupivacaine for pediatric supraclavicular brachial plexus block prolongs the duration of analgesia and motor block as compared to the dose of 0.5 μg.kg−1. However, this was at the cost of increased duration of motor block and sedation. Considering the clinical equivalence of the effect, a lower dose of clonidine would be preferable to avoid the undesirable effects.
Keywords: Brachial plexus block, bupivacaine, clonidine, ultrasound
|How to cite this URL:|
Sharma R, Kamal G, Agarwal S, Gupta A, Gupta A, Kalra B. Clinical evaluation of two different doses of clonidine as an adjuvant to bupivacaine in ultrasound-guided supraclavicular brachial plexus block for pediatric upper limb surgeries - A randomized trial. Anesth Essays Res [Epub ahead of print] [cited 2022 Oct 2]. Available from: https://www.aeronline.org/preprintarticle.asp?id=356417
| Introduction|| |
Nerve blocks have been used for various surgeries in the adult population as the main anesthetic technique and for improving analgesia and reducing the demand for analgesics after surgery. With the increasing use of real-time imaging (ultrasonography) in the operation theatre suites, the procedural complications of performing the nerve blocks have decreased drastically, while the accuracy of the deposition of drug perineurally has increased as one can see the spread of local anesthetics under the ultrasound guidance. This is even more significant for pediatric patients, as they have always been assumed to be at a higher risk of procedural complications such as pneumothorax, nerve injury, and arterial injury while performing a supraclavicular brachial plexus block.
Local anesthetics alone may not provide sufficient duration or quality of postoperative analgesia. The addition of adjuvants has been found to provide remarkably prolonged analgesia but may be associated with certain adverse effects.,
Many adjuvants have been added to local anesthetics such as clonidine, dexmedetomidine, dexamethasone, and fentanyl. One additive of particular interest that consistently prolongs local anesthetics' duration has been clonidine. However, at the clinically studied doses of 1 μg.kg−1 and 2 μg.kg−1, the use of clonidine is associated with bradycardia, sedation, and hypotension as side effects., Till now, there has been a paucity of studies evaluating the effect of different doses of clonidine in supraclavicular brachial plexus block in children and there is no study evaluating the effect of the use of a lower dose of 0.5 μg.kg−1 on the brachial plexus block characteristics using bupivacaine as a local anesthetic. Hence, we decided to investigate if clonidine in the dose of 0.5 μg.kg−1 when added to bupivacaine for the supraclavicular block would effectively prolong the duration of postoperative analgesia.
The primary outcome of the study was to compare the duration of analgesia for the two doses of clonidine as an adjuvant to local anesthetic for supraclavicular brachial plexus block. The secondary outcomes were the intraoperative fentanyl requirement, duration of motor block, number of patients requiring opioids for postoperative analgesia, parental satisfaction, and the incidence of any complications in both groups.
| Materials and Methods|| |
The study was a prospective, randomized, double-blind study conducted at a teriary care paediatric hospital in north India. American Society of Anesthesiologists Classes I and II patients within the age group of 3–12 years and requiring unilateral upper limb surgery at or below the elbow were included in the study. The patients that had contraindications to regional anesthesia, previous nerve injuries, history of allergy to study drugs, history of bleeding disorders, children with any mental disability which will confound pain assessment or inability to understand the pain scale used in the study, patients on anticoagulants, and any major systemic illness were excluded from the study. This prospective, randomized controlled trial was conducted after obtaining Institutional Ethical Committee clearance (IEC F1/IEC/CNBC/03/01/2019/2521 dated January 3, 2019) and was registered prospectively in the Clinical Trial Registry India (CTRI/2019/08/020961) and all the procedures followed the guidelines laid down in the Declaration of Helsinki.
The duration of postoperative analgesia was our primary outcome and was used as the outcome measure to calculate the sample size. The mean and standard deviation of the outcome variable for the dose of 0.5 μg.kg−1 dose of clonidine was 9.8 ± 1.1 h based on a pilot study of 5 cases. Thirty-eight patients (19 patients in each group) were required to detect a 10% increase in the time to first rescue analgesia from 9.8 h with clonidine 0.5 μg.kg−1 with an 80% power and 0.05 significance level. Considering the possibility of dropouts or noncompliance, we decided to recruit a total of 42 children (21 patients in each group).
Written informed consent was obtained from the parents/guardians of children enrolled in the study. Wong-Baker FACES® Pain Rating Scale (WBFPS) was shown to the child and explained. Forty-two patients were allocated to one of two groups of 21 patients each, labeled as Group “A” and Group “B,” respectively. Subjects were randomly assigned to receive one of the two doses of clonidine by using a computer-based random number generator and the numbers were maintained in sequentially numbered opaque sealed envelopes. Patients in Group “A” received 0.5 mL.kg−1 of 0.25% bupivacaine + clonidine 0.5 μg.kg−1 and the patients in Group “B” received 0.5 mL.kg−1 of 0.25% bupivacaine + clonidine 1 μg.kg−1.
After being wheeled to the operation room, standard monitoring was attached (only vital monitoring, including heart rate (HR), blood pressure (BP), respiratory rate, and Oxygen saturation, and all the patients were induced using inhalational induction with oxygen and 6%–8% Sevoflurane. An intravenous (i.v.) cannula was then secured, and monitors were attached. Inj. propofol 1–2 mg.kg−1 was supplemented as required to achieve proper depth of anesthesia for laryngeal mask airway (LMA) insertion. After an adequate plane of anesthesia was reached, an appropriate size Proseal LMA was inserted. The LMA was secured, and the anesthesia was maintained with oxygen + nitrous oxide (50:50) and Sevoflurane ≤2%. The surgeon was allowed to proceed only after 15 min had elapsed following the block procedure. If the hemodynamic parameters (HR or BP) increased to >20% following incision or at any time intraoperatively, fentanyl 1 μg.kg−1 was supplemented.
Following general anesthesia, under all aseptic precautions, ultrasound-guided supraclavicular brachial plexus block was performed using an in-plane approach with a 22G-50 mm insulated block needle (Stimuplex A, B. Braun Medical Inc, USA) and a 25 cm high-frequency linear probe (8–12MHz. Sonosite M Turbo, Fujifilm Sonosite, Inc. WA, USA) inside the operation theater by the senior anesthesiologist who had successfully performed at least 100 ultrasound-guided brachial plexus blocks in the past and who was blinded to the dose of clonidine that was prepared in the syringe. The dose was prepared in a sterile fashion by an independent anesthetist not involved in the study. The dose of clonidine for every case was prepared in a constant volume of 0.5 mL normal saline (using a 1 mL syringe) to maintain uniformity. This drug preparation was then handed over to the anesthesiologist performing the block procedure, who added it to 0.5 mL.kg−1 of 0.25% bupivacaine to be administered for the block. The recording of observations intraoperatively and postoperatively was also done by an investigator blind to the dose of the study drug used. If the hemodynamic parameters (HR or BP) increased to >20% following incision or at any time intraoperatively, fentanyl 1 μg.kg−1 was supplemented.
As the patients were anesthetized in the intraoperative period, assessment of analgesia, motor block, and sedation could only be done in the postoperative period.
The primary outcome was the time to first rescue analgesia which was defined as the time since the block performance till the first administration of any rescue analgesia in the postoperative period. WBFPS was used for pain assessment in both the groups at 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 12 h, and 24 h. The number of children with WBFPS >6 (severe pain) at any time point was recorded for both groups.
The secondary outcomes included the motor block characteristics, block failure, sedation, number of children requiring tramadol, and any procedural complications.
Motor block was assessed using a modified Bromage scale (0-normal function, 1-only able to move fingers, and 2-complete motor block) at 30 min and then at 1, 2, 3, 4, 6, 12, and 24 h. The duration of motor block was defined as the time elapsed from performance of the nerve block to full recovery of motor function in the blocked extremity.
Sedation was assessed as per the Ramsay Sedation Scale (1-Anxious, agitated, restless; 2-Cooperative, oriented; 3-Responsive to commands only; 4-Brisk response to a light glabellar tap or loud auditory stimulus; 5-Sluggish response to a light glabellar tap or loud auditory stimulus; and 6-No response to a light glabellar tap or loud auditory stimulus), which is easy to reproduce at the bedside at 5 min, 10 min, and then at 30 min.
Clinically, relevant bradycardia was defined as a HR decrease of >20% from baseline value and was treated with an injection of atropine 20 μg.kg−1 given intravenously. Clinically, relevant hypotension was defined as a decrease of 20% in mean arterial pressure from the baseline and appropriately treated with fluids and i.v. mephenteramine if required.
Paracetamol 15 mg.kg−1 was given intravenously at the end of the surgery and as scheduled in 6 hourly doses. The rescue analgesia was given when the WBFPS was more than 4 or on patient demand. At this point, inj. diclofenac 1 mg.kg−1 was administered, and the time of the first rescue analgesia was recorded. If the pain persisted after half an hour (WBFPS >4), tramadol 1 mg.kg−1 was given. The number of patients requiring opioids (tramadol) in the first 24 h was noted for both groups.
Failure of the supraclavicular block was defined as a complaint of severe pain in the immediate postoperative period (WBPS ≥6 within the first 30 min).
Adverse effects such as apnea, hypotension, bradycardia, postoperative nausea, and vomiting, and pneumothorax were recorded.
Statistical testing was conducted with the Statistical Package for the Social Sciences system version SPSS inc., SPSS Statistics for windows, version 17.0. (Chicago: SPSS Inc.). Continuous variables were presented as mean ± standard deviation (SD) or median if the data were unevenly distributed. Categorical variables were expressed as frequencies and percentages. The comparison of continuous variables between the groups was performed using the Student's t-test. Nominal categorical data between the groups were compared using the Chi-squared test or Fisher's exact test as appropriate. Nonnormal distribution continuous variables were compared using the Mann–Whitney U test. For all statistical tests, a P < 0.05 was taken to indicate a significant difference.
| Results|| |
This randomized interventional parallel-group trial was conducted in a tertiary care specialized pediatric center. Fifty-six children were assessed for eligibility out of which after exclusion of patients whose parents were not willing to consent or that ineligible to participate, 42 were finally recruited [Figure 1].
A total of 42 pediatric patients (21 in each group) were included in the study [Table 1]. There were 17 female and 25 male children in the study, the difference not being significant between the groups [Table 1].
The average ages were comparable in both the groups at 6.48 ± 2.54 years for the 0.5 μg.kg−1 group (Group A) and 6.50 ± 2.60 years for the 1 μg.kg−1 group (Group B). The average weight also did not differ significantly within the groups [Table 1].
The most commonly performed procedures were open reduction and internal fixation for fractures of the upper limb in both the groups being 42.9% and 54.5% in 0.5 μg.kg−1 and 1 μg.kg−1 groups, respectively. The second most common procedure was syndactyly release which constituted 19% in both the groups [Table 2].
The block was considered to be failed in one patient due to severe pain in recovery (WBPS >6). The mean duration of analgesia was 9.94 ± 1.04 h in Group A, while it was significantly higher at 11.35 ± 1.54 h in Group B, the P = 0.001. Similarly, the motor block duration was also significantly higher in Group B at 8.86 ± 1.0 h while it was only 7.77 ± 0.55 h in group A, the P = 0.001 [Table 3].
The mean (SD) Ramsay Sedation Score (RSS) was 1.40 (0.50) in Group A and it was 2.25 (0.55) in Group B at 1 h. Only one patient in Group A required tramadol while none of the patients in Group B required tramadol. One patient in Group A reported severe pain in the immediate postoperative period and the case was considered a failed block procedure [Table 3].
Only three patients, 1 in Group B and 2 in Group A, reported postoperative nausea or vomiting. One patient in Group B developed hypotension intraoperatively while none of the patients was observed to have bradycardia. None of the patients reported urinary retention, headache, pneumothorax, respiratory depression, and neurological complications. All the parents but one in Group A was satisfied with the quality of analgesia provided.
| Discussion|| |
We observed that the patients who received the higher dose of clonidine (1 μg.kg−1) had significantly enhanced duration of analgesia though with a prolonged motor block and higher sedation scores as compared to the group receiving clonidine 0.5 μg.kg−1 clonidine. There were no significant hemodynamic changes or other adverse effects in any group.
The additive effect of clonidine on local anesthetic in upper limb surgeries has been extensively studied in the adult population., In the adult population, a dose range of 30–300 μg has been used while performing various studies.,,, Although a dose of up to 150 μg was found to be safe and associated with only minimal side effects, there is always a concern about its associated hemodynamic complications. Singelyn et al. reported that a minimal dose of 0.5 μg.kg−1 was required to produce any significant prolongation of the local anesthetic block. Increasing the dose of clonidine further to 1.5 μg.kg−1 resulted in no significant benefit over the one already achieved with 0.5 μg.kg−1.
Clonidine was found to be a valuable adjuvant for peripheral nerve blocks when used as an additive to local anesthesia. The beneficial effect of clonidine was reported to be present with all tested local anesthetics in a meta-analysis by Pöpping et al. Pöpping et al. concluded that adding clonidine to long or intermediate-acting local anesthetics prolonged the duration of analgesia, along with increased motor block duration. The dose of clonidine in this study ranged from 30 μg to 300 μg and the side effects (hypotension and sedation), were seen with the dose above 150 μg in adult patients.
There is a paucity of studies regarding the dose of clonidine that can be used safely as an adjuvant to local anesthesia in supraclavicular brachial plexus block in the pediatric population. Pediatric patients are considered vulnerable to a higher rate of anesthesia-related complications, and clonidine has been associated with adverse effects such as bradycardia, hypotension, and sedation, we decided to investigate if a lower dose of 0.5 μg.kg−1 could provide effective postoperative analgesia compared to the commonly reported dose of 1 μg.kg−1.
There appeared to be a dose-dependent increase in the duration of the motor block as well as the duration of analgesia. This may occur due to the increase in potassium conductance by clonidine that blocks the conduction of A and C nerve fibers. In 2000, El Saied et al. added 150 μg of clonidine to ropivacaine for an axillary block in adult patients undergoing surgery. Similar to our study, they saw an increase in the duration of analgesia to 828 min, while in the group not given clonidine, the analgesia lasted for only 587 min. Hutschala et al. performed a similar study using 2 μg.kg−1 of clonidine. They also found a prolonged duration of analgesia in volunteers that were given clonidine in addition to bupivacaine for brachial plexus block, but unlike our study, this study was done in adult patients. Similar findings were also reported in previous studies by Singelyn et al., Bernard and Macaire, Iskandar et al., Iohom et al. and Duma et al.,,,, A prolonged duration of analgesia is a boon for surgical patients. The same cannot be said for the motor block though. Apart from a delay in recognition of a severe nerve injury, the prolonged motor block can be detrimental in ambulatory surgeries as delayed mobilization equals delayed rehabilitation. Hence, considering that the difference in the mean duration of analgesia was clinically irrelevant, the shorter motor block can be considered an advantage of the lower clonidine dose.
A very important side effect of clonidine is sedation. During our study, we did not notice any significant sedation postoperatively in any group. Among both groups, the level of sedation was almost the same when assessed in the postoperative period. All patients were comfortable and arousable with oral commands when assessed for the first time at 5 min and were completely awake at 10 min. This may also occur due to the use of “opioid-free anesthesia” and sevoflurane which gets washed out from the blood fast. Deeper levels of sedation with clonidine only occur consistently at high doses which were not used in our study. In our study, the majority of patients had an RSS of 1–3 which is a desirable level of sedation and none of the children was found to be deeply sedated (RSS >4). Therefore, with the doses used in our study, dangerous levels of sedation or respiratory depression are unlikely.
We would like to reiterate that clonidine at a dose of 0.5 and 1 μg kg−1 did not lead to any significant hemodynamic changes in our study except for one episode of hypotension with the dose of 1 μg.kg−1 when it was given perineurally, and therefore, both the doses can be considered a safe adjuvant to be added to local anesthetics while performing brachial plexus blocks in pediatric patients. This could be due to the lower doses of clonidine employed and that too was deposited around the brachial plexus. Similar findings were also reported by El Saied et al., Singelyn et al., Bernard and Macaire, and Murphy et al.,, However, our study was underpowered to detect any hemodynamic differences, and hence, the use of a lower dose can be considered safer while minimally compromising the postoperative analgesia duration.
Strengths and limitations
The main strength of the study lies in the lack of literature regarding the efficacy and safety of various doses of clonidine as an adjuvant to brachial plexus block in this patient population. Considering that brachial plexus block is a commonly used block for upper limb surgery in children and clonidine is a commonly used adjuvant, this study would add valuable evidence to the literature. One limitation of our study was that although the type of surgeries was similar in both the groups by statistics, there would have been subtle differences in the surgical procedure and the level of postoperative pain for every individual case. Furthermore, we did not compare the WBFPS scores or total rescue analgesic consumption over the first 24 h, which would have been further evidence of the analgesic efficacy of the drugs used in the study. However, we did note the need for tramadol which signified severe pain not relieved with paracetamol and diclofenac.
| Conclusions|| |
Clonidine 1 μg.kg−1 when added as an adjuvant to bupivacaine for pediatric supraclavicular brachial plexus block prolongs the duration of analgesia and motor block to a higher degree as compared to the dose of 0.5 μg.kg−1. However, this was at the cost of increased motor block duration and sedation. Considering the clinical equivalence of the effect, a lower dose of clonidine would be preferable to avoid the undesirable effects which can be associated with the higher dose of clonidine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]