TITLE: Pain relief after ambulatory hand surgery: A comparison between dexmedetomidine and clonidine as adjuvant in axillary brachial plexus block: A prospective, double-blinded, randomized controlled study

  ABSTRACT.BACKGROUND:
For ages various adjuvants have been tried to prolong axillary brachial plexus block. We compared the effect of adding dexmedetomidine versus clonidine to ropivacaine for axillary brachial plexus blockade. The primary endpoints were the onset and duration of sensory and motor block and duration of analgesia.

ABSTRACT.MATERIALS AND METHODS:
A total of 90 patients (20-40 years) posted for ambulatory elective hand surgery under axillary brachial plexus block were divided into two equal groups (groups ropivacaine dexmedetomidine [RD] and ropivacaine clonidine [RC]) in a randomized, double-blind fashion. In group RD (n = 45) 30 ml 0.5% ropivacaine + 100 μg of dexmedetomidine and group RC (n = 45) 30 ml 0.5% ropivacaine + 75 μg clonidine were administered in axillary plexus block. Sensory and motor block onset times and block durations, time to first analgesic use, total analgesic need, postoperative visual analog scale (VAS), hemodynamics and side-effects were recorded for each patient.

ABSTRACT.RESULTS:
Though with similar demographic profile in both groups, sensory and motor block in group RD (P < 0.05) was earlier than group RC. Sensory and motor block duration and time to first analgesic use were significantly longer and the total need for rescue analgesics was lower in group RD (P < 0.05) than group RC. Postoperative VAS value at 18 h were significantly lower in group RD (P < 0.05). Intraoperative hemodynamics were insignificantly lower in group RD (P < 0.05) without any appreciable side-effects.

ABSTRACT.CONCLUSION:
It can be concluded that adding dexmedetomidine to axillary plexus block increases the sensory and motor block duration and time to first analgesic use, and decreases total analgesic use with no side-effects.

BODY.INTRODUCTION:
Pain frequently hampers implementation of ambulatory surgery in spite of so many analgesic drugs and regimens.[1] Postoperative pain has a negative impact on patient's early mobilization and discharge as well as it causes unanticipated hospital admission particularly in a day care setting.[2]  Peripheral nerve block as an anesthetic technique plays an important role in modern regional anesthesia. The most important prerequisites for the use of peripheral regional anesthesia in daily clinical practice are success rate and safety. Upper limb surgeries especially hand surgeries below the elbow joint; commonly performed as an outpatient procedure; are mostly performed under peripheral blocks such as the axillary brachial plexus block.[3] Peripheral nerve blocks not only provide intraoperative anesthesia, but also extend analgesia in the postoperative period without major systemic side-effects by minimizing stress response and using minimal anesthetic drugs.[4]  Ropivacaine is an amino-amide local anesthetic that blocks the peripheral afferents acting on voltage dependent Na+ channels. It is less cardiac and central nervous system toxic than other long acting local anesthetics like bupivacaine.[5] During hand surgeries local anesthetics alone for axillary brachial plexus block provide good operative conditions, but have shorter duration of postoperative analgesia. So various adjuvants like opioids,[6] clonidine,[7] neostigmine, dexamethasone,[8] midazolam,[9] etc., were added to local anaesthetics in axillary brachial plexus block to achieve quick, dense and prolonged block, but the results are either inconclusive or associated with side-effects.  Clonidine is a selective α2 adrenergic agonist with some α1 agonist property. In clinical studies, the addition of clonidine to local anesthetic solutions improved peripheral nerve blocks by reducing the onset time, improving the efficacy of the block during surgery and extending postoperative analgesia.[1011]  Dexmedetomidine is highly selective (8 times more selective than clonidine),[12] specific and potent α2 -adrenergic agonist having analgesic, sedative, antihypertensive and anesthetic sparing effects when used in systemic route.[13] Adding dexmedetomidine to local anesthetics during peripheral nerve blockade and regional anesthesia procedures may also prove efficacious for the surgical patients.[1415]  The aim and objective of this study was to compare the analgesic efficacy of dexmedetomidine and clonidine as adjuvant to ropivacaine for axillary brachial plexus blockade in the in the first 20 h postoperative period of a day-care hand surgery. The severity of pain was recorded using visual analog scale (VAS) with choice options ranging from 0 (no pain) to 10 (worst possible pain).

BODY.MATERIALS AND METHODS:
After obtaining permission from Institutional Ethics Committee, written informed consent was taken. Totally 90 adult patients were randomly allocated to two equal groups (n = 45 in each group) using computer generated random number list. American Society of Anesthesiologists (ASA) physical status I and II, aged between 25 and 50 years of both sexes undergoing elective surgeries of hand under axillary brachial plexus block were enrolled in the study. Patients in group RC received 30 ml of 0.5% ropivacaine + 75 μg of clonidine for axillary block. Group RD received 30 ml 0.5% ropivacaine + 100 μg of dexmedetomidine for the same block. Adjuvants were made 1 ml in both the groups for blinding purpose after mixing it with normal saline.

BODY.MATERIALS AND METHODS.EXCLUSION CRITERIA:
Patient refusal, any known hypersensitivity or contraindication to ropivacaine, clonidine, dexmedetomidine; pregnancy, lactating mothers, hepatic, renal or cardiopulmonary abnormality, alcoholism, diabetes, long-term analgesic therapy, bleeding diathesis, local skin site infections were excluded from the study. Patients having history of significant neurological, psychiatric or neuromuscular disorders were also excluded. As we were dealing with day care surgery patients having no assistance in home and dwelling at more than 10 km from our institution were also excluded from this study.  In the preoperative assessment, the patients were enquired about any history of drug allergy, previous operations or prolonged drug treatment. General examination, systemic examinations and assessment of the airway were done. Preoperative fasting of minimum 6 h was ensured before the operation in all day care cases. All patients received premedication of tablet alprazolam 0.5 mg orally the night before surgery as per preanesthetic check-up direction to allay anxiety, apprehension and for sound sleep. The patients also received tablet ranitidine 150 mg in the previous night and in the morning of operation with sips of water.  All patients were clinically examined in the preoperative period, when whole procedure was explained. 10 cm VAS (0: No pain and 10: Worst pain imaginable) was also explained during preoperative visit. All patients are investigated for hemoglobin %, total leukocyte count, differential leukocyte count, erythrocyte sedimentation rate, platelet count, blood sugar, blood urea, serum creatinine and liver function tests. A 12 lead electrocardiography (ECG) and chest X-ray were also taken. On entering the patient in the operative room standard intraoperative monitors like ECG, pulse oximeter, non-invasive blood pressure were attached, and baseline parameter were recorded. Philips IntelliVue MP20 monitor used for this purpose. Intravenous (i.v.) infusion of Ringers' lactate started and oxygen given at 3 L/min via face mask. All patients received injection midazolam 0.04 mg/kg before procedure.  After proper explanation of technique and positioning, axillary block was performed in the supine position with the upper arm abducted at 90° and the elbow flexed at 90°. The area was shaved the day before and disinfected. The axillary artery was palpated in the proximal part of the axilla, and a skin wheal was injected using 1 ml of lignocaine 2%. A nerve stimulator (Stimuplex Kanule A 50, B Braun, Melsungen, Germany) was used to identify the plexus. The position of the needle was judged adequate when an output current of <0.5 mA still elicited a slight distal motor response. With intermittent negative aspiration, the total 31 ml volume was injected into the perivascular area. All the blocks were performed by the same anesthetist unaware of the constituent of the drug and allotment of the group and similarly resident doctors keeping records of different parameters were also unaware of group allotment. Thus blinding was properly maintained.  Sensory and motor blockade were assessed every 2 min after completion of injection till 30 min and then every 30 min after the end of surgery till first 12 h, thereafter hourly until the block had completely worn off. Sensory blockade of each nerve was assessed by pinprick. Onset time of motor blockade was defined as the time interval between the end of local anesthetic injection and paresis in all of the nerve distributions. The duration of sensory block was defined as the time interval between the onset of sensory block and the first postoperative pain. The duration of motor block was defined as the time interval between the onset of motor block and complete recovery of motor functions. After 30 min, if the block was considered to be adequate, surgery commenced. Heart rate, noninvasive blood pressure, respiratory rate, SpO2, ECG and pain VAS were recorded at 1st, 2nd, 4th, 6th, 9th, 12th, 16th, 18th and 20th postoperative h. Injection diclofenac sodium (75 mg intramuscular [IM]) was given as rescue analgesia if the pain VAS >3. First postoperative analgesia request time, total diclofenac used in first 20 h were recorded. All data will be collected by an observer who is unaware of patients' group assignment.

BODY.MATERIALS AND METHODS.STATISTICAL ANALYSIS:
Sample size was estimated using first rescue analgesic requirement among two groups as the main primary variable. The average duration in each group was 750 min and to detect a difference of 10% (i.e., 75 min), at the P < 0.05 level, with a probability of detecting a difference this large, if it exists, of 80% (1−beta = 0.80). On the basis of previous study assuming within group standard deviation of 150 min and we needed to study at least 44 patients per group to be able to reject the null hypothesis that the population means of the groups are equal with probability (power) 0.80. Raw data were entered into a MS Excel spreadsheet and analyzed using standard statistical software Statistical Package for the Social Sciences (SPSS) version 18.0 (SPSS Inc., Chicago, Illinois, USA). Categorical variables were analyzed using the Pearson's Chi-square test. Normally distributed continuous variables were analyzed using the independent sample t-test and P < 0.05 was considered as statistically significant.

BODY.RESULTS AND ANALYSIS:
We recruited 45 subjects per group, more than the calculated sample size. There were no dropouts. 45 patients in the ropivacaine dexmedetomidine group (RD) and 45 in the ropivacaine clonidine group (RC) were eligible for effectiveness analysis.  The age, body weight, sex distribution, ASA status and duration of surgery, tourniquet time, and anesthesia time in the two groups were found to be comparable [Table 1]. Indications for different hand surgeries were also similar and has no clinical significance (P > 0.05) [Table 2]. Onset of both sensory and motor block were earlier in RD group than group RC [Table 3] and they were clinically significant (P < 0.05). Table 3 also shows that sensory and motor block durations are significantly greater in the group receiving dexmedetomidine (RD) (P < 0.05) than clonidine group (RC).   Table 1 Comparison of demographic data between the two study groups   Table 2 Indications of upper limb orthopedic surgery for two groups   Table 3 Onset and duration time for sensory and motor block   The mean time from block placement to first request for pain medication, that is, the duration of analgesia was 821.11 min in the dexmedetomidine group, but 768.24 min in the clonidine group. This difference (about 52.87 min) was highly significant (P < 0.006) statistically as well as clinically [Table 4 and Figure 1].  Table 4 Rescue analgesic requirement in postoperative period (time and amount of IM diclofenac sodium injections)   Figure 1Duration of sensory and motor block  Table 4 and Figure 2 shows that group RD required less amount of diclofenac sodium injection as rescue analgesics than patients in group RC in first 20 h of postoperative period, and the difference is statistically highly significant (P < 0.01).  Figure 2Number of intramuscular diclofenac injection as rescue analgesic in first 24 h postoperative period  Figure 3 shows that VAS score was of much higher value in group RC than RD group. Again group RD suffered from bradycardia, which was statistically higher (P < 0.05) than group RC. Other side-effects were quiet comparable (P > 0.05) among two groups [Table 5].  Figure 3Comparison of visual analog scale score among group ropivacaine dexmedetomidine and group ropivacaine clonidine  Table 5 Comparison of side-effects 

BODY.DISCUSSION:
Day care surgery has proven over the years as the best method to reduce the burden on the health care resources, as well as the achievement of extreme patient satisfaction.[16] In developing countries, most of the patients avoid bearing expenses of prolonged hospital stay. At the same time, infrastructure in these countries is not organized uniformly to smoothly deliver the day care procedures. In the present day scenario, pain is the most common medical cause of delayed recovery and discharge after ambulatory surgery and a frequent cause of unplanned admission and subsequently delayed return to work.[17]  Axillary brachial plexus blocks are performed at the level of the brachial plexus cords for forearm and hand surgeries.[18] Here, almost the entire sensory, motor and sympathetic innervations of the forearm and hand are carried within axillary plexus sheath just as three nerve structures (cords), confined to a very small surface area. Consequently, typical features of this block include rapid onset, predictable and dense anesthesia along with its high success rate.[19] Local anesthetics alone for axillary brachial plexus block provide good operative conditions but have a shorter duration of postoperative analgesia. Hence, various drugs have been used as an adjuvant with local anesthetics in axillary plexus block to achieve quick, dense and prolonged block, but the results are either inconclusive or associated with side-effects.[678920]  Dexmedetomidine; a highly selective, α2 -adrenergic agonist; has analgesic, sedative, anesthetic sparing effects when used in the systemic route.[13] Use of dexmedetomidine as an adjuvant mixed with local anesthetics has been performed with neuraxial anesthesia in both adult and pediatric patients.[2122] Mixing dexmedetomidine as adjuvant with local anesthetics during peripheral nerve and nerve plexus blockade has recently been practiced by anesthesiologists.[2324]  In this prospective, randomized, double-blinded trial we had compared the effect of 100 μg of dexmedetomidine and 75 μg clonidine as an adjuvant to 30 ml 0.50% ropivacaine in axillary brachial plexus block, on the onset time and duration of sensory and motor block as well as on the postoperative rescue analgesic (injection diclofenac sodium) requirement for the patients undergoing ambulatory elective hand surgery.  The demographic profile, between two groups, which was statistically insignificant (P > 0.05) of our patients was quite similar to other research investigations and provided us the uniform platform to evenly compare the results obtained.[25]  From [Table 2] it is quite evident that indications of surgical procedures were almost similar in both the groups and had no statistical significance. The onset time of sensory block (10.92 ± 4.23 min in RD group vs. 12.83 ± 3.18 min in RC group) was significantly earlier in dexmedetomidine groups (P = 0.017) [Table 3]. These findings correlate with the studies of Ammar and Mahmoud,[26] Kaygusuz et al.[27] Significantly earlier onset of motor block (17.11 ± 2.8 min in RD group vs. 18.55 ± 3.2 min in group RC) was observed in RD group (P = 0.025). Similarly Ammar and Mahmoud,[26] in their study found that motor block onset was hastened by the use of dexmedetomidine adjuvant in brachial plexus block. Again Kanazi et al.[28] found both clonidine and dexmedetomidine hastens motor block in spinal anesthesia with bupivacaine. Again in a study conducted by Marhofer et al.[14] in 36 volunteers it has been found that dexmedetomidine as adjuvant though produced early onset of motor block, sensory block was not different from control group or i.v. group.  In our study, the duration of sensory block (810.34 ± 110.4 min in group RD vs. 730.25 ± 134.30 min in group RC) was significantly longer in the dexmedetomidine group than in the clonidine group (P < 0.002). The duration of motor block (610.44 ± 95.23 min in RD group vs. 565.44 ± 68.23 min in RC group) was also significantly longer in the dexmedetomidine group than in the clonidine group (P < 0.011). These findings lend support to the observations of various earlier studies by Marhofer et al.,[14] Esmaoglu et al.,[23] Ammar and Mahmoud.[26]  In our study, mean duration of the sensory block (analgesia) and motor block in the dexmedetomidine plus ropivacaine group were 810.34 min and 730.25 min, respectively. While the mean duration of analgesia and motor block in the dexmedetomidine plus bupivacaine group were 2.99 h and 2.59 h respectively, in the study conducted by Ammar and Mahmoud.[26] Again the median duration of sensory and motor block in the dexmedetomidine plus levobupivacaine group in infraclavicular brachial plexus block were 14.78 h and 12.88 h respectively, in the study by Esmaoglu et al.[23]  In our study, patients of RD group required significantly less amount of diclofenac sodium injection in first 20 h of postoperative period than the patients RC group (P < 0.05). This finding correlates with the studies of Kaygusuz et al.[27] Kaygusuz et al. found that 11 patients of levobupivacaine group required 75 mg IM injection of diclofenac sodium as rescue analgesic whereas dexmedetomidine plus levobupivacaine group required nothing and the result was also statistically significant.[27] Reduced requirement of rescue analgesic in the dexmedetomidine group during first 20 h of postoperative period is because of prolonged duration of sensory block. Again Ammar and Mahmoud[26] also experienced statistically much less amount (4.9 mg vs. 13.6 mg) of i.v. morphine administration as rescue analgesic in bupivacaine, dexmedetomidine group while comparing with plain bupivacaine group in infraclavicular brachial plexus block. In a study comparing intra- and post-operative analgesic effect of epidural clonidine and dexmedetomidine, Bajwa et al. found that dexmedetomidine produced longer postoperative analgesia than clonidine (316.64 vs. 296.72 min).[29]  In group RD, bradycardia was observed in four patients, and all of these patients were managed with atropine. There was no such episode of bradycardia in group RC. Side-effects-including pneumothorax, Horner syndrome though noted in both the groups, but the difference was not statistically insignificant (P > 0.05). Esmaoglu et al.[23] also found significant bradycardia in dexmedetomidine plus levobupivacaine group than levobupivacaine alone. However, they found significant hypotension with dexmedetomidine group, which was absent in our study. Bajwa et al. found that dry mouth was main side-effects among two groups.[29]  Ropivacaine, dexmedetomidine and clonidine dose was chosen as per the recommendation in the textbook as well as experience of our previous researchers.[2630313233] While writing this discussion, we have found the reference of lowest possible volume (10 ml) and concentration (0.375%) of ropivacaine for postoperative analgesia by Iwata et al.[34] However we had used a higher concentration and much higher volume for intra- as well as post-operative analgesia. However, the great drawback of our study was that we had not taken the equipotent dose of two above-mentioned α2 agonists due to nonavailability of proper pharmaceutical reference relating to dose equivalence. A control group was not included in our study because we regarded it as unethical to withhold any adjuvant in these patients for prolongation of postoperative pain management particularly when being posted for ambulatory surgery.  We do conclude that during day care hand surgery, addition of 100 mcg dexmedetomidine is more effective than 75 mcg clonidine; regarding early onset of sensory and motor blockade, prolongation of block duration, reducing the requirement of rescue analgesic in postoperative period; when added to ropivacaine 0.50% solution in axillary brachial plexus block without any appreciable side-effect.

BODY.DISCUSSION.FINANCIAL SUPPORT AND SPONSORSHIP:
Nil.

BODY.DISCUSSION.CONFLICTS OF INTEREST:
There are no conflicts of interest.

Question: Compared to 30 ml 0.5% ropivacaine + 75 Î1⁄4g clonidine (RC) what was the result of 30 ml 0.5% ropivacaine + 100 Î1⁄4g of dexmedetomidine (RD) on suffered from bradycardia?
Evidence: Again group RD suffered from bradycardia, which was statistically higher (P < 0.05) than group RC.
Answer: significantly increased