|Ahead of print publication
Efficacy of clonidine as an adjuvant to ropivacaine in transversus abdominis plane block in adult renal transplant recipients: A double-blinded randomized controlled trial
Sayan Nath1, Mahesh Kumar Arora2, Anjolie Chhabra1, Dalim Kumar Baidya1, Rajeshwari Subramaniam1, Ganga Prasad1
1 Department of Anaesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India
2 Department of Anaesthesia and Intensive Care, Institute of Liver and Biliary Sciences, New Delhi, India
|Date of Submission||09-Jun-2022|
|Date of Decision||28-Jul-2022|
|Date of Acceptance||08-Aug-2022|
|Date of Web Publication||19-Sep-2022|
Department of Anaesthesiology, Pain Medicine and Critical Care, Room 5011, 5th Floor, Teaching Block, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background and Aims: Transversus abdominis plane (TAP) block has been used to provide analgesia in renal transplant surgery with varying results. This study was designed to assess if the addition of clonidine in TAP block would decrease 24-h postoperative morphine consumption in adult renal transplant recipients. Materials and Methods: Forty adult patients undergoing renal transplantation under general anesthesia in a tertiary care hospital were randomized into either group RC (TAP block with 20 mL of 0.5% ropivacaine plus 2 μg.kg−1 clonidine) or group R (TAP block with 20 mL 0.5% ropivacaine) after induction of anesthesia. Postoperative analgesia was provided using patient-controlled morphine. The primary outcome was 24-h patient-controlled morphine consumption. The secondary outcomes were a) intraoperative hemodynamics, b) fentanyl and ephedrine requirement, c) postoperative pain using the Visual Analog Scale at 0, 2, 6, 12 and 24 hours, d) time to first postoperative analgesia, e) postoperative hemodynamics, and f) side effects. Results: There was no significant difference in postoperative morphine consumption between the groups (25 mg in group RC vs. 28.5 mg in group R) (median interquartile range) (P = 0.439). Postoperative pain scores were comparable between the groups. Intraoperatively, fewer patients required rescue fentanyl in group RC (7 patients) as compared to group R (17 patients) (P = 0.003). Significantly more patients in group RC required ephedrine boluses as compared to group R (9 patients in group RC vs. 2 in group R, P = 0.014). Conclusions: The addition of 2 μg.kg−1 clonidine to ropivacaine in TAP block did not reduce 24-h postoperative morphine consumption after renal transplantation. It reduced the need for intraoperative analgesics but increased the need for intraoperative ephedrine administration.
Keywords: Adjuvants, analgesia, anesthetics, clonidine, kidney transplantation, local, nerve block, pharmaceutical
|How to cite this URL:|
Nath S, Arora MK, Chhabra A, Baidya DK, Subramaniam R, Prasad G. Efficacy of clonidine as an adjuvant to ropivacaine in transversus abdominis plane block in adult renal transplant recipients: A double-blinded randomized controlled trial. Anesth Essays Res [Epub ahead of print] [cited 2022 Oct 2]. Available from: https://www.aeronline.org/preprintarticle.asp?id=356418
| Introduction|| |
Pain management after renal transplantation is challenging due to underlying comorbidities and deranged renal function., Nonsteroidal anti-inflammatory drugs are contraindicated due to their adverse effects on renal hemodynamics. Although epidural infusion of local anesthetics and opioids has been useful, preexisting neuropathy, borderline-to-low platelets, and thrombasthenia preclude central neuraxial blocks as the primary choice for analgesia in this patient population. The sole use of intravenous (i.v.) opioids for perioperative analgesia can result in multiple side effects, especially with morphine due to the accumulation of active metabolites in chronic kidney disease (CKD) patients., In the absence of alternatives, i.v. patient-controlled analgesia (PCA) with morphine or fentanyl is still being used.
Transversus abdominis plane block (TAP block) is a truncal block that has been used as a mode of analgesia for renal transplantation surgery.,,, However, studies assessing the effect of TAP block in renal transplantation had variable results. Intraoperative analgesic benefits of single-shot TAP block may not persist till the postoperative period. This has prompted the use of TAP catheters by some researchers.,, A meta-analysis has found both continuous and single-shot TAP blocks to be effective in decreasing postoperative opioid consumption. The use of continuous TAP catheters in kidney transplant patients is technically challenging and carries the risk of infection as these patients are on high-dose immunosuppressants. The use of clonidine (an alpha-2 receptor agonist) as an adjuvant to the local anesthetic may prolong postoperative analgesia without exposing patients to the risks related to catheters.
Clonidine has been found to enhance the sensory and motor blockade after peripheral nerve blocks.,,,, It enhances analgesic benefits when added to TAP block in lower abdominal surgeries.,, In the literature review, we found no study that had assessed the efficacy of clonidine as an adjuvant in TAP block for renal transplantation surgery.
This study was planned with the hypothesis that the addition of clonidine to ropivacaine would prolong the effect of the TAP block and result in reduced 24-h postoperative morphine consumption in patients undergoing renal transplant surgery.
| Materials and Methods|| |
Study design: Prospective double-blinded randomized controlled trial
After institutional ethics committee approval (RT-16/21.01.2015), the study was conducted in a tertiary care hospital in northern India from May 2015 to October 2016. The trial was registered in the Clinical Trials Registry of India (www.ctri.nic.in; CTRI/2017/07/009102). The study was conducted in accordance with the ethical principles for medical research involving human subjects (Helsinki Declaration 2013). The primary outcome was comparison of total 24-h postoperative morphine consumption. The secondary outcomes were comparison on a) intraoperative fentanyl requirement, b) postoperative pain using the Visual Analog Scale (VAS) at 0, 2, 6, 12 and 24 hours, c) need for rescue analgesia (number of morphine bolus) in 24 h postoperative period, and d) side effects such as hypotension, bradycardia, sedation, respiratory depression, pruritus, and postoperative nausea and vomiting (PONV) between the groups.
Adult patients (age 18–65 years) with end-stage renal disease undergoing renal transplantation surgery were included in the study. Informed written consent for participation in the study was taken from all patients fulfilling inclusion criteria. Exclusion criteria included refusal to participate; infection at the site of block; hypersensitivity to ropivacaine, clonidine, or opioids; and inability to use the PCA pump or report pain using VAS.
Randomization and blinding
Patients were randomized into two groups using computer-generated random number tables, and allocation was concealed using sealed-opaque envelopes. An anesthesiologist not a part of the study opened the envelopes and prepared the drugs as per randomization. An independent investigator, who was unaware of group allocation, noted outcome parameters.
Post induction, group “R” (control group) patients received TAP block with 20 mL of 0.5% ropivacaine and group “RC” (study group) patients received TAP block with 0.5% ropivacaine along with 2 μg.kg−1 clonidine (maximum 150 μg) to make a total volume of 20 mL.
During routine preanesthetic checkup, informed written consent was taken from the study subjects and they explained the functioning of PCA and the use of VAS (0–100). In the operation theater, routine monitoring was commenced: electrocardiogram (ECG), pulse oximetry (SpO2), noninvasive blood pressure (NIBP). Baseline parameters were recorded 5 minute before induction of general anesthesia. Anesthesia was induced with i.v. fentanyl (2 μg.kg−1), propofol (2–3 mg.kg−1), and atracurium (0.5 mg.kg−1), followed by endotracheal intubation. Anesthesia was maintained using inhaled oxygen, nitrous oxide (50%:50%), 1% inspired concentration of isoflurane, and controlled mechanical ventilation to ensure normocarbia. Atracurium i.v. infusion (4–12 μg.kg−1.min−1) with train-of-four monitoring and central venous pressure (CVP) monitoring was done through the surgery. Ipsilateral ultrasound (USG)-guided TAP block was performed in the supine position at the midaxillary line with an 18-G Tuohy needle using an in-plane approach under all aseptic precautions. Hemodynamic parameters were noted every 5 min up to and immediately after the surgical incision. Thereafter, these parameters were noted every 15 min till the end of surgery. Supplemental analgesia was provided with i.v. fentanyl boluses (0.5 μg.kg−1) if there was an increase in heart rate (HR) or mean arterial pressure (MAP) of >20% from baseline. Hypotension (fall in MAP of more than 20% of baseline) was managed with boluses of 3 mg ephedrine. All patients received ondansetron (0.1 mg.kg−1) and paracetamol 15 mg.kg−1 (maximum 1 g) i.v. intraoperatively. After extubation, the patients were shifted to the renal transplantation ward. Pain was assessed at rest and on deep breathing (movement) using VAS (0–100 mm line) with “0” corresponding to no pain and “100” corresponding to the worst imaginable pain at 0, 2, 6, 12, and 24 h. Patients with VAS >30 at rest were given rescue analgesia with morphine 2 mg i.v. every 5 min till their VAS score decreased to ≤30. Thereafter, they were started on i.v. PCA morphine with settings of 1 mg bolus, lockout interval of 7 min with a maximum dose of 30 mg per 4 h. All patients received paracetamol 15 mg.kg−1 (maximum 1 g) i.v. 8 hourly. The total PCA morphine consumption and rescue boluses were noted till 24 h into the postoperative period. Side effects such as hypotension, bradycardia, PONV, sedation, pruritus, and respiratory depression were also noted.
Sample size calculation
In a study by Freir et al. in 65 adult renal transplant recipients receiving TAP block with bupivacaine alone, the average 24-h postoperative PCA morphine requirement was 31.6 ± 5.6 mg and a 40% decrease in PCA morphine consumption was considered to be clinically significant. Assuming a 40% decrease in PCA morphine consumption after the addition of clonidine to the TAP block to be clinically significant, taking α error of 5% and power of 90%, the required number of samples per group came to be 5 for a superiority trial. For making the study clinically more relevant, we included 20 patients in each group.
Statistical analysis was carried out using Stata 12.0 (StataCorp, College Station, Texas, USA). Data were presented as number (percentage) or mean ± standard deviation or median (minimum–maximum) as appropriate. Categorical variables were compared using Fisher's exact test and continuous variables were compared using the Student's t-test for independent samples. The primary outcome (24-h morphine consumption) was compared between the groups using the Wilcoxon rank-sum test since the data were not following a normal distribution. The parameters which were measured over a period of time (HR, MAP, CVP, respiratory rate, and SpO2) were compared between/and within the groups using generalized estimating equation analysis since the data were correlated. P <0.05 was considered statistically significant.
| Results|| |
Forty-nine patients were screened and 40 patients were included in the study [Figure 1]. One patient in the study group was admitted to the intensive care unit postoperatively due to hemodynamic instability and received continuous i.v. fentanyl infusion. This patient was excluded from all analyses.
All the demographic and baseline data were comparable between the groups [Table 1]. There was no significant difference in total 24-h morphine consumption between the two groups. Twenty-four-hour PCA morphine requirement and the number of rescue morphine boluses were also similar between the groups. The mean time from TAP block to the first use of analgesics in the postoperative period was also similar between the groups [Table 2].
|Table 2: Postoperative analgesic requirement and Visual Analog Scale scores|
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Postoperative pain at rest and on movement was comparable between the groups at all time points studied [Table 2]. The median (interquartile range) intraoperative fentanyl bolus requirement in group RC was significantly lesser compared to group R (0 vs. 2 [2.5]; P = 0.0012). Significantly fewer patients required intraoperative rescue fentanyl bolus in group RC (7/19 [36.8%] in group RC vs. 17/20 [85.0%] in group R; P = 0.003). However, significantly more patients required ephedrine boluses in the RC group [Table 3].
The RC group had a significantly lower HR compared to group R throughout the intraoperative period till the end of surgery [Figure 2]. In group R, the HR increased significantly post incision (T4) and at 45 min after skin incision (T8). Immediate postoperative HR was comparable between the groups (83.8 ± 13.8/min in RC group vs. 90.6 ± 9.5/min in R group; P = 0.067). HR was comparable between the groups postoperatively except that a significant increase in HR was observed in group RC at 6 h and 12 h postoperatively (P = 0.001 and 0.049, respectively) [Figure 2]. Intraoperative MAP was not significantly different between the two groups at any time point except at T8 (45 min post incision) when MAP was significantly higher in group R (109.7 ± 9.7 mmHg in group RC vs. 118.7 ± 17.0 mmHg in group R; P = 0.022) [Figure 2]. Immediate postoperative MAP was also significantly higher in group R (119.2 ± 12.9 mmHg in group R vs. 110.9 ± 10.9 mmHg in group RC; P = 0.028). MAP in group RC increased significantly at 12 h and 24-h postoperatively (P = 0.004 and 0.008, respectively) [Figure 2]. There was no difference in intraoperative and postoperative CVP between the groups. There was no difference in the incidence of any serious adverse events between the groups in the postoperative period [Table 4]. No patient had respiratory depression, bradycardia, sedation, or pruritus during the 24-h postoperative period.
|Figure 2: Intraoperative and postoperative hemodynamic parameters. (a) Intraoperative heart rate. (b) Intraoperative mean arterial pressure. (c) Postoperative heart rate. (d) Postoperative mean arterial pressure|
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| Discussion|| |
In this randomized controlled trial in adult renal transplant recipients, we observed that the addition of clonidine to ropivacaine in a single-shot TAP block did not reduce 24-h postoperative morphine consumption. However, clonidine prevented incision response, and reduced intraoperative fentanyl requirement, at the cost of the increased intraoperative requirement of ephedrine boluses.
Studies assessing the efficacy of clonidine as an adjuvant in TAP block have shown variable outcomes in the past. Dhupia et al. used TAP block with either 150 μg or 300 μg clonidine in 60 patients undergoing unilateral inguinal hernioplasty and found that the usage of the higher dosage of clonidine resulted in significantly prolonged duration of analgesia but had more incidences of bradycardia and sedation. Even with such a high dose of clonidine, the difference in pain scores among the subjects was observed only up to 6 h postoperatively. A study by Sruthi et al. comparing the efficacy of varying doses of clonidine with levobupivacaine in TAP block on 80 patients undergoing laparoscopic-assisted vaginal hysterectomy under general anesthesia found that a higher dosage (150 μg) of clonidine offered significantly prolonged analgesia when given in TAP block compared to 75 μg clonidine. These two studies did not have a control group without clonidine. Singh et al. found a significant increase in the duration of postoperative analgesia and lower postoperative analgesic consumption when clonidine was added to bupivacaine in TAP block for cesarean section under spinal anesthesia. In contrast, Bollag et al. reported no added advantage of adding clonidine in TAP block for controlling immediate and late postoperative pain after cesarean sections. Few authors have questioned the efficacy of clonidine as an adjuvant to long-acting local anesthetics in the past., In a systematic review, Kirksey et al. concluded that clonidine is effective in block prolongation with bupivacaine but not with ropivacaine and levobupivacaine. Similarly, in our study, clonidine did not prolong analgesia when added with ropivacaine in the TAP block.
Clonidine has been used in multiple peripheral nerve blocks with an unclear mechanism of its adjuvant action. Many studies suggest a direct action on the nerves apart from its local vasoconstrictor effect which supposedly decreases the systemic absorption of local anesthetics from the block site, thus increasing the duration of action., However, Crawford et al. showed that adding up to 2 μg.kg−1 of clonidine to ropivacaine in TAP block did not reduce plasma ropivacaine concentration suggesting a lack of vasoconstrictor effect when given in TAP block. It is not known whether the analgesia is mediated by the systemic effect of clonidine rather than its action at the site of injection since the use of i.v. clonidine has also been shown to improve postoperative analgesia. In our study, we did not measure plasma ropivacaine concentration, but the addition of clonidine failed to prolong the analgesic action of ropivacaine in the TAP block either by its local effect or by its systemic effects.
All the previous studies that reported the analgesic benefit of clonidine in TAP block were performed on patients belonging to the American Society of Anesthesiologists classes I and II.,, In our study, the patient population was distinct and included only end-stage kidney disease patients. In the past, Adnan et al. reported the benefit of adding clonidine in axillary brachial plexus blockade with lidocaine in CKD patients. However, this study had a very small sample size, the prolongation of sensory blockade was only for about 2 h, and the local anesthetic used was a short-acting agent lignocaine. The authors did not provide any data about the postoperative pain scores either. Whether CKD significantly alters pharmacokinetics and pharmacodynamics of peripherally administered clonidine is not known. The result of our study throws light upon the effect of clonidine with a long-acting local anesthetic in TAP block in this distinct patient population.
Hypotension and bradycardia are known side effects of clonidine when added in peripheral nerve blocks. McCartney et al. concluded that these side effects are limited till dosages up to 150 μg. In our study, clonidine dosage did not cross 150 μg in any patient, but there was a significant lowering of HR from the baseline in the clonidine group which increased gradually over the first 6 h in the postoperative period. The overall intraoperative HR was much lower in the clonidine group compared to the plain ropivacaine group. The MAP decreased significantly from baseline in the clonidine group, thus requiring a significantly greater number of intraoperative ephedrine boluses to maintain MAP. Thus, the addition of clonidine resulted in the lowering of HR and clinically significant hypotension in the intraoperative period.
It must be remembered that hypotension and bradycardia are systemic side effects of clonidine. The apparent analgesic benefit, i.e. lesser opioid consumption, and the hemodynamic alterations with the addition of clonidine were both evident in the intraoperative period with the addition of clonidine in the TAP block whereas neither the analgesic benefit nor the hemodynamic alterations differed significantly between the two groups in the postoperative period. Thus, the postoperative hypotension observed in the few patients was unrelated to the effect of intraoperative usage of clonidine in our study population. There might be multiple causes of postoperative hypotension after renal transplantation such as intraoperative fluid shifts, intraoperative excessive diuretic use, blood loss during surgery, and postreperfusion syndrome.,
The study has few limitations. Many of the patients were on oral clonidine as these are routinely used as antihypertensives in chronic renal failure patients at our institution. This might have confounded the result. However, the percentage of patients on oral clonidine was similar between the groups (11 out of 19 patients in group RC [57.9%] and 12 out of 20 patients in group R [60.0%], P = 1.0). A post hoc analysis found no difference in morphine requirement between the two groups when patients on oral clonidine (P = 0.1854, Mann–Whitney U test) and those not on oral clonidine (P = 0.5987, Mann–Whitney U test) were separately analyzed. Oral clonidine does not have significant analgesic effects., However, it is important to recognize that it might have influenced the hemodynamic outcomes, both intraoperatively and postoperatively. Further studies on this topic should ideally exclude patients on oral clonidine.
Whether intraoperative clonidine use in TAP block is associated with any adverse outcome on long-term graft function was not studied.
| Conclusions|| |
The addition of 2 μg.kg−1 clonidine to ropivacaine in TAP block for renal transplantation surgery did not reduce 24-h postoperative analgesic consumption. Till further data are available, the addition of clonidine in TAP block for renal transplantation surgery should be based on individual choice and it should be a matter of caution since the apparent intraoperative analgesic benefit did not extend till the postoperative period and it caused significant hemodynamic alterations intraoperatively.
The authors would like to acknowledge the contribution of Mrs. M. Kalaivani, Scientist, Department of Biostatistics, AIIMS, New Delhi, for helping with statistical analysis in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]