Evaluation of clonidine as an adjuvant to bupivacaine in wound infiltration for providing postoperative analgesia after abdominal hysterectomy.

BACKGROUND: Clonidine is an effective adjuvant to local anesthetics in peripheral nerve blocks. We studied the effect of clonidine as an adjuvant in wound infiltration for postoperative analgesia. AIM: To evaluate the role of clonidine as an adjuvant to bupivacaine in wound infiltration in terms of quality and duration of postoperative analgesia in patients undergoing total abdominal hysterectomy. SETTINGS AND STUDY
DESIGN: Prospective, randomized, double-blinded study.
MATERIALS AND METHODS: One hundred patients of American Society of Anesthesiologists I-II posted for abdominal hysterectomy were randomly allotted to two groups. Group A received wound infiltration with 45 ml of 0.25% bupivacaine with 3 μg/kg clonidine while Group B received wound infiltration with 45 ml of 0.25% bupivacaine. A standard general anesthesia technique was used in all the patients. Postoperative analgesia was provided with injection ketorolac 0.5 mg/kg intravenous infusion and tramadol being the rescue analgesic. Postoperative pain score, duration of effective analgesia before the first rescue analgesic, percentage of patients requiring rescue analgesic at different time intervals, and total number of rescue analgesic doses in 24 h were compared between the groups. STATISTICAL ANALYSIS: Difference between the bivariate samples in independent groups with Mann-Whitney U-test. For categorical data, Chi-square test was used.
RESULTS: Clonidine group has better pain score, longer duration of effective analgesia, lower percentage of patients requiring rescue analgesic, and less number of doses of rescue analgesia in the first 24 h.
CONCLUSION: We conclude that Clonidine 3 μg/kg is an effective adjuvant to bupivacaine for wound infiltration in terms of quality and duration of postoperative analgesia following total abdominal hysterectomy.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Wound infiltration is a simple and effective means of providing postoperative analgesia.[1] Clonidine has potent antinociceptive properties.[2] The presence of a peripheral analgesic action for clonidine has been shown in previous clinical studies.[34] A recent study has shown clonidine to be an effective adjuvant to bupivacaine in wound infiltration as a part of multimodal analgesia in patients following open cholecystectomy.[5] The purpose of this study is to evaluate clonidine as an adjuvant to bupivacaine for wound infiltration following abdominal hysterectomy in terms of quality and duration of postoperative analgesia.

MATERIALS AND METHODS

With the Institute Ethics Committee approval and written informed consent from all the patients, this prospective, randomized, parallel group study was carried out in our Department of Anesthesiology, MKCG Medical College, Odisha, India over a period of 1-year duration. We hypothesized that addition of clonidine at 3 µg/kg as an adjuvant to bupivacaine for local infiltration analgesia did not improve the quality and duration of postoperative analgesia. The sample size of 50 in each group based on statistical power analysis arrived.

Patients of age 18–60 years and American Society of Anesthesiologists (ASA) physical status I and II posted for elective total abdominal hysterectomy with a Pfannenstiel incision are included in this study. The following patient category is excluded: ASA III and above, emergency surgery, expected duration >2 h, body mass index >35, previous abdominal surgeries, incision other than Pfannenstiel, malignancy, individuals with chronic pain, Reynaud's disease, hepatorenal insufficiency, bronchial asthmatics, or receiving adrenoreceptor agonists, antagonists or narcotics before operation were excluded. Duration >2 h is the expected drop outs.

All the patients underwent a thorough preoperative assessment on the previous day of surgery, and written informed consent was obtained for participation in the study. Randomization is by computer-generated random numbers and concealed by sealed envelope technique. The patients were randomly allocated into two groups. Group A–Patients received 45 ml of 0.25% bupivacaine with 3 µg/kg clonidine for wound infiltration by a three-layer technique. Group B–Patients received 45 ml of 0.25% bupivacaine for wound infiltration by the three-layer technique. The person who prepared the study drugs was blinded of the study protocol and is not involved in data collection.

Anesthesia was induced with propofol 2 mg/kg and fentanyl 2 µg/kg. Tracheal intubation was facilitated by vecuronium 0.1 mg/kg. Anesthesia was maintained by isoflurane 2% and 66% nitrous oxide in oxygen. The patients were monitored using Nihon Kohden Life Scope A, BSM-5100 India Pvt. Limited. Intraoperative monitoring included an electrocardiogram (lead II and V5), noninvasive blood pressure (at 5 min intervals), pulseoximetry, end-tidal carbon dioxide, and nasopharyngeal temperature. The patient lungs were ventilated by intermittent positive pressure ventilation using a circle system to maintain normocapnia. Fluid management is done with maintenance rate of ringer lactate infusion and transfusion as needed appropriately.

Heart rate and mean arterial pressure (MAP) were maintained within 20% of the preoperative value. Hypotension (MAP 20% of baseline or 60 mmHg) was treated with infusion of normal saline (NS) and if required injection ephedrine 6 mg intravenous (i.v.) boluses. Bradycardia (heart rate <60 beats/min) was treated with atropine 0.5 mg bolus.

Technique of study drug infiltration

Infiltration is done by the primary surgeon after the removal of the uterus. This surgeon is blinded to the group assignment. After the closure of the peritoneal layer 45 ml of the study drug is infiltrated with a 25-gauge Quincke spinal needle in layers covering the skin, subcutaneous tissue, muscle layers and sprayed over the peritoneal reflection. About 30 ml of the drug is used for the first three layers and 15 ml for the peritoneal reflection.

All the patients received i.v. infusion of ketorolac 0.5 mg/kg in a 100 ml NS and ondansetron 0.1 mg/kg i.v., half an hour before the completion of surgery. At the end of surgery, residual neuromuscular block was reversed with neostigmine and glycopyrrolate. Tracheal extubation was performed on meeting the standard criteria for extubation. Pain score was recorded immediately after extubation. The patients were shifted to the postanesthesia care unit where they were observed by an anesthesiologist who is blinded for the group assignment for 24 h. Pain score assessed by visual analog scale (VAS) (0 = no pain, and 10 = worst possible pain). Pain score recorded at immediate extubation (taken as 0 h) and after 1, 3, 6, 12, and 24 h later. Postoperative analgesia was provided with i.v. ketorolac 0.5 mg/kg diluted in 100 ml of NS infused over 10 min every 8th hourly.

Rescue analgesia was given with tramadol 1 mg/kg slow i.v. boluses on demand or whenever VAS pain score was ≥3. Tramadol was not given more than four doses per 24 h and not more than one dose per 6 h. The pain score was assessed 30 min after each rescue analgesic dose, and if pain score is still ≥3, injection fentanyl 1 µg/kg i.v. bolus was given. The total duration of study is 24 h from the time of extubation.

The primary outcomes measured are duration of effective analgesia (time for the first rescue analgesia); pain score at 0, 1, 3, 6, 12, and 24 h; percentage of patients that required rescue medication during various time intervals; number of doses of tramadol each patient received over 24 h; and number of doses of additional fentanyl boluses each patient received in the postoperative period over 24 h. Duration of effective analgesia is the time from extubation until the first rescue analgesic is administered by the anesthesiologist or demanded by the patient as per the study protocol. Figure 1 shows the flow diagram of the progress of the clinical study. The secondary outcome was incidence of hypotension or bradycardia between the groups.

Figure 1

Flow diagram

Statistical analysis

Sample size calculation was calculated from a pilot study done with 10 patients in each group. A total of 34 cases required for an effect size of 4. About 18 h difference in the mean time for the first rescue medication with a standard deviation (SD) of 6.02 and power of 80% and an alpha error of 0.05. Hence, with a 30% expected drop rate, we arrived at 50 numbers in each group for this study. The expected drop outs are need for extension of incision from surgical point of view, duration >2 h, and patient refusal after participation.

The collected data were analyzed with SPSS Inc., for windows, version 16.0, Chicago, IL, USA. To describe the data descriptive statistics frequency analysis, percentage analysis were used for categorical variables, and the mean and SD were used for continuous variables. To find the significant difference between the bivariate samples in independent groups, the Mann–Whitney U-test was used. To find the significance in categorical data, Chi-square test was used. In all the above statistical tools, the P = 0.05 is considered as significant level.

RESULTS

Both the groups are comparable with respect to age, height, and weight as shown in Table 1.

Table 1

Distribution of patient characteristics among the two groups

Table 2 shows the mean time for the first rescue analgesia in both groups. The mean time for the first rescue medication is 13.72 ± 9.67 in the group receiving clonidine along with bupivacaine (Group A) for local infiltration analgesia while it is less 7.97 ± 4.80 in Group B with bupivacaine alone. Mann–Whitney test was used which showed that Group A has a statistically significant longer duration of analgesia before the requirement for the first rescue analgesic (Z = −4.489, P = 0.001).

Table 2

Comparison of mean time for first rescue analgesic medication

Table 3 shows the distribution of mean pain score between the groups. Mann–Whitney test was used to compare the pain score between the groups. Mean pain score was significantly lower in Group A compared to Group B at all time intervals of the study up to 24 h into the postoperative period (P < 0.05). Mean pain score in Group A at 0 h was slightly more than Group B, but the difference is statistically insignificant (P = 0.345).

Table 3

Comparison of mean pain scores

Table 4 compares the mean number of doses of tramadol required in both the groups. Mann–Whitney test was used to compare the mean number of doses between the groups. It shows that clonidine group (Group A) required statistically significant (P < 0.001) decreased number of doses compared to Group B.

Table 4

Comparison of mean number of doses of tramadol in 24 h between both the groups

None of the patients required fentanyl bolus, the second rescue analgesic in both groups within the 24 h study period as per the study protocol as stated earlier.

Figure 2 shows the percentage of patients that required rescue medication during various time intervals between both the groups. Two contingency tables for evaluating the percentage of patients receiving rescue analgesia at various intervals are tabulated, and Chi-square test done to find the significance of difference at each time interval and the results are grouped up in tabular form in Table 5. The percentage of patients receiving rescue analgesia in Group A is significantly lower than in Group B at all time intervals. Except that at 6th h interval, Group A still had lower percentage of patients receiving rescue medication, but it was not statistically significant compared to Group B.

Figure 2

Percentage of patients that required rescue medication during various time intervals

Table 5

Percentage of patients that required rescue medication during various time intervals

Thus, clonidine, when added as an adjuvant to bupivacaine for local infiltration, prolonged the duration of analgesia and hence delayed the need for rescue analgesia and furthermore, it has improved the mean pain scores. The addition of clonidine also decreased the requirement of the number of rescue tramadol boluses in the first 24 h of the postoperative period.

DISCUSSION

In this study, we have shown that clonidine was an effective adjuvant to 0.25% bupivacaine for local wound infiltration analgesia following abdominal hysterectomy and has improved the quality and duration of postoperative analgesia in the first 24 h of the postoperative period. We have used a multilayer infiltration technique including the preperitoneal instillation, muscle and subcutaneous infiltration in patients undergoing abdominal hysterectomy with Pfannenstiel incision. Addition of clonidine has prolonged the duration of effective analgesia before the need for the rescue analgesia improved pain scores and reduced amount of rescue analgesic-tramadol in the first 24 h into the postoperative period.

Local infiltrative analgesia with local anesthetics is an established method of providing postoperative analgesia. At present, intraarticular local infiltrative analgesia following knee arthroplasty[67] has been gaining importance among anesthesiologist for postoperative analgesia. A recent study has shown that clonidine is an effective adjuvant to bupivacaine in wound infiltration as a part of multimodal analgesia in patients following open cholecystectomy.[5] The authors believe that open cholecystectomy is equally as invasive as abdominal hysterectomy, and hence the degree of postoperative pain and discomfort. However, the previous study[8] investigating the clonidine as an adjuvant to bupivacaine in wound infiltration and ilioinguinal nerve block in patients with inguinal hernia repair has shown that clonidine did not reduce postoperative analgesic consumption. In this study, they have given both local wound infiltration as well as direct ilioinguinal and iliohypogastric nerve blocks during the surgery. The authors have reasoned that the enhancement of pharmacological action of local anesthetic by clonidine would have been concealed by the prolonged analgesia provided by the block itself. Moreover, the dosage of clonidine and volume of bupivacaine used for wound infiltration is less compared to our study. We used 45 ml of 0.25% bupivacaine and clonidine 3 µg/kg while they have used 29 ml of 0.25% of bupivacaine and 150 mcg of clonidine in their study.[8] We have to notice that the amount of bupivacaine used is well within the recommended dosage to avoid toxicity. Thus, clonidine is an effective adjuvant to bupivacaine in local infiltration analgesia for a variety of surgical procedures.[9]

The precise mechanism of topical clonidine is not yet established. It has been attributed to the fact that sympathetic neural activity and norepinephrine have an excitatory effect on nociceptive discharge after cutaneous injury.[10] Since clonidine inhibits the norepinephrine release from prejunctional α2-adrenoceptors in the periphery, it may inhibit nociceptive pathway activity.[11] Other possible mechanisms are enhancement of effect of local anesthetics by selectively blocking the Aδ and C fibers, and also by release of enkephalin-like substances.[2] One study[12] in mice has shown that topical clonidine has antinociception action by blocking the emerging pain signals at peripheral terminals through α2 receptors without producing the undesirable central effects of systemic administration. In our study, we had no incidence of hypotension and bradycardia similar to an earlier study comparing systemic and topical clonidine.[5]

The limitations of our study

We have studied only the first 24 h of the postoperative period. Furthermore, we did not study the effect of this analgesic modality on the wound infection rate, role in early ambulation, and discharge from the hospital. We did not compare varied doses of clonidine as adjuvant to bupivacaine. We took the dosage what the earlier study[5] had used. These are the limitations of our study.

The clinical importance of our study is that it has proved that clonidine is an effective adjuvant to bupivacaine for local infiltrative analgesia ensuring improved postoperative analgesia which can be recommended for adoption in clinical practice in these groups of surgical population.

Our study also leads the scope for further research. The role of clonidine for local infiltrative analgesia and its influence on postoperative ambulation and hospital discharge rate are the area of interest and scope for further research.

To conclude, clonidine is an effective adjuvant to bupivacaine for local infiltrative analgesia in improving the quality and duration of postoperative analgesia in patients who have undergone total abdominal hysterectomy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.