|Year : 2017 | Volume
| Issue : 2 | Page : 127-132
Comparison of analgesic efficacy of levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine in wound infiltration technique for abdominal surgeries: A prospective randomized controlled study
B Jyothi, Kirthiha Govindaraj, Pratishruthi, Safiya I Shaikh
Department of Anaesthesiology, Karnataka Institute of Medical Sciences, Hubli, Karnataka, India
|Date of Web Publication||6-Sep-2017|
Department of Anaesthesiology, Karnataka Institute of Medical Sciences, Hubli - 580 021, Karnataka
Source of Support: None, Conflict of Interest: None
Background: This study was designed to evaluate the postoperative analgesic efficacy of levobupivacaine (L) alone and its combination with clonidine (C) or dexmedetomidine (D) in wound infiltration technique for abdominal surgeries. Materials and Methods: After ethical committee approval, a double-blind randomized controlled study was conducted on 90 patients (power of study 80%), physical status American Society of Anesthesiologists Grade I and II, aged 18–60 years scheduled for abdominal surgeries over 1 year duration. A standard general anesthetic technique was used. Patients were randomly allocated into three groups, by computer-generated random number table. Patients received wound infiltration during wound closure. Group L received 29 ml of 0.25% levobupivacaine plus 1 ml 0.9% normal saline, Group LC received 29 ml of 0.25% levobupivacaine with 1 ml (3 mcg/kg) clonidine, and Group LD received 29 ml of 0.25% levobupivacaine with 1 ml (2 mcg/kg) dexmedetomidine. Postoperative rescue analgesia was provided with injection tramadol. Statistical analysis for duration of analgesia was determined by one-way analysis of variance and side effects by Chi-square test. Results: The total duration of analgesia in LD group was 23.4 h, when compared to LC group 20.9 h and L group 11.65 h (P = 0.0001) with excellent to good quality of analgesia in adjuvant group (P < 0.001) and incidence of minimal side effects such as sedation, nausea, and vomiting. Conclusion: Clonidine and dexmedetomidine were the effective adjuvants to levobupivacaine for single shot wound infiltration analgesic technique; however, dexmedetomidine was found to be superior to clonidine.
Keywords: Analgesia, clonidine, dexmedetomidine, infiltration, levobupivacaine, postoperative pain
|How to cite this article:|
Jyothi B, Govindaraj K, Pratishruthi, Shaikh SI. Comparison of analgesic efficacy of levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine in wound infiltration technique for abdominal surgeries: A prospective randomized controlled study. Indian J Pain 2017;31:127-32
|How to cite this URL:|
Jyothi B, Govindaraj K, Pratishruthi, Shaikh SI. Comparison of analgesic efficacy of levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine in wound infiltration technique for abdominal surgeries: A prospective randomized controlled study. Indian J Pain [serial online] 2017 [cited 2019 Sep 15];31:127-32. Available from: http://www.indianjpain.org/text.asp?2017/31/2/127/214115
| Introduction|| |
Pain relief after surgery continues to be a major medical challenge in clinical practice. Acute postoperative pain following abdominal surgeries results in hemodynamic instability, decreased postoperative pulmonary function, delayed recovery, and discharge from hospital., Modern anesthesia has advanced, at which all patients can be guaranteed a pain-free intraoperative period. Unfortunately, we often fall short when it comes to providing post-operative pain relief. Various modalities of providing postoperative analgesia are being used such as intravenous (IV) nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids, epidural analgesia, regional nerve blocks, and also wound infiltration techniques.
Wound infiltration with local anesthetics is a simple concept for providing effective postoperative analgesia for a variety of surgical procedures without any major side effects. As significant proportion of surgical pain originates from the surgical wound, it is meaningful or effective to use local anesthetics at the site of surgery to manage perioperative pain. Wound infiltration technique acts by blocking the transmission of pain from nociceptive afferents directly from the wound surface and also decreases the local inflammatory response to injury.
A single shot wound infiltration with long acting local anesthetics provides analgesia for 4–8 h. Various adjuvants when added with local anesthetics such as opioids, nonopioids, vasoconstrictors, N-methyl D-aspartate antagonists, alpha 2 agonists, and neostigmine can prolong postoperative analgesic effect. Alpha 2 adrenergic agonists (clonidine [C] and dexmedetomidine [D]) have both analgesic and sedative properties, lacking respiratory depression.,, Clonidine is a centrally acting partial alpha adrenergic agonist with selectivity to alpha 2:alpha 1 = 220:1., Dexmedetomidine, a potent alpha 2 agonist, is eight times more specific for alpha 2 receptors than clonidine with alpha 2:alpha 1 selectivity ratio of 1620:1.,, The peripheral analgesic effects of alpha 2 adrenergic agonists potentiates the action of local anesthetics, which is mediated by binding to alpha 2A-adrenergic receptor. A study has established that the dose of clonidine is 1.5–2 times higher than the dose of dexmedetomidine; however, there is a paucity of studies comparing the dose equivalence of clonidine and dexmedetomidine.
Based on this, we conducted a study to evaluate the postoperative analgesic effect of levobupivacaine (L) alone and in combination with alpha 2 adrenergic agonists (clonidine or dexmedetomidine) as an adjunct in single shot wound infiltration technique for the patients undergoing abdominal surgeries under general anesthesia. Our primary aim was to determine the duration of analgesia and the secondary aim was to evaluate rescue analgesic requirement, quality of analgesia, and side effects of adjuvants used.
| Materials and Methods|| |
A prospective, double-blind, randomized clinical study was conducted for 1 year (January 2015–December 2015) on 90 patients scheduled for abdominal surgeries under general anesthesia. The approval of our institutional ethical committee was obtained REF/2017/02/013548. Patients with physical status American Society of Anesthesiologists (ASA) Grade I and II, of either gender aged between 18 and 60 years, with no history of allergy to drugs such as local anesthetics and alpha 2 agonists were included in the study. Patients with morbid obesity, Raynaud's disease, thromboangiitis obliterans, and hepatorenal disease; patients receiving adrenoceptors agonists, antagonists, narcotics, and corticosteroids; the patient who was already having chronic pain and on treatment; and pregnancy were excluded from the study.
All the patients who met the inclusion criteria were evaluated a day before surgery. Basic laboratory investigations were routinely carried out in all patients. Electrocardiogram (ECG) was done for the patients aged above 40 years and chest radiograph was obtained if indicated. The entire procedure of general anesthesia, wound infiltration at the end of the surgery, visual analog scale (VAS) score were explained to the patient and they were also taught to express the degree of pain on the VAS. The patients were asked to notify whenever they experience pain after surgery. A valid informed written consent was taken from the patient. All the patients were instructed to receive tablet diazepam 10 mg and tablet ranitidine 150 mg orally at night before surgery and kept nil per oral 8 h before surgery.
Patients were randomly allocated into one of the three groups by a computer-generated random number table. Each group consists of 30 patients. In the operating room, monitors such as ECG, noninvasive blood pressure (NIBP), pulse oximetry (SPO2), and end-tidal carbon dioxide (EtCO2) were connected. Peripheral 18-gauge IV line was secured. Ringer lactate infusion was started. Injection ranitidine 50 mg and injection ondansetron 4 mg IV were given. The patient was premedicated with IV injection midazolam 0.05 mg/kg, injection glycopyrrolate 0.004 mg/kg, and injection morphine 0.1 mg/kg. The patient was preoxygenated with 100% oxygen for 3 min and induced with injection propofol 2–3 mg/kg IV, intubated using appropriate-sized endotracheal tube, with injection succinylcholine 2 mg/kg IV. Anesthesia was maintained with nitrous oxide: oxygen 5:3, injection propofol infusion at a rate of 100 mcg/kg/min and injection vecuronium 0.1 mg/kg IV. Intraoperatively, ECG, EtCO2, NIBP, SPO2, respiratory rate (RR), and pulse rate (PR) were monitored. This standard general anesthetic technique was used for all patients. The patient and the anesthesia provider were blinded in the study.
In our study, dose selection of clonidine and dexmedetomidine was taken from previous two separate studies using clonidine (3 mcg/kg) and dexmedetomidine (2 mcg/kg) for wound infiltration technique. The anesthetic drug solution was prepared by an anesthesiologist not taking part in the study, using 1 ml solution in an ampoule containing either clonidine 150 mcg (3 mcg/kg) or dexmedetomidine 100 mcg (2 mcg/kg) or 1 ml of 0.9% normal saline mixed with 29 ml of 0.25% levobupivacaine. All the three drugs, namely, levobupivacaine 0.25%, clonidine (150 mcg/ml), and dexmedetomidine (100 mcg/ml), were used from the same manufacturer. All patients received total drug volume of 30 ml [Table 1]. At the end of procedure, operating surgeon was requested to infiltrate the study drug at the wound site. Drug was administered into the following layers – muscles, fascia, subcutaneous tissue, and skin. The incision size was measured using the sterile measuring tape in centimeter. At the end of surgery, patients were reversed with injection neostigmine 0.05 mg/kg and injection glycopyrrolate 0.01 mg/kg IV and extubated on meeting the standard criteria of extubation. The following parameters were noted by a third anesthesiologist unaware of the prepared drug solution.
The postoperative analgesic effect of each patient was assessed at the time of arrival to postanesthesia care unit (PACU) and then at 30 min and 1, 2, 4, 6, and 24 h after surgery using VAS score (0–10). Postoperative rescue analgesia was given with injection tramadol 100 mg IV boluses on demand or whenever VAS score ≥4 over a period of 24 h. The assessment of analgesia was done using 10 cm VAS score with 0 = no pain and 10 = maximum pain [Figure 1].
Number of patients requiring rescue analgesia during the first 24 h after surgery was recorded. PR, NIBP, and RR were recorded at baseline and then intraoperatively and postoperatively at PACU arrival and then at 30 min, 1, 2, 4, and 6 h. Other side effects such as sedation, nausea, and vomiting of each patient were also assessed postoperatively. Injection mephentermine 6 mg IV and injection atropine 40 mcg/kg IV bolus were made readily available to manage episodes of hypotension (<20% from the baseline or mean arterial pressure <60 mmHg) and bradycardia (heart rate of <40 beats/min), respectively, during intraoperative and postoperative period.
Incidence and severity of nausea and vomiting were assessed by a four-point categorical scale  which includes 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Injection ondansetron 4 mg IV was given for severe nausea or vomiting. Sedation was assessed using four-point sedation scale  (ranging 0–3) which includes 0 = awake and oriented, 1 = drowsy but responding to command, 2 = sleepy but easy to arouse (by loud command or glabellar tap), and 3 = deep sleep (difficult to arouse).
At the end of the study, the patients were asked about the effectiveness of wound infiltration technique in relieving pain. Depending on the subjective response, quality of analgesia  was assessed, noted, and compared [Table 2]. All the observations and particulars of each patient were recorded in a pro forma and the patient belonging to the study group was disclosed after 24 h postoperatively.
Sample size calculated on the basis of a pilot study done in all three groups of patients with the difference in total duration of analgesia of 4 h in levobupivacaine + clonidine (LC) and levobupivacaine + dexmedetomidine (LD) groups compared to the control group (L) using power of study 80%, confidence interval 95%, and alpha error of 0.05. The statistical analysis of data was done by using International Business Machine Statistical Package for the Social Science evaluation version 20.0 (Armonk, NY, USA). Results were expressed as mean and standard deviation. Frequencies were expressed as a number and percentage. One-way analysis of variance and Kruskal–Wallis test were used for multiple-group comparison and categorical data were analyzed by Chi-square test. P < 0.05 was considered significant and P < 0.0001 as highly significant.
| Results|| |
The characteristics of the three groups were comparable in terms of age, height, weight, ASA classification, gender, and types of surgery [Table 3]. The mean PR at different time points showed statistically no significant difference among the three groups [Figure 2]. Intraoperatively, there was statistically significant fall in systolic blood pressure (SBP) in L group compared to the LC and LD groups but clinically insignificant and did not require vasopressors. It is unrelated to the study as the drug was administered at the end of the wound closure. Postoperatively, at 1st and 6th h, there was statistically significant fall in SBP and diastolic blood pressure in both LC and LD groups, when compared to control L group, but it was clinically insignificant [Figure 3] and [Figure 4].
|Figure 2: Comparison of pulse rate at various time points in levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine groups|
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|Figure 3: Comparison of systolic blood pressure (mmHg) in levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine groups|
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|Figure 4: Comparison of diastolic blood pressure (mmHg) in levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine groups|
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|Table 3: Comparison of demographic characteristics and type of surgery in levobupivacaine, levobupivacaine plus clonidine and levobupivacaine plus dexmedetomidine groups|
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The total duration of analgesia showed a statistically significant difference in all the three groups, when compared between the groups, with P = 0.0001, which is highly significant. In LD group, the duration of analgesia was 23.4 h when compared to LC group 20.9 h and L group 11.65 h [Figure 5]. All patients in L group (100%) required rescue analgesic when compared to the other two groups, whereas in LC group, 60% (18 patients) and LD group 16.67% (5 patients) required rescue analgesia postoperatively for 24 h [Figure 6]. The three groups did not differ significantly with respect to incision size [Figure 7]. Number of patients who had excellent quality of analgesia in LD group was 73.3% and LC group 46.7%. When compared to adjuvant group (LC and LD), L group had satisfactory analgesia (50%) with statistically significant P < 0.001 [Table 4].
|Figure 5: Comparison of total duration of analgesia in levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine groups postoperatively for 24 h|
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|Figure 6: Comparison of rescue analgesic requirement in levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine groups postoperatively for 24 h|
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|Figure 7: Comparison of incision size (cm) among levobupivacaine, levobupivacaine and clonidine, and levobupivacaine and dexmedetomidine groups|
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|Table 4: Comparison of quality of analgesia in levobupivacaine, levobupivacaine plus clonidine and levobupivacaine plus dexmedetomidine groups|
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Decrease in the RR was seen in the LD group but was clinically insignificant as there was no respiratory depression. In L group, there was no incidence of nausea and vomiting, whereas in LC group and LD groups, nausea was seen in few patients; one patient in LD group received an antiemetic for vomiting. Sedation in LC and LD groups was seen up to 2 h postoperatively (P< 0.0001) with sedation score of 2 compared to L group where it was seen only in 10% of the patients with sedation score of 1 [Table 5].
|Table 5: Comparison of side effects of adjuvants used in levobupivacaine plus clonidine and levobupivacaine plus dexmedetomidine group with levobupivacaine group|
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| Discussion|| |
Postoperative pain relief results in early mobilization of the patient, better hemodynamic stability, oral intake on the 1st postoperative day, and better satisfaction from patient and family. When compared to various modes of providing postoperative analgesia, wound infiltration technique is the older technique with better analgesia and least side effect profile. The goal is to prevent the origin of pain at surgical site and the administration of IV analgesics that produces multiple side effects.
Preincisional infiltration can be planned for shorter duration surgeries that can alter the surgical anatomy and also the duration of analgesia which depends upon the duration of action of local anesthetics. Cnar et al. concluded that there was no significant difference in the parameters between pre- and post-incisional infiltration. Wound infiltration, administered at the end of surgery during wound closure, results in immediate postoperative pain relief that provides the peak action of infiltrated local anesthetics after extubation. It can be either a single shot wound infiltration with local anesthetics and adjuvants or continuous wound infiltration technique for postoperative analgesia. Other modes of analgesia such as IV analgesia with NSAIDs or opioids, which results in opioid side effects and also intraperitoneal instillation of local anesthetics was not proved to be superior to wound infiltration  in providing analgesia. Epidural or continuous spinal analgesia causes disturbances in the hemodynamic parameters. Wound infiltration with local anesthetics not only provides adequate pain control but also reduces the inflammatory responses and catecholamines level secondary to surgery, which also has an added benefit of enhancing wound healing by increasing wound perfusion and oxygenation.
Our study was planned to provide postoperative analgesia in patients undergoing abdominal surgeries with single shot wound infiltration technique. Levobupivacaine has similar analgesic efficacy like bupivacaine with reduced cardiovascular and central nervous system toxicity but more effective than ropivacaine. The incision size in our study ranged between 10 and 18 cm which was comparable among three groups and the volume of drug infiltrated was adequate.
A study conducted by El-labban et al. showed that postoperative abdominal pain and consumption of rescue analgesia were lower in intraincisional group from 30 min till 24 h postoperatively. Ugley et al. concluded in their study that in patients undergoing elective total abdominal hysterectomy, the postoperative VAS score was significantly lower in LD group (P< 0.003). In our study, the total duration of analgesia in LD group was 23.4 h, when compared to LC group 20.9 h and L group 11.65 h (P = 0.0001). Thus, the efficacy of postoperative analgesic duration of levobupivacaine can be doubled by adding the adjuvant clonidine or dexmedetomidine by its additive effect.
The rescue analgesic requirement was high in L group (100%), when compared to adjuvant groups, in which 40% of patients in LC group and 83.33% in LD group did not require rescue analgesia postoperatively for 24 h [Figure 3]. The three groups did not differ significantly with respect to incision size. This shows that levobupivacaine when added to alpha 2 adrenergic agonists prolongs the duration of analgesia and reduces the total analgesic consumption. In our study, excellent to good quality of analgesia was seen in maximum number of patients in LD and LC groups compared to L group (P< 0.001).
A study by Elliott et al. showed bradycardia occurring in one patient in clonidine and bupivacaine infiltration group compared to control group, whereas in our study there was no episode of bradycardia or hypotension in the adjuvant group. A study conducted by Bharti et al. showed that the sedation scores were significantly higher postoperatively in the IV clonidine group when compared to the infiltration group. Similarly, in a study conducted by Abdel-Ghaffer and Abdel-Haleem, the sedation scores were significantly higher in the IV dexmedetomidine group when compared to infiltration group. However, in our study, sedation score of 2 was seen postoperatively for 2 h in LC and LD groups when compared to L group.
The studies conducted by Bharti et al. and Mandal et al. showed nausea and vomiting occurred in control as well as study group, but in our study, none of the patients in control group had nausea and vomiting, only in LC and LD groups, few patients had nausea and one patient in LD group received an antiemetic for vomiting.
Our study had some limitations, the surgeon's acceptance for general anesthesia in case of lower abdominal surgeries was less and hence the selection of same type of surgery was not possible in our study. Furthermore, in abdominal surgeries involving manipulation of visceral structures, a single shot wound infiltration alone may not be sufficient in providing postoperative analgesia. We suggest further studies on this topic in elderly patients where regional or neuraxial analgesia is difficult or not possible, postoperative analgesia can be provided with long acting local anesthetics by wound infiltration technique. In addition, further studies are required to compare these two alpha 2 adrenergic agonists (clonidine and dexmedetomidine) for wound infiltration technique.
| Conclusion|| |
Appropriate use of wound infiltration technique results in better patient satisfaction and outcome. Both clonidine and dexmedetomidine are effective adjuvants to levobupivacaine for wound infiltration analgesic technique in patients undergoing abdominal surgeries. However, levobupivacaine and dexmedetomidine combination resulted in enhancement of postoperative analgesia and excellent to good quality of analgesia with minimal side effect profile.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]