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ORIGINAL ARTICLE
Year : 2022  |  Volume : 11  |  Issue : 2  |  Page : 126-133

A comparative study to evaluate the efficacy of intraperitoneal instillation of 0.25% levobupivacaine with or without clonidine (0.75 μg/kg) for postoperative analgesia in patients undergoing laparoscopic cholecystectomy


Department of Anaesthesiology, J.L.N. Medical College and Hospital, Ajmer, Rajasthan, India

Date of Submission30-Aug-2021
Date of Decision25-Feb-2022
Date of Acceptance23-Mar-2022
Date of Web Publication3-Aug-2022

Correspondence Address:
Dr. Surendra K Sethi
Flat No. 202, Shiv Enclave, Civil Lines, Ajmer, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jdrntruhs.jdrntruhs_119_21

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  Abstract 


Background: In recent years, the use of intraperitoneal instillation of local anesthetics with adjuvants has become popular for postoperative analgesia in laparoscopic cholecystectomy. This study aimed to compare the analgesic efficacy and safety of levobupivacaine alone or with clonidine as an adjuvant given through intraperitoneal instillation in laparoscopic cholecystectomy under general anesthesia.
Material and Methods: In this prospective randomized double-blind study, 100 patients, aged 18–60 years belonging to ASA physical status I or II, were randomly allocated into two groups. Group L (n = 50) received 0.25% levobupivacaine 28 ml + 2 ml normal saline, whereas Group LC (n = 50) received 0.25% levobupivacaine 28 ml + clonidine 0.75 μg/kg (diluted in 2 ml normal saline) as intraperitoneal instillation before removing trocar. The duration of analgesia, pain scores, total number of doses, and amount of rescue analgesic consumed in 24 h, sedation score, hemodynamics, and adverse effects was noted.
Results: Duration of analgesia was significantly prolonged in Group LC (744.10 ± 96.72 min) compared to Group L (525.20 ± 67.91 min) (P < 0.05). Pain scores (VAS) were significantly lower in Group LC (P < 0.05). The total number of doses and amount of rescue analgesic consumption in 24 hours were less in Group LC as compared to Group L (P < 0.05). Sedation, hemodynamics, and side effect profile were comparable in two groups (P > 0.05).
Conclusion: Clonidine (0.75 μg/kg) was found to be a safe and effective adjuvant to 0.25% levobupivacaine for intraperitoneal instillation in laparoscopic cholecystectomy in terms of prolonged postoperative analgesia, lower pain scores, reduced rescue analgesic consumption along with no significant sedation, hemodynamic changes, and adverse effects.

Keywords: Clonidine, duration of analgesia, intraperitoneal instillation, laparoscopic cholecystectomy, levobupivacine, rescue analgesic


How to cite this article:
Jain N, Sethi SK, Soni B, Patodi V, Jain K, Garg DK. A comparative study to evaluate the efficacy of intraperitoneal instillation of 0.25% levobupivacaine with or without clonidine (0.75 μg/kg) for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. J NTR Univ Health Sci 2022;11:126-33

How to cite this URL:
Jain N, Sethi SK, Soni B, Patodi V, Jain K, Garg DK. A comparative study to evaluate the efficacy of intraperitoneal instillation of 0.25% levobupivacaine with or without clonidine (0.75 μg/kg) for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. J NTR Univ Health Sci [serial online] 2022 [cited 2022 Dec 10];11:126-33. Available from: https://www.jdrntruhs.org/text.asp?2022/11/2/126/353213




  Introduction Top


Laparoscopic cholecystectomy is nowadays practiced as a day care procedure, so providing adequate postoperative analgesia is very important in these patients.[1] The origin of postoperative pain after laparoscopic cholecystectomy is multifactorial with different pain components. The different pain mechanisms responsible for it include somatic pain from incisional site, visceral pain due to intra-abdominal trauma caused by gall bladder removal, and referred shoulder pain from diaphragmatic irritation caused by residual CO2 in the peritoneal cavity.[2]

Local anesthetic agents[3] with or without adjuvants like opioids (tramadol, fentanyl, etc.)[4] and alpha-2 agonists (clonidine or dexmedetomidine)[5],[6] have shown to reduce the postoperative pain after laparoscopic cholecystectomy. The main advantage of local anesthetic agents is that they act directly on the tissue where they are applied and have no adverse effects associated with various intravenous opioids like nausea or vomiting, postoperative sedation, gastrointestinal paralysis, and respiratory depression.[7],[8]

The local anesthetic agents inhibit nociception by affecting nerve membrane–associated proteins and by inhibiting the release and action of prostaglandins and other agents that sensitize the nociceptors and contribute to inflammation.[9] Levobupivacaine, a newer local anesthetic,[10] is currently considered as one of the safest, long acting local anesthetic agent in terms of better safety profile or wider safety margin compared with other local anesthetics, such as bupivacaine. Intraperitoneal levobupivacaine has been shown to be effective at reducing pain without developing clinical toxicity.

Clonidine is a mixed alpha-1 and alpha-2 adrenoceptor agonist with a predominant alpha-2 action. Its primary effect is sympatholytic and it reduces peripheral norepinephrine release by stimulation of the prejunctional inhibitory alpha-2 adrenoceptors in the spinal neurons. It has both analgesic and sedative properties.[11] Clonidine as an adjunct to local anesthetics has shown the prolongation of the local anesthetic effect when used intraperitoneally.[1],[12],[13]

Very few studies have evaluated the analgesic effect of intraperitoneal clonidine in laparoscopic procedures.[1],[13] So we hypothesized that intraperitoneal instillation of clonidine (0.75 μg/kg) would enhance the analgesic effect of levobupivacaine along with stable hemodynamics and minimal side effects which should be a desirable property of an adjuvant within recommended dosage range. In the present study, we evaluated the efficacy and safety of intraperitoneal instillation of clonidine (0.75 μg/kg) used as an adjunct to 0.25% levobupivacaine in patients undergoing laparoscopic cholecystectomy in terms of duration of postoperative analgesia as a primary outcome measure while pain scores (visual analogue scale score), total number of doses and amount of rescue analgesic consumption, sedation score, hemodynamic changes, and adverse effects or complications as secondary outcome measures.


  Material and Methods Top


After the approval from institutional ethical committee (979/Acad-III/MCA/2019, dated: 15/05/2019) and written informed consent, this prospective randomized double-blinded study was conducted in a total of 100 patients of either sex, aged between 18 and 60 years belonging to American Society of Anaesthesiologists (ASA) physical status I or II. Patients who refused to participate in the study, patients belonging to ASA PS III and above, with known allergy to the study drugs, pregnant and lactating females, patients with severe cardiac, pulmonary or neurological disease, patients with choledocholithiasis, in whom abdominal drain was put or procedure converted into open cholecystectomy were excluded from this study.

The present study is registered with Clinical Trials Registry-India (CTRI/2020/08/026963) and conducted during August 2020 to February 2021. Among 113 patients who were enrolled for this trial, 13 patients were excluded. Hence, a total of 100 patients were allocated into two groups of 50 each. All these patients finished the study and were available for follow-up and data collection [Figure 1]. Patients were randomly allocated to one of the two groups using computer generated table of random numbers, and allocation concealment was done using a sequentially numbered opaque-sealed envelope technique. Group L (n = 50) received intraperitoneal instillation of 0.25% levobupivacaine 28 ml + 2 ml normal saline (total volume = 30 ml), whereas Group LC (n = 50) received intraperitoneal instillation of 0.25% levobupivacaine 28 ml + clonidine 0.75 μg/kg diluted with 2 ml normal saline (total volume = 30 ml). For the purpose of double blinding, the study drugs were prepared by a resident anesthesiologist who was not involved in the study while another resident anesthesiologist, who observed the patient after the intraperitoneal instillation of study drug, and the patient, both were unaware of the study groups until the completion of the study.
Figure 1: CONSORT flow diagram

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Thorough preoperative evaluation was done according to standard protocol. All patients were shifted to the operating room without any premedication. On arrival to the operating room, an 18-gauge intravenous (IV) cannula was secured and IV fluid (ringer's lactate) was started. A multipara monitor which include electrocardiography (ECG), non-invasive blood pressure (NIBP), and oxygen saturation (SpO2) probe was attached and baseline values of heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and SpO2 were recorded. All patients were premedicated with glycopyrrolate 0.004 mg/kg and tramadol 2 mg/kg IV. Preoxygenation was done with 100% oxygen (O2) for 3 min. General anesthesia was induced with propofol 2.0 mg/kg IV followed by succinylcholine 1.5 mg/kg IV to facilitate orotracheal intubation. Tracheal intubation was done with an appropriately sized cuffed endotracheal tube. Anesthesia was maintained using O2 and air mixture (50:50) with 1–2% sevoflurane. The loading dose of IV vecuronium bromide (0.1 mg/kg) followed by intermittent boluses was used to achieve intraoperative muscle relaxation. EtCO2 was continuously monitored and minute ventilation was adjusted accordingly to maintain normocapnia, i.e., EtCO2 between 35 and 40 mm Hg. A ryle's tube of appropriate size was also inserted. Patients were placed in 15-20° reverse Trendelenburg's position with the left side tilt position. The intra-abdominal pressure was maintained preferably at 10–12 mm Hg after creating pneumoperitonium and during the laparoscopic procedure.

The study solution was given intraperitoneally before removal of trocar in Trendelenburg's position as per group allocation. The equal volumes of study solution, i.e., 10 ml into the hepato-diaphragmatic space, 10 ml on gall bladder bed, and 10 ml near and above hepatoduodenal ligament followed with CO2 evacuation and removal of trocar. The neuromuscular blockade was antagonized with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg, and the trachea was extubated after fulfilling the criteria of extubation. The ryle's tube was removed thereafter, and the patient shifted to post-anesthesia care unit (PACU) for further observation.

The postoperative pain was assessed using 10-point visual analogue scale[14] (VAS) score (Score 0: no pain and Score 10: worst possible pain) at 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours after surgery. Diclofenac sodium aqueous (75 mg IV) was given as rescue analgesic when VAS ≥4 or on patient demand. The duration of postoperative analgesia, i.e., from the time of extubation to the time of first rescue analgesic requirement and total rescue analgesic consumption in terms of number of doses and amount of rescue analgesic consumed in 24 hours postoperative period were also noted.

Sedation was recorded using 6-point Ramsay sedation scale (RSS) score[15] postoperatively. RSS was graded as follows: Score 1—anxious and agitated or restless or both; Score 2—co-operative, oriented, and tranquil; Score 3—responding to commands only; Score 4—brisk response to light glabellar tap or loud auditory stimulus; Score 5—sluggish response to light glabellar tap or loud auditory stimulus; and Score 6—no response to stimulus. The various hemodynamic parameters (HR, SBP, DBP, MAP, and SpO2) were also recorded at 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours postoperatively. Patients were also observed for various side effects or complications postoperatively such as postoperative nausea and vomiting (PONV), bradycardia (fall in HR >20% from baseline value), hypotension (fall in SBP >20% from baseline value), shoulder pain, respiratory depression, excessive sedation (RSS >3), and pruritus up to 24 hours postoperatively. Patients who complained of nausea or vomiting were given ondansetron 4 mg IV. All other complications were managed accordingly.

Statistical analysis

Based on a pilot study on 10 patients, an estimated sample size of 43 patients in each group was required to obtain a significant mean difference (30%) in duration of postoperative analgesia as a primary outcome measure with an alpha error of 0.05 and power of 80% with 95% confidence interval. So, by assuming 10% drop outs (attrition) during follow-up of patients in both groups, 50 patients in each group with a total sample size of 100 patients were calculated for this study. All the numerical data were presented as mean ± standard deviation, whereas the categorical data were presented as numbers or frequency (%). SPSS software version 16.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. Standard qualitative and quantitative tests (paired and unpaired student t-test, Chi-Square test, etc.) were used to compare the data between two groups. Continuous variables were analyzed and compared using an unpaired student t-test, whereas categorical variables were analyzed using Chi-square test. P < 0.05 was considered as statistically significant and P > 0.05 was considered as statistically insignificant.


  Results Top


In the present study, there was no significant difference in the two groups with respect to mean age, sex, and weight and ASA PS classification (P > 0.05) [Table 1].
Table 1: Demographic profile in two groups

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The mean VAS scores were significantly lower in Group LC than in Group L at all time intervals (P < 0.05) [Figure 2]. The mean duration of analgesia was 525.20 ± 67.91 min in Group L with a range of 360 to 620 min, whereas in Group LC, the mean duration of analgesia was 744.10 ± 96.72 min with a range of 510 to 845 min. The difference in the mean duration of analgesia was statistically highly significant (P < 0.0001). The mean total rescue analgesic consumption was less in Group LC (85.50 ± 26.29 mg) as compared to Group L (153 ± 36.99 mg) and was statistically significant (P < 0.05) [Table 2].
Figure 2: Mean pain score (VAS) in two groups

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Table 2: Duration of analgesia and total rescue analgesic consumption in 24 hours

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The total number of doses of rescue analgesic required was less in Group LC as compared to Group L. In Group L, 7 patients (14%) required 3 doses of rescue analgesic, whereas none of the patients required 3 doses of rescue analgesic in Group LC. In Group L, 2 doses were required in 38 patients (76%) and 1 dose in 7 patients (14%). In Group LC, 7 patients (14%) required 2 doses and 43 (86%) patients required only one dose of rescue analgesic. So, the total number of doses of rescue analgesic required was significantly less in Group LC (P < 0.0001) [Table 3].
Table 3: Number of doses of rescue analgesic given in 24 hours

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The mean difference in the hemodynamic parameters (HR, SBP, DBP, MAP, and SpO2) between the two groups was found to be statistically insignificant at various time intervals (P > 0.05) [Figure 3] and [Figure 4].
Figure 3: Mean heart rate (bpm) in two groups

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Figure 4: MAP (mm of Hg) in two groups

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Mean sedation score (RSS) in the postoperative period was found to be less than 2 at all time intervals in both groups. On intergroup comparison, the difference in the RSS between the two groups was observed to be statistically insignificant (P > 0.05) [Figure 5].
Figure 5: Mean sedation score (RSS) in two groups

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Among adverse effects or complications, postoperative nausea and vomiting (PONV) was observed in 4 (8%) patients in Group L as compared to 2 (4%) patients in Group LC. (P > 0.05) Shoulder pain was observed in 4 (8%) patients in Group L, whereas none of patients had shoulder pain in group LC. The two groups were comparable in terms of incidence of adverse effects (P > 0.05). There was no incidence of bradycardia, hypotension, and pruritus in any of the patients in two groups, except PONV and shoulder pain [Table 4].
Table 4: Incidence of adverse effects

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  Discussion Top


In the present study, we evaluated the effect of adding clonidine to levobupivacaine for intraperitoneal instillation[16] after gallbladder dissection for postoperative analgesia in terms of duration of postoperative analgesia, pain assessed by VAS score, total number of doses, and amount of rescue analgesic consumed in 24 hours. The results have showed that addition of clonidine (0.75 μg/kg) significantly increased the duration of postoperative analgesia, which was our primary outcome measure, without having any significant adverse effects.

A dose of 0.5–3.0 μg/kg (150 μg maximum) is the recommended dose of clonidine through various routes. Although clonidine is being used for intraperitoneal instillation in a very few studies where they have used it in a dose of 1 μg/kg. It has been reported that there is significant association of increased doses with hemodynamic alterations such as hypotension and bradycardia. So to avoid any significant hemodynamic changes or side effects, we have chosen a dose less than 1 μg/kg (0.75 μg/kg) which has not been used so far for intraperitoneal instillation.

Our results are in concordance with Jyothi et al.[12] who noted a significantly prolonged duration of analgesia in both Group LC (3 μg/kg clonidine) and Group LD (2 μg/kg dexmedetomidine) when compared with Group L (levobupivacaine alone) in wound infiltration technique for abdominal surgeries. The total duration of analgesia in Group LC and Group L was 20.9 h and 11.65 h, respectively. They observed prolonged duration of analgesia in clonidine group (~1260 min) as compared to our study (~744 min). This significantly prolonged duration of analgesia in clonidine group in their study might be due to a higher dose of clonidine (3 μg/kg) used in their study. The probable mechanism by which clonidine as an adjuvant to local anesthetics enhanced the analgesic effect might be inhibition of transmission of nociceptive stimuli in the dorsal horn of the spinal cord.

Govil et al.[1] compared 0.9% normal saline (Group Ⅰ), 0.5% levobupivacaine (Group ⅠⅠ), and 0.5% levobupivacaine with 1 μg/kg clonidine (Group ⅠⅠⅠ) for intraperitoneal instillation in laparoscopic cholecystectomy. They observed that the mean total rescue analgesic consumption was 130 mg in Group Ⅰ, 74 mg in Group ⅠⅠ, and 60 mg in Group ⅠⅠⅠ which was significantly less in Group ⅠⅠⅠ (clonidine group). These findings suggest that clonidine (1 μg/kg) when added to levobupivacaine given intraperitoneally significantly reduced the rescue analgesic consumption with adequate postoperative analgesia as compared to levobupivacaine alone which concurs with our study and favors the use of clonidine as an adjuvant with levobupivacaine for intraperitoneal instillation in laparoscopic cholecystectomy.

Memis et al.[13] had used intraperitoneal instillation of 0.5% bupivacaine alone or in combination of tramadol (1mg/kg) or clonidine (1 μg/kg) undergoing total abdominal hysterectomy. They found a significantly lower VAS scores in 24 h in Group III which had received clonidine as compared to Group I which had received only bupivacaine. This has shown that patients in the clonidine group required less rescue analgesics with better postoperative analgesia.

Although Govil et al.[1] and Memis et al.[13] did not evaluate the duration of postoperative analgesia as a primary outcome measure but they have shown significantly lower pain scores (VAS) along with less rescue analgesic consumption during early postoperative period which improved the duration of postoperative analgesia after intraperitoneal instillation of clonidine.

There are several factors which can influence the quality of postoperative analgesia such as dose and concentration of both local anesthetic and adjuvant, site of instillation, timing and position during local anesthetic instillation, spillage of blood or bile along with the dose and timing of postoperative rescue analgesia. Thus, on the basis of results obtained, the dose and concentration of levobupivacaine (0.25%) and clonidine (0.75 μg/kg) that has been chosen for intraperitoneal instillation in our study seems to be an optimal dose in terms of improved quality of analgesia with minimal adverse effects or complications, particularly in patients undergoing laparoscopic cholecystectomy.

The mean RSS remained <2 at all-time intervals in both L and LC groups in the postoperative period which showed that patients in both groups remained arousable with no excessive sedation. Similar findings were observed by Govil et al.[1] and Praveena et al.[17]

The hemodynamic parameters remained stable in the postoperative period which could be attributed to the rescue analgesic which was given on demand or whenever VAS ≥4. Hence, there was no significant rise in both heart rate and blood pressure due to pain in any of two groups. Moreover, the clonidine (0.75 μg/kg) used as an adjuvant to levobupivacaine did not lead to bradycardia or hypotension in any of the patients in Group LC, which has justified the chosen dose of clonidine as an adjuvant in terms of hemodynamic stability as well. Govil et al.[1] has also revealed the similar findings in their study.

Among various adverse effects, the shoulder pain was observed in some patients in levobupivacaine group only, but no patient had experienced this in levobupivacaine with clonidine group. The shoulder pain might be due to diaphragmatic stretching induced by pneumoperitoneum followed by referred pain from surgical site. The possible explanation for no incidence of shoulder pain in Group LC could be the nociceptive blockade from the inflamed diaphragm and peritoneum by instillation of levobupivacaine with clonidine. Kucuk et al.[18] reported that shoulder pain is a frequent complication in patients who had not received any adjuvant with local anesthetic, whereas a significantly lower incidence was noted in patients who had received an adjuvant along with a local anesthetic with a favorable adverse effect profile.

As far as limitations of our study are concerned, the pain intensity which was assessed by VAS scores is a subjective experience and thorough objective observation is difficult. The population enrolled was in the age group of 18–60 years which were healthy patients of ASA PS I and II, so the effect of clonidine as an adjuvant in older patients with cardiovascular comorbidities (ASA III or above) is yet to be investigated to prove its safety profile. The total rescue analgesic consumption could be calculated more precisely if the postoperative study period was longer with a larger sample size. Thus, due to scarcity of literature, further studies need to be conducted with different doses of clonidine and a larger sample size to evaluate its efficacy as well as safety profile and to strengthen the evidence regarding its optimal dose and safety profile.


  Conclusion Top


From this study, we concluded that clonidine (0.75 μg/kg) was found to be a safe and effective adjuvant to 0.25% levobupivacaine for intraperitoneal instillation in laparoscopic cholecystectomy as it leads to prolonged postoperative analgesia, lower pain scores, reduced rescue analgesic consumption, and minimal sedation along with no significant hemodynamic changes and adverse effects.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Jyothi B, Govindaraj K, 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.  Back to cited text no. 12
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