Intraperitoneal Levobupivacaine with or without Clonidine for Pain Relief after Laparoscopic Cholecystectomy: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Irrigation of local anesthetic intraperitoneally in combination with opioids and non-opioids agents has been used to provide pain relief with varying success in laparoscopic surgeries. This randomized double blind placebo controlled study is designed to study the effect of intraperitoneal instillation of levo-bupivacaine along with clonidine for pain relief after laparascopic cholecystectomy.
METHODS: 75 patients were randomized to receive 20 ml of 0.9% normal saline as placebo (group I), 20 ml of 0.5% levo bupivacaine (group II) and 20 ml of 0.5% levo bupivacaine with 1mcg/kg clonidine (group III) intraperitoneally. The degree of postoperative pain was assessed using the VAS and VRS on the immediate arrival in the recovery room after surgery and thereafter at 2, 4, 8, 12 and 24 hours, postoperatively. Statistical analysis was performed with ANOVA, the Kruskal-Wallis test followed by the Wilcoxon matched pairs rank test was used and P < 0.05 were considered significant.
RESULTS: VAS was maximum in placebo (group I) than in levobupivacaine alone (group II) and was minimum in levobupivacaine with clonidine (group III) at all time intervals. The difference between group I and II is statistically significant at immediate and at 2 hours postoperatively but no difference were found between group I and II after 2 hour. However, there is statistically significant difference (P < 0.05) between group I and III and group II and III at all time intervals.
CONCLUSION: Intraperitoneal instillation of levobupivacaine along with clonidine in a dose of 1mcg/kg is superior to levobupivacaine alone without having any significant adverse effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Pain after laparoscopic cholecystectomy is a common complaint that prolongs the duration of hospital stay and thus increases morbidity.[1] This is especially concerning for centers which are performing laparoscopic cholecystectomy as a day care procedure. Postoperative visceral and shoulder pain occurring after laparoscopic cholecystectomy results from peritoneal and diaphragmatic stretching and irritation of nerves, changes in intra-abdominal pH, release of inflammatory mediators, and retention of the insufflated gas in the abdominal cavity.[2]

Irrigation of local anesthetic intraperitoneally in combination with opioids and nonopioids agents has been used to provide pain relief with varying success.[34] Many studies have used levobupivacaine by the various routes and various strengths to decrease postoperative pain in laparoscopic surgeries.[56]

Clonidine is a centrally acting sympatholytic that diminishes catecholamine's level and hence stabilizes blood pressure. Another novel property of clonidine is its analgesic property as well as augmenting the effect and duration of local anesthetic when added with them.[7] However, no significant work has been done to assess pain relief after adding clonidine to the local anesthetic.

Hence, we decided to plan a novel study to assess the dose efficacy and any side effects of adding clonidine to levobupivacaine for pain relief after laparoscopic cholecystectomy.

This randomized, double-blind, placebo-controlled study is designed to study the effect of intraperitoneal instillation of levobupivacaine along with clonidine for pain relief after laparoscopic cholecystectomy. Pain relief is assessed in respect to severity, duration of pain control and requirement of postoperative analgesia. Secondarily, the frequency of nausea and vomiting, cardiovascular stability in the postoperative period as well as any other side effects of clonidine or levobupivacaine was also assessed.

METHODS

We started this randomized, double-blind study after getting approval from the Ethical Committee of Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun. After getting explained and written consent, we enrolled 75 adult patients aged 18–60 years of either sex belonging to American Society of Anesthesiologists physical status of I-III, scheduled for laparoscopic cholecystectomy.

Patient having a diagnosis of acute pancreatitis, or having any chronic pain syndrome, history of allergy to drug used in this study, moderate to severe hepatic or renal impairment, history of addiction to alcohol, tranquilizers, opioids or chronic nonsteroidal anti-inflammatory drug users, any cognitive impairment or pregnant or lactating mother were excluded from this study.

Laparoscopy was done by standard four port surgical technique and pneumoperitoneum was created with nonhumidified carbon dioxide (CO2) at an intraabdominal pressure between 12 and 14 mm Hg. Patients were premedicated with midazolam 1–2 mg 30 min before surgery and was induced with propofol 2–3 mg/kg, fentanyl 2 µg/kg, and rocuronium 1 mg/kg for endotracheal intubation. Anesthesia was maintained with 60:40 N2O: O2, propofol at 4–6 mg/kg/h and fentanyl bolus of 1–2 µg/kg to maintain mean arterial pressure (MAP) and heart rate within 20% of baseline. Rocuronium 0.2 mg/kg was given at regular intervals to maintain train of four (TOF) count of 1–2. An orogastric tube and nasopharyngeal temperature probe were placed and ended tidal CO2 was maintained between 30 and 35 mm Hg. The CO2 was carefully evacuated at the end of surgery by manual compression of the abdomen with open trocars. All patients received ondansetron 4 mg and acetaminophen 15 mg/kg intravenous (IV) by infusion and thereafter every 6 hourly for 24 h and as per need in next 24 h, i.e., the 2nd postoperative day. Residual muscle paralysis was reversed with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg, and patient extubated when TOF criteria were achieved.

Before induction of anesthesia, the patients were instructed how to use a visual analog scale (VAS) and verbal rating scale (VRS). The degree of postoperative pain was assessed using the VAS and VRS on the immediate arrival in the recovery room after surgery and thereafter at 2, 4, 8, 12, and 24 h, postoperatively. If the patients had VAS >−40, the nursing staff administered a bolus of 75 mg diclofenac sodium IV in 100 ml normal saline over 15 min. Time to first analgesic requirement, total analgesic requirement in the first 24 h postoperatively and occurrence of adverse events was also recorded.

After the dissection of the gall bladder and before deflation of pneumoperitoneum, the patients were randomized into one of the groups using a computer-generated table of random numbers.

Group I patients received 20 ml of 0.9% normal saline as placebo, Group II patients received 20 ml of 0.5% levobupivacaine, and Group III patients received 20 ml of 0.5% levobupivacaine with 1 µg/kg clonidine intraperitoneally at gall bladder bed and under the domes of diaphragm.

After ascertaining patient eligibility, the solution was prepared by an assistant who had not participated in the study. Surgeon and the anesthetist in the postanesthesia care unit were unaware of the treatment to which each patient was randomized.

Data were collected by assistants who were not aware of group allocation for baseline patient's characteristic, intraoperative vitals and opioids use, duration, and difficulty of surgery. In the postoperative period, VAS and VRS at different time intervals were recorded. Analgesic requirement in the postoperative period and any adverse events were also recorded till 48 h after surgery.

Patients were discharged after 48 h after fulfilling the standardized discharge criteria.

Statistical analysis

We decided that a clinically relevant treatment should reduce the incidence of severe or moderate overall pain to 0% (minimal relevant difference = 30%) with type I error of 0.05 and a type II error of 0.2, the necessary sample size would be 21 patients in each group. To increase the power of this study, we had recruited 25 patients in each group. Statistical analysis was performed with ANOVA and P < 0.05 was considered statistically significant. Data are being presented as mean ± standard deviation, proportion or n (%). The analysis of variance and Chi-square test were used to check that the study groups were matched in terms of demographic data. The Chi-square or Fisher's exact tests were used to compare the adverse events. For some of the relevant variables (heart rate, blood pressure, respiratory rate), a repeated-measures analysis of variance test was performed. For VAS and VRS, the Kruskal–Wallis test followed by the Wilcoxon matched pairs rank test was used.

RESULTS

We found that there is no significant difference in the baseline patient's characteristics, baseline preoperative variables, and intraoperative requirement of fentanyl and propofol among the three groups [Tables 1 and 2].

Table 1

Patients clinical characteristic

Table 2

Anesthetic drug consumption

The intensity of pain as measured by VAS and VRS were shown in Figures 1 and 2. The pain was most severe in intensity at the immediate postoperative period and in the next 2 h after the operation, but thereafter it decreases in intensity among all the three groups. Furthermore, VAS was maximum in Group I than in Group II and was minimum in Group III at all time intervals. The difference between Groups I and II is statistically significant at immediate and at 2 h postoperatively, but no difference was found between Groups I and II after 2 h. However, there is statistically significant difference (P < 0.05) between Groups I and III and Groups II and III at all time intervals.

Figure 1

VAS scores at immediate postoperative period, at 2,4,8,12 and 24 hours.

Figure 2

VRS at different time intervals.

Similarly, VRS was maximum in Group I than in Group II and was minimum in Group III. The difference is statistically significant between Groups I and II and Groups I and III at all time intervals, while it is significant between Groups II and III at immediate postoperative period only.

Time to first supplemental analgesic requirement was maximum in Group III than in Group II and was minimum in Group I and the difference is statistically significant (P < 0.01) among Groups I and II, Groups II and III and Groups I and III. Furthermore, the total analgesic consumption was maximum in Group I (mean, 130) than in Group II (mean, 74) and was minimum in Group III (mean 60) and this difference is statistically significant (P < 0.01) among all the three groups.

Emetic symptoms were similar in all the groups. The incidence of hypotension and bradycardia was maximal in Group III (8%), but it is statistically nonsignificant. Shoulder pain was maximum in Group I than in Groups II and III, but the difference is again statistically nonsignificant.

DISCUSSION

In this study, we evaluated the effect of adding clonidine to levobupivacaine for intraperitoneal instillation at the end of gallbladder dissection under the two dome of diaphragm and gall bladder bed for postoperative pain relief, pain was assessed using VAS and VRS score for shoulder tip pain, pain at port site, and deep pain on coughing and/or at rest.

The main conclusion we draw is that intraperitoneal levobupivacaine produces postoperative analgesia better than intraperitoneal placebo and combining clonidine in a dose of 1 µg/kg significantly increases the duration of analgesia without having any significant adverse events.

Various adjuvants including opioids were added in the past to augment the efficacy of local anesthetic instillation intraperitoneally,[8] but no studies were conducted with clonidine added intraperitoneally. In this study, clonidine was given intraperitoneally at the end of surgery and besides prolonging duration of analgesia it also suppresses blood pressure and decreases heart rate as compared to the group which received placebo and levobupivacaine alone. Although at no time there was the incidence of bradycardia, hypotension, and sedation.

Time to unassisted mobilization and thus patient discharge were not prolonged in any of the group. Even patients in Group III were found to be more comfortable when they start ambulating on day 2. There were no signs of levobupivacaine toxicity noted at 0.5% concentration of 20 ml drug.[9]

Previous studies have shown variable results with local anesthetic use in peritoneum due to various methods of introduction such as nebulization[10] versus instillation, timing[11] (preoperatively or postoperatively), and site of instillation (subdiaphragmatic or subhepatic). Use of humidified CO2 for pneumoperitoneum creation, setting the low intraabdominal pressure in pneumoperitoneum, concomitant port site infiltration, concentration and volume of levobupivacaine and differences in perioperative analgesic regimen are some of the important factors that are also important to attenuate the pain in the postoperative period.

Memis et al.[12] added clonidine 1 µg/kg or tramadol 100 mg to intraperitoneal bupivacaine for pain relief in abdominal hysterectomy to evaluate its effect on postoperative analgesia. They found that there was a significant reduction in postoperative analgesic requirement especially in an early postoperative period when tramadol and clonidine were added to bupivacaine though there were no significant differences between tramadol and clonidine.

Shukla et al.[13] added dexmedetomidine or tramadol to intraperitoneal bupivacaine 0.25% in elective laparoscopic cholecystectomy with the better analgesic result in respect to VAS score over 24 h and overall analgesic requirement. This finding collaborated with this study also where VAS score was significantly lower up to 24 h in the Group II and Group III.

Various studies have given clonidine or magnesium in a dose of 0.5–1 µg/kg in premedication orally, intramuscularly as well as intravenously to suppress the hemodynamic changes seen with pneumoperitoneum.[14] We have given clonidine intraperitoneally at the end of surgery in a dose of 1 µg/kg and found that significant reduction was noted in heart rate and MAP in the Groups II and III in the postoperative period when compared to placebo. This may require further studies to strengthen this finding. This may be due to sympatholytic effect of clonidine though the adverse events in the form of bradycardia were not noted in any of the patient.

CONCLUSION

Hence, we conclude that intraperitoneal instillation of local anesthetic is an easy, cheap, and noninvasive method which provides good analgesia in the immediate postoperative period after laparoscopic surgery. Intraperitoneal levobupivacaine produces postoperative analgesia better than what was obtained with intraperitoneal placebo. The combination of intraperitoneal levobupivacaine and clonidine is superior to the plain levobupivacaine for the relief of postoperative pain in patients undergoing laparoscopic cholecystectomy without any significant increase in adverse events. There has been no study in the past on the addition of clonidine to intraperitoneal levobupivacaine for pain relief after laparoscopic surgeries. Hence, we recommend further studies with different doses of clonidine, timing and root of administration with different concentration of intraperitoneal local anesthetic, which could provide the maximal benefit in terms of postoperative pain relief and hemodynamic stability after laparoscopic surgeries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.