Post-operative Analgesia with Intraperitoneal Bupivacaine Alone and with Dexmedetomidine Following Laparoscopic Cholecystectomy

By Anees Ahmad¹, Ambreen Khan², Syed Shakeel Ahmed³, Saima Noreen¹, Mohammad Idrees¹, Shahryar⁴

Doi: https://doi.org/10.36283/ziun-pjmd14-1/007

How to cite: Ahmad A, Khan A, Ahmed SS, Noreen S, Idrees M, Shahryar Post-Operative Analgesia with Intraperitoneal Bupivacaine Alone and with Dexmedetomidine Following Laparoscopic Cholecystectomy. Pak J Med Dent. 2025 Jan ;14(1): 39-46. Doi: https://doi.org/10.36283/ziun-pjmd14-1/007.

Received: Tue, September 03, 2024 Accepted: Wed, December 11, 2024 Published: Fri, January 10, 2025

Background: Laparoscopic cholecystectomy (LC) is a customary treatment for patients with symptomatic cholelithiasis. This study aimed to compare the mean duration of analgesia (DOA) of intraperitoneal bupivacaine (BPV) with dexmedetomidine (DEX) to intraperitoneal BPV alone in patients undergoing LC.

Methods: This randomized controlled trial was done at the Department of Anesthesiology, Bahawalpur Victoria Hospital, Bahawalpur, Pakistan, from October 2023 to March 2024. A simple random sampling technique was adopted. A total of 68 cases undergoing LC were enrolled and randomly allocated to either Group-B (n=34) who received intraperitoneal BPV 50 ml 0.25%+5 ml normal saline and Group-BD (n=34) who were served intraperitoneal BPV 50 ml 0.25%+ DEX 1 μg/kg with normal saline 5 ml. The postoperative pain intensity for both groups was recorded and compared using a 10-point visual analogue score (VAS) at 0, 30 minutes, 1 hour, 2, 4, 6, 8, 12, and 24 hours. Independent sample t-test and chi-square test were used to compare data between groups taking p<0.05 as significant.

Results: The mean DOA in the patients in group B was 4.42±3.95 hours, and in group BD, it was 7.63±2.65 hours (p=0.0002). It was noted that pain scores were significantly low in Group BD at 1 hour (2.63±0.53 vs. 2.26±0.64, p=0.0116), 2 hours (2.81±0.56 vs. 2.43±0.73, p=0.0188), 4-hours (3.70±0.73 vs. 3.32±0.52, p=0.0160), and 6-hours (3.93±0.48 vs. 3.50±0.46, p=0.0003). BD group offered a significantly longer DOA (p=0.0002), an extended spell for rescue analgesia (p=0.0001), and a lesser dose of diclofenac (p=0.0137).

Conclusion: Intraperitoneal instillation of DEX 1 μg/kg with local anesthetic 0.25% BPV 50 ml at the end of surgery in patients undergoing LC significantly reduced the postoperative pain, especially up to six hours postoperatively.

Trial Registration:

#NCT06560892 at https://clinicaltrials.gov/study/NCT06560892?term=NCT06560892&rank=1

Keywords: Bupivacaine, Cholecystectomy, Dexmedetomidine, Intraperitoneal Instillation, Laparoscopy.

Presently, laparoscopic cholecystectomy (LC) is a relatively popular procedure that has taken the place of open cholecystectomy in the treatment of cholilithiasis. This is because open surgery increases the risk of infection for the patient. LC causes less postoperative pain, less hemorrhage, better cosmetic results, a shorter recovery time, and lower morbidity and mortality than conventional open cholecystectomy, resulting in a reduced stay in the hospital and less expense¹. The word pain is derived from the word “Poena”, which means punishment or penalty. After LC, two components are involved in pain. The 1^st is the visceral component because of anterior abdominal wall tissue damage while inserting trocar by surgeons, and the second is the complaint of shoulder tip pain in around 50% of patients because of irritation of the diaphragm produced by spilling of blood or bile and elongation of the peritoneum triggered by pneumoperitoneum^2,3.

Despite intensely increased scientific evidence, management of clinical pain after surgery is still needed. Many patients experience acute pain after surgery and some experience chronic pain. Poor postoperative pain management results in adverse events such as psychological trauma and functional limitations⁴. Improvement in post-operative pain is an important issue in clinical settings due to the increasing role of ambulatory surgery⁵. Postoperative pain control is very important for patients to start their normal activities. Generally, opioid analgesics are given as perioperative analgesia, but their extensive use causes a range of side effects, such as nausea and vomiting. Furthermore, traditional methods of administering intramuscular opioids may result in side effects or insufficient analgesia. As a result, surgeons and anesthesiologists are gradually moving to alternative techniques as adjuvants for pain management⁶. Local anesthetics are used as adjuvants for postoperative pain control. In several interventional studies in LC, intraperitoneal instillation of local anesthetic in combination with general anesthesia was explored. About half of the studies showed a decrease in post-operative pain. Despite its advantages, it also has drawbacks like post-operative pain. Normally, pain arises on the 1^st day after surgery, and this pain may be shoulder, parietal, or visceral⁷. Bupivacaine (BPV) is a recommended local anesthetic in anesthesia, and it is widely used in medical practice to treat acute and chronic pain⁸. Dexmedetomidine (DEX) is a commonly used anesthetic agent as it gives analgesia with little respiratory depression as well as a calming effect that resembles natural sleep⁹. Considering all this we planned this study to compare intraperitoneal BPV with DEX to intraperitoneal BPV alone in patients undergoing LC.

This randomized control trial (RTC) was carried out at “The Department of Anesthesiology”, Bahawal Victoria Hospital, Bahawalpur, Pakistan, from October 2023 to March 2024. Approval from “Institutional Ethical Committee” was required before the commencement of this research (Letter Number: 377/DME/QAMC Bahawalpur, Dated: 21-07-2020). With a confidence interval of 95% and 95% power of the study, while taking the mean duration of analgesia (DOA) in patients undergoing LC with BPV alone vs BPV plus DEX to be 5.81±0.71 hours vs 7.61±0.56 hours, respectively, the minimum required sample size was calculated to be 26 (13 in each group).¹⁰ We considered 68 (34 in the group) patients in this study adopting a simple random sampling technique. This clinical trial was registered #NCT06560892www.clinicaltrials.govhttps://clinicaltrials.gov/study/NCT06560892?term=NCT06560892&rank=1. Patients of either gender, aged 20-70 years, having “American Society of Anesthesiologists (ASA)” classification status I and II, and undergoing LC under general anesthesia were enrolled. The exclusion criteria were patients who were sensitive to local anesthetics and those having acute cholecystitis, choledocholithiasis, or ascending cholangitis (temperature≥38.6°C, serum bilirubin≥1.2mg/dl, and ultrasound showing common bile duct diameter of ≥1cm). Patients with uncontrolled diabetes (FBS≥110 mg/dl), uncontrolled blood pressure (SBP≥140 mmHg), ischemic heart disease (EF≤40%), and pulmonary dysfunction (FEV≤70 percent of normal) were also excluded from the study. Details of the study regarding objective, safety, and secrecy were shared with all of the patients/caregivers to obtain consent (informed and written) from them.

Demographic data and detailed patient history were collected. Patients were randomly assigned to study groups. In Group B, patients received an intraperitoneal injection of 50 ml of 0.25% BPV combined with 5 ml of normal saline. In Group DB, patients were administered an intraperitoneal injection of 50 ml of 0.25% BPV combined with 1 μg/kg of DEX and 5 ml of normal saline. All patients were confirmed to be nil per os. Pre-medication included 10 mg of oral diazepam and 150 mg of oral ranitidine, administered at 10:00 pm the night before surgery and again at 7:00 am on the day of the surgery. No premedication was given before transport to the operating room. Upon arrival, an 18-gauge IV catheter was placed, and intraoperative fluid infusion was set at 6 ml/kg/h of crystalloid. LC was performed on patients presenting with right upper quadrant pain lasting ≥6 weeks and ultrasound-confirmed cholelithiasis (gallstones visible as echogenic shadows), under general anesthesia in a reverse Trendelenburg position, using four conventional ports spaced 5 cm apart. Following general anesthesia, orotracheal intubation was performed with a cuffed orotracheal tube of suitable size, lubricated with 2% lidocaine jelly. During the laparoscopy, intra-abdominal pressure was kept at 12-14 mmHg. At the end of the procedure, CO2 was carefully evacuated manually from the abdomen through an open trocar. BPV alone or combined with DEX was administered intraperitoneally in the Trendelenburg position, into the hepato-diaphragmatic space, on the gallbladder bed, and around the hepatoduodenal ligament before the trocar was removed. For additional analgesia, xylocaine 0.5% was injected at the port sites. Neuromuscular blockade was reversed with “neostigmine (0.05 mg/kg)” and “glycopyrrolate (0.01 mg/kg)”, and the trachea was extubated. The patients were transferred to the “post-anesthesia care unit (PACU)” for 2 hours.

The intensity of pain was assessed using 10 points of the “Visual Analog Scale (VAS)” at baseline, 30 minutes, 1, 2, 4, 6, 12, and 24 hours after surgery by an observer who was unaware of the solution instilled. The DOA for each patient was calculated. It was defined as the time in minutes starting after the dressing of the patient in the operation room until the patient had a VAS≥3. Injection diclofenac sodium (1.5 mg/kg IM) was given as rescue analgesia. In the case of a VAS≥3, a tramadol 2 mg/kg IV injection was given for analgesia. In all cases, general anesthesia was given by the same consultant from the anesthesia department. The same surgical team, including the candidate, performed all surgeries to eliminate bias.

Data were entered in “IBM-SPSS Statistics version 26.0”. The qualitative data, like gender and ASA physical status, were determined by using frequencies and percentages. For quantitative data, which included age, duration of surgery, DOA, and pain score, mean and standard deviation (SD) were calculated. Independent sample t-test and chi-square test were used to compare data between groups taking p<0.05 as significant.

In a total of 68 patients, 51 (75.0%) were male. The mean age was 40.25±9.82 years. There were 37 (54.4%) patients who were ASA classification status I. The mean age of the patients in group B was 41.70±10.51 years, and in group BD, it was 38.7±9.53, with an overall age range of 20-70 years. Male and female contributions in group B were 26 (76.5%) and 8 (23.5%), respectively. Whereas there were 25 (73.5%) male and 9 (26.5%) female patients in group BD. In group B, 16 (47.1%) patients, and in group BD, 21 (61.8%) were of ASA-I. Whereas, 18 (52.9%) patients in group B and 13 (38.2%) in group BD were of ASA-II status in Table 1.

Table -1: Demographic Representation of Patients (N=68)

Group-B: Intraperitoneal bupivacaine; Group-BD: Intraperitoneal bupivacaine+ dexmedetomidine; ASA: American Society of Anesthesiologist

Details about the comparison of baseline laboratory parameters among patients of both study groups are shown in Table 2. It was found that no statistically significant differences were observed in terms of laboratory parameters among patients of both study groups.

Table- 2: Comparison of Baseline Complete Blood Count, Electrolyte Levels, Renal Function Tests, And Liver Function Tests in Both Study Groups (N=68)

The mean DOA in the patients in group B was 4.42±3.95 hours, and in group BD, it was 7.63±2.65 hours (p=0.0002). The mean total dose of analgesics (diclofenac) administered in group B was 80.00±30.36 mg, whereas in group BD, it was 60.00±34.40 mg (p=0.0137). BPV plus DEX offered a significantly longer DOA (p=0.0002), an extended spell for rescue analgesia (p=0.0001), and a lesser dose of diclofenac (p=0.0137). Although, fewer cases of shoulder tip pain were reported in the combination group (14.7% vs. 29.7%, the difference did not reach statistical significance (p=0.1437).

Table 3 shows a comparison of the duration of surgery, DOA, time to rescue analgesia, dose of diclofenac, and shoulder tip pain in both study groups.

Table 3: Comparison of Duration of Surgery, Duration of Analgesia, Time for Rescue Analgesia, Dose of Diclofenac, And Shoulder Tip Pain in Both Study Groups (N=68)

Group-B: Intraperitoneal bupivacaine; Group-BD: Intraperitoneal bupivacaine + dexmedetomidine

It was noted that pain scores were significantly low in Group-BD at 1 hour (2.63±0.53 vs. 2.26±0.64, p=0.0116), 2-hours (2.81±0.56 vs. 2.43±0.73, p=0.0188), 4-hours (3.70±0.73 vs. 3.32±0.52, p=0.0160), and 6-hours (3.93±0.48 vs. 3.50±0.46, p=0.0003), as shown in Fig -1.

Figure 1: Comparison of VAS Pain Scores

A comparison of heart rate and systolic and diastolic blood pressure across both study groups at post-surgery intervals is shown in Table 4.

Table-4: Comparison of Heart Rate, Blood Pressure, and Pain on VAS of Patients at Different Intervals of Time (N=68)

Group-B: Intraperitoneal bupivacaine; Group-BD: Intraperitoneal bupivacaine + dexmedetomidine.

In the present study, the mean DOA for the patients who underwent LC in group B was 4.42±3.95 hours, and in group BD, it was 7.63±2.65 hours (p=0.0002). It was also noted that the reduction in VAS scores was significant in the BD group when compared to Group B in the first 6 hours postoperatively. However, the VAS scores concerning 12 and 24 hours in Group B were still relatively high when compared to Group BD. Our results are comparable with the results of Shukla and Bairwa, who compared intraperitoneal BPV alone or combined with DEX in post-LC patients¹¹. The difference in mean VAS was significant in two groups at 8 hours, 12 hours, 16 hours, and 20 hours, with 2.27±0.74, 3.03±0.67, 3.5±0.63, and 4.03±0.72 in group B and 1.7±1.36, 2.1±1.09, 2.6±1.22, and 3.03±1.09 in group BD, respectively. They concluded that intraperitoneal instillation of BPV with DEX is superior to BPV alone which is similar to what we revealed in the present study. In another study, it was also discovered that intra-peritoneal instillation of BPV in combination with DEX provided better postoperative analgesia than BPV or a tramadol and BPV mixture following LC than BPV or a tramadol and BPV mixture¹². Oza et al from India concluded that intraperitoneal instillation of DEX along with BPV significantly prolonged the span of post-surgery analgesia in comparison to BPV alone¹³. The authors also described that there was less need for several rescue analgesia in the combination group.

Our findings stand aligned with what Shankar et al where they showed that intraperitoneal administration of DEX at 1 µg/kg combined with 0.25% BPV in elective LC significantly decreases postoperative pain and reduces the need for analgesics compared to the use of 0.25% BPV alone following LC¹⁴. In a recently published randomized controlled trial, Bhatia et al indicated that 0.25% BPV alone had a shorter duration of action compared to its combination with DEX¹⁵. Administering these drugs intraperitoneally while the laparoscope is still in the abdominal cavity ensures accurate placement, ease of administration, and a favorable safety profile due to direct visualization. The use of BPV combined with DEX for postoperative analgesia shows great promise as part of a multimodal analgesia approach in LC. Narasimham and Rao also revealed similar findings¹⁶. Furthermore, compared the effectiveness of intraperitoneal BPV with or without fentanyl and DEX for postoperative analgesia after laparoscopic surgery¹⁷. The VAS pain score was significantly reduced in the first eight hours of surgery. In patients having LC, they found that intra-peritoneal instillation of BPV in conjunction with DEX considerably decreased postoperative pain ratings when compared to BPV alone. Another study also concluded that adding dexmedetomidine with bupivacaine prolonged the duration of the need for post-surgery analgesia which corroborates well with this study¹⁸. Other studies like Prakash et al, and Shaker et al also reported similar findings^19,20.

Perioperative analgesia has traditionally relied on opioid analgesics; however, extensive use of opioids can lead to several perioperative side effects, including respiratory depression, drowsiness, sedation, postoperative nausea and vomiting, pruritus, urinary retention, ileus, and constipation. These effects can contribute to delayed hospital discharge and decreased patient satisfaction^21-23. To mitigate these issues, the intraperitoneal administration of local anesthetics in conjunction with general anesthesia during LC has emerged as an effective alternative^24,25.

This study has strengths and limitations as well. This study supports previous findings that intraperitoneal local anesthetic instillation is more successful when administered towards the end of an operation rather than at the beginning for patients undergoing LC. The primary benefit of local anesthetics is their lack of narcotic side effects, which can impede healing and hospital discharge. A small sample size and single-center study place were some of the limitations of this research.

This study concluded that intraperitoneal instillation of DEX 1 μg/kg with local anesthetic 0.25% BPV 50 ml at the end of surgery in patients undergoing LC significantly reduced the postoperative pain, especially up to the six hours postoperatively. Hence, the combination of DEX and BPV is superior to BPV alone for intraperitoneal instillation in LC for postoperative analgesia.

The authors are thankful to Muhammad Aamir Latif (RESnTEC) for his assistance in trial registration of this research project at www.clinicaltrials.gov

The permission was obtained from the Institutional Ethics Committee of the Quaid e Azam Medical College / Bahawal Victoria Hospital, Bahawalpur, with letter number 377/DME/QAMC Bahawalpur, dated: 21-07-2020.

The authors have no conflict of interest.

AA: did data collection, drafting, and responsibility for the data’s integrity and AK: designed, conceived the idea, supervised, and proofread, SSA: conceived the idea, did data analysis, critical review, and final review SN: did manuscript editing, data analysis, data interpretation MI: did data collection, manuscript editing, literature review and approved for publication. S: did manuscript editing, proofreading, critical revisions

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