INTRODUCTION
Laparoscopic cholecystectomy is the standard of care for symptomatic cholecystitis and cholelithiasis. Despite being a minimally invasive technique, patients can still experience significant pain and discomfort [1,2]. Pain that follows laparoscopic cholecystectomy is complex and consists of several clinical components and etiology. The three main pain components are somatic, visceral, and referred visceral pain (shoulder discomfort after surgery) [3]. The degree and duration of postoperative pain following laparoscopic cholecystectomy vary greatly between patients. Multiple studies have demonstrated that patients frequently experience moderate to severe postoperative pain that is not adequately managed by conventional analgesic regimens [4,5]. This higher-than-expected pain intensity can delay recovery and prolong hospital stays. According to current evidence, pain is most intense on the day of the procedure and decreases subsequently. However, approximately 13% of patients may experience severe discomfort for the entire first week following surgery [3]. Thus, early recovery, minimizing adverse effects induced by opioid intake such as nausea and vomiting, and decreasing hospital stays all depend on effective analgesia [6].
Among the recent opioid-sparing analgesic modalities, the transversus abdominis plane (TAP) block has gained significant popularity. This regional anesthesia technique works by blocking the parietal and incisional components of pain in the anterior abdominal wall. It also has the advantages of decreased opioid consumption, early recovery, and better patient satisfaction in abdominal surgeries especially those done via laparoscopy [7,8].
The subcostal technique for TAP block is particularly effective as it provides analgesia from T6 to T9 dermatomes and hence may effectively cover the epigastric port site [9]. Oksar et al. [10] reported in their study that 85% of patients who undergo laparoscopic cholecystectomy receiving a subcostal TAP block required no additional analgesic postoperatively as compared to only 35% in the control group.
A meta-analysis conducted by Siddiqui et al. [11] concluded that the TAP block was effective in lowering postoperative pain and narcotic usage after laparoscopic cholecystectomy.
In addition, perioperative intravenous lidocaine infusion is a modality that has grown in popularity in recent times. Multiple studies have demonstrated that intravenous lidocaine has been particularly effective at relieving acute postoperative pain and reducing overall opioid demand [12,13]. A meta-analysis of randomized control studies comparing intravenous lidocaine and placebo in patients undergoing laparoscopic cholecystectomy found that visual analog scale (VAS) scores were substantially higher in control arms than in intravenous lidocaine arms at 12, 24, and 48 h [14]. Multiple recent meta-analyses showed that intravenous lidocaine substantially lowered postoperative pain scores, the demand for opioids, and associated adverse effects including attenuation of laparoscopy-induced sympathetic responses and early recovery of bowel function following laparoscopic cholecystectomy [15-17].
While both techniques have demonstrated effectiveness in reducing pain and opioid consumption and are almost equally cost-effective in resource-limited setups, there is limited evidence directly comparing their outcomes. This study aimed to compare intravenous lidocaine infusion with bilateral subcostal TAP block for postoperative analgesia following laparoscopic cholecystectomy and establish the technique with superior outcomes for patients in terms of decreasing postoperative pain, total analgesic consumption, and adverse events.
MATERIALS AND METHODS
This investigation was an open-label, single-center, randomized, controlled trial with a three-group parallel design involving one control and two intervention groups. It was carried out at a University Hospital after obtaining Clinical Trials Unit (CTU # NCT05231941) approval and Institutional Ethics Review Committee (ERC # 2020-5515-14848) approval on 15th November 2020 followed by registration under the ClinicalTrials.gov registry on 9th February 2021. Furthermore, the study was performed according to the Helsinki Declaration of 1975 (revised 2013) and was conducted between February 2022 and November 2022.
Study participants
After obtaining written and informed consent, patients between the ages of 18 and 65 years who were scheduled for an elective laparoscopic cholecystectomy and had American Society of Anesthesiologists I and II status were enrolled for this study. Exclusions from the trial were patients with a history of chronic opioid use, known seizure disorders, or hypersensitivity to study drugs.
Randomization and blinding
A computer-generated random sequence was used to assign the patients to study groups by the clinical trials unit. Blinding was not used in this trial; nevertheless, the pain nurse who collected postoperative data remained unaware of the group allocation. The study drugs were dispensed by the CTU pharmacy and prepared by the primary anesthesiologist who was not involved in the study. TAP block was performed by a single co-investigator with adequate experience to minimize bias. The study recruited 90 patients who were randomly assigned to one of the three groups:
Intervention
1. Lidocaine group
After induction of anesthesia, a bolus of 2 mg/kg intravenous lidocaine (Xyloaid, Barrett Hodgson Pakistan) was given followed by lidocaine infusion at the rate of 1.5 mg/kg/h which was stopped at the end of surgery.
2. TAP group
After completion of the procedure and before extubating, a bilateral ultrasound-guided subcoastal TAP block was performed. After taking aseptic measures with the patient in the supine position, a high frequency (6-13 MHz) linear ultrasound probe (Mindray TE7) was placed obliquely just inferior to the costal margin over the anterior abdominal wall. With the help of a 22G, 100 mm needle, 20 ml of 0.375% ropivacaine (Ropicain, Lahore Chemical and Pharmaceutical Works) was injected between the rectus sheath and fascia of the transversus abdominis muscle, bilaterally, for a total volume of 40 ml.
Anesthesia protocol
General anesthesia was administered similarly to each participant. Patients were preoxygenated for 3 min following American Society of Anesthesiologists routine monitoring (non-invasive blood pressure, electrocardiogram, and pulse oximetry). Propofol (1.5-2.5 mg/kg), nalbuphine (0.1 mg/kg), and cis-atracurium (0.15-0.2 mg/kg) were used to induce general anesthesia. Oral endotracheal intubation with an appropriately sized tube was performed to allow mechanical ventilation with a tidal volume of 6-8 ml/kg. Maintenance was accomplished using isoflurane (1-2%) in an oxygen and air mixture to produce a minimum alveolar concentration of 1.0. All patients received paracetamol (15 mg/kg) 30 min before the surgery was concluded. All patients received dexamethasone (0.1 mg/kg) following induction and ondansetron (0.1 mg/kg) 20 min before completing the procedure to prevent postoperative nausea and vomiting (PONV). Patients either received an intervention as per their assigned group or no intervention in the case of the control group. Glycopyrrolate/neostigmine (0.5 mg/2.5 mg) was used to reverse neuromuscular blockade after the surgery was concluded. Patients were extubated and shifted to recovery where they were assessed on several parameters. For postoperative pain management, each patient received 1 g of intravenous paracetamol every 6 h and 30 mg of intravenous ketorolac every 8 h. If the VAS score was 4 or higher, intravenous tramadol 50 mg was administered as a rescue analgesic.
Outcome assessment
Postoperative assessment and data collection were done upon arrival in the post-anesthesia care unit (PACU) and at 2 h, 4 h, 6 h, 12 h, and 24 h.
1. Primary outcome
The primary outcome was 24 h mean pain score, measured using VAS in the PACU and ward (where 0 means no pain and 10 worst pain imaginable) till 24 h postoperatively at various time intervals (In PACU, and at 2, 4, 6, 12 and 24 h) and averaged to provide a comprehensive measure of pain intensity in the first 24 h.
2. Secondary outcomes
The postoperative rescue analgesic consumption of tramadol was compared in all three groups. Similarly, PONV was evaluated at the same time points using the Bellville Scoring Scale (0: no nausea/vomiting, 1: nausea, 2: nausea with belching, and 3: vomiting). Patient satisfaction after the 24 h period was assessed using the five-point Likert scale (with 1 being strongly disagree and 5 being strongly agree). Any immediate complications like hypotension (blood pressure < 90/60 mmHg), bradycardia (heart rate < 60 min), arrhythmia, and nausea/vomiting were managed by the primary anesthesiologists as per their feasibility. All adverse events including local anesthesia-related adverse events were assessed, reported, and treated intraoperatively by the primary anesthesiologist, in PACU by nurses, and postoperatively till 24 h by the investigators, primary physicians, and nurses.
Sample size calculation
Song et al. [18] reported an average postoperative pain score of 3.67 in the control group on the VAS score as compared to the lidocaine group with an average standard deviation of 0.59. The primary outcome of this trial was the mean pain score. A 20% reduction in 24 h mean pain score in the intervention groups as compared to the control group (which corresponded to a mean pain score of 2.94 in the intervention groups) was considered clinically significant with 1% type I error. The common standard deviation within a group was assumed to be 0.59. Using the above data and one-way analysis of variance (ANOVA) power analysis for three group comparisons, 25 patients in each group were required to reach 90% power to identify the mean pain difference between groups. Accounting for a 20% dropout rate, 30 participants were required in each group to reach statistical significance.
Statistical analysis
Statistical Packages for Social Science version 23 (SPSS Inc.) was used to perform the statistical analysis. The frequency and percentages of categorical variables were calculated. For quantitative variables, mean and standard deviation were calculated. Stratification analysis was performed to control the effect modifiers to observe the outcome in three groups. The normality assumption of the quantitative variables, such as age, pain scores (VAS), nausea and vomiting scores, was tested using the Shapiro-Wilk test. Based on the normality or non-normality assumption, the Kruskal-Wallis test or ANOVA was utilized to evaluate the statistically significant difference among the three groups. To determine pairwise comparison difference, a post-hoc Tukey, or Wilcoxon rank-sum test by adjusting the P value with the Bonferroni method, was applied. A P value < 0.05 was regarded as statistically significant.
RESULTS
One hundred and six patients were evaluated for eligibility, with nine failing to meet the inclusion criteria. Ninety-seven patients were approached to participate in the trial, however, seven more patients were excluded as they did not give consent to participate. Hence, 90 patients were enrolled in the study. Thirty patients each were randomly assigned to the control, lidocaine, and TAP groups. No dropouts or loss to follow-ups were observed in the control or TAP group, however, two patients withdrew consent after randomization and were excluded from the lidocaine arm (Fig. 1).
All three groups were comparable in terms of age, gender, weight, height, body mass index, American Society of Anesthesiologists status, or duration of surgery (Table 1). No adverse drug or intervention-related adverse effects were reported in any of the groups.
Primary outcome
1. 24 h mean pain score
The lidocaine group had significantly reduced 24 h average pain scores as compared to both the TAP block and control groups. The mean difference with 95% confidence interval [CI] between the control and lidocaine group was 2.47 (1.94, 3.00) (P < 0.001) whereas the mean difference with 95% CI between the TAP block and lidocaine group was 1.14 (0.56, 1.72) (P < 0.001). The TAP block group also had a significantly lower 24 h average pain score than the control group 1.33 (0.61, 2.05) (P < 0.001) (Table 2).
2. Pain scores by time interval
The lidocaine group had significantly reduced pain scores on the VAS at all time intervals than the control group (Table 2).
Additionally, at 0, 2, and 4 h, the TAP group's pain scores were considerably lower than those of the control group; however, no differences in VAS were observed between the control and TAP groups at 6, 12 and 24 h, postoperatively (Table 2).
Comparing pain scores in the lidocaine and TAP groups, the lidocaine group had significantly reduced VAS scores after 0, 2, 4, and 6 h. No difference between the two groups was observed at 12 and 24 h following surgery (Table 2).
Secondary outcomes
1. Rescue analgesic consumption
The control and TAP groups consumed considerably more rescue analgesic (tramadol) than the lidocaine group (Fig. 2).
2. Number of rescue analgesic boluses
During our 24 h trial period, no rescue analgesic bolus was administered to any of the patients in the lidocaine group. Conversely, 56.7% of patients in the TAP group and 93.4% of patients in the control group required a single rescue analgesic bolus, whereas, 46.7% and 6.7% of patients required a second bolus in the control and TAP groups, respectively (Fig. 3).
3. PONV
Compared to the TAP block and control groups, patients in the lidocaine group had a significantly reduced proportion of patients with PONV scores on the Bellvile scale ≥1 (Fig. 4).
4. Length of hospital stay
There was no clinically relevant difference in length of hospital stay between the three groups.
5. Patient satisfaction
Compared to the TAP block and control groups, patient satisfaction was substantially greater in the lidocaine group (Fig. 5).
DISCUSSION
This study compared subcostal TAP block and intravenous lidocaine infusion for postoperative pain management, evaluating pain scores, PONV, and rescue analgesic consumption. The outcomes demonstrated that the lidocaine group had considerably lower postoperative mean VAS scores along with lower VAS scores at several intervals, particularly in the early postoperative period (0, 2, 4, 6 h) than the control and TAP block groups. Upon arrival in PACU, the mean pain scores for control, TAP block, and lidocaine groups were 3.83, 1.47, and 0.179, respectively. There was no apparent difference in VAS scores between the TAP block and lidocaine groups at 12 and 24 h, but the lidocaine group had lower VAS values than the control group.
After upper abdominal procedures such as laparoscopic cholecystectomy, TAP block, especially the subcostal approach guided by ultrasonography, effectively blocks sensory impulses to the anterior abdominal wall and provides postoperative analgesia [19,20]. In a randomized controlled trial, Shin et al. [21] reported that the subcostal TAP group had significantly lower verbal numeric rating pain scores than the control group at various time points in the early postoperative period and that the TAP group required less overall opioid than the control group. Additionally, studies by Sahin et al. [22], Petersen et al. [23] and Baral and Poudel [24] found that TAP block decreased pain scores, decreased opioid usage, and reduced the incidence of adverse effects.
Intravenous lidocaine is emerging as an effective technique for pain management following major and minor abdominal procedures due to its analgesic, anti-hyperalgesic, and anti-inflammatory properties [15]. Although the Procedure-Specific Pain Management review update regarding pain management in laparoscopic cholecystectomy does not recommend the use of intravenous lidocaine infusion despite positive results owing to the need for close monitoring and the possibility of overdose [25], nonetheless, numerous meta-analyses have consistently demonstrated that intravenous lidocaine infusion is useful in reducing patients' postoperative discomfort, pain, and narcotic usage after laparoscopic cholecystectomy [15-17]. These studies also reported fewer adverse events in the lidocaine group. A comprehensive meta-analysis of randomized controlled trials comparing intravenous lidocaine and placebo in laparoscopic cholecystectomy found a decrease in VAS scores and opioid consumption at 12, 24, and 48 h postoperatively in the lidocaine group [15]. Furthermore, significant differences in the frequency of postoperative ileus, nausea, and vomiting were noted [15-17].
In the lidocaine group, almost no rescue analgesia was required, and in comparison to the control group, the TAP block group similarly showed a considerable decrease in the amount of postoperative rescue analgesic use. Around 20% of patients in the TAP block group and 56.7% of patients in the control group required rescue analgesic bolus when they first arrived in the PACU (0 h). With the lidocaine group, the pain-free interval (reported as the time to first rescue analgesic use) was substantially longer than TAP block and control groups, lasting up to 24 h. This demonstrates that the lidocaine group had excellent postoperative pain control, significantly reducing the amount of rescue analgesics than the other groups.
At 2 and 4 h postoperatively, the PONV significantly decreased in the lidocaine group (P < 0.05); nevertheless, scores at subsequent intervals were similar and generally at the lower end of the spectrum across all groups. Lidocaine is known to prevent PONV, especially in the early postoperative period attributed to several mechanisms. These include early postoperative gastrointestinal recovery and preventing stasis, reduced opioid consumption as opioids not only contribute to PONV but also reduce gastrointestinal motility and direct antiemetic properties [26,27]. This could also be due to intraoperative dual antiemetic prophylaxis with dexamethasone and ondansetron.
No significant differences in surgery duration or hospital stay were observed. Furthermore, 92.9% of patients in the group treated with lidocaine expressed satisfaction with their pain management, compared to 73.3% in the control group, supporting the superiority of lidocaine for postoperative analgesia and reduced rescue analgesic use. Adverse events from continuous lidocaine infusion may include central nervous system symptoms (such as dizziness, tinnitus, metallic taste, confusion, and seizures), and cardiovascular symptoms (such as bradycardia, hypotension, arrhythmia, allergic reactions, and methemoglobinemia. However, toxicity with lidocaine infusion is rare, none of which were observed in our patients. This could be attributed to several reasons. Lidocaine infusion in the perioperative setting is used in a controlled environment with appropriate monitoring and low and controlled doses with bolus dose and infusion doses not reaching beyond 1-2 mg/kg and 1-2 mg/kg/h respectively. Furthermore, lidocaine infusion is used for shorter durations in the perioperative setting, thus minimizing the likelihood of accumulation and toxicity [27].
We identified several limitations in our study. First, this was a single-center study, which could affect the findings' applicability to different demographics. Second, despite efforts to blind the pain nurse gathering postoperative data, the trial was open-label, which may have created bias. To double-blind the study, we would have resorted to the placement of sham blocks which most of the authors considered unethical. Further research with larger and more diverse populations is required to corroborate these results.
Our results show that the lidocaine group had considerably lower pain scores at various postoperative intervals than both the control and TAP block groups, particularly during the first 6 h. The use of rescue analgesics was nonexistent in the lidocaine group, demonstrating its efficacy in pain management after surgery. Furthermore, the lidocaine group experienced a significant decrease in postoperative nausea and vomiting at early time points.
Overall, our findings support the use of intravenous lidocaine infusion for superior postoperative analgesia in laparoscopic cholecystectomy, providing better pain control and requiring less rescue analgesics than the TAP block and control groups. This approach not only improves patient comfort but also leads to less adverse events and higher patient satisfaction.
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