Study was designed as a randomised controlled, double blinded study. The scheme has been shown in CONSORT 2010 flow chart in [Table/Fig-1]. The study was conducted in a teaching hospital in Sikkim, the north-east state of India. The duration of the study was 12 months spanning between May 2018 to April 2019. The study was approved by Institutional Research Protocol Evaluation Committee (IRPEC) with IRPEC number SMIMS/IRPEC/2018-78 dated 20^th April 2018 and Institutional Ethics Committee (IEC) with IEC number SMIMS/IEC/2018-031 dated 26^th May 2018.

[Table/Fig-1]:

CONSORT 2010 flow diagram for transparent reporting of trials.

Total number of laparoscopic cholecystectomies done in the hospital during the study period was 596 with an average of 500-700 LC being done every year. Sample size was calculated for randomised comparison of three groups, for α-error of 5% (significance 0.05) and power of study (1-β) 90%. During the study period, 105 patients were enrolled for the study and were randomised into three groups (having 35 patients in each group).

Inclusion criteria: Patients undergoing elective LC for symptomatic cholelithiasis.

Exclusion criteria:

Volumes and dilution to be given to patient were decided by a computer-generated random allocation list. The preparations of different volume and dilutions of lignocaine were made in operation room shortly before the start of the surgery depending on this allocation:

All patients were blinded with regard to the group they were assigned. Since blinding of the operating and anaesthesia team was not possible due to different volumes of the lignocaine used, they were not exposed to postoperative data till the end of the study. A separate team of observers recorded the postoperative data and they remained blinded regarding the group of the patient till the analysis of data completed by a separate team.

All the patients and their relatives were explained about the process of randomisation and blinding. They were told if any patient in any of the group experienced more pain, they would be given rescue analgesia. They were also told that if they opt out of the study, they would receive standard care as per Department protocols. The median duration of session explaining all the procedure was 16 minutes.

Procedure was standardised and the scheme is shown in [Table/Fig-2].

[Table/Fig-2]:

Scheme followed during the study.

GB: Gall bladder; VAS: Visual analog score; HR: Heart rate; PONV: Postoperative nausea vomiting; MBP: Mean blood (arterial) pressure (MAP)

Operating surgeons neither collected the intra or postoperative data nor took part in its analysis. To keep the uniformity, all the cases were done by a single anaesthesiologist who was also never exposed to data collection or analysis. The instillation of lignocaine solution was done in Morrison’s pouch and GB bed area where dissection was carried out after bringing the patient in neutral/supine position. Extra solution was allowed to go spontaneously to other areas including right paracolic gutter, lesser sac and right sub-phrenic area. Rescue analgesia was also standardised. All the patients in study were given intravenous paracetamol (1 g) and ondansetron (4 mg) at 8^th, 16^th, and 24^th hour. After that, all the injectables were stopped and the patients were given combination of aceclofenac (100 mg) and paracetamol (325 mg) twice a day. Intravenous aqueous diclofenac (75 mg) was offered as rescue analgesia followed by intravenous tramadol (50 mg) and ondansetron (4 mg) if not controlled by the former.

Three groups were compared for postoperative pain (using VAS score), requirement of rescue analgesia, nausea and vomiting, vital parameters (heart rate, respiratory rate, mean arterial pressure, transcutaneous saturation) at 1, 2, 4, 6, 12 and 24 hours after surgery and hospital stay. Data was recorded in a proforma validated by experts from Department of Surgery and Anaesthesia. Analysis of Variance (ANOVA) was used to compare mean and χ² test was used to compare categorical data. Tabulation and analysis were done in IBM^©SPSS^©21 using appropriate statistical tools.

Statistical comparisons of demographic parameters were done to exclude any chance bias between population and sample. Female to male ratio in population sample was 3.22 and 2.66, respectively (p>0.05) and mean age was 41.17 and 39.87 years respectively (p>0.05).

A comparison of preoperative parameters has been presented in [Table/Fig-3] showing the similarities or differences among the three groups. The intraoperative findings have been mentioned in [Table/Fig-4].

The mean VAS of group B (100 mg lignocaine in 100 mL of normal saline) was lower than the overall mean VAS at different postoperative time intervals and consistently lower than those of groups A and C. The difference was statistically significant {p-value (ANOVA) <0.05} at all postoperative intervals it was assessed. This was followed by group A (100 mg lignocaine in 10 mL of normal saline) while group C (100 mg lignocaine in 500 mL of normal saline) fared the worst. A post-hoc analysis of pain between genders and different age groups did not show any significant differences. The study found a consistent (r=0.15 to 0.33) and significant (p<0.05 at all-time intervals) positive correlation between pain and duration of surgery. A subset analysis for each of the three groups for all time intervals though showed positive correlation but the values were not significant. An important observation was that in group B, correlation was negative. As the value of VAS was significantly lower in immediate postoperative period, it may imply that the patient with longer duration of surgery had the maximum beneficiary of dilution and volume used in group B (100 mg lignocaine in 100 mL normal saline) [Table/Fig-5].

Pulse rate, as a surrogate for postoperative pain, was least in all postoperative time and significantly lower at 4^th hour. The difference in mean arterial pressures and respiratory rate among the three groups was not significant statistically [Table/Fig-5].

There were only 4 instances of nausea and none of vomiting in all three groups together and the finding was insignificant [Table/Fig-5].

The difference in the requirement of rescue analgesia was significant as shown in [Table/Fig-6].

The data presented in [Table/Fig-7] seems to be conflicting as the patients who experienced least pain stayed in the hospital for a longer time. But the data needs to be interpreted along with socio-geographic data. The area is a hilly terrain and there are only two hospitals in the state of four districts offering surgeries. So, the hospital stay or discharge is invariably affected by the fact how far the patient belong to and how much patient requires to walk and climb from the road to reach the home.

As various studies around the globe concentrate more on diversity of agents as well as timing, this study demonstrates the efficacy to differ for different volumes and dilutions for a similar dose of drug (lignocaine in present study which was 5 mL of 2% solution amounting to 100 mg of lignocaine). This study showed that a 100 mL solution of 5 mL of 2% lignocaine is significantly better than a 10 mL solution or a 500 mL solution of a similar dose of lignocaine in alleviating pain up to 24 hours postoperatively after LC. The only study which comes close to this one is that by Al-Kizwini GAM which compared two different strengths of lignocaine and found similar results against placebo but could not find any difference between the two intervention groups [5]. Agrawal S and Pai S did not find any difference between placebo and intraperitoneal analgesia [6]. Murdoch J et al., compared intravenous or intraperitoneal analgesia in controlling postoperating pain and told that both were equally effective analgesic when compared to placebo but did not differ significantly when compared against each other [7]. Roberts KJ et al., inferred that the benefits of elective LC in terms of controlling postoperative pain could not be extended to emergency LC [8]. Most of the studies found that intraperitoneal instillation of local anaesthetic agents did help in experiencing less postoperative pain as well as decreases the requirement of postoperative analgesia [9-14]. A summary of the review of all these studies has been presented in [Table/Fig-8] [5-14].

The study lacks the immediate post discharge as well as long term follow-up data of the patients. Pain was assessed only by VAS and no other scale or method was applied. The study did not assess the overall effect of pain relief on health related quality of life as well as return of normal activity.

The study concluded that the different concentration (or dilution) and volume of a similar dose of intraperitoneal lignocaine instillation have different analgesic effect in postoperative period following LC in patients of symptomatic uncomplicated cholelithiasis. For a 100 mg total dose of lignocaine, 100 mL solution is more effective compared to 10 mL or 500 mL solution.