Methods of intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy

Abstract

Background

Intraperitoneal local anaesthetic instillation may decrease pain in people undergoing laparoscopic cholecystectomy. However, the optimal method to administer the local anaesthetic is unknown.

Objectives

To determine the optimal local anaesthetic agent, the optimal timing, and the optimal delivery method of the local anaesthetic agent used for intraperitoneal instillation in people undergoing laparoscopic cholecystectomy.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization International Clinical Trials Registry Platform portal (WHO ICTRP) to March 2013 to identify randomised clinical trials for assessment of benefit and comparative non‐randomised studies for the assessment of treatment‐related harms.

Selection criteria

We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing different methods of local anaesthetic intraperitoneal instillation during laparoscopic cholecystectomy for the review.

Data collection and analysis

Two review authors collected the data independently. We analysed the data with both fixed‐effect and random‐effects models using Review Manager 5 analysis. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).

Main results

We included 12 trials with 798 participants undergoing elective laparoscopic cholecystectomy randomised to different methods of intraperitoneal local anaesthetic instillation. All the trials were at high risk of bias. Most trials included only people with low anaesthetic risk. The comparisons included in the trials that met the eligibility criteria were the following; comparison of one local anaesthetic agent with another local anaesthetic agent (three trials); comparison of timing of delivery (six trials); comparison of different methods of delivery of the anaesthetic agent (two trials); comparison of location of the instillation of the anaesthetic agent (one trial); three trials reported mortality and morbidity.
 There were no mortalities or serious adverse events in either group in the following comparisons: bupivacaine (0/100 (0%)) versus lignocaine (0/106 (0%)) (one trial; 206 participants); just after creation of pneumoperitoneum (0/55 (0%)) versus end of surgery (0/55 (0%)) (two trials; 110 participants); just after creation of pneumoperitoneum (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (one trial; 30 participants); end of surgery (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (one trial; 30 participants).
 None of the trials reported quality of life, the time taken to return to normal activity, or the time taken to return to work. The differences in the proportion of people who were discharged as day‐surgery and the length of hospital stay were imprecise in all the comparisons included that reported these outcomes (very low quality evidence). There were some differences in the pain scores on the visual analogue scale (1 to 10 cm) but these were neither consistent nor robust to fixed‐effect versus random‐effects meta‐analysis or sensitivity analysis.

Authors' conclusions

The currently available evidence is inadequate to determine the effects of one method of local anaesthetic intraperitoneal instillation compared with any other method of local anaesthetic intraperitoneal instillation in low anaesthetic risk individuals undergoing elective laparoscopic cholecystectomy. Further randomised clinical trials of low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment.

Plain language summary

Methods of intra‐abdominal local anaesthetic administration in people undergoing laparoscopic cholecystectomy

Background

About 10% to 15% of the adult western population have gallstones. Between 1% and 4% become symptomatic each year. Removal of the gallbladder (cholecystectomy) is the mainstay treatment for symptomatic gallstones. More than half a million cholecystectomies are performed per year in the US alone. Laparoscopic cholecystectomy (removal of gallbladder through a keyhole, also known as port) is now the preferred method of cholecystectomy. Pain is one the major reasons for delayed hospital discharge after laparoscopic cholecystectomy. Administration of local anaesthetics (drugs that numb part of the body, similar to the ones used by the dentist to prevent the people from feeling pain) into the tummy (abdomen) is considered to be an effective way of decreasing the pain after laparoscopic cholecystectomy. However, the best method of administration of local anaesthetics is not known. The controversies include which drug to use, when to administer it, whether it should be administered in the form of liquid or in the form of misty spray, and to which part of the tummy it should be administered. We sought to answer these questions by reviewing the medical literature and obtaining information from randomised clinical trials for assessment of benefit. When conducted well, such studies provide the most accurate information on the best treatment. We included comparative non‐randomised studies for the assessment of treatment‐related harms. Two authors searched the literature and obtained information from the studies thereby minimising errors.

Study characteristics

We identified 12 randomised clinical trials involving 798 people undergoing planned laparoscopic cholecystectomy. The trials compared different methods addressing the various controversies mentioned above. The choice of the method of administration of the local anaesthetic was determined by a method similar to the toss of a coin so that the treatments compared were conducted in participants who were as similar as possible.

Key results

There were no deaths or serious complications in either group in the comparisons that reported these. None of the trials reported quality of life, the time taken to return to normal activity, or the time taken to return to work. The differences in hospital stay between the methods being compared was imprecise in all the comparisons that reported hospital stay. Although there were some differences in the pain scores on the visual analogue scale (a chart that rates the amount of pain on a scale of 1 to 10 cm), these differences were neither consistent nor robust to different methods of statistical analysis. The evidence currently available is inadequate to determine the effects of one method of local anaesthetic intraperitoneal instillation compared with any other method of local anaesthetic intraperitoneal instillation in low anaesthetic risk individuals undergoing elective laparoscopic cholecystectomy.

Quality of evidence

Most of the trials were of high risk of bias, that is, there is possibility of arriving at wrong conclusions overestimating benefits or underestimating harms of one method or the other because of the way that the study was conducted. The overall quality of evidence was very low.

Future research

Further trials are necessary. Such trials should include outcomes such as quality of life, the time taken to return to normal activity, and the time taken to return to work, which are important for the person undergoing the procedure and the people who provide funds for the treatment.

Summary of findings

Summary of findings for the main comparison. Methods of intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy.

Methods of intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy
Patient or population: people undergoing laparoscopic cholecystectomy Settings: secondary or tertiary Comparison: various comparisons
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of participants (trials)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Intervention
Mortality	Not estimable (as there was no mortality in either group in this comparison)		Not estimable	Bupivacaine versus lignocaine: 206 participants (1 trial). Just after creation of pneumoperitoneum versus end of surgery: 110 participants (2 trials). Just after creation of pneumoperitoneum versus after the end of surgery: 30 participants (1 trial). End of surgery versus after the end of surgery: 30 participants (1 trial).	⊕⊝⊝⊝ very low1,2
Morbidity	Not estimable (as there was no morbidity in either group in this comparison)		Not estimable	Bupivacaine versus lignocaine: 206 participants (1 trial). Just after creation of pneumoperitoneum versus end of surgery: 110 participants (2 trials). Just after creation of pneumoperitoneum versus after the end of surgery: 30 participants (1 trial). End of surgery versus after the end of surgery: 30 participants (1 trial).	⊕⊝⊝⊝ very low1,2
Proportion discharged as day‐surgery
Just after creation of pneumoperitoneum versus end of surgery	733 per 1000	719 per 1000 (477 to 1000)	RR 0.98 (0.65 to 1.5)	33 (1 study)	⊕⊝⊝⊝ very low1,2
Subdiaphragmatic instillation versus gallbladder bed instillation	220 per 1000	342 per 1000 (167 to 700)	RR 1.56 (0.76 to 3.19)	82 (1 study)	⊕⊝⊝⊝ very low1,2
Hospital stay
Bupivacaine versus lignocaine	The mean hospital stay ‐ bupivacaine versus lignocaine in the control groups was 1 day	The mean hospital stay ‐ bupivacaine versus lignocaine in the intervention groups was 0.1 higher (0.16 lower to 0.36 higher)	‐	206 (1 study)	⊕⊝⊝⊝ very low1,3
Aerosol versus liquid	The mean hospital stay ‐ aerosol versus liquid in the control groups was 1 day	The mean hospital stay ‐ aerosol versus liquid in the intervention groups was 0 higher (0.13 lower to 0.13 higher)	‐	60 (1 study)	⊕⊝⊝⊝ very low1,3
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹ The trial(s) was (were) of high risk of bias (2 points).
 ² The confidence intervals overlapped 1 and either 0.75 or 1.25 or both. The number of events in the intervention and control group was fewer than 300 (2 points).
 ³ Fewer than 400 participants were included in this comparison (1 point).

Background

Description of the condition

About 5% to 25% of the adult western population have gallstones (GREPCO 1984; GREPCO 1988; Bates 1992; Halldestam 2004). The annual incidence of gallstones is about 1 in 200 people (NIH 1992). Only 2% to 4% of people with gallstones become symptomatic with biliary colic (pain), acute cholecystitis (inflammation), obstructive jaundice, or gallstone pancreatitis in a year (Attili 1995; Halldestam 2004). Cholecystectomy (removal of gallstones) is the preferred option in the treatment of symptomatic gallstones (Strasberg 1993) and every year, 1.5 million cholecystectomies are performed in the US and 60,000 in the UK (Dolan 2009; HES 2011). Approximately 80% of the cholecystectomies are performed laparoscopically (keyhole incision) (Ballal 2009).

Pain is one of the important reasons for delayed discharge after laparoscopic cholecystectomy (Gurusamy 2008a; Gurusamy 2008b). The pain after laparoscopic cholecystectomy could be incisional pain, shoulder pain, or abdominal pain (Ng 2004). The aetiology of abdominal pain and shoulder pain after laparoscopic cholecystectomy is not clear. Peritoneal irritation, caused by carbonic acid and creation of space between diaphragm and liver, leading to loss of suction support of the heavy liver have been suggested as possible mechanisms of pain (Alexander 1987). However, use of overnight drain to let out the gas has not been effective in the reduction of pain (Gurusamy 2013).

Description of the intervention

Intraperitoneal instillation of local anaesthetic agents such as bupivacaine (Alkhamesi 2007), levobupivacaine (Ng 2004; Louizos 2005), lidocaine (Elhakim 2000), and ropivacaine (Gupta 2002) has been suggested as a way of reduction of abdominal and shoulder pain. The instillation can be performed either before or after the development of the pneumoperitoneum (Barczynski 2006), or towards the end of the surgery (Louizos 2005; Alkhamesi 2007). The intraperitoneal instillation of the local anaesthetic could be by washing the gallbladder bed of the liver with the local anaesthetic (Alkhamesi 2007), instillation under diaphragm (Abdel‐Raouf 2004), or as an aerolised spray in the general peritoneum (Alkhamesi 2007). The instillation can be either performed as a bolus or as a continuous infusion (Bayar 1998).

Other routes by which local anaesthetic can be administered to decrease pain after laparoscopic cholecystectomy include wound infiltration (Gurusamy 2014a), paravertebral block (Naja 2011), transversus abdominis plane (TAP) block (Petersen 2012), and epidural block (Nandate 2003).

How the intervention might work

Local anaesthetics inhibit the voltage‐gated sodium channels. This results in decreased excitability of nerves (Butterworth 1990).

Why it is important to do this review

We have assessed whether local anaesthetic wound infiltration is effective in decreasing pain in a Cochrane review (Gurusamy 2014a). We have assessed whether intraperitoneal local anaesthetic instillation is effective in decreasing pain in another Cochrane review (Gurusamy 2014b). These reviews have shown that the wound infiltration and intraperitoneal instillation with local anaesthetics decreased pain scores without significant clinical benefit, although there were no treatment‐related serious adverse events (Gurusamy 2014a; Gurusamy 2014b). There have been no meta‐analyses or systematic reviews comparing the different methods of intraperitoneal local anaesthetic instillation.

Objectives

To determine the optimal local anaesthetic agent, the optimal timing, and the optimal delivery method of the local anaesthetic agent used for intraperitoneal instillation in people undergoing laparoscopic cholecystectomy.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised clinical trials (irrespective of language, blinding, publication status, or sample size) for inclusion. We excluded quasi‐randomised trials (where the method of allocating participants to a treatment were not strictly random, eg, date of birth, hospital record number, alternation) and non‐randomised studies regarding assessment of benefit, but planned to include these studies regarding assessment of treatment‐related harms.

Types of participants

People undergoing laparoscopic cholecystectomy irrespective of age, elective or emergency surgery, and the reason why the laparoscopic cholecystectomy was performed.

Types of interventions

We planned to include the following interventions:

• comparison of one local anaesthetic agent with another local anaesthetic agent;

• comparison of timing of delivery (eg, before surgery versus towards the end of surgery);

• comparison of different methods of delivery of the anaesthetic agent (eg, bolus versus continuous infusion; aerosol spray versus washout);

• comparison of location of the instillation of the anaesthetic agent (eg, under the diaphragm versus in the gallbladder bed of the liver).

We allowed co‐interventions if carried out equally in the trial groups. We did not include trials comparing intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation in this patient group as this has been covered in a different review (Gurusamy 2014b).

Types of outcome measures

Primary outcomes

1. Mortality.

2. Serious adverse events defined as any event that would increase mortality, was life‐threatening, required inpatient hospitalisation, resulted in a persistent or significant disability, or any important medical event that might have jeopardised the participant or required intervention to prevent it (ICH‐GCP 1997). We classified complications such as bile duct injury; re‐operations; intra‐abdominal collections requiring drainage (radiological or surgical); infected intra‐abdominal collections; bile leaks requiring drainage, stent, or surgery; convulsions; cardiac arrhythmias that required additional monitoring and hence increased the hospital stay as serious adverse events. Complications such as wound infections, bile leaks, or abdominal collections that did not require any treatment and settle spontaneously were not considered serious adverse events.

3. Patient quality of life (however defined by authors using a validated scale such as Euro‐QoL or 36‐item Short Form (SF‐36)) (EuroQol 1990; Ware 1992; McHorney 1993).

Secondary outcomes

1. Hospital stay (length of hospital stay, proportion discharged as day‐surgery laparoscopic cholecystectomy).

2. Pain (overall pain scores) at different time points (4 to 8 hours and 9 to 24 hours) using a visual analogue scale.

3. Return to activity.

4. Return to work.

We have reported all the outcomes with at least one trial in the Table 1.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003), and the World Health Organization International Clinical Trials Registry Platform portal (WHO ICTRP) (apps.who.int/trialsearch/) to March 2013. The WHO ICTRP portal allows search of various trial registers including clinicaltrials.gov and ISRCTN among other registers. We have given the search strategies in Appendix 1 with the time span for the searches.

Searching other resources

We also searched the references of the identified trials to identify further relevant trials.

Data collection and analysis

We performed the systematic review according to the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2014).

Selection of studies

Two review authors (KSG and CT, GPG, or MZ) identified the trials for inclusion independently of each other. We have also listed the excluded studies with the reasons for the exclusion.

Data extraction and management

Two review authors (KSG, MN, CT, GPG, or MZ) extracted the following data independently of each other.

1. Year and language of publication.

2. Country in which the trial was conducted.

3. Year of trial.

4. Inclusion and exclusion criteria.

5. Sample size.

6. Elective surgery or acute cholecystitis.

7. Local anaesthetic agent used.

8. Dose of local anaesthetic agent (per kilogram body weight or total dose however reported by authors).

9. Timing of administration.

10. Location where instilled.

11. Physical form of local anaesthetic agent (aerosol, liquid).

12. Duration of administration (bolus/infusion period).

13. Drain or no drain.

14. Peri‐laparoscopic‐portal infiltration with local anaesthetic.

15. Other co‐interventions.

16. Outcomes (Primary outcomes; Secondary outcomes).

17. Risk of bias (Assessment of risk of bias in included studies).

We sought any unclear or missing information by contacting the authors of the individual trials. If there was any doubt whether the trials shared the same participants ‐ completely or partially (by identifying common authors and centres) ‐ we planned to contact the authors of the trials to clarify whether the trial report had been duplicated.

We resolved any differences in opinion through discussion with or arbitration of the third author (BRD).

Assessment of risk of bias in included studies

We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2014). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012a; Savovic 2012b), we assessed the risk of bias of the trials based on the following bias risk domains.

Allocation sequence generation

• Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial.

• Uncertain risk of bias: the method of sequence generation was not specified.

• High risk of bias: the sequence generation method was not random.

Allocation concealment

• Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (eg, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).

• Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.

• High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.

Blinding of participants and personnel

• Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.

• Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to introduce bias on the results.

• High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.

Blinding of outcome assessors

• Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.

• Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.

• High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.

Incomplete outcome data

• Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data.

• Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

• High risk of bias: the results were likely to be biased due to missing data.

Selective outcome reporting

• Low risk of bias: all outcomes were pre‐defined and reported, or all clinically relevant and reasonably expected outcomes were reported. For this purpose, the trial should have been registered either on the www.clinicaltrials.gov website or a similar register with sufficient evidence that the protocol had not been revised during the update, or there should be a protocol, for example, published in a paper journal. In the case when the trial was run and published in the years when trial registration was not required, we carefully scrutinized all publications reporting on the trial to identify the trial objectives and outcomes, and determine whether usable data were provided in the publications results section on all outcomes specified in the trial objectives.

• Uncertain risk of bias: it is unclear whether all pre‐defined and clinically relevant (mortality and morbidity) and reasonably expected outcomes were reported.

• High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

For‐profit bias

• Low risk of bias: the trial appeared to be free of industry sponsorship or other type of for‐profit support that may have manipulated the trial design, conductance, or results of the trial.

• Uncertain risk of bias: the trial may or may not be free of for‐profit bias as no information on clinical trial support or sponsorship was provided.

• High risk of bias: the trial was sponsored by the industry or had received other kind of for‐profit support.

We considered trials that were classified as low risk of bias in all the above domains as trials with low risk of bias, and the remaining as trials with high risk of bias.

Measures of treatment effect

For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval (CI). We also calculated the risk difference with 95% CI. We planned to report the risk difference only if the conclusions were different from those of the RR. Risk difference includes 'zero event trials' (trials in which both groups have no events) for calculating the summary treatment effect, while such trials will not be taken into account while calculating the summary treatment effect in the case of RR. It should be noted that we used RR as the primary measure of the treatment effect and so we did not report comparisons in which there were no events in either groups in all the trials included under the comparison. For continuous variables, we calculated the mean difference (MD) with 95% CI for outcomes such as total hospital stay or standardised mean difference (SMD) with 95% CI for outcomes such as quality of life, where different authors use different scales of quality of life.

Unit of analysis issues

The units of analysis was the person about to undergo laparoscopic cholecystectomy and randomised to the different methods of intraperitoneal local anaesthetic instillation.

Dealing with missing data

We performed an intention‐to‐treat analysis (Newell 1992), whenever possible. We planned to impute data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best‐case scenario, and worst‐case scenario (Gurusamy 2009; Gluud 2014).

For continuous outcomes, we used available‐case analysis. We imputed the standard deviation from P values according to the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and we used the median for the meta‐analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the CI, we planned to impute the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation would decrease the weight of the study for calculation of MDs and bias the effect estimate to no effect in the case of SMD (Higgins 2011).

Assessment of heterogeneity

We explored heterogeneity using the Chi² test with significance set at a P value < 0.10, and measured the quantity of heterogeneity using the I² statistic (Higgins 2002). We also used overlapping of CIs on the forest plot to determine heterogeneity.

Assessment of reporting biases

We planned to use visual asymmetry on a funnel plot to explore reporting bias if 10 or more trials were identified (Egger 1997; Macaskill 2001). We planned to perform the linear regression approach described by Egger 1997 to determine the funnel plot asymmetry. Selective reporting was also considered as evidence for reporting bias.

Data synthesis

We performed the meta‐analyses using the software package Review Manager 5 (RevMan 2012), and following the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2014). We used both a random‐effects model (DerSimonian 1986), and a fixed‐effect model (DeMets 1987) meta‐analysis. In the case of discrepancy between the two models, we have reported both results; otherwise, we have reported the results of the fixed‐effect model. We planned to use the generic inverse method to combine the hazard ratios for time‐to‐event outcomes.

Trial sequential analysis

The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We added the trials according to the year of publication, and, if more than one trial was published in a year, the trials were added alphabetically according to the last name of the first author. On the basis of the required information size, we constructed trial sequential monitoring boundaries. These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. In contrast, if the boundaries are not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).

We applied trial sequential analysis (CTU 2011; Thorlund 2011) using a required sample size calculated from an alpha error of 0.05, a beta error of 0.20, a control event proportion obtained from the results, and a relative risk reduction of 20% for binary outcomes if there were two or more trials reporting the outcome to determine whether more trials are necessary on this topic (if the trial sequential alpha‐spending monitoring boundary or the futility zone is crossed, then more trials may be unnecessary) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). Since trial sequential analysis cannot be performed for SMD, we did not plan to perform the trial sequential analysis for quality of life. For pain, we calculated the required sample size from an alpha error of 0.05, a beta error of 0.20, the variance estimated from the meta‐analysis results of low risk of bias trials (if possible), and a mean difference of 1 cm on the visual analogue scale (Todd 1996). For length of hospital stay, return to work, and return to activity, we planned to calculate the required sample size using a mean difference of one day with the remaining parameters kept the same as that for pain.

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses.

• Trials with low risk of bias compared to trials with high risk of bias.

• Peri‐laparoscopic‐portal infiltration with local anaesthetic.

• Elective versus emergency laparoscopic cholecystectomy.

We planned to use the 'test for subgroup differences' available through Review Manager 5 (RevMan 2012) to identify the differences between subgroups. We also planned to use meta‐regression (in the presence of adequate number of trials) to determine the influence of other factors apart from the main comparison performed such as local anaesthetic agent used, timing of instillation, and location of instillation on the effect estimate. We planned to do this for pain at 4 to 8 hours and pain at 9 to 24 hours (as these are the times at which day‐procedure laparoscopic cholecystectomy and overnight stay laparoscopic cholecystectomy patients are discharged).

Sensitivity analysis

We planned to perform a sensitivity analysis by imputing data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best‐case scenario, and worst‐case scenario (Gurusamy 2009; Gluud 2014). Since there were no post‐randomisation drop‐outs in the only trial that reported binary outcomes, we did not perform the sensitivity analysis. We performed a sensitivity analysis by excluding the trials in which the mean and the standard deviation were imputed.

Summary of findings table

We have summarised the results of all the reported outcomes in Table 1 prepared using GRADEPro 3.6 (ims.cochrane.org/revman/gradepro).

Results

Description of studies

Results of the search

We identified 474 references through electronic searches of CENTRAL (N = 85), MEDLINE (N = 127), EMBASE (N = 105), and Science Citation Index Expanded (N = 157). We did not identify any new trials from the trial registers. We excluded 84 duplicates and 371 clearly irrelevant references through reading abstracts. We did not identify any quasi‐randomised studies or comparative non‐randomised studies that reported treatment‐related harms. We identified one reference, which was published after the search date, during the peer review process. This trial is awaiting classification (Ingelmo 2013). We retrieved 19 references for further assessment. No references were identified through scanning reference lists of the identified randomised trials. We excluded five references for the reasons listed in the Characteristics of excluded studies table. Fourteen references of 12 randomised trials fulfilled the inclusion criteria. The reference flow is shown in Figure 1.

1.

Study flow diagram.

Included studies

A total of 798 participants were randomised to different groups in the 12 trials (Rademaker 1994; Pasqualucci 1996; Lee 2001; Karadeniz 2003; Paulson 2003; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Kucuk 2007; Bucciero 2011; Roberts 2011; Khan 2012). All the participants in the trials underwent elective laparoscopic cholecystectomy. The participants in 11 trials were American Society of Anesthesiologists classifications (ASA) 1 or 2 (Rademaker 1994; Pasqualucci 1996; Lee 2001; Paulson 2003; Karadeniz 2003; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Kucuk 2007; Roberts 2011; Khan 2012) or ASA (1 to 3) (Bucciero 2011), that is, low anaesthetic risk patients. Additional wound infiltration with local anaesthetic was used in four trials (Barczynski 2006; Alkhamesi 2007; Roberts 2011; Khan 2012). In one trial, it was possible to use two comparisons, one with local anaesthetic wound infiltration and one without local anaesthetic wound infiltration (Lee 2001). In the remaining trials, local anaesthetic wound infiltration was not clearly stated but probably was not used (Rademaker 1994; Pasqualucci 1996; Karadeniz 2003; Paulson 2003; Karaaslan 2006; Kucuk 2007; Bucciero 2011). We could infer that a drain was not used in two trials since trial participants were excluded when a drain was used (Karadeniz 2003; Paulson 2003). A perfusion pump was used in one of the groups to infuse local anaesthetically continuously after the end of surgery (Karadeniz 2003). It was not clear whether this perfusion was done through a drain. In another trial, drains were used selectively but the reasons for drain use in these selected participants was not stated (Roberts 2011). Drain usage was not reported in the remaining trials but probably were not used. The local anaesthetics used included bupivacaine (all trials) (Rademaker 1994; Pasqualucci 1996; Lee 2001; Karadeniz 2003; Paulson 2003; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Kucuk 2007; Bucciero 2011; Roberts 2011; Khan 2012), ropivacaine (Kucuk 2007), and lignocaine (Rademaker 1994; Khan 2012). The mean age in the participants was 29 to 52 years in the trials that provided this information. The proportion of female participants was 46.3% to 88.3% in the trials that provided this information. The comparisons included in the different trials were as follows:

• comparison of one local anaesthetic agent with another local anaesthetic agent (Rademaker 1994; Kucuk 2007; Khan 2012);

• comparison of timing of delivery (Pasqualucci 1996; Lee 2001; Karadeniz 2003; Paulson 2003; Barczynski 2006; Karaaslan 2006);

• comparison of different methods of delivery of the anaesthetic agent (Alkhamesi 2007; Bucciero 2011);

• comparison of location of the instillation of the anaesthetic agent (Roberts 2011).

In one trial, continuous infusion was used for the participants who received the local anaesthetic after the end of the surgery. Since this was related to the timing, we included these two trials under the comparison of timing of delivery (Karadeniz 2003).

Further details about sample size, participant characteristics, the inclusion and exclusion criteria used in the trials, post‐randomisation drop‐outs, intervention and control, comparisons, outcomes reported in the trials, and the risk of bias in the trials are shown in the Characteristics of included studies table and Table 2.

1. Summary characteristics table.

Study name	Number randomised	Post‐randomisation drop‐outs (%)	Revised sample size	Intervention		Control		Comparison	Wound local anaesthetic infiltration	Drain use	Outcomes reported
				Number randomised	Local anaesthetic	Number randomised	Local anaesthetic
Alkhamesi 2007	40	Not stated	40	20	Bupivacaine	20	Bupivacaine	Form	Yes	Not stated	Pain
Barczynski 2006	60	0 (0%)	60	30	Bupivacaine	30	Bupivacaine	Timing	Yes	Not stated	Intra‐operative complications and pain
Bucciero 2011	60	3 (5%)	57	30	Ropivacaine	30	Ropivacaine	Form	Not stated	Not stated	Local anaesthetic‐related complications, hospital stay, and pain
Karaaslan 2006	62	12 (19.4%)	50	16	Bupivacaine	18	Bupivacaine	Timing	Not stated	Not stated	Local anaesthetic‐related complications
Karaaslan 2006§	Not applicable			16	Bupivacaine	18	Bupivacaine	Timing	Not stated	Not stated	Local anaesthetic‐related complications
Karadeniz 2003	52	7 (13.5%)	45	15	Bupivacaine	15	Bupivacaine	Timing	Not stated	No	Mortality, morbidity, and pain
Karadeniz 2003§	Not applicable			15	Bupivacaine	15	Bupivacaine	Timing	Not stated	Possibly for the continuous infusion group	Mortality, morbidity, and pain
Karadeniz 2003§	Not applicable			15	Bupivacaine	15	Bupivacaine	Timing	Not stated	Possibly for the continuous infusion group	Mortality, morbidity, and pain
Khan 2012	224	18 (8%)	206	100	Bupivacaine	106	Lignocaine	Different local anaesthetic	Yes	Not stated	Mortality, morbidity, and hospital stay
Kucuk 2007	60	Not stated	60	20	Ropivacaine	10*	Bupivacaine	Different local anaesthetic	No	Not stated	Local anaesthetic‐related complications and pain
Kucuk 2007§	Not applicable			20	Ropivacaine	10*	Bupivacaine	Different local anaesthetic	No	Not stated	Local anaesthetic related complications and pain
Lee 2001	88	8 (9.1%)	80	20	Bupivacaine	19	Bupivacaine	Timing	Yes	Not stated	Mortality and morbidity
Lee 2001§	not applicable			20	Bupivacaine	21	Bupivacaine	Timing	No	Not stated	Mortality and morbidity
Pasqualucci 1996	60	6 (10%)	54	26	Bupivacaine	28	Bupivacaine	Timing	Not stated	Not stated	Local anaesthetic‐related complications and pain
Paulson 2003	33	Not stated	33	18	Bupivacaine	15	Bupivacaine	Timing	Not stated	No	Local anaesthetic‐related complications and discharge as day‐surgery
Rademaker 1994	30	Not stated	30	15	Bupivacaine	15	Lignocaine	Different local anaesthetic	Not stated	Not stated	Local anaesthetic‐related complications and pain
Roberts 2011	84	1 (1.2%)	83	41	Bupivacaine	41	Bupivacaine	Location	Yes	Selectively (reasons not stated)	Hospital stay and pain

§ Multiple groups from the same trial.

* Sample size divided by 2 as otherwise the same participants would be included twice in the meta‐analysis.

Risk of bias in included studies

All the trials were at high risk of bias. The risk of bias in the included trials is summarised in the 'Risk of bias' graph (Figure 2) and 'Risk of bias' summary (Figure 3).

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Only four trials described random sequence generation and allocation concealment adequately (Karadeniz 2003; Barczynski 2006; Bucciero 2011; Khan 2012). These four trials were considered to be at low risk of selection bias.

Blinding

Seven trials reported that the participants, healthcare personnel involved in patient care, and outcome assessors were blinded and were considered to be at low risk of performance and detection bias (Lee 2001; Paulson 2003; Karaaslan 2006; Alkhamesi 2007; Bucciero 2011; Roberts 2011; Khan 2012).

Incomplete outcome data

Only one trial had no post‐randomisation drop‐outs and was considered to be at low risk of attrition bias (Barczynski 2006).

Selective reporting

Three trials reported mortality and morbidity and were considered to be at low risk of selective reporting bias (Lee 2001; Karadeniz 2003; Khan 2012).

Other potential sources of bias

Two trials were considered to be at low risk of 'for‐profit' bias (Bucciero 2011; Khan 2012).

Effects of interventions

See: Table 1

The main results are summarised in the Table 1.

Mortality and morbidity

Three trials clearly mentioned that there was no mortality or morbidity in either group (Lee 2001; Karadeniz 2003; Khan 2012). The total number of participants in these trials was 331. There were multiple comparisons in two of the three trials (Karadeniz 2003; Khan 2012). We have presented these comparisons below. It should be noted some participants were included in more than one comparison. The comparisons and the number of participants in each comparison are shown below.

• Bupivacaine (0/100 (0%)) versus lignocaine (0/106 (0%)) (Khan 2012).

• Just after creation of pneumoperitoneum (0/55 (0%)) versus end of surgery (0/55 (0%)) (Lee 2001; Karadeniz 2003).

• Just after creation of pneumoperitoneum (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (Karadeniz 2003).

• End of surgery (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (Karadeniz 2003).

Trial sequential analysis was performed for the comparison 'just after creation of pneumoperitoneum versus end of surgery' since this was the only comparison with more than one trial. Since there was no mortality in either group, we were unable to use the control group proportion for the calculation of the required information size of the trial sequential analysis. Instead, we used a proportion of 0.2% in the control group based on data from approximately 30,000 people included in a database in Switzerland as before (Giger 2011). The proportion of information accrued was only 0.03% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 4). The cumulative Z curve did not cross the conventional statistical boundaries.

4.

Trial sequential analysis of mortality (just after creation of pneumoperitoneum versus end of surgery) 
 The diversity‐adjusted required information size (DARIS) was calculated to 352,564 participants, based on the proportion of participants in the control group with the outcome of 0.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 110 participants in two trials, only 0.03% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.

Since there was no serious adverse event in either group, we were unable to use the control group proportion for the calculation of the required information size of the trial sequential analysis as before. Laparoscopic cholecystectomy is generally considered to have low morbidity in people with low anaesthetic risk. We used a control group proportion of 2%. The proportion of information accrued was only 0.32% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 5). The cumulative Z curve did not cross the conventional statistical boundaries.

5.

Trial sequential analysis of morbidity (just after creation of pneumoperitoneum versus end of surgery) 
 The diversity‐adjusted required information size (DARIS) was calculated to 34,685 participants, based on the proportion of participants in the control group with the outcome of 2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 110 participants in two trials, only 0.32% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.

Although the remaining trials did not report the overall morbidity, one trial (60 participants) reported that there were no intra‐operative complications (Barczynski 2006). Six trials (284 participants) stated that there were no complications related to local anaesthetic (Rademaker 1994; Pasqualucci 1996; Paulson 2003; Karaaslan 2006; Kucuk 2007; Bucciero 2011). Two participants in one trial developed mild bradycardia that settled spontaneously (Khan 2012). One trial did not report the complications adequately but stated that one person developed lactic acidosis but this was not considered to be due to the local anaesthetic since the person had developed a similar problem with previous anaesthesia (Roberts 2011). Bupivacaine was used in this trial.

Patient quality of life

None of the trials reported patient quality of life.

Hospital stay

Proportion discharged as day surgery

Two trials reported the proportion of participants discharged as day‐surgery but did not report the reasons for the delayed discharge in participants who were not discharged as day‐surgery (Paulson 2003; Roberts 2011). There were no significant differences in the proportion of participants discharged as day‐surgery whether the local anaesthetic was administered just after creation of pneumoperitoneum or at the end of surgery (RR 0.98; 95% CI 0.65 to 1.50) (Paulson 2003) or whether the local anaesthetic was administered subdiaphragmatically or in the gallbladder bed (RR 1.56; 95% CI 0.76 to 3.19) (Roberts 2011) (Analysis 1.1). The number of post‐randomisation drop‐outs was not reported in one trial (Paulson 2003). The results did not change by imputation of different scenarios mentioned in the Sensitivity analysis section. Trial sequential analysis was not performed because of the presence of only one trial under each comparison.

1.1. Analysis.

Comparison 1 Intervention versus control, Outcome 1 Proportion discharged as day‐surgery.

Length of hospital stay

Two trials reported the length of hospital stay (Bucciero 2011; Khan 2012). There were no significant differences in the length of hospital stay irrespective of whether bupivacaine or lignocaine was used as the local anaesthetic agent (MD 0.10 days; 95% CI ‐0.16 to 0.36) (Khan 2012) or whether the local anaesthetic was administered in the aerosol or liquid form (Bucciero 2011) (MD 0.00 days; 95% CI ‐0.13 to 0.13) (Analysis 1.2). Neither the mean nor the standard deviation was imputed in either of these trials. Therefore, a sensitivity analysis was not performed. Trial sequential analysis was not performed because of the presence of only one trial under each comparison.

1.2. Analysis.

Comparison 1 Intervention versus control, Outcome 2 Hospital stay.

Pain

Pain at 4 to 8 hours

Eight trials reported pain at 4 to 8 hours (Rademaker 1994; Pasqualucci 1996; Karadeniz 2003; Barczynski 2006; Alkhamesi 2007; Kucuk 2007; Bucciero 2011; Roberts 2011). The comparisons, the number of participants in each comparison, the trials contributing to the analysis, and the effect estimates are shown below (Analysis 1.3). The statistically significant results are shown in italics.

1.3. Analysis.

Comparison 1 Intervention versus control, Outcome 3 Pain 4 to 8 hours.

• Bupivacaine versus lignocaine (one trial; 30 participants (Rademaker 1994)) (MD ‐2.00 cm VAS; 95% CI ‐6.53 to 2.53).

• Ropivacaine versus bupivacaine (one trial; 60 participants (Kucuk 2007)) (MD ‐0.22 cm VAS; 95% CI ‐0.79 to 0.35).

• Before pneumoperitoneum versus just after pneumoperitoneum (one trial; 60 participants (Barczynski 2006)) (MD ‐0.30 cm VAS; 95% CI ‐0.53 to ‐0.07).

• Just after creation of pneumoperitoneum versus end of surgery (two trials; 84 participants (Pasqualucci 1996; Karadeniz 2003)) (MD ‐0.60 cm VAS; 95% CI ‐1.41 to 0.20).

• Just after creation of pneumoperitoneum versus after end of surgery (one trial; 30 participants (Karadeniz 2003)) (MD 1.28 cm VAS; 95% CI 0.08 to 2.48).

• End of surgery versus after end of surgery (one trial; 30 participants (Karadeniz 2003)) (MD 0.95 cm VAS; 95% CI ‐0.41 to 2.31).

• Aerosol versus liquid (two trials; 97 participants (Alkhamesi 2007; Bucciero 2011)) (fixed‐effect model: MD ‐2.20 cm VAS; 95% CI ‐2.89 to ‐1.50; random‐effects model: MD ‐3.19 cm VAS; 95% CI ‐9.66 to 3.28).

• Subdiaphragmatic instillation versus gallbladder bed instillation (one trial; 83 participants (Roberts 2011)) (MD ‐0.30 cm VAS; 95% CI ‐1.01 to 0.41).

Trial sequential analysis was performed for two comparisons with more than one trial.

Just after creation of pneumoperitoneum versus after end of surgery

Trial sequential analysis revealed that the information fraction was too small (14.92%) to draw the futility area and the trial sequential boundaries for benefits or harms of the intervention were not crossed (Figure 6). The conventional statistical boundaries were also not crossed.

6.

Trial sequential analysis of pain (4 to 8 hours) (just after creation of pneumoperitoneum versus end of surgery) 
 The diversity‐adjusted required information size (DARIS) was 563 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 7.09, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D²) of 60.45%. After accruing 84 participants in two trials, only 14.92% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. Neither the conventional statistical boundaries (dotted red line) or the trial sequential monitoring boundaries (continuous red line) for benefits or harms of just after creation of pneumoperitoneum versus end of surgery were crossed by the cumulative Z curve (blue line).

Aerosol versus liquid

The proportion of information accrued was only 0.58% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 7). Although the cumulative Z‐curve crossed the conventional statistical boundaries when the fixed‐effect model was used, the Z‐curve did not cross the conventional statistical boundaries when the random‐effects model was used.

7.

Trial sequential analysis of pain (4 to 8 hours) (aerosol versus liquid) 
 The diversity‐adjusted required information size (DARIS) was 17,109 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 6.3, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D²) of 98.34%. After accruing 97 participants in two trials, only 0.58% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the trial sequential monitoring boundaries or the information size. Although the conventional statistical boundaries (dotted red line) is crossed by the cumulative Z‐curve (blue line) favouring aerosol, the conventional statistical boundaries were not crossed when the random‐effects model was used.

Sensitivity analysis

Either the mean or the standard deviation or both were imputed in four trials (Rademaker 1994; Pasqualucci 1996; Alkhamesi 2007; Roberts 2011). Only two of the trials were involved in meta‐analysis (two different comparisons). Exclusion of these trials resulted in alteration of the results, that is, the significant differences in these comparisons were lost when these trials were excluded.

Pain at 9 to 24 hours

Six trials reported this outcome (Pasqualucci 1996; Karadeniz 2003; Barczynski 2006; Alkhamesi 2007; Kucuk 2007; Bucciero 2011). The comparisons, the number of participants in each comparison, the trials contributing to the analysis, and the effect estimates are shown below (Analysis 1.4). The statistically significant results are shown in italics.

1.4. Analysis.

Comparison 1 Intervention versus control, Outcome 4 Pain 9 to 24 hours.

• Ropivacaine versus bupivacaine (one trial; 60 participants (Kucuk 2007)) (MD ‐0.05 cm VAS; 95% CI ‐0.25 to 0.16).

• Before pneumoperitoneum versus just after pneumoperitoneum (one trial; 60 participants (Barczynski 2006)) (MD 0.00 cm VAS; 95% CI ‐0.18 to 0.18).

• Just after creation of pneumoperitoneum versus end of surgery (two trials; 84 participants (Pasqualucci 1996; Karadeniz 2003)) (MD ‐0.31 cm VAS; 95% CI ‐1.64 to 1.02).

• Just after creation of pneumoperitoneum versus after end of surgery (one trial; 30 participants (Karadeniz 2003)) (MD 0.06 cm VAS; 95% CI ‐0.70 to 0.82).

• End of surgery versus after end of surgery (one trial; 30 participants (Karadeniz 2003)) (MD ‐0.30 cm VAS; 95% CI ‐1.32 to 0.72).

• Aerosol versus liquid (two trials; 100 participants (Alkhamesi 2007; Bucciero 2011)) (fixed‐effect model: MD ‐1.27 cm VAS; 95% CI ‐1.80 to ‐0.74; random‐effects model: MD ‐2.48 cm VAS; 95% CI ‐7.38 to 2.42).

We performed trial sequential analysis for two comparisons with more than one trial.

Just after creation of pneumoperitoneum versus after end of surgery

Trial sequential analysis revealed that the information fraction was too small (13.72%) to draw the futility area and the trial sequential boundaries for benefits or harms of the intervention were not crossed (Figure 8). The conventional statistical boundaries were also not crossed.

8.

Trial sequential analysis of pain (9 to 24 hours) (just after creation of pneumoperitoneum versus end of surgery) 
 The diversity‐adjusted required information size (DARIS) was 612 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 4.79, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D²) of 75.35%. After accruing 84 participants in two trials, only 13.72% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. Neither the conventional statistical boundaries (dotted red line) or the trial sequential monitoring boundaries (continuous red line) for benefits or harms of just after creation of pneumoperitoneum versus end of surgery were crossed by the cumulative Z curve (blue line).

Aerosol versus liquid

The proportion of information accrued was only 1.02% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 9). Although cumulative Z‐curve crossed the conventional statistical boundaries when the fixed‐effect model was used, the Z‐curve did not cross the conventional statistical boundaries when the random‐effects model was used.

9.

Trial sequential analysis of pain (9 to 24 hours) (aerosol versus liquid) 
 The diversity‐adjusted required information size (DARIS) was 9847 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 3.68, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D²) of 98.82%. After accruing 97 participants in two trials, only 1.02% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the trial sequential monitoring boundaries or the information size. Although the conventional statistical boundaries (dotted red line) is crossed by the cumulative Z‐curve (blue line) favouring aerosol, the conventional statistical boundaries were not crossed when the random‐effects model was used.

Sensitivity analysis

Either the mean or the standard deviation or both were imputed in two trials contributing to two different comparisons (Pasqualucci 1996; Alkhamesi 2007). Exclusion of these trials resulted in alteration of the results, that is, the significant differences in these comparisons were lost when these trials were excluded.

Return to normal activity

None of the trials reported return to normal activity.

Return to work

None of the trials reported return to work.

Subgroup analysis

We did not perform a subgroup analysis because all the trials were at high risk of bias and because of the few trials included under each comparison.

Reporting bias

We did not explore reporting bias by funnel plots because of the few trials included under each comparison.

Discussion

Summary of main results

In this review, we have compared the different methods of intraperitoneal instillation of local anaesthetic to reduce pain during laparoscopic cholecystectomy. We included 12 randomised clinical trials involving 798 participants for this systematic review. There were no significant differences in mortality or morbidity between the different methods of intraperitoneal instillation. The overall mortality after laparoscopic cholecystectomy is low (0.2%) (Giger 2011). In this review, the trials excluded high‐risk participants and we would anticipate that mortality would be even lower in these studies. To detect a 20% relative risk difference in mortality, more than 350,000 people are necessary. It is unlikely that trials will be powered to measure differences in mortality during laparoscopic cholecystectomy. Major complications are also rare. Three trials (331 participants) reported no serious complications due to surgery (Lee 2001; Karadeniz 2003; Khan 2012), or local anaesthetic and six trials (284 participants) stated that there were no complications related to local anaesthetic (Rademaker 1994; Pasqualucci 1996; Paulson 2003; Karaaslan 2006; Kucuk 2007; Bucciero 2011). One trial did not report the intra‐operative complications adequately but stated that one person developed lactic acidosis (Roberts 2011). Bupivacaine was used in this trial. Lactic acidosis has not been reported as a complication of local anaesthetic use (Martindale 2011). Overall, there were no serious adverse events related to local anaesthetics in the participants included in this review. The morbidity associated with local anaesthetics is very low with a reporting rate of approximately five adverse drug reactions per one million ampoules sold (Fuzier 2009). About 45% of these adverse drug reactions were serious (Fuzier 2009). Given the low morbidity associated with local anaesthetics and considering that laparoscopic cholecystectomy is performed under general anaesthesia with people likely to be monitored because of the use of other anaesthetic agents, the lack of adverse events reported in the trials is not surprising.

None of the trials reported quality of life, return to normal activity, and return to work. The main purpose of the local anaesthetic is to decrease pain enabling the participants to be discharged from hospital and to return to normal activity and work as early as possible. These outcomes are not only important for the patients but also important for the state‐funded health system.

While quality of life is the outcome that is used for assessing the cost‐effectiveness of an intervention, return to normal activity and return to work may also have relevance to the state in terms of lack of productivity of the individual. There were no significant differences in the hospital stay either in terms of proportion discharged as day‐surgery or in terms of the length of the hospital stay in the comparisons that reported these outcomes (Analysis 1.1; Analysis 1.2). These outcomes are important for the patients in a private health setting and for the state in a state‐funded health system because of the costs associated with hospital stay. However, only four trials reported this important outcome (Paulson 2003; Bucciero 2011; Roberts 2011; Khan 2012). Future trials on this topic should include these outcomes.

Although there were significant differences in the pain in some comparisons (Analysis 1.3; Analysis 1.4), these differences were not consistent or have been based on observation in a single trial and as such importance should not be attached to these differences. The clinical importance of these differences can be questioned with no significant differences in the reported clinical outcomes.

Overall completeness and applicability of evidence

All the trials included in this review included only people undergoing elective laparoscopic cholecystectomy (Included studies; Characteristics of included studies). Most trials included only low anaesthetic risk participants undergoing laparoscopic cholecystectomy (Included studies; Characteristics of included studies). The findings of this review are applicable only to such people.

Quality of the evidence

The overall quality of evidence is very low (Table 1). Although it is difficult to blind many interventions in surgery, this is one of the few interventions in which adequate blinding can be achieved and high‐quality evidence is possible. Nevertheless, this is the best evidence that is currently available.

Potential biases in the review process

We performed a thorough search of literature. However, we included 'pain' as one of the domains in this search strategy. Considering that reduction in pain is the main reason for the use of intraperitoneal local anaesthetic instillation, we expected that all the trials related to the topic would be identified, and given the number of trials included in this review, it is likely that most of the trials on this topic have been identified, However, it is possible that trials did not mention pain or words related to pain, and such trials might have been missed by this search strategy. The impact of this is likely to be small since it is likely that most trials would have mentioned the purpose of the use of the intervention. At least two review authors independently identified trials for inclusion and extracted data, thus minimising errors. However, we imputed the mean and standard deviation when these were not available. We performed a sensitivity analysis excluding the trials, which changed the results. This adds further confirmation that any significant differences noted in the trials were unreliable. The alternative was to present the data without imputing these values, which would have been even more confusing.

Agreements and disagreements with other studies or reviews

This is the first systematic review to compare the different methods of intraperitoneal local anaesthetic instillation in people undergoing laparoscopic cholecystectomy. We disagree with the authors of many trials in this review who recommended that it was preferable to administer the local anaesthetics by a certain method (Pasqualucci 1996; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Bucciero 2011; Roberts 2011). The reasons for different conclusions are likely to be the importance given to clinical outcomes in this review and the requirement for consistency in the effect to make firm recommendations.

Authors' conclusions

Implications for practice.

The evidence currently available is inadequate to determine the effects of one method of local anaesthetic intraperitoneal instillation compared with any other method of local anaesthetic intraperitoneal instillation in low anaesthetic risk individuals undergoing elective laparoscopic cholecystectomy.

Implications for research.

1. Further randomised clinical trials are necessary to evaluate the different methods of local anaesthetic intraperitoneal instillation in the emergency and in the elective set‐up.

2. Future trials should include quality of life, hospital stay, return to normal activity, and return to work as outcomes.

3. Future trials need to be designed according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (www.spirit‐statement.org/) and conducted and reported according to the CONSORT (Consolidated Standards for Reporting of Trials) Statement (www.consort‐statement.org).

Notes

This is one part of a protocol that was split following comments that the review was not readable because of the multiple outcomes and multiple analysis (Gurusamy 2008c). The protocol has been updated in line with the version 5.0.2 of the Cochrane Handbook for Systematic Reviews of Interventions, which was the latest version available at the time of writing the protocol (Higgins 2009).
 Change in authors and author order: Kurinchi Selvan Gurusamy, Myura Nagendran, Clare D Toon, Gian P Guerrini, Murat Zinnuroglu, Brian R Davidson.

Appendices

Appendix 1. Search strategies

Database	Period of search	Search strategy used
The Cochrane Central Register of Controlled Trials (CENTRAL)	Issue 1 of 12, 2013.	#1 laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop* #2 cholecystectom* #3 MeSH descriptor Cholecystectomy, Laparoscopic explode all trees #4 (( #1 AND #2 ) OR #3) #5 MeSH descriptor Injections, Intraperitoneal explode all trees #6 MeSH descriptor Peritoneum explode all trees #7 intraperitoneal OR intra‐peritoneal OR peritoneum #8 (#5 OR #6 OR #7) #9 MeSH descriptor Anesthetics, Local explode all trees #10 MeSH descriptor Anesthesia, Local explode all trees #11 MeSH descriptor Amides explode all trees #12 anaesthesia OR anesthesia OR anaesthetic OR anesthetic OR "Huneke neural therapy" OR "Neural therapy of Huneke" OR benzocaine OR bensokain OR "Aminobenzoic Acid" OR "Aminobenzoate" OR bupivacain* OR buvacaina OR sensorcaine OR marcain* OR svedocain* OR levobupivacaine OR carticain* OR articain* OR dibucaine OR cinchocaine OR Cincain OR Nupercain* OR Sovcaine OR etidocaine OR duranest OR "W19053" OR "W 19053" OR "W‐19053" OR Lidocaine OR Lignocaine OR Octocaine OR Xylesthesin OR Xylocaine OR Dalcaine OR Xylocitin OR Xyloneural OR Mepivacain* OR Carbocaine OR Polocaine OR isocaine OR isogaine OR Scandicain* OR prilocaine OR Propitocaine OR Tetracaine OR Tetrakain OR Amethocaine OR Dicaine OR Pantocaine OR Pontocaine OR Trimecaine OR Mesocaine OR ropivacaine #13 (#9 OR #10 OR #11 OR #12) #14 MeSH descriptor Pain explode all trees #15 pain OR ache* OR suffering* #16 (#14 OR #15) #17 (#4 AND #8 AND #13 AND #16)
MEDLINE (PubMed)	January 1987 to March 2013.	(laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*) AND (cholecystectom* OR "cholecystectomy, laparoscopic"[MeSH]) AND ("Injections, Intraperitoneal"[Mesh]) OR "Peritoneum"[Mesh] OR intraperitoneal OR intra‐peritoneal OR peritoneum) AND ("Anesthetics, Local"[Mesh] OR "Anesthesia, Local"[Mesh] OR "Anesthetics, Local "[Pharmacological Action] OR "Amides"[Mesh] OR anaesthesia OR anesthesia OR anaesthetic OR anesthetic OR "Huneke neural therapy" OR "Neural therapy of Huneke" OR benzocaine OR bensokain OR "Aminobenzoic Acid" OR "Aminobenzoate" OR bupivacain* OR buvacaina OR sensorcaine OR marcain* OR svedocain* OR levobupivacaine OR carticain* OR articain* OR dibucaine OR cinchocaine OR Cincain OR Nupercain* OR Sovcaine OR etidocaine OR duranest OR "W19053" OR "W 19053" OR "W‐19053" OR Lidocaine OR Lignocaine OR Octocaine OR Xylesthesin OR Xylocaine OR Dalcaine OR Xylocitin OR Xyloneural OR Mepivacain* OR Carbocaine OR Polocaine OR isocaine OR isogaine OR Scandicain* OR prilocaine OR Propitocaine OR Tetracaine OR Tetrakain OR Amethocaine OR Dicaine OR Pantocaine OR Pontocaine OR Trimecaine OR Mesocaine) AND ("Pain"[Mesh] OR pain OR ache* OR suffering*) AND (((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp]) NOT (animals [mh] NOT human [mh]))))
EMBASE (OvidSP)	January 1987 to March 2013.	1 exp CROSSOVER PROCEDURE/ 2 exp DOUBLE BLIND PROCEDURE/ 3 exp SINGLE BLIND PROCEDURE/ 4 exp RANDOMIZED CONTROLLED TRIAL/ 5 (((RANDOM* or FACTORIAL* or CROSSOVER* or CROSS) and OVER*) or PLACEBO* or (DOUBL* and BLIND*) or (SINGL* and BLIND*) or ASSIGN* or ALLOCAT* or VOLUNTEER*).af. 6 1 or 2 or 3 or 4 or 5 7 (laparoscop* or coelioscop* or celioscop* or peritoneoscop*).af. 8 "cholecystectom*".af. 9 8 and 7 10 exp Cholecystectomy/ 11 exp Laparoscopic Surgery/ 12 11 and 10 13 9 or 12 14 exp Local Anesthetic Agent/ 15 (anaesthesia or anesthesia or anaesthetic or anesthetic or Huneke neural therapy or Neural therapy of Huneke or benzocaine or bensokain or Aminobenzoic Acid or Aminobenzoate or bupivacain* or buvacaina or sensorcaine or marcain* or svedocain* or levobupivacaine or carticain* or articain* or dibucaine or cinchocaine or Cincain or Nupercain* or Sovcaine or etidocaine or duranest or W19053 or W 19053 or W‐19053 or Lidocaine or Lignocaine or Octocaine or Xylesthesin or Xylocaine or Dalcaine or Xylocitin or Xyloneural or Mepivacain* or Carbocaine or Polocaine or isocaine or isogaine or Scandicain* or prilocaine or Propitocaine or Tetracaine or Tetrakain or Amethocaine or Dicaine or Pantocaine or Pontocaine or Trimecaine or Mesocaine or ropivacaine).af. 16 14 or 15 17 exp Pain/ 18 (pain or ache* or suffering*).af. 19 17 or 18 21 6 and 13 and 17 and 20
Science Citation Index Expanded (Web of Knowledge)	January 1987 to March 2013.	#1 TS=(laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*) #2 TS=(cholecystectom*) #3 TS=(intraperitoneal OR intra‐peritoneal OR peritoneum) #4 TS=(anaesthesia OR anesthesia OR anaesthetic OR anesthetic OR (Huneke neural therapy) OR (Neural therapy of Huneke) OR benzocaine OR bensokain OR (Aminobenzoic Acid) OR Aminobenzoate OR bupivacain* OR buvacaina OR sensorcaine OR marcain* OR svedocain* OR levobupivacaine OR carticain* OR articain* OR dibucaine OR cinchocaine OR Cincain OR Nupercain* OR Sovcaine OR etidocaine OR duranest OR W19053 OR (W 19053) OR (W‐19053)) #5 TS=( Lidocaine OR Lignocaine OR Octocaine OR Xylesthesin OR Xylocaine OR Dalcaine OR Xylocitin OR Xyloneural OR Mepivacain* OR Carbocaine OR Polocaine OR isocaine OR isogaine OR Scandicain* OR prilocaine OR Propitocaine OR Tetracaine OR Tetrakain OR Amethocaine OR Dicaine OR Pantocaine OR Pontocaine OR Trimecaine OR Mesocaine OR ropivacaine) #6 #5 OR #4 #7 TS=(pain OR ache* OR suffering*) #8 #7 AND #6 AND #3 AND #2 AND #1

Data and analyses

Comparison 1. Intervention versus control.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion discharged as day‐surgery	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 Just after creation of pneumoperitoneum versus end of surgery	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.65, 1.50]
1.2 Subdiaphragmatic instillation versus gallbladder bed instillation	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	1.56 [0.76, 3.19]
2 Hospital stay	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.1 Aerosol versus liquid	1	60	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.13, 0.13]
2.2 Bupivacaine versus lignocaine	1	206	Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.16, 0.36]
3 Pain 4 to 8 hours	8		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1 Bupivacaine versus lignocaine	1	30	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐6.53, 2.53]
3.2 Ropivacaine versus bupivacaine	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.22 [‐0.79, 0.35]
3.3 Before pneumoperitoneum versus just after creation of pneumoperitoneum	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐0.53, ‐0.07]
3.4 Just after creation of pneumoperitoneum versus end of surgery	2	84	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐1.41, 0.20]
3.5 Just after creation of pneumoperitoneum versus after end of surgery	1	30	Mean Difference (IV, Fixed, 95% CI)	1.28 [0.08, 2.48]
3.6 End of surgery versus after end of surgery	1	30	Mean Difference (IV, Fixed, 95% CI)	0.95 [‐0.41, 2.31]
3.7 Aerosol versus liquid	2	100	Mean Difference (IV, Fixed, 95% CI)	‐2.20 [‐2.89, ‐1.50]
3.8 Subdiaphragmatic versus gallbladder bed instillation	1	82	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.01, 0.41]
4 Pain 9 to 24 hours	6		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
4.1 Ropivacaine versus bupivacaine	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.25, 0.16]
4.2 Before pneumoperitoneum versus just after creation of pneumoperitoneum	1	60	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.18, 0.18]
4.3 Just after creation of pneumoperitoneum versus end of surgery	2	84	Mean Difference (IV, Fixed, 95% CI)	‐0.28 [‐0.95, 0.38]
4.4 Just after creation of pneumoperitoneum versus after end of surgery	1	30	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.70, 0.82]
4.5 End of surgery versus after end of surgery	1	30	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.32, 0.72]
4.6 Aerosol versus liquid	2	100	Mean Difference (IV, Fixed, 95% CI)	‐1.27 [‐1.80, ‐0.74]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Alkhamesi 2007.

Methods	Randomised clinical trial.
Participants	Country: UK. Sample size: 80. Post‐randomisation drop‐out: not stated. Revised sample size: 40. Females: 35 (87.5%). Mean age: 50 years. Inclusion criteria: Elective laparoscopic cholecystectomy. ASA I or II. Age ≥ 18 years. Exclusion criteria: Allergy to bupivacaine or other drugs used in the protocol. History of drug abuse. Regular NSAID intake. Diagnosed malignancy.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: bupivacaine; 0.5%; 10 mL; aerosol ; end of surgery; diffuse; bolus administration (n = 20). Group 2: bupivacaine; 0.5%; 10 mL; liquid ; end of surgery; gallbladder bed; bolus administration (n = 20).
Outcomes	Pain.
Notes	Authors provided information on random sequence generation in April 2008. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the selection was based on computer program" (author replies).
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "All the patients, junior medical staff, and nursing staff in recovery and the wards were blinded to the study. The operating surgeons and the anesthetist were aware of the study protocol, but were blinded to the contents of the aerosol and the injected solutions".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and serious adverse events were not reported.
For‐profit bias	High risk	Quote: "We also acknowledge the help of Northgate Technologies, Chicago, USA, and Trudell Medical, Ontario, Canada, for their help in manufacturing the nebulizer machine and the intraperitoneal catheters". Comment: Probably sponsored by industry.

Barczynski 2006.

Methods	Randomised clinical trial.
Participants	Country: Poland. Sample size: 60. Post‐randomisation drop‐out: 0 (0%). Revised sample size: 60. Females: 53 (88.3%). Mean age: 49 years. Inclusion criteria: Uncomplicated, symptomatic cholelithiasis. ASA I or II. Age ≥ 18 years. Exclusion criteria: Allergy to local anaesthetics. Regular NSAID intake. Pregnancy and lactation. Previous extensive abdominal surgery.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: bupivacaine; 1 mg/kg; diluted in 200 mL with saline; liquid; before pneumoperitoneum ; diffuse; bolus administration (n = 30). Group 2: bupivacaine; 1 mg/kg; diluted in 200 mL with saline; liquid; just after creation of pneumoperitoneum ; diffuse; bolus administration (n = 30).
Outcomes	Intra‐operative complications and pain.
Notes	Attempts were made to contact the authors in August 2013. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomization was based on each patient receiving a sealed envelope containing a random number selected from the table".
Allocation concealment (selection bias)	Low risk	Quote: "The randomization was based on each patient receiving a sealed envelope containing a random number selected from the table".
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Quote: "Double‐blinded". Comment: The groups that were blinded was not stated.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: There were no post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Authors reported that there were no intra‐operative complications. It was not clear whether there were any post‐operative complications.
For‐profit bias	Unclear risk	Comment: This information was not available.

Bucciero 2011.

Methods	Randomised clinical trial.
Participants	Country: Italy. Number randomised: 60. Post‐randomisation drop‐outs: 3 (5%). Revised sample size: 57. Mean age: 48 years. Females: 32 (56.1%). Inclusion criteria: Age 18 to 70 years. ASA status I to III. Scheduled to undergo elective laparoscopic cholecystectomy. Exclusion criteria: Clinical diagnosis of acute pancreatitis. Acute preoperative pain other than biliary colic. Required chronic pain treatment or antiepileptic drugs. History of alcohol or drug addiction. Severe hepatic or renal impairment. Allergy to the study drugs. Pregnant or lactating. Predictable possibility of requiring open cholecystectomy. Cognitive impairment or communication problems.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: ropivacaine; 0.5%; 3 mL twice; aerosol ; just after creation of pneumoperitoneum and end of surgery; diffuse; bolus administration (n = 27). Group 2: ropivacaine; 0.5%; 20 mL twice; liquid ; just after creation of pneumoperitoneum and end of surgery; gallbladder bed; bolus administration (n = 30).
Outcomes	Local anaesthetic‐related complications, pain, and hospital stay.
Notes	Reasons for post‐randomisation drop‐outs: converted to open procedure (n = 3 in aerosol group). The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomized to 1 of 2 groups using a computer‐generated randomization sequence".
Allocation concealment (selection bias)	Low risk	Quote: "A research assistant not involved in patient care confirmed patient eligibility, obtained written consent, and gave the sealed white envelope containing patient allocation and instructions for the solution preparation to a previously trained anesthesia nurse who was not involved in the study".
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "The solutions were prepared in one 20‐mL transparent syringe containing ropivacaine 0.5% or normal saline and two 5‐mL transparent syringes containing 3 mL of ropivacaine 1% or 3 mL of normal saline according to the randomization sequence. To maintain blinding, the re‐ search assistant was not allowed to enter the operating room when the study solutions were being prepared. In case of an emergency related to or possibly related to the study or study drugs, the nurse was authorized to disclose the contents of the syringe to the anesthesiologist in charge of the case who was not involved in the study and to the research assistant".
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Low risk	Quote: "Financial support from departmental and institutional funding of the Department of Experimental Medicine Milan Bicocca University, Italy, and from the Service d’Anesthesiologie ‐ Reanimation Chirurgicale, CHU de Hautepierre, Strasbourg, France".

Karaaslan 2006.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Sample size: 62. Post‐randomisation drop‐out: 12 (19.4%). Revised sample size: 50. Females: 31 (62.0%). Mean age: 51 years. Inclusion criteria: Elective laparoscopic cholecystectomy. ASA I or II. Exclusion criteria: Allergy to local anaesthetics. Requiring fentanyl in the last 30 minutes of operation. Requiring naloxone at the end of operation. Required pethidine after operation.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: bupivacaine; 0.5%; 20 mL; liquid; before pneumoperitoneum ; gallbladder bed; bolus administration (n = 16). Group 2: bupivacaine; 0.5%; 20 mL; liquid; just after creation of pneumoperitoneum ; gallbladder bed; bolus administration (n = 18). Group 3: bupivacaine; 0.5%; 20 mL; liquid; end of surgery ; gallbladder bed; bolus administration (n = 16).
Outcomes	Local anaesthetic‐related complications.
Notes	Reasons for post‐randomisation drop‐out: Required opiates intraoperatively (n = 9) and postoperatively (n = 3). Attempts were made to contact the authors in April 2008. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "Patients were blinded as to the analgesic regimen that they received intraoperatively……. All assessments were performed by a single observer who was blinded to group allocations".
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Karadeniz 2003.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Sample size: 51. Post‐randomisation drop‐out: 6 (11.8%). Revised sample size: 45. Females: 34 (75.6%). Mean age: 29 years. Inclusion criteria: Elective laparoscopic cholecystectomy. Aged 25 to 65 years. ASA I or II. Exclusion criteria: Allergy to local anaesthetics. Acute cholecystitis.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: bupivacaine; 0.5%; 20 mL; liquid; just after creation of pneumoperitoneum ; subdiaphragmatic and gallbladder bed; bolus administration (n = 15). Group 2: bupivacaine; 0.5%; 20 mL; liquid; end of surgery ; subdiaphragmatic and gallbladder bed; bolus administration (n = 15). Group 3: bupivacaine; 0.5%; 20 mL; liquid; after end of surgery ; subdiaphragmatic and gallbladder bed; continuous infusion (n = 15).
Outcomes	Mortality, morbidity, and pain.
Notes	Reasons for post‐randomisation drop‐out: conversion to open cholecystectomy (n = 3) and requirement for drain insertion (n = 3). Attempts were made to contact the authors in April 2008. Authors provided replies in April 2008. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "We used random number table".
Allocation concealment (selection bias)	Low risk	Quote: "It was held by third party".
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	Low risk	Comment: Mortality and morbidity were reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Khan 2012.

Methods	Randomised clinical trial.
Participants	Country: Pakistan. Number randomised: 224. Post‐randomisation drop‐outs: 18 (8%). Revised sample size: 206. Mean age: 44 years. Females: 136 (66.0%). Inclusion criteria: Adults undergoing elective laparoscopic cholecystectomy. ASA status I or II. Exclusion criteria: Refused consent. Acute cholecystitis. History of long‐term analgesic use. Allergy to local anaesthetic agents. Pre‐operative cholangiogram or common bile duct exploration. People with stone spillage during the procedure. Conversion to open procedure or re‐exploration.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: b upivacaine; 0.5%; 10 mL; liquid; just after creation of pneumoperitoneum and end of surgery; subdiaphragmatic and gallbladder bed; bolus administration (n = 100). Group 2: l ignocaine; 2%; 10 mL; liquid; just after creation of pneumoperitoneum and end of surgery; subdiaphragmatic and gallbladder bed; bolus administration (n = 106).
Outcomes	Mortality, morbidity, and hospital stay.
Notes	Reasons for post‐randomisation drop‐outs: converted to open procedure (n = 3); additional procedure performed (n = 2); gallbladder perforation and stone spillage during procedure (n = 13). Attempts were made to contact the authors in August 2013. Authors provided replies. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed by computer‐generated envelopes".
Allocation concealment (selection bias)	Low risk	Quote: "The sequence were generated randomly and each sequence was separately printed. The printed papers were sequentially placed in opaque envelopes and numbered accordingly. A new envelope was sequentially opened and used for the patients" (author replies).
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "The patient, surgeon, and data collectors were unaware of the medication given to the patient".
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	Low risk	Comment: Mortality and morbidity were reported.
For‐profit bias	Low risk	Quote: "This project was funded by Grant 091026SUR from the University Research Council of the Aga Khan University".

Kucuk 2007.

Methods	Randomised clinical trial.
Participants	Country: Turkey. Sample size: 60. Post‐randomisation drop‐out: not stated. Revised sample size: 60. Females: 52 (86.7%). Mean age: 49 years. Inclusion criteria: Laparoscopic cholecystectomy. ASA I or II. Exclusion criteria: Morbid obesity. Severe chronic disease. Allergic reactions to NSAIDs or local anaesthetics. Chronic opioid treatment. Acute cholecystitis. Conversion to an open procedure.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: ropivacaine ; 1.5%; 10 mL; liquid; end of surgery; subdiaphragmatic and gallbladder bed; bolus administration (n = 20). Group 2: ropivacaine ; 1%; 10 mL; liquid; end of surgery; subdiaphragmatic and gallbladder bed; bolus administration (n = 20). Group 3: bupivacaine ; 0.5%; 10 mL; liquid; end of surgery; subdiaphragmatic and gallbladder bed; bolus administration (n = 20). All 3 groups had 1 mL of 1:200,000 adrenaline (epinephrine) added.
Outcomes	Local anaesthetic‐related complications and pain.
Notes	Attempts were made to contact the authors in April 2008. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: This was a placebo‐controlled trial. However, the groups that were blinded to the drug were not reported.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Lee 2001.

Methods	Randomised clinical trial.
Participants	Country: South Korea. Sample size: 88. Post‐randomisation drop‐out: 8 (9.1%). Revised sample size: 80. Females: 37 (46.3%). Mean age: 47 years. Inclusion criteria: Elective laparoscopic cholecystectomy. ASA I or II. Exclusion criteria: Allergic to local anaesthetics. Severe systemic disease. Chronic pain diseases other than gallstone disease were excluded. Acute cholecystitis before the operation.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: bupivacaine; 0.25%; 40 ml; liquid; just after creation of pneumoperitoneum ; subdiaphragmatic and gallbladder bed; bolus administration (n = 20). Group 2: bupivacaine; 0.25%; 40 ml; liquid; end of surgery ; subdiaphragmatic and gallbladder bed; bolus administration (n = 19). Group 3: same as group 1 but without wound infiltration with local anaesthetic (n = 20). Group 4: same as group 2 but without wound infiltration with local anaesthetic (n = 21). All 4 groups had 1:200,000 epinephrine (adrenaline).
Outcomes	Mortality and morbidity.
Notes	Reasons for post‐randomisation drop‐out: not stated. Attempts were made to contact the authors in April 2008. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "No patients or observers were informed of the treatment group (preoperative or postoperative)".
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	Low risk	Comment: Mortality and morbidity were reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Pasqualucci 1996.

Methods	Randomised clinical trial.
Participants	Country: Italy. Sample size: 60. Post‐randomisation drop‐out: 6 (10.0%). Revised sample size: 54. Females: 31 (57.4%). Mean age: 45 years. Inclusion criteria: Elective laparoscopic cholecystectomy. ASA I or II. Exclusion criteria: Allergy to local anaesthetics. History of severe pulmonary or hormonal diseases. Acute cholecystitis.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: bupivacaine; 0.5%; 20 mL; liquid; just after creation of pneumoperitoneum ; subdiaphragmatic and gallbladder bed; bolus administration (n = 26). Group 2: bupivacaine; 0.5%; 20 mL; liquid; end of surgery ; subdiaphragmatic and gallbladder bed; bolus administration (n = 28). Both groups received 1:200,000 epinephrine (adrenaline).
Outcomes	Local anaesthetic‐related complications and pain.
Notes	Reasons for post‐randomisation drop‐out: not stated Attempts were made to contact the author in April 2008. Although authors replied, no additional information was provided. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Paulson 2003.

Methods	Randomised clinical trial.
Participants	Country: USA. Sample size: 33. Post‐randomisation drop‐out: not stated. Revised sample size: 33. Females: 26 (78.8%). Mean age: 40 years. Inclusion criteria: Elective laparoscopic cholecystectomy starting before noon. ASA I or II. Age > 18 years. Exclusion criteria: Allergy to study medications.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: bupivacaine; 0.5%; 15 mL; liquid; just after creation of pneumoperitoneum ; subdiaphragmatic and gallbladder bed; bolus administration (n = 18). Group 2: bupivacaine; 0.5%; 15 mL; liquid; end of surgery ; subdiaphragmatic and gallbladder bed; bolus administration (n = 15).
Outcomes	Local anaesthetic‐related complications and discharge as day‐surgery.
Notes	Attempts were made to contact the authors in April 2008. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Low risk	Quote: "The pharmacy randomized the patients to one of four study groups" (only 2 groups were included for this review).
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "The pharmacy then sent two syringes (A and B) containing either 15 cc of 0.5% bupivacaine or 15 cc of normal saline with the patient to the operating room". Comment: Syringe A was used just after creation of pneumoperitoneum and Syringe B was used towards the end of surgery. This ensured blinding.
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Rademaker 1994.

Methods	Randomised clinical trial.
Participants	Country: Netherlands. Sample size: 30. Post‐randomisation drop‐out: not stated. Revised sample size: 30. Females: 24 (80.0%). Mean age: 46 years. Inclusion criteria: Elective laparoscopic cholecystectomy. ASA I or II.
Interventions	The participants were randomly assigned to 1 of the following groups. Group 1: b upivacaine ; 0.25%; 20 mL; liquid; end of surgery; subdiaphragmatic area; bolus administration (n = 15). Group 2: l ignocaine ; 0.5%; 20 mL; liquid; end of surgery; subdiaphragmatic area; bolus administration (n = 15).
Outcomes	Local anaesthetic‐related complications and pain.
Notes	Attempts were made to contact the authors in April 2008. The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: This information was not available.
Allocation concealment (selection bias)	Unclear risk	Comment: This information was not available.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Comment: This information was not available.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: This information was not available.
Selective reporting (reporting bias)	High risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

Roberts 2011.

Methods	Randomised clinical trial.
Participants	Country: UK. Number randomised: 84. Post‐randomisation drop‐outs: 1 (1.2%). Revised sample size: 83. Mean age: 52 years. Females: 66 (79.5%). Inclusion criteria: Adults undergoing elective laparoscopic cholecystectomy. Exclusion criteria: Emergency laparoscopic cholecystectomy. Undergoing additional planned procedures intraoperatively.
Interventions	Participants were randomly assigned to 1 of the following groups. Group 1: bupivacaine; 0.25%; 20 mL; liquid; just after creation of pneumoperitoneum; subdiaphragmatic area ; bolus administration (n = 42). Group 2: bupivacaine; 0.25%; 20 mL; liquid; just after creation of pneumoperitoneum; gallbladder bed ; bolus administration (n = 41).
Outcomes	Hospital stay and pain.
Notes	Reasons for post‐randomisation drop‐outs: Converted to open procedure (n = 1); acidosis following anaesthesia (n = 1). The main difference between the intervention and control are shown in bold and italics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: This information was not available. Quote: "The randomisation sequence (computer‐generated) and sample size calculation were kindly provided by Dr. N. Parsons, medical statistician at the University of Warwick, UK".
Allocation concealment (selection bias)	Unclear risk	Quote: "Randomisation was performed by opening sequentially numbered sealed envelopes in the operating theatre as part of the nursing staff’s preparation, with the operating surgeons outside of theatre". Comment: Not clear whether envelopes were opaque.
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "Patients, anaesthetists, operating surgeons, recovery nursing, ward medical, and nursing staff were all blinded to the study".
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: There were post‐randomisation drop‐outs.
Selective reporting (reporting bias)	Unclear risk	Comment: Mortality and morbidity were not reported.
For‐profit bias	Unclear risk	Comment: This information was not available.

ASA: American Society of Anesthesiologists; NSAID: non‐steroidal anti‐inflammatory drug.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Ahmed 2008	30 (15%) participants were excluded because of various reasons and were replaced by other participants. We consider that this will result in inadequate randomisation.
Alptekin 2010	The doses in the 2 groups were different.
Bayar 1998	Not a randomised clinical trial. This trial did not report treatment‐related complications.
Pappas‐Gogos 2008	7 participants (5.8%) were excluded post‐randomisation and were replaced by new participants to 'maintain homogeneity'. This introduced selection bias.
Pasqualucci 1994	In this trial, the dose of local anaesthetic varied in addition to the timing of local anaesthetic instillation.

Differences between protocol and review

1. The outcomes have been revised based on importance to the participants and not according to the expected treatment effect. As a result, pain was moved to a secondary outcome as mortality was considered to be more important than pain. With regards to quality of life, we accepted only validated scales of quality of life such as Euro‐QoL, SF‐36 since using unvalidated other scales may be misleading. With regards to pain, we limited pain to 4 to 8 hours and 9 to 24 hours since this is the time period that most people are discharged. We also included only trials that reported pain on the visual analogue scale. Even this is difficult to interpret (see Discussion) but using other scales would make it even more difficult to interpret. We added other outcomes, such as return to normal activity and return to work, which are very important to the patient. We have excluded analgesic requirement, which was considered a surrogate to pain. Any clinically significant differences in pain would be captured by quality of life, return to normal activity, and return to work. By altering the outcomes, we have harmonised the outcomes in this review with other reviews aimed at decreasing pain in people undergoing laparoscopic cholecystectomy.

2. We have added an additional subgroup analysis 'elective versus emergency laparoscopic cholecystectomy' in the methods section. We did not perform any subgroup analysis because of the few trials included under each comparison.

3. We have added section on trial sequential analysis to control for random errors.

Contributions of authors

KS Gurusamy assessed the trials for inclusion, extracted data for some studies, performed the analysis, interpreted the information, and wrote the review.

C Toon, GP Guerrini, and M Zinnuroglu independently assessed the trials for inclusion and extracted data on some included trials.

M Nagendran extracted data for some included studies.

BR Davidson critically commented on the review.

All authors agreed on the final version of the review.

Sources of support

Internal sources

• None, Other.

External sources

• National Institute for Health Research, UK.

Declarations of interest

None known.

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