Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy.

Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy (Review) Gurusamy KS, Nagendran M, Guerrini GP, Toon CD, Zinnuroglu M, Davidson BR

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 3 http://www.thecochranelibrary.com

Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . . . Figure 7. . . . . . . . . . . . . . . . . . . Figure 8. . . . . . . . . . . . . . . . . . . Figure 9. . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . NOTES . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . .

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[Intervention Review]

Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy Kurinchi Selvan Gurusamy1 , Myura Nagendran2 , Gian Piero Guerrini3 , Clare D Toon4 , Murat Zinnuroglu5 , Brian R Davidson1 1 Department of Surgery, Royal Free Campus, UCL Medical School, London, UK. 2 UCL Division of Surgery and Interventional Science, Department of Surgery, London, UK. 3 Department of Surgery, Ravenna Hospital, Ravenna, Italy. 4 Public Health, West Sussex County Council, Chichester, UK. 5 Gazi University Medical Faculty, Physical Medicine and Rehabilitation/Algology and Clinical Neurophysiology, Ankara, Turkey

Contact address: Kurinchi Selvan Gurusamy, Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK. [email protected]. Editorial group: Cochrane Hepato-Biliary Group. Publication status and date: New, published in Issue 3, 2014. Review content assessed as up-to-date: 14 March 2013. Citation: Gurusamy KS, Nagendran M, Guerrini GP, Toon CD, Zinnuroglu M, Davidson BR. Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD007337. DOI: 10.1002/14651858.CD007337.pub3. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background While laparoscopic cholecystectomy is generally considered less painful than open surgery, pain is one of the important reasons for delayed discharge after day surgery and overnight stay laparoscopic cholecystectomy. The safety and effectiveness of intraperitoneal local anaesthetic instillation in people undergoing laparoscopic cholecystectomy is unknown. Objectives To assess the benefits and harms of intraperitoneal instillation of local anaesthetic agents in people undergoing laparoscopic cholecystectomy. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded to March 2013 to identify randomised clinical trials of relevance to this review. Selection criteria We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing local anaesthetic intraperitoneal instillation versus placebo, no intervention, or inactive control during laparoscopic cholecystectomy for the review with regards to benefits while we considered quasi-randomised studies and non-randomised studies for treatment-related harms. 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). Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results We included 58 trials, of which 48 trials with 2849 participants randomised to intraperitoneal local anaesthetic instillation (1558 participants) versus control (1291 participants) contributed data to one or more of the outcomes. All the trials except one trial with 30 participants were at high risk of bias. Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. Various intraperitoneal local anaesthetic agents were used but bupivacaine in the liquid form was the most common local anaesthetic used. There were considerable differences in the methods of local anaesthetic instillation including the location (subdiaphragmatic, gallbladder bed, or both locations) and timing (before or after the removal of gallbladder) between the trials. There was no mortality in either group in the eight trials that reported mortality (0/236 (0%) in local anaesthetic instillation versus 0/210 (0%) in control group; very low quality evidence). One participant experienced the outcome of serious morbidity (eight trials; 446 participants; 1/236 (0.4%) in local anaesthetic instillation group versus 0/210 (0%) in the control group; RR 3.00; 95% CI 0.13 to 67.06; very low quality evidence). Although the remaining trials did not report the overall morbidity, three trials (190 participants) reported that there were no intra-operative complications. Twenty trials reported that there were no serious adverse events in any of the 715 participants who received local anaesthetic instillation. None of the trials reported participant quality of life, return to normal activity, or return to work. The effect of local anaesthetic instillation on the proportion of participants discharged as day surgery between the two groups was imprecise and compatible with benefit and no difference of intervention (three trials; 242 participants; 89/160 (adjusted proportion 61.0%) in local anaesthetic instillation group versus 40/82 (48.8%) in control group; RR 1.25; 95% CI 0.99 to 1.58; very low quality evidence). The MD in length of hospital stay was 0.04 days (95% CI -0.23 to 0.32; five trials; 335 participants; low quality evidence). The pain scores as measured by the visual analogue scale (VAS) were significantly lower in the local anaesthetic instillation group than the control group at four to eight hours (32 trials; 2020 participants; MD -0.99 cm; 95% CI -1.10 to -0.88 on a VAS scale of 0 to 10 cm; very low quality evidence) and at nine to 24 hours (29 trials; 1787 participants; MD -0.53 cm; 95% CI -0.62 to -0.44; very low quality evidence). Various subgroup analyses and meta-regressions to investigate the influence of the different local anaesthetic agents, different methods of local anaesthetic instillation, and different controls on the effectiveness of local anaesthetic intraperitoneal instillation were inconsistent. Authors’ conclusions Serious adverse events were rare in studies evaluating local anaesthetic intraperitoneal instillation (very low quality evidence). There is very low quality evidence that it reduces pain in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is unknown and likely to be small. 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 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 incision, also known as a port) is now the preferred method of cholecystectomy. While laparoscopic cholecystectomy is generally considered less painful than open surgery, 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) may be an effective way of decreasing the pain after laparoscopic cholecystectomy. However, the benefits and harms of intra-abdominal administration of local anaesthetics is unknown. We sought to answer these questions by reviewing the medical literature and obtaining information from randomised clinical trials with regards to benefits and other comparative study designs for treatment-related harms. When conducted correctly, randomised clinical studies provide the most accurate information on the best treatment. Two review authors searched the literature and obtained information from the studies thereby minimising errors. Study characteristics Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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We identified 58 trials, of which 48 randomised clinical trials involving 2849 people undergoing laparoscopic cholecystectomy contributed data to one or more of the outcomes. Most participants in the trials were low anaesthetic risk people undergoing planned laparoscopic cholecystectomy. The choice of whether the participants received local anaesthetic agents (or not) was determined by a method similar to the toss of a coin so that the treatments compared were conducted in people who were as similar as possible. Key results There were no deaths in either group in eight trials (446 participants) that reported deaths. The studies reported very few or no serious complications in the groups. There were no local anaesthetic-related complications in nearly 1000 participants who received intraabdominal local anaesthetic administration in the different trials that reported complications. 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 small differences in hospital stay between the two groups were imprecise. Pain scores were lower in the participants who received intra-abdominal local anaesthetic administration compared with those who received controls at four to eight hours and at nine to 24 hours as measured by the visual analogue scale (a chart that rates the amount of pain on a scale of 1 to 10). Quality of evidence Most of the trials were of high risk of bias, that means that 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. Overall, the quality of evidence was very low. Conclusions Serious adverse event rates were low in studies evaluating local anaesthetic intra-abdominal administration (very low quality evidence). There is very low quality evidence that local anaesthetic intra-abdominal administration reduces pain in low anaesthetic risk people undergoing planned laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is likely to be small. 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 laparoscopic cholecystectomy and the people who provide funds for the treatment.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Intraperitoneal local anaesthetic instillation compared with control for people undergoing laparoscopic cholecystectomy Patient or population: people undergoing laparoscopic cholecystectomy. Settings: secondary or tertiary. Intervention: intraperitoneal local anaesthetic instillation. Comparison: control. Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Control

Intraperitoneallocal anaesthetic instillation

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Mortality

No mortality in either group

Not estimable

446 (8 studies)

⊕

very low1,2

Serious adverse events

Moderate

RR 3 (0.13 to 67.06)

446 (8 studies)

⊕

very low1,2

RR 1.25 (0.99 to 1.58)

242 (3 studies)

⊕

very low1,2,3

20 per 1000

Proportion discharged as day 488 per 1000 surgery

60 per 1000 (3 to 1000) 610 per 1000 (439 to 771)

Hospital stay

The mean hospital stay in the The mean hospital stay in the control groups was intervention groups was 2.1 days 0.04 higher (0.23 lower to 0.32 higher)

335 (5 studies)

⊕⊕

low1

Pain (4 to 8 hours)

The mean pain (4 to 8 hours) The mean pain (4 to 8 hours) in the control groups was in the intervention groups was 3.5 cm VAS 0.99 lower (1.1 to 0.88 lower)

2020 (32 studies)

⊕

very low1,3

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Pain (9 to 24 hours)

The mean pain (9 to 24 hours) The mean pain (9 to 24 hours) in the control groups was in the intervention groups was 2.05 cm VAS 0.53 lower (0.62 to 0.44 lower)

1787 (29 studies)

⊕

very low1,3

*The basis for the assumed risk was the mean control group risk across studies for day-surgery proportion. Since there were no events in the control group in the trials included for serious adverse events, the control group proportion used was 2%. 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. 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. 3 There was severe heterogeneity as noted by the I2 statistic and the lack of overlap of confidence intervals. 2

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BACKGROUND

How the intervention might work Local anaesthetics inhibit voltage-gated sodium channels. This results in decreased excitability of nerves transmitting pain ( Butterworth 1990).

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, 0.5 million cholecystectomies are performed in the US and 70,000 in the UK (CDC 2013; HES 2013). Approximately 80% to 90% of the cholecystectomies are performed laparoscopically (keyhole surgery) (Ballal 2009; NHS Reference Costs 2013). While laparoscopic cholecystectomy is generally considered less painful than open surgery, pain is one of the important reasons for delayed discharge after laparoscopic cholecystectomy (Gurusamy 2008; Vaughan 2013). 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 unclear. 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 an overnight drain to let out the gas on the presumption that carbon dioxide in the subdiaphragmatic space is the reason for the pain has not been effective in the reduction of pain (Gurusamy 2013b).

Why it is important to do this review A review by Boddy 2006 et al. revealed that intraperitoneal instillation of local anaesthetic resulted in a reduction of the mean pain score although no reduction in analgesic requirement was noted). There were no adverse effects attributable to local anaesthetic. Another review reported similar results, although the meta-analysis in the review included only three trials and found no significant difference between local anaesthetic intraperitoneal instillation and placebo (Gupta 2005). In another review of randomised clinical trials, Bisgaard did not recommend routine use of intraperitoneal local anaesthetics because of conflicting results (Bisgaard 2006). We found no Cochrane systematic reviews assessing the benefits and harms of local anaesthetic agents in people undergoing laparoscopic cholecystectomy.

OBJECTIVES To assess the benefits and harms of intraperitoneal instillation of local anaesthetic agents in people undergoing laparoscopic cholecystectomy.

METHODS

Criteria for considering studies for this review 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 after laparoscopic cholecystectomy. 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 the diaphragm (Abdel-Raouf 2004), or as an aerolised spray in the general peritoneum (Alkhamesi 2007). The instillation can be performed either as a bolus or as a continuous infusion (Bayar 1998).

Types of studies We considered all randomised clinical trials (irrespective of language, blinding, publication status, or sample size) for inclusion. We excluded quasi-randomised studies (where the method of allocating participants to a treatment are not strictly random, for example, date of birth, hospital record number, alternation) and nonrandomised 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.


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Types of interventions We included only trials comparing intraperitoneal instillation of local anaesthetic agent (irrespective of the local anaesthetic agent used, timing of delivery, and the method of delivery) with no intraperitoneal instillation of local anaesthetic agent. We accepted any of the following control groups: normal saline, another placebo, or no instillation of any drug or fluid. Co-interventions were allowed if carried out equally in the trial groups.

(WHO ICTRP) (apps.who.int/trialsearch/) to March 2013. The WHO ICTRP portal allows search of various trial registers including clinicaltrials.gov and International Standard Randomised Controlled Trial Number (ISRCTN). 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.

Types of outcome measures

Data collection and analysis 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 person or required intervention to prevent it (ICH-GCP 1997). We classified complications such as bile duct injury; reoperations; 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. We classified complications such as wound infections, bile leaks, or abdominal collections that did not require any treatment and settled spontaneously as non-serious adverse events. 3. Patient quality of life (however defined by study authors using a validated scale such as Euro-QoL or 36-item Short-Form (SF-36)). Secondary outcomes

1. Hospital stay (length of hospital stay, proportion discharged as day-surgery laparoscopic cholecystectomy). 2. Pain (overall pain) at different time points (4 to 8 hours and 9 to 24 hours) using visual analogue scale (VAS). 3. Return to activity. 4. Return to work. We have reported all the outcomes that have at least one trial in the Summary of findings for the main comparison.

Search methods for identification of studies Electronic searches We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2013), MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003), and the World Health Organization International Clinical Trials Registry Platform portal

We performed the systematic review according to the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato-Biliary Group Module (Gluud 2013). 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 (Characteristics of excluded studies). 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 (see Primary outcomes; Secondary outcomes). 17. Risk of bias (see 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.


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We resolved any differences in opinion through discussion or arbitration of the third review 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 2013). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012a; Savovic 2012b), the risk of bias of the trials was assessed 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, have been 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. • 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 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 (eg, 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 publication’s results section on all outcomes specified in the trial objectives. 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 manipulate the trial design, conductance, or results of the trial. • Uncertain risk of bias: the trial may or may not have been free of for-profit bias as no information on clinical trial support or sponsorship was provided.


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• High risk of bias: the trial was sponsored by the industry or received other type 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.

Assessment of reporting biases We used visual asymmetry on a funnel plot to explore reporting bias since we identified more than 10 trials (Egger 1997; Macaskill 2001). We performed the linear regression approach described by Egger 1997 to determine the funnel plot asymmetry. Selective reporting was also considered as evidence for reporting bias.

Measures of treatment effect

Data synthesis

For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval (CI). We also calculated the risk difference (RD) with 95% CI. We planned to report the RD only if the conclusions were different from those of the RR. RD includes ’zero event trials’ (trials in which both groups had 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 the RR. 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 study authors use different scales of quality of life.

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 2013). We used both a random-effects model (DerSimonian 1986), and a fixedeffect 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.

Unit of analysis issues The units of analysis was the person about to undergo laparoscopic cholecystectomy and randomised to the intraperitoneal local anaesthetic instillation or control. Dealing with missing data We performed an intention-to-treat analysis whenever possible ( Newell 1992). We imputed data for binary outcomes using various scenarios such as best-best scenario, best-worst scenario, worstbest scenario, and worst-worst scenario (Gurusamy 2009; Gluud 2013). For continuous outcomes, we used an 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 less than 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.

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 will add the trials according to the year of publication, and, if more than one trial was published in a year, we will add the trials alphabetically according to the last name of the first author. On the basis of the required information size, we will construct 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 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 SMDs, 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, and an


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MD of 1 cm on the VAS (Todd 1996). For length of hospital stay, return to work, and return to activity, we planned to calculate the required sample size using an MD of one day with the remaining parameters kept the same as that for pain.

best-worst scenario, worst-best scenario, and worst-worst scenario (Gurusamy 2009; Gluud 2013). We performed a sensitivity analysis by excluding the trials in which the mean and the standard deviation were imputed.

Subgroup analysis and investigation of heterogeneity

’Summary of findings’ table

We planned to perform the following subgroup analyses. • Trials with low bias risk compared to trials with high bias risk. • Elective compared to emergency laparoscopic cholecystectomy. • Different local anaesthetic agents. • Maximum safe dose used (ie, whether the trials used the dose based on body weight). • Different timing of instillation. • Different locations of instillation. • Physical forms of local anaesthetic agent. • Bolus and continuous infusion. • Drain or no drain. • Peri-laparoscopic-portal infiltration with local anaesthetic. • Routine supplemental analgesia compared to no routine (’on-demand’) supplemental analgesia.

We have summarised the results of all the reported outcomes in Summary of findings for the main comparison, which was prepared using GRADEPro 3.6 (ims.cochrane.org/revman/ gradepro).

We used the ’test for subgroup differences’ available through Review Manager 5 (RevMan 2012) to identify the differences between subgroups. We used the random-effects model for this purpose. We also used meta-regression (in the presence of adequate number of trials) to determine the influence of the above factors on the effect estimate. We performed this for pain at four to eight hours and pain at nine to 24 hours (as these are the times at which day-procedure laparoscopic cholecystectomy and overnight stay laparoscopic cholecystectomy patients are discharged) using the ’metareg’ command of Stata/IC 11 (StataCorp LP). Sensitivity analysis We performed a sensitivity analysis by imputing data for binary outcomes using various scenarios such as best-best scenario,

RESULTS

Description of studies Results of the search We identified 474 references through electronic searches of CENTRAL (85 references), MEDLINE (127 references), EMBASE (105 references), and Science Citation Index Expanded (157 references). We did not identify any new trials from the trial registers. We excluded 84 duplicates and 289 clearly irrelevant references through reading abstracts. We retrieved 101 references for further assessment. We found no references through scanning reference lists of the identified randomised trials. We excluded 39 references for the reasons listed in the Characteristics of excluded studies table. Sixty-two references fulfilled the inclusion criteria. Of these 62 references, five were duplicate reports of the same trial (Joris 1995; Fuhrer 1996; Karadeniz 2003; Feroci 2009; Kim 2010). One report contained two trials (Raetzell 1995a; Raetzell 1995b). Thus, 58 randomised clinical trials were reported in the 62 included references. We did not identify any quasi-randomised studies or comparative non-randomised studies that reported treatment-related harms. The reference flow is shown in Figure 1.


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Figure 1. Study flow diagram.


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Included studies Of the 58 randomised clinical trials that fulfilled the inclusion criteria, nine trials did not provide any information for this systematic review (Joris 1995; Kilic 1996; Elhakim 2000; Abdel-Raouf 2004; Ng 2004; Jabbour-Khoury 2005; Hasan 2007; Razman 2010; El-Labban 2011). These trials reported some specific aspects of pain, for example, shoulder pain or abdominal pain, used other scales of pain or reported other outcomes such as stress response. One other trial did not report the number of participants randomised to the local anaesthetic and control groups (Raetzell 1995a). Thus, 48 randomised clinical trials including 2849 participants randomised to intraperitoneal local anaesthetic instillation (1558 participants) and control (1291 participants) were included in this review. In 28 trials, two arms were included for this review (Chundrigar 1993; Raetzell 1995b; Fornari 1996; Fuhrer 1996; Szem 1996; Mraovic 1997; Kolsi 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Maestroni 2002; Rudra 2002; Lepner 2003; Razek 2003; Hazinedaroglu 2006; Verma 2006; Garcia 2007; Alper 2009; Feroci 2009; Fu 2009; Golubovic 2009; Todorov 2009; Kim 2010; Zimmer 2010; Gvozdenovic 2011; Kallel 2011; Castillo-Garza 2012), that is, although some of these trials randomised participants to more than two arms, only two arms were eligible for inclusion in this review. In 20 trials, multiple arms were included for this review (Pasqualucci 1994; Rademaker 1994; Scheinin 1995; Pasqualucci 1996; Weber 1997; Ahmad 1998; Elfberg 2000; Lee 2001; Labaille 2002; Alagöl 2003; Karadeniz 2003; Paulson 2003; Louizos 2005; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Kucuk 2007; Nicolau 2008; Alptekin 2010; Roberts 2011). Thus, 72 comparisons were possible in the 48 randomised clinical trials that contributed data for this review.

Participant characteristics

Forty-one trials clearly stated that they included participants undergoing elective laparoscopic cholecystectomy (Chundrigar 1993; Pasqualucci 1994; Rademaker 1994; Fornari 1996; Fuhrer 1996; Pasqualucci 1996; Szem 1996; Mraovic 1997; Elfberg 2000; Kolsi 2000; Zmora 2000; Lee 2001; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Labaille 2002; Maestroni 2002; Rudra 2002; Karadeniz 2003; Lepner 2003; Paulson 2003; Razek 2003; Louizos 2005; Barczynski 2006; Hazinedaroglu 2006; Karaaslan 2006; Verma 2006; Alkhamesi 2007; Garcia 2007; Kucuk 2007; Nicolau 2008; Alper 2009; Feroci 2009; Fu 2009; Golubovic 2009; Alptekin 2010; Kim 2010; Zimmer 2010; Gvozdenovic 2011; Roberts 2011; Castillo-Garza 2012). In one trial, it was clear from the characteristics tables that people with acute cholecystitis were included (Todorov 2009). The inclusion of people

with acute cholecystitis was not reported in the remaining six trials (Raetzell 1995b; Scheinin 1995; Weber 1997; Ahmad 1998; Alagöl 2003; Kallel 2011). Thirty-three trials stated that they included only American Society of Anesthesiologists (ASA) status I or II (Pasqualucci 1994; Rademaker 1994; Scheinin 1995; Fornari 1996; Fuhrer 1996; Pasqualucci 1996; Mraovic 1997; Elfberg 2000; Kolsi 2000; Lee 2001; Bhardwaj 2002; Jiranantarat 2002; Labaille 2002; Maestroni 2002; Alagöl 2003; Karadeniz 2003; Paulson 2003; Razek 2003; Louizos 2005; Barczynski 2006; Hazinedaroglu 2006; Karaaslan 2006; Verma 2006; Alkhamesi 2007; Garcia 2007; Kucuk 2007; Alper 2009; Feroci 2009; Fu 2009; Golubovic 2009; Zimmer 2010; Kallel 2011; Roberts 2011). In one trial, only people who were ASA status I were included (Rudra 2002). In two trials, only people who were ASA status I to III were included (Lepner 2003; Kim 2010). In the remaining 12 trials, the ASA status of the participants was not reported (Chundrigar 1993; Raetzell 1995b; Szem 1996; Weber 1997; Ahmad 1998; Zmora 2000; Tunca 2001; Nicolau 2008; Todorov 2009; Alptekin 2010; Gvozdenovic 2011; Castillo-Garza 2012). Intervention

The details of the intervention in the different trials are summarised in the Characteristics of included studies table and Table 1. Control

In 38 trials, intraperitoneal normal saline (of equivalent volume as the intervention) was used for the control group (Chundrigar 1993; Pasqualucci 1994; Rademaker 1994; Raetzell 1995b; Scheinin 1995; Fornari 1996; Fuhrer 1996; Pasqualucci 1996; Szem 1996; Mraovic 1997; Ahmad 1998; Elfberg 2000; Kolsi 2000; Lee 2001; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Labaille 2002; Maestroni 2002; Rudra 2002; Alagöl 2003; Lepner 2003; Paulson 2003; Razek 2003; Louizos 2005; Barczynski 2006; Hazinedaroglu 2006; Garcia 2007; Kucuk 2007; Nicolau 2008; Alper 2009; Golubovic 2009; Todorov 2009; Kim 2010; Gvozdenovic 2011; Kallel 2011; Roberts 2011; Castillo-Garza 2012). In three trials, no intervention was used for the control (Karaaslan 2006; Feroci 2009; Alptekin 2010). In three trials, other controls such as fibrin sealant (Fu 2009) and normal salinesoaked cellulose strips (Zmora 2000; Verma 2006) were used. In these trials, local anaesthetic mixed with fibrin sealant (Fu 2009) or local anaesthetic-soaked cellulose strips were used as interventions (Zmora 2000; Verma 2006). One trial stated that a placebo was used without providing further information as to what the placebo solution was (Karadeniz 2003). In one trial, sterile water was used for the control (Zimmer 2010). In one four-armed


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trial, the control used was normal saline and normal saline aerosol (Alkhamesi 2007). In one three-armed trial, the control used was sterile water and no intervention (Weber 1997).

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 1.

Co-intervention

The details of norepinephrine (noradrenaline) use, the use of perilaparoscopic portal local anaesthetic wound infiltration, drain use, whether routine analgesia was used for supplemental analgesia in both groups are shown in Table 1. Further details about sample size, participant characteristics, the

Risk of bias in included studies One trial was at low risk of bias (Feroci 2009). All the remaining 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).

Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.


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Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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Allocation

Other potential sources of bias

Only six trials (6/58 (10.3%)) described random sequence generation and allocation concealment adequately (Joris 1995; Fornari 1996; Szem 1996; Barczynski 2006; Feroci 2009; Kim 2010). These six trials were considered to be at low risk of selection bias.

Four trials (4/58 (6.9%)) were considered to be at low risk of ’forprofit’ bias (Feroci 2009; Todorov 2009; Zimmer 2010; El-Labban 2011).

Blinding

Effects of interventions

Twenty-one trials (21/58 (36.2%)) 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 (Chundrigar 1993; Raetzell 1995a; Raetzell 1995b; Elfberg 2000; Zmora 2000; Lee 2001; Tunca 2001; Rudra 2002; Lepner 2003; Paulson 2003; Ng 2004; Hazinedaroglu 2006; Karaaslan 2006; Alkhamesi 2007; Garcia 2007; Alper 2009; Feroci 2009; Golubovic 2009; Kim 2010; Zimmer 2010; Roberts 2011).

See: Summary of findings for the main comparison Intraperitoneal local anaesthetic instillation compared with control for people undergoing laparoscopic cholecystectomy The main results are summarised in the Summary of findings for the main comparison.

Incomplete outcome data Fourteen trials (14/58 (24.1%)) had no post-randomisation dropouts and was considered to be at low risk of attrition bias (Lepner 2003; Razek 2003; Barczynski 2006; Hazinedaroglu 2006; Alper 2009; Feroci 2009; Fu 2009; Golubovic 2009; Todorov 2009; Kim 2010; Zimmer 2010; El-Labban 2011; Castillo-Garza 2012). Selective reporting Nine trials (9/58 (15.5%)) reported mortality and morbidity and were considered to be at low risk of selective reporting bias (Raetzell 1995a; Raetzell 1995b; Fornari 1996; Lee 2001; Karadeniz 2003; Lepner 2003; Feroci 2009; Zimmer 2010; Castillo-Garza 2012).

Mortality There was no mortality in either group in the eight trials that reported mortality (0/236 (0%) in local anaesthetic instillation versus 0/210 (0%) in control group) (Raetzell 1995b; Fornari 1996; Lee 2001; Lepner 2003; Karadeniz 2003; Feroci 2009; Zimmer 2010; Castillo-Garza 2012). 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 (Giger 2011). The proportion of information accrued was only 0.13% 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.


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Figure 4. Trial sequential analysis of mortalityThe 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 Zcurve (blue line). After accruing 446 participants in eight trials, only 0.13% 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.

Morbidity Eight trials reported serious adverse events (Raetzell 1995b; Fornari 1996; Lee 2001; Karadeniz 2003; Lepner 2003; Feroci 2009; Zimmer 2010; Castillo-Garza 2012). There was no significant difference in the proportion of people who developed the serious adverse events between intraperitoneal local anaesthetic instillation and inactive control groups (RR 3.00; 95% CI 0.13 to 67.06) (Analysis 1.2). There was only one serious adverse event in the local anaesthetic instillation group (1/236 (0.4%)) compared with no serious adverse events in the control group (0/210 (0%)) (Analysis 1.2). The serious adverse event was thrombophlebitis, which was unrelated to the local anaesthetic instillation. 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. Although the remaining trials did not report overall morbidity, three trials (190 participants; 100 participants received local anaesthetic and 90 participants received control) reported that there were no intra-operative complications (Barczynski 2006; Alptekin 2010; Kim 2010). Twenty trials reported that there were no serious adverse events in any of the 715 participants who received local anaesthetic instillation (Scheinin 1995; Pasqualucci 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Tunca 2001; Labaille 2002; Maestroni 2002; Rudra 2002; Paulson 2003; Razek 2003; Louizos 2005; Hazinedaroglu 2006; Karaaslan 2006;


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Garcia 2007; Kucuk 2007; Nicolau 2008; Alper 2009; Kallel 2011). The remaining trials did not report about the complications that participants developed. Since there was no serious adverse event in the control group in the meta-analysis, 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 1.29% 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. Figure 5. Trial sequential analysis of morbidityThe 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 446 participants in eight trials, only 1.29% 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.

Patient quality of life

None of the trials reported patient quality of life.

Hospital stay

Proportion discharged as day surgery


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Three trials (242 participants; 160 participants received local anaesthetic and 82 participants received control) reported the proportion of participants discharged as day surgery (Paulson 2003; Zimmer 2010; Roberts 2011). There were no significant differences between the two groups (RR 1.25; 95% CI 0.99 to 1.58) (Analysis 1.3). There was no change in the results by using random-effects model. There were no changes in the results by imputing missing outcome data using various scenarios (Analysis 2.1). However, when RD was used, the proportion of participants who

were discharged as day surgery was significantly higher in the local anaesthetic instillation group than the control group using the fixed-effect model (RD 0.11; 95% CI 0.01 to 0.22) but not by the random-effects model (RD 0.11; 95% CI -0.05 to 0.28). The trial sequential analysis revealed that the proportion of information accrued was only 0.02% of the diversity-adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 6). The cumulative Z curve did not cross the conventional statistical boundaries.

Figure 6. Trial sequential analysis of proportion discharged as day surgeryThe diversity-adjusted required information size (DARIS) was calculated to 1,419,571 participants, based on the proportion of participants in the control group with the outcome of 48.78%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 99.94%. To account for zero event groups (or groups in which all the participants were discharged as day surgery), a continuity correction of 0.01 was used in the calculation of the cumulative Zcurve (blue line). After accruing 242 participants in three trials, only 0.02% 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.

Length of hospital stay

Five trials (335 participants; 175 participants received local anaesthetic and 160 participants received control) reported the length of hospital stay (Scheinin 1995; Fornari 1996; Szem 1996; Jiranantarat 2002; Todorov 2009). There were no significant differences between the two groups (MD 0.04 days; 95% CI -0.23 to 0.32) (Analysis 1.4). Either the mean or the standard devia-

tion or both were not reported and had to be imputed in three trials (Fornari 1996; Szem 1996; Jiranantarat 2002). The standard deviation was zero in the control group as all participants were discharged on the first postoperative day in one of the trials (Todorov 2009). To include this trial in the analysis, we imputed the standard deviation in this trial also. Exclusion of these trials did not result in change in the conclusions (MD 0.53 days; 95%


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CI -0.14 to 1.21) (Analysis 2.2). The trial sequential analysis suggested that it is unlikely that future trials are likely to demonstrate any significant difference in the length of hospital stay between local anaesthetic instillation and no local anaesthetic instillation since the cumulative Z-curve had entered the futility area and did not cross the conventional statistical boundaries (Figure 7). Figure 7. Trial sequential analysis of length of hospital stayThe diversity-adjusted required information size (DARIS) was 107 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 3.39, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. After accruing 335 participants in five trials, the cumulative Z-curve (blue line) has crossed the trial sequential monitoring boundaries (red line) but lies within the futility area and the conventional statistical boundaries (dotted red line). This suggests that it is unlikely that future trials are likely to demonstrate any significant difference in the length of hospital stay between local anaesthetic instillation and no local anaesthetic instillation.

Pain

Pain at four to eight hours

Thirty-two trials (2020 participants; 1081 participants received local anaesthetic and 939 participants received control) reported this outcome (Chundrigar 1993; Pasqualucci 1994; Rademaker 1994; Raetzell 1995b; Fornari 1996; Pasqualucci 1996; Szem 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Maestroni 2002; Alagöl 2003; Karadeniz 2003; Razek 2003; Barczynski

2006; Hazinedaroglu 2006; Verma 2006; Alkhamesi 2007; Kucuk 2007; Nicolau 2008; Feroci 2009; Fu 2009; Golubovic 2009; Todorov 2009; Kim 2010; Roberts 2011; Castillo-Garza 2012). The pain scores as measured by the VAS were significantly lower in the local anaesthetic instillation group than the control group (MD -0.99 cm VAS; 95% CI -1.10 to -0.88) (Analysis 1.5). There were no changes in the interpretation of results by using a random-effects meta-analysis. Either the mean or the standard deviation was imputed in 22 trials (Chundrigar 1993; Rademaker 1994; Raetzell 1995b; Fornari 1996; Pasqualucci 1996; Szem 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Maestroni 2002; Alagöl 2003; Razek 2003;


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Hazinedaroglu 2006; Alkhamesi 2007; Fu 2009; Golubovic 2009; Roberts 2011; Castillo-Garza 2012). Exclusion of these trials did not alter the results (MD -1.04 cm VAS; 95% CI -1.17 to -0.90) (Analysis 2.3). One trial contributed to more than 50% of the weight of the analysis (Barczynski 2006). It was not clear whether the values were standard deviation or standard error. Therefore, we performed another sensitivity analysis excluding this trial along with the other trials where mean or standard deviation was imputed. There was no change in the results by excluding this trial also (MD -0.76 cm VAS; 95% CI -1.01 to -0.51). All the trial sequential monitoring boundaries were crossed by cumulative Zcurve favouring local anaesthetic instillation. The findings were consistent with local anaesthetic instillation decreasing pain between four and eight hours compared with no local anaesthetic instillation without the risk of random errors (Figure 8). Figure 8. Trial sequential analysis of pain (4 to 8 hours)The diversity-adjusted required information size (DARIS) was 796 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 3.19, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 87.32%. The conventional statistical boundaries (dotted red line) are crossed by the cumulative Z-curve (blue line) after the second trial. All the trial sequential monitoring boundaries (red line) are crossed by cumulative Z-curve after the seventeenth trial. The findings are consistent with local anaesthetic instillation decreasing pain between 4 and 8 hours compared with no local anaesthetic instillation without the risk of random errors.

Pain at nine to 24 hours

Twenty-nine trials (1787 participants; 940 participants received

local anaesthetic and 847 participants received control) reported this outcome (Pasqualucci 1994; Raetzell 1995b; Fornari 1996; Pasqualucci 1996; Mraovic 1997; Weber 1997; Elfberg


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2000; Kolsi 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Maestroni 2002; Alagöl 2003; Karadeniz 2003; Razek 2003; Barczynski 2006; Hazinedaroglu 2006; Verma 2006; Alkhamesi 2007; Kucuk 2007; Nicolau 2008; Feroci 2009; Fu 2009; Golubovic 2009; Todorov 2009; Kim 2010; Zimmer 2010; Castillo-Garza 2012). The pain scores as measured by the VAS were significantly lower in the local anaesthetic instillation group than the control group (MD -0.53 cm VAS; 95% CI -0.62 to -0.44) (Analysis 1.6). There were no changes in the interpretation of results by using a random-effects meta-analysis. Either the mean or the standard deviation was imputed in 17 trials (Raetzell 1995b; Fornari 1996; Pasqualucci 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Maestroni 2002; Alagöl 2003; Razek 2003; Hazinedaroglu 2006; Alkhamesi 2007; Fu 2009; Golubovic 2009; Zimmer 2010). Ex-

clusion of these trials did not alter the results (MD -0.38 cm VAS; 95% CI -0.48 to -0.28) (Analysis 2.4). One trial contributed to more than 50% of the weight of the analysis (Barczynski 2006). It was not clear whether the values were standard deviation or standard error. Therefore, we performed another sensitivity analysis excluding this trial along with the other trials where mean or standard deviation was imputed. There was also no change in the results by excluding this trial (MD -0.34 cm VAS; 95% CI 0.52 to -0.16). All the trial sequential monitoring boundaries were crossed by cumulative Z-curve favouring local anaesthetic instillation. The findings were consistent with local anaesthetic instillation decreasing pain between nine and 24 hours compared with no local anaesthetic instillation without the risk of random errors (Figure 9).

Figure 9. Trial sequential analysis of pain (9 to 24 hours)The diversity-adjusted required information size (DARIS) was 580 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 2.06, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 88.81%. The conventional statistical boundaries (dotted red line) are crossed by the cumulative Z-curve (blue line) after the fifth trial . All the trial sequential monitoring boundaries (red line) are crossed by cumulative Z-curve after the twelfth trial. The findings are consistent with local anaesthetic instillation decreasing pain between 9 and 24 hours compared to no local anaesthetic instillation without the risk of random errors.

None of the trials reported return to normal activity. Return to normal activity Return to work Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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None of the trials reported return to work. Subgroup analysis and meta-regression Only pain at four to eight hours and pain at nine to 24 hours were suitable for various subgroup analyses because of the paucity of data in the other outcomes. We did not perform the following subgroup analysis or meta-regression. • Trials with low bias risk compared to trials with high bias risk: only one trial was at low risk of bias (Feroci 2009). • Elective compared to emergency laparoscopic cholecystectomy: none of the trials reported data for emergency laparoscopic cholecystectomy separately. • Drain or no drain. The only trial that reported drain use in all the participants did not report any of the outcomes of interest for this review (El-Labban 2011). The remaining trials in which drain use was reported in some participants and provided data for this review did not report the data separately for participants in whom the drain was used (Nicolau 2008; Roberts 2011). We included all the other variables except peri-portal local anaesthetic infiltration and routine supplemental analgesia in the metaregression because of missing information for these two variables. Therefore, these two variables were used alone in two other metaregression models. Therefore, there were three meta-regression models for each of pain at four to eight hours and pain at nine to 24 hours. Pain at four to eight hours

The test for subgroup differences was significant only for peri-portal infiltration with local anaesthetic (P value = 0.007) (Analysis 3.8) and for routine supplemental analgesia (P value < 0.0001) (Analysis 3.9). The intraperitoneal local anaesthetic instillation was more effective in participants who did not have peri-portal infiltration with local anaesthetic than those who had peri-portal local anaesthetic infiltration. The intraperitoneal local anaesthetic instillation was more effective in participants who received routine supplemental analgesia than those who received on-demand supplemental analgesia. The tests for subgroup differences were not significant for the following subgroup analyses. • Different local anaesthetic agents (Analysis 3.1). • Maximum safe dose used (ie, whether the trials used the dose based on body weight) (Analysis 3.2). • Different physical forms of instillation (Analysis 3.3). • Different timing of instillation (Analysis 3.4). • Different locations of instillation (Analysis 3.5). • Norepinephrine use (Analysis 3.6). • Control used (Analysis 3.7). The findings of the meta-regression were as follows. Ropivacaine was associated with a lower treatment effect than other local anaesthetics. The form of local anaesthetic delivered in

terms of liquid or other forms significantly affected the effect estimates. Other forms of local anaesthetic, such as aerosol or soaked in cellulose strips, were more effective than liquid form. Local anaesthetic delivery at the end of surgery was less effective than other times of drug delivery, such as just after creation of pneumoperitoneum or delivered twice - just after pneumoperitoneum and end of surgery. Meta-regression also revealed that the local anaesthetics were more effective when norepinephrine was added to the local anaesthetic. None of the other factors influenced the effect estimate significantly.

Pain at nine to 24 hours

The test for subgroup differences was significant for the following subgroups. • Dose of local anaesthetic used (P value = 0.04). The local anaesthetics were more effective when a fixed dose of local anaesthetic rather than a dose based on body weight was used (Analysis 3.11). • Time of administration (P value = 0.04). Local anaesthetic delivery at the end of surgery was less effective than other times of drug delivery, such as just after creation of pneumoperitoneum or delivered twice - just after pneumoperitoneum and end of surgery (Analysis 3.13). • Peri-portal infiltration with local anaesthetic (P value = 0.01). The intraperitoneal local anaesthetic instillation was more effective in participants who did not have peri-portal infiltration with local anaesthetic than those who had peri-portal local anaesthetic infiltration (Analysis 3.17). • Routine supplemental analgesia (P value = 0.004). The intraperitoneal local anaesthetic instillation was more effective in participants who received routine supplemental analgesia than those who received on-demand supplemental analgesia. The tests for subgroup differences were not significant for the following subgroup analyses for pain between nine and 24 hours. • Different local anaesthetic agents (Analysis 3.10). • Different physical forms of instillation (Analysis 3.12). • Different locations of instillation (Analysis 3.14). • Norepinephrine use (Analysis 3.15). • Control used (Analysis 3.16). The findings of the meta-regression were as follows. Other forms of local anaesthetic administration such as aerosol or soaked in cellulose strips were more effective than liquid form. None of the other factors influenced the effect estimate significantly.

Reporting bias We explored reporting bias only for pain at four to eight hours and for pain at nine to 24 hours by funnel plots because of the presence of adequate number of trials for these two outcomes only. The


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funnel plots did not reveal any evidence of reporting bias (P value = 0.227). The Egger’s test did not reveal any evidence of reporting bias (P value = 0.099).

DISCUSSION Summary of main results In this review, we have compared the intraperitoneal instillation of local anaesthetic agents versus no installation of local anaesthetic agents to reduce pain during laparoscopic cholecystectomy. We included 48 randomised clinical trials including 2849 participants randomised to intraperitoneal local anaesthetic instillation (1558 participants) and control (1291 participants) that contributed to one or more of the outcomes. There were no significant differences in mortality or morbidity between intraperitoneal instillation of local anaesthetic and no 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 during laparoscopic cholecystectomy are also rare. There was only one serious adverse event in the local anaesthetic instillation group (1/236 (0.4%)) compared with no serious adverse events in the control group (0/ 210 (0%)) (Analysis 1.2). The serious adverse event was thrombophlebitis, which was unrelated to the local anaesthetic instillation. One trial did not report the complications adequately but stated that one person developed lactic acidosis (Roberts 2011). Lactic acidosis has not been reported as a complication of local anaesthetic use (Martindale 2013). Although the remaining trials did not report the overall morbidity, three trials (190 participants) reported that there were no intra-operative complications (Barczynski 2006; Alptekin 2010; Kim 2010). In addition, 20 trials reported that there were no serious adverse events in any of the 715 participants who received local anaesthetic instillation (Scheinin 1995; Pasqualucci 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Tunca 2001; Labaille 2002; Maestroni 2002; Rudra 2002; Paulson 2003; Razek 2003; Louizos 2005; Hazinedaroglu 2006; Karaaslan 2006; Garcia 2007; Kucuk 2007; Nicolau 2008; Alper 2009; Kallel 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 this low morbidity associated with local anaesthetics and considering that the laparoscopic cholecystectomy is performed under general anaesthesia with people likely to be moni-

tored because of the use of the general anaesthetic agent, one can conclude that local anaesthetics are generally safe to use in people undergoing laparoscopic cholecystectomy without allergy to local anaesthetic. 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 people 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 1.3; Analysis 1.4). 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 eight trials reported this important outcome (Scheinin 1995; Fornari 1996; Szem 1996; Jiranantarat 2002; Paulson 2003; Todorov 2009; Zimmer 2010; Roberts 2011). Future trials on this topic should include these outcomes. The pain at four to eight hours and at nine to 24 hours were significantly reduced in the intraperitoneal local anaesthetic instillation. The findings were robust to different sensitivity analysis. The trial sequential analysis also confirmed the risk of random errors in concluding that intraperitoneal instillation decreased pain is low. Although some subgroup analyses and meta-regression showed significant influence of some factors over the effect estimates, these were not consistent. Thus, there is no evidence from this review to suggest that one method of local anaesthetic intraperitoneal instillation is better than another method. These findings are consistent with our findings in a systematic review comparing different methods of local anaesthetic intraperitoneal instillation, which concluded that there is no evidence to suggest that one method of local anaesthetic intraperitoneal instillation is better than another method (Gurusamy 2013a). The mean reduction in pain was about 1 cm on the 0 to 10 cm VAS for four to eight hours and about 0.5 cm for nine to 24 hours. Differences in pain scores of between 0.9 and 1.8 cm are generally considered clinically significant (Todd 1996). Thus, it appears that intraperitoneal local anaesthetic instillation may have a role in increasing the proportion of laparoscopic cholecystectomies performed as day-surgery since patients undergoing day-surgery laparoscopic cholecystectomy are discharged between four and eight hours after surgery. There was no significant difference in the proportion of participants who were discharged as day surgery in this review. It does not appear from the description in the trials that day surgery was attempted in most trials. Future trials should investigate the role of intraperitoneal local anaesthetic instillation in the day-surgery


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laparoscopic cholecystectomy setting.

Overall completeness and applicability of evidence Most of the trials in this review involved mainly 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. A number of local anaesthetic agents were used in different doses, time with relation to surgery, and locations. Although there were some differences noted in the subgroup analysis, another review that compared different methods of intraperitoneal instillation did not find any significant difference between different methods of intraperitoneal local anaesthetic instillation (Gurusamy 2013a). A safe dose of local anaesthetic that takes into account any local anaesthetic administered for wound infiltration is recommended. For bupivacaine, the most common local anaesthetic used in the trials included in this review, this is approximately 2 mg/kg (Martindale 2013).

Agreements and disagreements with other studies or reviews A review by Boddy et al. revealed that intraperitoneal instillation of local anaesthetic resulted in a reduction of the mean pain score although no reduction in analgesic requirement was noted (Boddy 2006). There were no adverse effects attributable to local anaesthetic. Another review reported similar results, although the meta-analysis in the review included only three trials and found no significant difference between local anaesthetic instillation and placebo (Gupta 2005). In another review of randomised clinical trials, Bisgaard did not recommend routine use of intraperitoneal local anaesthetics because of conflicting results (Bisgaard 2006). In another review, Kahokehr et al. concluded that intraperitoneal local anaesthetic instillation reduced pain and no further trials were necessary (Kahokehr 2010). Our conclusions are similar in some aspects to some of the above reviews in that we have found that the rate of adverse events in studies of local anaesthetic intraperitoneal instillation are low and reduces pain in low anaesthetic-risk people undergoing elective laparoscopic cholecystectomy. However, we have concluded that more trials are necessary to investigate the clinical impact of this reduction in pain.

Quality of the evidence The overall quality of evidence was very low. 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 the 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 such trials but this did not change the results significantly thus demonstrating the minimal impact of missing mean or standard deviation.

AUTHORS’ CONCLUSIONS Implications for practice Serious adverse events were rare in studies evaluating local anaesthetic intraperitoneal instillation (very low quality evidence). There is very low quality evidence that it reduces pain in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is likely to be small.

Implications for research 1. Further randomised clinical trials are necessary to evaluate the role of local anaesthetic intraperitoneal instillation in the emergency and in the elective set-up particularly in the daysurgery elective laparoscopic cholecystectomy. 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/) (SPIRIT 2013a; SPIRIT 2013b), and conducted and reported according to the CONSORT (Consolidated Standards for Reporting of Trials) statement (www.consort-statement.org).


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ACKNOWLEDGEMENTS To the Cochrane Hepato-Biliary Group for the support that they have provided. Peer reviewers: Amir Taefi, USA; Arman Adam Kahokehr, New Zealand. Contact editor: Saboor Khan, UK; Christian Gluud, Denmark. This project was funded by the National Institute for Health Research. Disclaimer of the Department of Health: “The views and opinions expressed in the review are those of the authors and do not necessarily reflect those of the National Institute for Health Research (NIHR), National Health Services (NHS), or the Department of Health”.

REFERENCES

References to studies included in this review Abdel-Raouf 2004 {published data only} Abdel-Raouf M, Amer H. Postoperative analgesic effects of intraperitoneal NMDA receptor antagonists (ketamine and magnesium) in patients undergoing laparoscopic cholecystectomy. Egyptian Journal of Anaesthesia 2004;20 (2):107–11. Ahmad 1998 {published data only} Ahmad SM, Hassanally D, Harris G, Simson J. Is local and intraperitoneal instillation of bupivacaine after laparoscopic cholecystectomy effective for pain?. British Journal of Surgery 1998;85(Suppl 1):47. Alagöl 2003 {published data only} Alagöl A, Karamanlioglu B, Turan FN, Pamukçu Z. The analgesic efficacy of intraperitoneally administered ondansetron in laparoscopic cholecystectomies. Turk Anesteziyoloji ve Reanimasyon 2003;31(2):95–9. Alkhamesi 2007 {published data only} Alkhamesi NA, Peck DH, Lomax D, Darzi AW. Intraperitoneal aerosolization of bupivacaine reduces postoperative pain in laparoscopic surgery: a randomized prospective controlled double-blinded clinical trial. Surgical Endoscopy 2007;21(4):602–6.

Barczynski 2006 {published data only} Barczynski M, Konturek A, Herman RM. Superiority of preemptive analgesia with intraperitoneal instillation of bupivacaine before rather than after the creation of pneumoperitoneum for laparoscopic cholecystectomy: a randomized, double-blind, placebo-controlled study. Surgical Endoscopy 2006;20(7):1088–93. Bhardwaj 2002 {published data only} Bhardwaj N, Sharma V, Chari P. Intraperitoneal bupivacaine instillation for postoperative pain relief after laparoscopic cholecystectomy. Indian Journal of Anaesthesia 2002, issue 1:49–52. Castillo-Garza 2012 {published data only} Castillo-Garza G, Diaz-Elizondo JA, Cuello-Garcia CA, Villegas-Cabello O. Irrigation with bupivacaine at the surgical bed for postoperative pain relief after laparoscopic cholecystectomy. Journal of the Society of Laparoendoscopic Surgeons 2012;16(1):105–11. Chundrigar 1993 {published data only} Chundrigar T, Hedges AR, Morris AR, Stamatakis JD. Intraperitoneal bupivacaine for effective pain relief after laparoscopic cholecystectomy. Annals of the Royal College of Surgeons of England 1993; Vol. 75, issue 6:437–9.

Alper 2009 {published data only} Alper I, Ulukaya S, Ertugrul V, Makay O, Uyar M, Balcioglu T. Effects of intraperitoneal levobupivacaine on pain after laparoscopic cholecystectomy: a prospective, randomized, double-blinded study. Agri 2009;21(4):141–5.

Elfberg 2000 {published data only} Elfberg BA, Sjövall-Mjöberg S. Intraperitoneal bupivacaine does not effectively reduce pain after laparoscopic cholecystectomy: a randomized, placebo-controlled and double-blind study. Surgical Laparoscopy, Endoscopy and Percutaneous Techniques 2000; Vol. 10, issue 6:357–9.

Alptekin 2010 {published data only} Alptekin H, Sahin M. Gallbladder bed irrigation with bupivacaine improves pulmonary functions after laparoscopic cholecystectomy. Langenbeck’s Archives of Surgery 2010;395(5):501–4.

Elhakim 2000a {published data only} Elhakim M, Elkott M, Ali NM, Tahoun HM. Intraperitoneal lidocaine for postoperative pain after laparoscopy. Acta Anaesthesiologica Scandinavica 2000;44 (3):280–4.


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El-Labban 2011 {published data only} El-Labban G, Hokkam E, El-Labban M, Morsy K, Saadl S, Heissam K. Intraincisional vs intraperitoneal infiltration of local anaesthetic for controlling early post-laparoscopic cholecystectomy pain. Journal of Minimal Access Surgery 2011;7(3):173–7. Feroci 2009 {published data only} Feroci F, Kroning KC, Moraldi L, Borrelli A, Ottaviano A, De Prizio M, et al.A new effective method to reduce pain after laparoscopic cholecystectomy. Giornale di Chirurgia 2010;31(10):423–8. ∗ Feroci F, Kröning KC, Scatizzi M. Effectiveness for pain after laparoscopic cholecystectomy of 0.5% bupivacainesoaked Tabotamp placed in the gallbladder bed: a prospective, randomized, clinical trial. Surgical Endoscopy 2009;23(10):2214–20. Fornari 1996 {published data only} Fornari M, Miglietta C, Di-Gioia S, Garrone C, Morino M. The use of bupivacaine through intraoperative topic way in the control of the postoperative pain after laparoscopic cholecystectomy. Minerva Chirurgica 1996; Vol. 51, issue 10:881–5. Fu 2009 {published data only} Fu JZ, Li J, Yu ZL. Effect of implanting fibrin sealant with ropivacaine on pain after laparoscopic cholecystectomy. World Journal of Gastroenterology 2009;15(46):5851–4. Fuhrer 1996 {published data only} ∗ Fuhrer Y, Charpentier C, Boulanger G, Menu N, Grosdidier G, Laxenaire C. Analgesia after laparoscopic cholecystectomy using intraperitoneal bupivacaine. Annales Francaises d’Anesthesie et de Reanimation 1996;15(2): 128–34. Fuhrer Y, Charpentier C, Menu N, Boulanger G, Grosdidier G, Faffet P, et al.Effects on postoperative pain and pharmacokinetics of intraperitoneal bupivacaine after laparoscopic cholecystectomy. British Journal of Anaesthesia 1995;74(Suppl 1):141. Garcia 2007 {published data only} Garcia JBS, Alencar JAM, Dos SCEC. Intraperitoneal administration of 50% enantiomeric excess (S75-R25) bupivacaine in postoperative analgesia of laparoscopic cholecystectomy. Revista Brasileira de Anestesiologia 2007; Vol. 57, issue 4:344–55.

A placebo-controlled randomized trial of local infiltration and intra peritoneal administration of ropivacaine 0.25%. Acta Anaesthesiologica Belgica 2007; Vol. 58, issue 2:150. Hazinedaroglu 2006 {published data only} Hazinedaroglu SM, Kayaoglu HA, Ates Y, Ertürk S, Butuner C, Turkcapar AG. Intraperitoneal bupivacaine for postoperative pain relief after laparoscopic cholecystectomy. Pain medicine 2006; Vol. 7, issue 6:539–41. Jabbour-Khoury 2005 {published data only} Jabbour-Khoury SI, Dabbous AS, Gerges FJ, Azar MS, Ayoub CM, Khoury GS. Intraperitoneal and intravenous routes for pain relief in laparoscopic cholecystectomy. JSLS 2005; Vol. 9, issue 3:316–21. Jiranantarat 2002 {published data only} Jiranantarat V, Rushatamukayanunt W, Lert-Akyamanee N, Sirijearanai R, Piromrat I, Suwannanonda P, et al.Analgesic effect of intraperitoneal instillation of bupivacaine for postoperative laparoscopic cholecystectomy. Journal of the Medical Association of Thailand 2002; Vol. 85, issue Suppl 3:S897–S903. Joris 1995 {published data only} ∗ Joris J, Thiry E, Paris P, Weerts J, Lamy M. Pain after laparoscopic cholecystectomy: characteristics and effect of intraperitoneal bupivacaine. Anesthesia and Analgesia 1995; 81(2):379–84. Thiry E, Paris P, Weerts J, Joris J. Intraperitoneal bupivacaine does not reduce postoperative pain after laparoscopic cholecystectomy. British Journal of Anaesthesia 1994; Vol. 72, issue Suppl 1:120. Kallel 2011 {published data only} Kallel S, Ben Soltana MH, Djemal W, Triki Z, Chaari M, Karoui A. Peritoneal block analgesia after laparoscopic cholecystectomy. European Journal of Anaesthesiology 2011; 28(Suppl 48):123. Karaaslan 2006 {published data only} Karaaslan D, Sivaci RG, Akbulut G, Dilek ON. Preemptive analgesia in laparoscopic cholecystectomy: a randomized controlled study. Pain Practice 2006;6(4):237–41.

Golubovic 2009 {published data only} Golubovic S, Golubovic V, Cindric- Stancin M, Tokmadzic VS. Intraperitoneal analgesia for laparoscopic cholecystectomy: bupivacaine versus bupivacaine with tramadol. Collegium Antropologicum 2009;33(1):299–302.

Karadeniz 2003 {published data only} Karadeniz U, Erdemli O, Unver S, Ayoglu H, Ayogu F, Ebil S. Intraperitoneal bupivacaine injection and infusion via subphrenic catheter for postoperative pain management in laparoscopic cholecystectomy [abstract]. British Journal of Anaesthesia 1998;80(Suppl 1):172. ∗ Karadeniz Ü, Erdemli Ö, Ünver S, Yasitli H, Ayoglu H. Intraperitoneal bupivacaine infusion and injection for postoperative pain management in laparoscopic cholecystectomy. Anestezi Dergisi 2003;11(3):226–30.

Gvozdenovic 2011 {published data only} Gvozdenovic LV, Milic SD, Ivanov D, Pajtic V, Mancic N, Gvozdenovic NV. Crucial role of multimodale analgesia for laparoscopic cholecystectomy. European Journal of Anaesthesiology 2011;28(Suppl 48):202–3.

Kilic 1996 {published data only} Kilic A, Basgul E, Ozdemir A, Erdem MK. The efficacy of the intraperitoneal bupivacaine application on early postoperative pain and blood gas values after laparoscopic cholecystectomy. Agri Dergisi 1996; Vol. 8, issue 3:20–6.

Hasan 2007 {published data only} Hasan S, Lauwers M, Van H, Van NY, Camu F. Postoperative vain relief after laparoscopic cholecystectomy.

Kim 2010 {published data only} Kang H, Baek CW, Woo YC, Kim JY, Park SG, Park JS. Intraperitoneal ropivacaine washout for reduction of


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pain after laparoscopic cholecystectomy: a prospective randomized study. Pain Medicine 2009;10(6):1153–4. ∗ Kim TH, Kang H, Park JS, Chang IT, Park SG. Intraperitoneal ropivacaine instillation for postoperative pain relief after laparoscopic cholecystectomy. Journal of the Korean Surgical Society 2010;79(2):130–6. Kolsi 2000 {published data only} Kolsi K, Ghozzi H, Masmoudi A, Mzali R, Sahnoun Z, Zeghal K, et al.Intraperitoneal lignocaine for analgesia after laparoscopic cholecystectomy. Acute Pain 2000; Vol. 3, issue 4:200–5. Kucuk 2007 {published data only} Kucuk C, Kadiogullari N, Canoler O, Savli S. A placebocontrolled comparison of bupivacaine and ropivacaine instillation for preventing postoperative pain after laparoscopic cholecystectomy. Surgery Today 2007;37(5): 396–400. Labaille 2002 {published data only} Labaille T, Mazoit JX, Paqueron X, Franco D, Benhamou D. The clinical efficacy and pharmacokinetics of intraperitoneal ropivacaine for laparoscopic cholecystectomy. Anesthesia and Analgesia 2002; Vol. 94, issue 1:100–5. Lee 2001 {published data only} Lee IO, Kim SH, Kong MH, Lee MK, Kim NS, Choi YS, et al.Pain after laparoscopic cholecystectomy: the effect and timing of incisional and intraperitoneal bupivacaine. Canadian Journal of Anaesthesia 2001;48(6):545–50. Lepner 2003 {published data only} Lepner U, Goroshina J, Samarütel J. Postoperative pain relief after laparoscopic cholecystectomy: a randomised prospective double-blind clinical trial. Scandinavian Journal of Surgery 2003; Vol. 92, issue 2:121–4. Louizos 2005 {published data only} Louizos AA, Hadzilia SJ, Leandros E, Kouroukli IK, Georgiou LG, Bramis JP. Postoperative pain relief after laparoscopic cholecystectomy: a placebo-controlled doubleblind randomized trial of preincisional infiltration and intraperitoneal instillation of levobupivacaine 0.25%. Surgical Endoscopy 2005;19(11):1503–6. Maestroni 2002 {published data only} Maestroni U, Sortini D, Devito C, Pour-Morad-KohanBrunaldi F, Anania-Pavanelli L, Pasqualucci A, et al.A new method of preemptive analgesia in laparoscopic cholecystectomy. Surgical Endoscopy 2002; Vol. 16, issue 9:1336–40. Mraovic 1997 {published data only} Mraovic B, Jurisic T, Kogler-Majeric V, Sustic A. Intraperitoneal bupivacaine for analgesia after laparoscopic cholecystectomy. Acta Anaesthesiologica Scandinavica 1997; Vol. 41, issue 2:193–6. Ng 2004 {published data only} Ng A, Swami A, Smith G, Robertson G, Lloyd DM. Is intraperitoneal levobupivacaine with epinephrine useful for analgesia following laparoscopic cholecystectomy? A randomized controlled trial. European Journal of Anaesthesiology 2004; Vol. 21, issue 8:653–7.

Nicolau 2008 {published data only} Nicolau AE, Merlan V, Grecu I, Nicolau M, Micu B. Multimodal analgesia in elective laparoscopic cholecystectomy. A double-blind randomized control trial. Chirurgia 2008;103(5):547–51. [: 1221–9118] Pasqualucci 1994 {published data only} Pasqualucci A, Contardo R, Da Broi U, Colo F, Terrosu G, Donini A, et al.The effects of intraperitoneal local anesthetic on analgesic requirements and endocrine response after laparoscopic cholecystectomy: a randomized double-blind controlled study. Journal of Laparoendoscopic Surgery 1994;4 (6):405–12. Pasqualucci 1996 {published data only} Pasqualucci A, De Angelis V, Contardo R, Colo F, Terrosu G, Donini A, et al.Preemptive analgesia: intraperitoneal local anesthetic in laparoscopic cholecystectomy: a randomized, double-blind, placebo-controlled study. Anesthesiology 1996;85(1):11–20. Paulson 2003 {published data only} Paulson J, Mellinger J, Baguley W. The use of intraperitoneal bupivacaine to decrease the length of stay in elective laparoscopic cholecystectomy patients. 45th Annual Meeting of the Midwest-Surgical-Association 2002:275–8. ∗ Paulson J, Mellinger J, Baguley W. The use of intraperitoneal bupivacaine to decrease the length of stay in elective laparoscopic cholecystectomy patients. The American Surgeon 2003;69(4):275–9. Rademaker 1994 {published data only} Rademaker BMP, Kalkman CJ, Odoom JA, Dewit L, Ringers J. Intraperitoneal local-anesthetics after laparoscopic cholecystectomy - effects on postoperative pain, metabolic responses and lung-function. British Journal of Anaesthesia 1994;72(3):263–6. Raetzell 1995a {published data only} Raetzell M, Maier C, Schroder D, Wulf H. Intraperitoneal application of bupivacaine during laparoscopic cholecystectomy - risk or benefit?. Anesthesia and Analgesia 1995; Vol. 81, issue 5:967–72. Raetzell 1995b {published data only} Raetzell M, Maier C, Schroder D, Wulf H. Intraperitoneal application of bupivacaine during laparoscopic cholecystectomy - risk or benefit?. Anesthesia and Analgesia 1995; Vol. 81, issue 5:967–72. Razek 2003 {published data only} Razek EA. Intraperitoneal levobupivacaine for analgesia after laparoscopic cholecystectomy. Egyptian Journal of Anaesthesia 2003; Vol. 19, issue 3:249–54. Razman 2010 {published data only} Razman J, Ramasamy R, Yan YW, Muthupalaniappan K. Intraperitoneal 0.5% bupivacaine instillation in trendelenburg position for postoperative pain relief in laparoscopic cholecystectomy. HPB 2010;12(Suppl S1): 106–7. Roberts 2011 {published data only} Roberts KJ, Gilmour J, Pande R, Nightingale P, Tan LC, Khan S. Efficacy of intraperitoneal local anaesthetic


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techniques during laparoscopic cholecystectomy. Surgical Endoscopy and Other Interventional Techniques 2011;25(11): 3698–705. Rudra 2002 {published data only} Rudra A, Biswas BN, Mukhopadhya S, Mukhopadhya M, Bagchi D, Bar B. Intraperitoneal bupivacaine for pain relief after laparoscopic cholecystectomy. Journal of Anaesthesiology, Clinical Pharmacology 2002; Vol. 18, issue 4:409–11. Scheinin 1995 {published data only} Scheinin B, Kellokumpu I, Lindgren L, Haglund C, Rosenberg PH. Effect of intraperitoneal bupivacaine on pain after laparoscopic cholecystectomy. Acta Anaesthesiologica Scandinavica 1995; Vol. 39, issue 2:195–8. Szem 1996 {published data only} Szem JW, Hydo L, Barie PS. A double-blinded evaluation of intraperitoneal bupivacaine vs saline for the reduction of postoperative pain and nausea after laparoscopic cholecystectomy. Surgical Endoscopy 1996; Vol. 10, issue 1:44–8. Todorov 2009 {published data only} Todorov G, Tzaneva P, Lukanova T, Velev G, Kojtchev A. The effect of intraperitoneal levobupivacain (Chirocaine) application on postoperative pain in laparoscopic cholecystectomy - a prospective study. Khirurgiia 2009;4-5: 32–5. Tunca 2001 {published data only} Tunca T, Basoglu M, Kürsat H, Cesur M. The evaluation of the effects of intraperitoneal morphine+bupivacaine versus bupivacaine for postoperative analgesia. Turk Anesteziyoloji ve Reanimasyon 2001; Vol. 29, issue 6:281–4. Verma 2006 {published data only} Verma GR, Lyngdoh TS, Kaman L, Bala I. Placement of 0.5% bupivacaine-soaked Surgicel in the gallbladder bed is effective for pain after laparoscopic cholecystectomy. Surgical Endoscopy and Other Interventional Techniques 2006; Vol. 20, issue 10:1560–4. Weber 1997 {published data only} Weber A, Muñoz J, Garteiz D, Cueto J. Use of subdiaphragmatic bupivacaine instillation to control postoperative pain after laparoscopic surgery. Surgical Laparoscopy & Endoscopy 1997; Vol. 7, issue 1:6–8. Zimmer 2010 {published data only} Zimmer PW, McCann MJ, O’Brien MM. Bupivacaine use in the Insuflow device during laparoscopic cholecystectomy: results of a prospective randomized double-blind controlled trial. Surgical Endoscopy 2010;24(7):1524–7. Zmora 2000 {published data only} Zmora O, Stolik-Dollberg O, Bar-Zakai B, Rosin D, Kuriansky J, Shabtai M, et al.Intraperitoneal bupivacaine does not attenuate pain following laparoscopic cholecystectomy. JSLS 2000; Vol. 4, issue 4:301–4.

References to studies excluded from this review

Ahmed 2008 {published data only} Ahmed BH, Ahmed A, Tan DF, Awad ZT, Al-Aali AY, Kilkenny J, et al.Post-laparoscopic cholecystectomy pain: effects of intraperitoneal local anesthetics on pain control - a randomized prospective double-blinded placebo-controlled trial. The American Surgeon 2008;74(3):201–9. Alexander 1997 {published data only} Alexander DJ. Randomized trial of periportal peritoneal bupivacaine for pain relief after laparoscopic cholecystectomy - reply. British Journal of Surgery 1997;84(5):730. Bayar 1998 {published data only} Bayar M, Ilhan Y, Onal A, Akkus M, Cifter C. Evaluation of postoperative analgesia and catecholamine levels in laparoscopic cholecystectomy after injection of intraperitoneal bupivacaine. Agri 1998;10(2):30–4. Beqiri 2012 {published data only} Beqiri AI, Domi RQ, Sula HH, Zaimi EQ, Petrela EY. The combination of infiltrative bupivacaine with lowpressure laparoscopy reduces postcholecystectomy pain. A prospective randomized controlled study. Saudi Medical Journal 2012;33(2):134–8. Berven 1995 {published data only} Berven S, Horvath K, Brooks DC. The effect of topical intraperitoneal bupivacaine on post-operative pain following laparoscopic cholecystectomy. Minimally Invasive Therapy 1995;4(2):67–71. Bisgaard 1999 {published data only} Bisgaard T, Klarskov B, Kristiansen VB, Callesen T, Schulze S, Kehlet H, et al.Multi-regional local anesthetic infiltration during laparoscopic cholecystectomy in patients receiving prophylactic multi-modal analgesia: a randomized, doubleblinded, placebo-controlled study. Anesthesia and Analgesia 1999;89(4):1017–24. Busley 1999 {published data only} Busley R, Blobner M, Jelen-Esselborn S, Feussner H, Kochs E. Intraperitoneal local anaesthetics via subphrenic catheter following laparoscopic cholecystectomy: pain relief and pulmonary function. Minimally Invasive Therapy & Allied Technologies 1999; Vol. 8, issue 4:219–25. Celik 2000 {published data only} Celik J, Tuncer S, Reisli R, Okesli S, Otelcioglu S. Intraperitoneal versus interpleural analgesia on postoperative pain to laparoscopic cholecystectomy. Turk Anesteziyoloji ve Reanimasyon 2000; Vol. 28, issue 6: 317–21. Cha 2012 {published data only} Cha SM, Kang H, Baek CW, Jung YH, Koo GH, Kim BG, et al.Peritrocal and intraperitoneal ropivacaine for laparoscopic cholecystectomy: a prospective, randomized, double-blind controlled trial. Journal of Surgical Research 2012;175(2):251–8. Cunniffe 1998 {published data only} Cunniffe MG, McAnena OJ, Dar MA, Calleary J, Flynn N. A prospective randomized trial of intraoperative bupivacaine irrigation for management of shoulder-tip pain following


28

laparoscopy. American Journal of Surgery 1998;176(3): 258–61. Di Pace 2009 {published data only} Di Pace MR, Cimador M, Catalano P, Caruso A, Sergio M, Casuccio A, et al.Efficacy of periportal infiltration and intraperitoneal instillation of ropivacaine after laparoscopic surgery in children. Journal of Laparoendoscopic & Advanced Surgical Techniques 2009;19(6):821–5. Elhakim 2000b {published data only} Elhakim M, Amine H, Kamel S, Saad F. Effects of intraperitoneal lidocaine combined with intravenous or intraperitoneal tenoxicam on pain relief and bowel recovery after laparoscopic cholecystectomy. Acta Anaesthesiologica Scandinavica 2000;44(8):929–33. Gharaibeh 2000 {published data only} Gharaibeh KIA, Al-Jaberi TM. Bupivacaine instillation into gallbladder bed after laparoscopic cholecystectomy: does it decrease shoulder pain?. Journal of Laparoendoscopic & Advanced Surgical Techniques - Part A 2000;10(3):137–41. Gupta 2002 {published data only} Gupta A, Thörn SE, Axelsson K, Larsson LG, Agren G, Holmström B, et al.Postoperative pain relief using intermittent injections of 0.5% ropivacaine through a catheter after laparoscopic cholecystectomy. Anesthesia and Analgesia 2002;95(2):450–6. Hernández-Palazón 2003 {published data only} Hernández-Palazón J, Tortosa JA, Nuño de la Rosa V, Giménez-Viudes J, Ramírez G, Robles R. Intraperitoneal application of bupivacaine plus morphine for pain relief after laparoscopic cholecystectomy. European Journal of Anaesthesiology 2003; Vol. 20, issue 11:891–6. Hilvering 2011 {published data only} Hilvering B, Draaisma WA, Bilt JD, Valk RM, Kofman KE, Consten EC. Randomized clinical trial of combined preincisional infiltration and intraperitoneal instillation of levobupivacaine for postoperative pain after laparoscopic cholecystectomy. British Journal of Surgery 2011;98(6): 784–9. Inan 2004 {published data only} Inan A, Sen M, Dener C. Local anesthesia use for laparoscopic cholecystectomy. World Journal of Surgery 2004;28(8):741–4. Johnson 1999 {published data only} Johnson RC, Hedges AR, Morris R, Stamatakis JD. Ideal pain relief following laparoscopic cholecystectomy. International Journal of Clinical Practice 1999;53(1):16–8. Lauwick 2008 {published data only} Lauwick S, Kim do J, Michelagnoli G, Mistraletti G, Feldman L, Fried G, et al.Intraoperative infusion of lidocaine reduces postoperative fentanyl requirements in patients undergoing laparoscopic cholecystectomy. Canadian Journal of Anaesthesia 2008;55(11):754–60. Lindgren 1997 {published data only} Lindgren L. Pain after laparoscopic cholecystectomy - do we do our best?. Acta Anaesthesiologica Scandinavica 1997;41 (2):191–2.

Mack 1995 {published data only} Mack P. Intraperitoneal local anesthetic after laparoscopic cholecystectomy. Journal of Laparoendoscopic Surgery 1995; 5(5):343–4. Maharjan 2009 {published data only} Maharjan SK, Shrestha S. Intraperitoneal and periportal injection of bupivacaine for pain after laparoscopic cholecystectomy. Kathmandu University Medical Journal 2009;7(25):50–3. Memedov 2010 {published data only} Memedov C, Mentes O, Simsek A, Kece C, Yagci G, Harlak A, et al.Comparison of analgesic effects of intraperitoneal lornoxicam and ropivacaine administration in laparoscopic cholecystectomy. [Turkish]. Trakya Universitesi Tip Fakultesi Dergisi 2010;27(2):142–9. Michaloliakou 1996 {published data only} Michaloliakou C, Chung F, Sharma S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesthesia and Analgesia 1996; Vol. 82, issue 1:44–51. Moreira 2000 {published data only} Moreira RW, Amatto PE, Bessa-Jr RC, Silva JB. Intraperitoneal bupivacaine for pain relief after laparoscopic cholecystectomy. Revista Brasileira de Anestesiologia 2000; Vol. 50, issue 4:283–8. Newcomb 2007 {published data only} Newcomb W, Lincourt A, Hope W, Schmelzer T, Sing R, Kercher K, et al.Prospective, double-blinded, randomized, placebo-controlled comparison of local anesthetic and nonsteroidal anti-inflammatory drugs for postoperative pain management after laparoscopic surgery. The American Surgeon 2007;73(6):618–24. Ng 2002 {published data only} Ng A, Smith G. Intraperitoneal administration of analgesia: is this practice of any utility?. British Journal of Anaesthesia 2002; Vol. 89, issue 4:535–7. Özkoçak 2002 {published data only} Özkoçak I, Kirdemir P, Rasa K, Aksu C, Gögüs N. The comparison of preemptive intraperitoneal analgesic effects of tramadol, pethidine and bupivacaine. Anestezi Dergisi 2002; Vol. 10, issue 1:49–52. Paech 2008 {published data only} Paech MJ, Ilett KF, Hackett LP, Page-Sharp M, Parsons RW. Disposition and clinical outcome after intraperitoneal meperidine and ropivacaine administration during laparoscopic surgery. Anesthesia and Analgesia 2008;106(1): 278–86. Papadima 2009 {published data only} Papadima A, Lagoudianakis EE, Antonakis P, Filis K, Makri I, Markogiannakis H, et al.Repeated intraperitoneal instillation of levobupivacaine for the management of pain after laparoscopic cholecystectomy. Surgery 2009;146(3): 475–82. Pappas-Gogos 2008 {published data only} Pappas-Gogos G, Tsimogiannis KE, Zikos N, Nikas K, Manataki A, Tsimoyiannis EC. Preincisional and


29

intraperitoneal ropivacaine plus normal saline infusion for postoperative pain relief after laparoscopic cholecystectomy: a randomized double-blind controlled trial. Surgical Endoscopy 2008; Vol. 22, issue 9:2036–45.

Attili 1995 Attili AF, De Santis A, Capri R, Repice AM, Maselli S. The natural history of gallstones: The GREPCO experience. The GREPCO group. Hepatology 1995;21(3):655–60.

Rizzotti 2002 {published data only} Rizzotti L, Roussakis G, Barsakis A, Efstathiou G, Laopodis B, Katsoulis E. Subdiaphragmatic instillation of ropivacaine, via epidural catheter, for post-operative pain control, after laparoscopic cholecystectomy. Recent Views of Clinical Pain - Proceedings of the 10th International Pain Clinic. Sardinia, Italy, 2002:211–4.

Ballal 2009 Ballal M, David G, Willmott S, Corless DJ, Deakin M, Slavin JP. Conversion after laparoscopic cholecystectomy in England. Surgical Endoscopy 2009;23(10):2338–44.

Schulte-Steinberg 1995 {published data only} Schulte-Steinberg H, Weninger E, Jokisch D, Hofstetter B, Misera A, Lange V, et al.Intraperitoneal versus interpleural morphine or bupivacaine for pain after laparoscopic cholecystectomy. Anesthesiology 1995;82(3):634–40. Sozbilen 2007 {published data only} Sozbilen M, Yeniay L, Unalp M, Makay O, Pirim A, Ulukaya S, et al.Effects of ropivacaine on pain after laparoscopic cholecystectomy: a prospective, randomized study. Advances in Therapy 2007; Vol. 24, issue 2:247–57. Stempin 2007 {published data only} Stempin S, Gajdosz R. Intraperitoneal morphine for prevention of postoperative shoulder pain after laparoscopic cholecystectomy. Anestezjologia Intensywna Terapia 2007; Vol. 39, issue 1:18–20. Tsimoyiannis 1998a {published data only} Tsimoyiannis EC, Lekkas ET, Glantzounis G, Siakas P, Jabarin M, Tzourou H. Intraperitoneal bupivacaine and normal saline infusion for reduction of postoperative pain after laparoscopic cholecystectomy. 6th World Congress of Endoscopic Surgery, Parts 1 and 2. 1998:A49–53. Tsimoyiannis 1998b {published data only} Tsimoyiannis EC, Glantzounis G, Lekkas ET, Siakas P, Jabarin M, Tzourou H. Intraperitoneal normal saline and bupivacaine infusion for reduction of postoperative pain after laparoscopic cholecystectomy. Surgical Laparoscopy & Endoscopy 1998;8(6):416–20. Tsimoyiannis 1998c {published data only} Tsimoyiannis EC, Siakas P, Tassis A, Lekkas ET, Tzourou H, Kambili M. Intraperitoneal normal saline infusion for postoperative pain after laparoscopic cholecystectomy. World Journal of Surgery 1998;22(8):824–8. Wallace 1996 {published data only} Wallace DH, Serpell MG, O’Dwyer PJ. Effect of bupivacaine on postoperative pain and pulmonary function after laparoscopic cholecystectomy. British Journal of Surgery 1996;83(11):1637.

Additional references Alexander 1987 Alexander JI, Hull MG. Abdominal pain after laparoscopy: the value of a gas drain. British Journal of Obstetrics and Gynaecology 1987;94(3):267–9.

Bates 1992 Bates T, Harrison M, Lowe D, Lawson C, Padley N. Longitudinal study of gall stone prevalence at necropsy. Gut 1992;33(1):103–7. Bisgaard 2006 Bisgaard T. Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology 2006;104(4):835–46. Boddy 2006 Boddy AP, Mehta S, Rhodes M. The effect of intraperitoneal local anesthesia in laparoscopic cholecystectomy: a systematic review and meta-analysis. Anesthesia and Analgesia 2006;103(3):682–8. Brok 2008 Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. Journal of Clinical Epidemiology 2008;61(8):763–9. Brok 2009 Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive - trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. International Journal of Epidemiology 2009;38(1):287–98. Butterworth 1990 Butterworth JF 4th, Strichartz GR. Molecular mechanisms of local anesthesia: a review. Anesthesiology 1990;72(4): 711–34. CDC 2013 Centers for Disease Control and Prevention. Discharges with at least one procedure in nonfederal short-stay hospitals, by sex, age, and selected procedures: United States, selected years 1990 through 2009-2010. www.cdc.gov/nchs/data/ hus/2012/098.pdf 2013 (accessed 11 March 2014). CTU 2011 Copenhagen Trial Unit. TSA - Trial Sequential Analysis. ctu.dk/tsa/ 2011 (accessed 11 March 2013). DeMets 1987 DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987; 6(3):341–50. DerSimonian 1986 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177–88.


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Egger 1997 Egger M, Davey SG, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ (Clinical Research Ed.) 1997;315(7109):629–34.

Database of Systematic Reviews 2011, Issue 3. Art. No.: CD009060. DOI: 10.1002/14651858.CD009060., 2013, issue Under editorial.

Elhakim 2000 Elhakim M, Elkott M, Ali NM, Tahoun HM. Intraperitoneal lidocaine for postoperative pain after laparoscopy. Acta Anaesthesiologica Scandinavica 2000;44 (3):280–4.

Gurusamy 2013b Gurusamy KS, Koti R, Davidson B. Routine abdominal drainage versus no abdominal drainage for uncomplicated laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2013, Issue 9. [DOI: 10.1002/ 14651858.CD006004.pub4]

Fuzier 2009 Fuzier R, Lapeyre-Mestre M, Samii K, Montastruc JL. Adverse drug reactions to local anaesthetics: a review of the French pharmacovigilance database. Drug Safety 2009;32 (4):345–56.

Halldestam 2004 Halldestam I, Enell EL, Kullman E, Borch K. Development of symptoms and complications in individuals with asymptomatic gallstones. British Journal of Surgery 2004;91 (6):734–8.

Giger 2011 Giger U, Ouaissi M, Schmitz SF, Krahenbuhl S, Krahenbuhl L. Bile duct injury and use of cholangiography during laparoscopic cholecystectomy. British Journal of Surgery 2011;98(3):391–6.

HES 2013 HESonline. Hospital Episode Statistics. Admitted Patient Care, England - 2012-13. www.hscic.gov.uk/hes 2013 (accessed 11 March 2014).

Gluud 2013 Gluud C, Nikolova D, Klingenberg SL, Alexakis N, AlsNielsen B, Colli A, et al.Cochrane Hepato-Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2013, Issue 6. Art. No.: LIVER. GREPCO 1984 GREPCO. Prevalence of gallstone disease in an Italian adult female population. Rome group for the epidemiology and prevention of cholelithiasis (GREPCO). American Journal of Epidemiology 1984;119(5):796–805. GREPCO 1988 GREPCO. The epidemiology of gallstone disease in Rome, Italy. Part i. Prevalence data in men. The Rome group for epidemiology and prevention of cholelithiasis (GREPCO). Hepatology 1988;8(4):904–6. Gupta 2005 Gupta A. Local anaesthesia for pain relief after laparoscopic cholecystectomy - a systematic review. Best Practice and Research in Clinical Anaesthesiology 2005;19(2):275–92. Gurusamy 2008 Gurusamy K, Junnarkar S, Farouk M, Davidson BR. Metaanalysis of randomized controlled trials on the safety and effectiveness of day-case laparoscopic cholecystectomy. British Journal of Surgery 2008;95(2):161–8. Gurusamy 2009 Gurusamy KS, Gluud C, Nikolova D, Davidson BR. Assessment of risk of bias in randomized clinical trials in surgery. British Journal of Surgery 2009;96(4):342–9. Gurusamy 2013a Gurusamy KS, Nagendran M, Toon C, Guerrini GPiero, Zinnuroglu M, Davidson BR. Methods of intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews. Gurusamy KS, Guerrini GP, Zinnuroglu M, Davidson BR. Methods of intra–peritoneal local anaesthetic instillation for laparoscopic cholecystectomy (Protocol). Cochrane

Higgins 2002 Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539–58. Higgins 2009 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009].. The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Colloboration, 2011. Available from www.cochrane-handbook.org. ICH-GCP 1997 International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice CFR & ICH Guidelines. Vol. 1, PA 19063-2043, USA: Barnett International/PAREXEL, 1997. Kahokehr 2010 Kahokehr A, Sammour T, Soop M, Hill AG. Intraperitoneal use of local anesthetic in laparoscopic cholecystectomy: systematic review and metaanalysis of randomized controlled trials. Journal of Hepato-Biliary-Pancreatic Sciences 2010;17 (5):637–56. Kjaergard 2001 Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of Internal Medicine 2001;135(11):982–9. Lundh 2012 Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.MR000033.pub2]


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Macaskill 2001 Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta-analysis. Statistics in Medicine 2001;20(4):641–54. Martindale 2013 Sweetman S (editor). Martindale: the complete drug reference (online version). www.pharmpress.com/product/ MC˙MART/martindale-the-complete-drug-reference 2011 (accessed 11 March 2014); Vol. 37th Edition. Moher 1998 Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al.Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? . Lancet 1998;352(9128):609–13. Newell 1992 Newell DJ. Intention-to-treat analysis: implications for quantitative and qualitative research. International Journal of Epidemiology 1992;21(5):837–41. NHS Reference Costs 2013 Department of Health. NHS reference costs 2012 to 2013. www.gov.uk/government/publications/nhs-reference-costs2012-to-2013 2013 (accessed 11 March 2014). NIH 1992 NIH. NIH consensus statement on gallstones and laparoscopic cholecystectomy. consensus.nih.gov/1992/ 1992GallstonesLaparoscopy090html.htm 1992 (accessed 11 March 2014). RevMan 2012 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012. Royle 2003 Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591–603. Savovic 2012a Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al.Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Health Technology Assessment 2012;16(35):1–82. Savovic 2012b Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al.Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Annals of Internal Medicine 2012;157(6):429–38. Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408–12. SPIRIT 2013a Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krle a-Jeri K, et al.SPIRIT 2013 Statement: defining

standard protocol items for clinical trials. Annals of Internal Medicine 2013;158:200–7. SPIRIT 2013b Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin J, et al.SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ (Clinical Research Ed.) 2013;346:e7586. Strasberg 1993 Strasberg SM, Clavien PA. Overview of therapeutic modalities for the treatment of gallstone diseases. American Journal of Surgery 1993;165(4):420–6. Thorlund 2009 Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al.Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses. International Journal of Epidemiology 2009; 38(1):276–86. Thorlund 2010 Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clinical Epidemiology 2010;2:57–66. Thorlund 2011 Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). ctu.dk/tsa/files/tsa˙manual.pdf 2011 (accessed 11 March 2014). Todd 1996 Todd KH, Funk JP. The minimum clinically important difference in physician-assigned visual analog pain scores. Academic Emergency Medicine 1996;3(2):142–6. [PUBMED: 8808375] Vaughan 2013 Vaughan J, Gurusamy KS, Davidson BR. Day-surgery versus overnight stay surgery for laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 10.1002/14651858.CD006798.pub4] Wetterslev 2008 Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of Clinical Epidemiology 2008;61(1):64–75. Wetterslev 2009 Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Medical Research Methodology 2009;9:86. Wood 2008 Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al.Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601–5. ∗ Indicates the major publication for the study


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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Abdel-Raouf 2004 Methods

Randomised clinical trial.

Participants

Country: Egypt. Sample size: 40. Post-randomisation drop-outs: not stated. Revised sample size: 40. Mean age: 39 years. Females: 40 (100%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. 3. Females. Exclusion criteria 1. Previous abdominal surgery. 2. Magnesium therapy or on drugs containing magnesium. 3. Central nervous system dysfunction. 4. Psychotropic drugs. (Note: magnesium was used in 1 of the arms not included in this review)

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.25% 50 mL (n = 20). Group 2: normal saline (n = 20).

Outcomes

None of the outcomes of interest for this review were reported

Notes

Attempts were made to contact the authors in April 2008.

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

Comment: This information was not available.

Allocation concealment (selection bias)

Unclear risk


Blinding of participants and personnel Unclear risk (performance bias) All outcomes


Blinding of outcome assessment (detection Unclear risk bias) All outcomes



33

Abdel-Raouf 2004

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Unclear risk


Selective reporting (reporting bias)

High risk

Comment: Mortality and morbidity were not reported.

For-profit bias

Unclear risk


Ahmad 1998 Methods


Participants

Country: UK. Sample size: 40. Post-randomisation drop-outs: not stated. Revised sample size: 40. Mean age: not stated. Females: not stated. Inclusion criteria 1. People undergoing laparoscopic cholecystectomy.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.25% 40 mL (n = 10). Group 2: normal saline (n = 10). Group 3: same as group 1 with peri-portal local anaesthetic infiltration (n = 10) Group 4: same as group 2 with peri-portal local anaesthetic infiltration (n =10)

Outcomes

Pain.

Notes

Pain scores were not reported. The authors stated that there were no significant differences in pain scores between people who received local anaesthetics versus normal saline Attempts were made to contact the authors in April 2008.

Risk of bias Bias






Unclear risk







34

Ahmad 1998

(Continued)


Unclear risk



High risk


For-profit bias

Unclear risk


Alagöl 2003 Methods


Participants

Country: Turkey. Sample size: 82. Post-randomisation drop-outs: not stated. Revised sample size: 82. Mean age: 49 years. Females: 55 (67.1%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Drug allergy. 2. Ischaemic heart disease. 3. Arrhythmias. 4. Elevation of liver enzymes.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 20 mL (n = 20). Group 2: normal saline (n = 20). Group 3: same as group 1 with intraperitoneal ondansetron (n = 22) Group 4: same as group 2 with intraperitoneal ondansetron (n = 20)

Outcomes

Pain.

Notes


Risk of bias Bias



Support for judgement Quote: “After the removal of the gallbladder, a sealed envelope was drawn...” Comment: Unclear as to whether the random sequence was generated by drawing shuffled sealed envelopes or whether they were sequentially numbered


35

Alagöl 2003

(Continued)


Unclear risk

Quote: “After the removal of the gallbladder, a sealed envelope was drawn...” Comment: Unclear as to whether the random sequence was generated by drawing shuffled sealed envelopes or whether they were sequentially numbered






Unclear risk



High risk


For-profit bias

Unclear risk


Alkhamesi 2007 Methods


Participants

Country: UK. Sample size: 80. Post-randomisation drop-outs: not stated. Revised sample size: 80. Mean age: 49 years. Females: 69 (86.3%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. 3. Aged ≥ 18 years. Exclusion criteria 1. Allergy to bupivacaine or other drugs used in the protocol. 2. History of drug abuse. 3. Regular NSAID intake. 4. Diagnosed malignancy.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 10 mL aerosol (n = 20). Group 2: bupivacaine 0.5% 10 mL liquid (n = 20). Group 3: normal saline aerosol (n = 20). Group 4: no intervention (n = 20).

Outcomes

Pain.


36

Alkhamesi 2007

(Continued)

Notes

Attempts were made to contact the authors in April 2008. Authors provided information on random sequence generation in April 2008

Risk of bias Bias



Random sequence generation (selection Low risk bias)

Quote: “The selection was based on computer program” (author replies)



Unclear risk

Blinding of participants and personnel Low risk (performance bias) All outcomes

Quote: “All the patients, junior medical sta , and nursing sta 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”

Blinding of outcome assessment (detection Low risk bias) All outcomes

Quote: “All the patients, junior medical sta , and nursing sta 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”


Unclear risk



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.

Alper 2009 Methods


Participants

Country: Turkey. Number randomised: 40. Post-randomisation drop-outs: 0 (0%). Revised sample size: 40. Mean age: 44 years. Females: 34 (85%). Inclusion criteria


37

Alper 2009

(Continued)

1. ASA status I or II. 2. Scheduled for laparoscopic cholecystectomy. Exclusion criteria 1. Acute cholecystitis. 2. Hypersensitivity to local anaesthetics. 3. Morbid obesity. Interventions

The participants were randomised to the following groups. Group 1: levobupivacaine 0.25% 40 mL (n = 20). Group 2: normal saline (n = 20).

Outcomes

Local anaesthetic-related complications.

Notes

Attempts were made to contact the authors in July 2013.

Risk of bias Bias




Quote: “…patients were randomly assigned to one of two groups using a computer-generated random number table…”



Unclear risk


Quote: “Solutions were prepared by another anesthesiologist so that neither the surgeon performing the intraperitoneal instillation nor the anesthesiologist following up the patient was aware of which drug was injected”


Quote: “Solutions were prepared by another anesthesiologist so that neither the surgeon performing the intraperitoneal instillation nor the anesthesiologist following up the patient was aware of which drug was injected”


Low risk

Comment: There were no post-randomisation drop-outs.


High risk


For-profit bias

Unclear risk



38

Alptekin 2010 Methods


Participants

Country: Turkey. Sample size: 30. Post-randomisation drop-outs: not stated. Revised sample size: 30. Mean age: not stated. Females: not stated. Inclusion criteria 1. Females with symptomatic cholelithiasis undergoing laparoscopic cholecystectomy. 2. Aged < 45 years. Exclusion criteria 1. Acute cholecystitis. 2. Choledocholithiasis. 3. Previous cardiopulmonary disease. 4. Smoking history. 5. Previous upper abdominal operations. 6. Iatrogenic gallbladder perforation.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 20 mL (n = 10). Group 2: bupivacaine 0.5% 20 mL at the end of surgery + bupivacaine 0.5% 10 mL via catheter for 24-hour period (n = 10). Group 2: no intervention (n = 10).

Outcomes

Intraoperative complications.

Notes

Attempts were made to contact the authors in August 2013.

Risk of bias Bias






Unclear risk








Unclear risk


39

Alptekin 2010

(Continued)


High risk


For-profit bias

Unclear risk


Barczynski 2006 Methods


Participants

Country: Poland. Sample size: 120. Post-randomisation drop-outs: 0 (0%). Revised sample size: 120. Mean age: 49 years. Females: 108 (90%). Inclusion criteria 1. Uncomplicated, symptomatic cholelithiasis. 2. ASA I or II. 3. Aged ≥ 18 years. Exclusion criteria 1. Allergy to local anaesthetics. 2. Regular NSAID intake. 3. Pregnancy and lactation. 4. Previous extensive abdominal surgery.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 1 mg/kg diluted in 200 mL with saline before pneumoperitoneum (n = 30) Group 2: bupivacaine 1 mg/kg diluted in 200 mL with saline just after pneumoperitoneum (n = 30). Group 3: normal saline before pneumoperitoneum (n = 30). Group 4: normal saline just after pneumoperitoneum (n = 30).

Outcomes

Intraoperative complications and pain.

Notes

Attempts were made to contact the authors in Augsut 2013.

Risk of bias Bias




Quote: “The randomization was based on each patient receiving a sealed envelope containing a random number selected from the table”


Quote: “The randomization was based on each patient receiving a sealed envelope containing a random number selected from the table”

Low risk


40

Barczynski 2006

(Continued)


Quote: “Double-blinded”. Comment: The groups that were blinded were not stated.


Quote: “Double-blinded” Comment: The groups that were blinded were not stated.


Low risk



High risk

Comment: Authors report that there were no intra-operative complications. It was not clear whether there were any postoperative complications

For-profit bias

Unclear risk


Bhardwaj 2002 Methods


Participants

Country: India. Sample size: 40. Post-randomisation drop-outs: not stated. Revised sample size: 40. Mean age: 34 years. Females: 36 (90%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I and II. 3. Aged 20 to 40 years. Exclusion criteria 1. People with acute cholecystitis. 2. Did not give consent. 3. Did not understand VAS and verbal rating score.

Interventions


Outcomes

Pain.

Notes

Attempts were made to contact the authors in March 2009.

Risk of bias Bias




41

Bhardwaj 2002

(Continued)




Unclear risk





Quote: “The observer was blinded to the solution instilled”.


Unclear risk



High risk


For-profit bias

Unclear risk


Castillo-Garza 2012 Methods


Participants

Country: Mexico. Sample size: 60. Post-randomisation drop-outs: 0 (0%). Revised sample size: 60. Mean age: 33 years. Females: 55 (91.7%). Inclusion criteria 1. Aged 15 to 60 years. 2. Elective laparoscopic cholecystectomy. Exclusion criteria 1. Pregnancy. 2. Open cholecystectomy. 3. Acute cholecystitis. 4. Chronic treatment with analgesics or anti-inflammatories.

Interventions


Outcomes

Mortality, morbidity, and pain.

Notes


Risk of bias Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

42

Castillo-Garza 2012

(Continued)

Bias




Quote: “randomization was performed using a computer program (www.randomized.com)”


Unclear risk

Quote: “…with concealment of the random sequence…”. Comment: Further details were not available.


Comment: A placebo was used but the groups blinded were not reported


Comment: A placebo was used but the groups blinded were not reported


Low risk



Low risk

Comment: Mortality and morbidity were reported.

For-profit bias

Unclear risk


Chundrigar 1993 Methods


Participants

Country: UK. Sample size: 60. Post-randomisation drop-outs: 2 (3.3%). Revised sample size: 58. Mean age: 48 years. Females: 53 (91.4%). Inclusion criteria 1. Elective laparoscopic cholecystectomy for symptomatic gallstones

Interventions


Outcomes

Pain.

Notes

Reasons for post-randomisation drop-out: conversion to open cholecystectomy. Attempts were made to contact the authors in April 2008.

Risk of bias Bias




43

Chundrigar 1993

(Continued)





Unclear risk


Quote: “The solutions were given and the subsequent assessment were performed in a double blind manner”


Quote: “The solutions were given and the subsequent assessment were performed in a double blind manner”


High risk

Comment: There were post-randomisation drop-outs.


High risk


For-profit bias

Unclear risk


El-Labban 2011 Methods


Participants

Country: Egypt. Sample size: 126. Post-randomisation drop-outs: 0 (0%). Revised sample size: 126. Mean age: 41 years. Females: 69 (54.8%). Inclusion criteria 1. Aged 25 to 64 years. 2. ASA status I or II. Exclusion criteria 1. Known allergy to local anaesthetics. 2. Acute cholecystitis. 3. Conversion to open procedure. 4. Intra-operative complications. 5. Morbid obesity. 6. Chronic medical diseases. 7. Chronic opioid treatment.

Interventions

The participants were randomised to the following groups. Group 1: levobupivacaine 0.25% 20 mL (n = 63). Group 2: no intervention (n = 63).

Outcomes



44

El-Labban 2011

(Continued)

Notes


Risk of bias Bias






Quote: “…using a blind envelope system”. Comment: Further details were not available.

Unclear risk




Quote: “The residents…were trained to obtain the VAS score…they were blinded to the patient’s status concerning local analgesia” Comment: The VAS score refers to abdominal pain and not overall pain


Low risk



High risk


For-profit bias

Low risk

Quote: “No grants or funds from any pharmaceutical industry were obtained for the study”

Elfberg 2000 Methods


Participants

Country: Sweden. Sample size: 65. Post-randomisation drop-outs: 1 (1.5%). Revised sample size: 64. Mean age: 49 years. Females: 37 (57.8%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 2 mg/kg (n = 33). Group 2: normal saline (n = 32).


45

Elfberg 2000

(Continued)

Outcomes

Local anaesthetic-related complications and pain.

Notes

Reasons for post-randomisation drop-out: conversion to open cholecystectomy. Attempts were made attempts to contact the authors in April 2008

Risk of bias Bias







Unclear risk


Quote: “The solutions were administered, and subsequent assessment was performed in a double-blind manner”




High risk



High risk


For-profit bias

Unclear risk


Elhakim 2000a Methods


Participants

Country: Egypt. Sample size: 50. Post-randomisation drop-outs: not stated. Revised sample size: 50. Mean age: 45 years. Females: 38 (76%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I or II.

Interventions

The participants were randomised to the following groups. Group 1: lignocaine 0.1% 200 mL (n = 25). Group 2: normal saline (n = 25).

Outcomes



46

Elhakim 2000a

(Continued)

Notes

Attempts were made attempts to contact the authors in April 2008

Risk of bias Bias







Unclear risk


Quote: “The surgeon was blinded to the nature of the solution used” Comment: Not clear if participants and others caring for the participant were blinded


Quote: “The investigator, who was blind to the group allocation of the patient and to any postoperative analgesia administered, assessed the patients postoperatively with reference to pain and respiratory function tests”


Unclear risk



High risk


For-profit bias

Unclear risk


Feroci 2009 Methods


Participants

Country: Italy. Sample size: 30. Post-randomisation drop-outs: 0 (0%). Revised sample size: 30. Mean age: 54 years. Females: 19 (63.3%). Inclusion criteria 1. Laparoscopic cholecystectomy for gallstones. 2. Aged > 18 years. 3. ASA 1 or 2. Exclusion criteria 1. Acute cholecystitis. 2. Pregnant women. 3. Upper abdominal surgery. 4. Acute pancreatitis. 5. Conversion to open surgery.


47

Feroci 2009

(Continued)

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 2 mg/kg in absorbable cellulose strips (n = 15). Group 2: no intervention (n = 15).

Outcomes


Notes

Attempts were made to contact the authors in August 2010. Authors provided further information in August 2010

Risk of bias Bias




Quote: “The randomization was obtained through a computer-generated program” (author replies)


Low risk

Quote: “It consisted with an ordered series of numbers with a corresponding letter for each group. This series of numbers … in closed envelopes by a secretary not involved in patients’ assistance. The envelopes were opaque and sealed” (author replies)


Quote: “The surgeon who performed the intervention was not included in the follow-up. Neither the patients nor the investigating doctors were informed about the way in which bupivacaine was administered” (author replies)


Quote: “The surgeon who performed the intervention was not included in the follow-up. Neither the patients nor the investigating doctors were informed about the way in which bupivacaine was administered” (author replies)


Low risk



Low risk


For-profit bias

Low risk

Quote: “For the study we didn’t receive any fund from industry. All material used in the study (tabotamp and bupivacaine) was property of the hospital that authorized its use for the study” (author replies)


48

Fornari 1996 Methods


Participants

Country: Italy. Sample size: 104. Post-randomisation drop-outs: 4 (3.8%). Revised sample size: 100. Mean age: 46 years. Females: 64 (64%). Inclusion criteria 1. Elective laparoscopic cholecystectomy for symptomatic cholelithiasis. 2. ASA I or II. Exclusion criteria 1. Requiring drain insertion. 2. Perforation of gallbladder during operation.

Interventions


Outcomes

Mortality, morbidity, hospital stay, and pain.

Notes

Reasons for post-randomisation drop-out: perforation of gallbladder during surgery. Attempts were made to contact the authors in April 2008. The authors replied in April 2008

Risk of bias Bias




Quote: “computer generated” (author replies).


Quote: “sealed envelope” (author replies).

Low risk


Quote: “This liquid, whose nature was recognized only by the anesthesiologist but not by the surgeon” Comment: Further details were not available.


Quote: “This liquid, whose nature was recognized only by the anesthesiologist but not by the surgeon” Comment: Further details were not available.


High risk



Low risk


For-profit bias

Unclear risk



49

Fu 2009 Methods


Participants

Country: China. Sample size: 40. Post-randomisation drop-outs: 0 (0%). Revised sample size: 40. Mean age: 42 years. Females: 12 (30%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I or II. 3. Ability to understand VAS scores. Exclusion criteria 1. Previous upper abdominal surgeries. 2. Choledocholithiasis. 3. Acute cholecystitis. 4. Conversion to open cholecystectomy. 5. Body mass index > 35 kg/m2 . 6. Diminished kidney or liver function.

Interventions

The participants were randomised to the following groups. Group 1: ropivacaine 1 mg/kg mixed with 5-mL fibrin sealant (n = 20). Group 2: no intervention (5 mL of fibrin sealant) (n = 20).

Outcomes

Pain.

Notes

Attempts were made to contact the author in October 2010.

Risk of bias Bias




Quote: “The patients were randomly divided into 3 equal groups with the help of computer-generated randomization numbers”


Unclear risk







Low risk



High risk



50

Fu 2009

(Continued)

For-profit bias

Unclear risk


Fuhrer 1996 Methods


Participants

Country: France. Sample size: 24. Post-randomisation drop-outs: 2 (8.3%). Revised sample size: 22. Mean age: 60 years. Females: 15 (68.2%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Drug addicts. 2. People with epilepsy. 3. Poor liver function. 4. Cardiac dysfunction. 5. Use of beta-blockers or H2 blockers. 6. Allergy to anaesthetic agents.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.38% 0.6 mL/kg (n = 12). Group 2: normal saline (n = 10).

Outcomes

Pain.

Notes

Reasons for post-randomisation drop-out: conversion to open cholecystectomy Pain scores were reported in a graph but it was not possible to identify the lines that indicated the intervention and those that indicated the control. The authors state that there were no significant differences in pain scores between people who received local anaesthetics versus normal saline. Attempts were made to contact the authors in April 2008.

Risk of bias Bias






Unclear risk





51

Fuhrer 1996

(Continued)




High risk



High risk


For-profit bias

Unclear risk


Garcia 2007 Methods


Participants

Country: Brazil. Sample size: 40. Post-randomisation drop-outs: 8 (20%). Revised sample size: 32. Mean age: 46 years. Females: 26 (81.3%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Allergy to drugs used in the protocol. 2. Cardiac problems. 3. Cognitive deficit.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine (S75-R25) 0.125% 80 mL (n = 19). Group 2: normal saline (n = 13).

Outcomes


Notes

Reasons for post-randomisation drop-outs: impossibility of completing the protocol Attempts were made to contact the authors in April 2008.

Risk of bias Bias






Quote: “Both with 20 patients each, for a double-blind study, using sealed envelopes chosen immediately before the procedure”

Unclear risk


52

Garcia 2007

(Continued)

Comment: Further details were not available. Blinding of participants and personnel Low risk (performance bias) All outcomes

Quote: “The investigator was unaware which group the patient belonged to until the end of the study....The solution for intraperitoneal instillation was prepared a member of the team who had no other role in the study”


Quote: “The investigator was unaware which group the patient belonged to until the end of the study....The solution for intraperitoneal instillation was prepared a member of the team who had no other role in the study”


High risk



High risk


For-profit bias

Unclear risk


Golubovic 2009 Methods


Participants

Country: Croatia. Sample size: 60. Post-randomisation drop-outs: 0 (0%). Revised sample size: 60. Mean age: 53 years. Females: 38 (63.3%). Inclusion criteria 1. ASA status I or II. 2. Elective laparoscopic cholecystectomy for cholelithiasis. Exclusion criteria 1. Contraindications to tramadol or bupivacaine. 2. Intra-operative complications. 3. Conversion to open procedure.

Interventions


Outcomes

Pain.

Notes


Risk of bias Bias




53

Golubovic 2009

(Continued)





Unclear risk


Quote: “The test solution were drawn into coded syringes and given to surgeons who did not know their content. The drugs were administered…by...recovery nurse with no knowledge of peri-operative analgesia administration”


Quote: “This was a prospective, randomized, doubleblinded study.... The drugs were administrated on demand by an experienced recovery nurse with no knowledge of perioperative analgesia administration”


Low risk



High risk


For-profit bias

Unclear risk


Gvozdenovic 2011 Methods


Participants

Country: Serbia. Sample size: 60. Post-randomisation drop-outs: not stated. Revised sample size: 60. Mean age: not stated. Females: not stated. Inclusion criteria 1. People undergoing elective laparoscopic cholecystectomy.

Interventions


Outcomes

Pain.

Notes

Pain scores were not reported. The authors state that there were no significant differences in pain scores between those who received local anaesthetics versus normal saline Attempts were made to contact the authors in August 2013.

Risk of bias


54

Gvozdenovic 2011

(Continued)

Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk


Hasan 2007 Methods


Participants

Country: Belgium. Sample size: 36. Post-randomisation drop-outs: not stated. Revised sample size: 36. Mean age: not stated. Females: not stated. Inclusion criteria 1. People undergoing laparoscopic cholecystectomy.

Interventions

The participants were randomised to the following groups. Group 1: ropivacaine 0.25% 20 mL (n = not stated). Group 2: normal saline (n = not stated). Group 3: same as group 1 with peri-portal local anaesthetic infiltration (n = not stated) Group 4: same as group 2 with peri-portal local anaesthetic infiltration (n = not stated)

Outcomes


Notes


Risk of bias Bias




55

Hasan 2007

(Continued)




Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk


Hazinedaroglu 2006 Methods


Participants

Country: Turkey. Sample size: 50. Post-randomisation drop-outs: 0 (0%). Revised sample size: 50. Mean age: not stated. Females: not stated. Inclusion criteria 1. Adults undergoing elective laparoscopic cholecystectomy. 2. Symptomatic gallstones. 3. ASA I or II. Exclusion criteria 1. History of diabetes mellitus. 2. Prior abdominal surgery. 3. Allergy to bupivacaine. 4. Chronic corticosteroid, NSAID, or immunosuppressive treatment. 5. Gall bladder perforation. 6. Bile contamination of the peritoneum. 7. Surgical manipulation that necessitated the elongation of the incision at 1 of the trocar sites (eg, stone extraction, open laparoscopy, and haemostasis of the port sites). 8. Repeated trocar entry attempts more than twice. 9. Overt intra-abdominal adhesions. 10. Conversion to open surgery. 11. 1Surgical complication that required further medical or surgical intervention.


56

Hazinedaroglu 2006

(Continued)

Interventions


Outcomes


Notes


Risk of bias Bias






Low risk

Quote: “50 adult elective LC [laparoscopic cholecystectomy] patients were randomly allocated into two groups by envelopes” Comment: Further details were not available.


Quote: “Surgical and anesthesiology teams were blind to the contents”


Quote: “Surgical and anesthesiology teams were blind to the contents”


Low risk



High risk


For-profit bias

Unclear risk


Jabbour-Khoury 2005 Methods


Participants

Country: Lebanon. Sample size: 80. Post-randomisation drop-outs: not stated. Revised sample size: 80. Mean age: 47 years. Females: 44 (55%). Inclusion criteria 1. Elective laparoscopic cholecystectomy without intra-operative cholangiography. 2. ASA I or II.


57

Jabbour-Khoury 2005

(Continued)

3. Aged between 20 and 60 years. Exclusion criteria 1. Chronic pain diseases other than gallstone disease. 2. Chronic use of opioids, tranquillizers, steroids, NSAIDs. 3. Alcohol. 4. Amide local anaesthetic allergy. 5. Contraindications to NSAIDs (allergy, peptic ulcer disease, gastro-oesophageal reflux disease, renal insufficiency, coagulopathy). 6. Conversion to an open cholecystectomy. 7. Postoperative complications that increased postoperative pain. 8. Pain evaluation judged unreliable because of neurological disease. 9. Intraoperative need for more than 2 µg/kg fentanyl. 10. Heart rate not controlled by increasing sevoflurane concentration for 5 minutes. Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.25% 40 mL (n = 20). Group 2: normal saline (n = 20). Group 3: same as group 1 but received intravenous ketoprofen (n = 20). Group 4: same as group 2 but received intravenous ketoprofen (n = 20)

Outcomes


Notes


Risk of bias Bias







Unclear risk


Quote: “A surgical scrub nurse who had no further involvement in the study prepared the solutions administered intraperitoneally to the study patients”


Quote: “A surgical scrub nurse who had no further involvement in the study prepared the solutions administered intraperitoneally to the study patients”


Unclear risk



High risk


For-profit bias

Unclear risk



58

Jiranantarat 2002 Methods


Participants

Country: Thailand. Sample size: 80. Post-randomisation drop-outs: not stated. Revised sample size: 80. Mean age: 52 years. Females: 57 (71.3%). Inclusion criteria 1. Elective laparoscopic cholecystectomy for symptomatic gallstones. 2. ASA I or II. Exclusion criteria 1. Arrhythmias

Interventions


Outcomes

Hospital stay and pain.

Notes


Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk



59

Joris 1995 Methods


Participants

Country: Belgium. Sample size: 43. Post-randomisation drop-outs: 3 (7%). Revised sample size: 40. Mean age: 48 years. Females: 29 (72.5%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Acute cholecystitis

Interventions


Outcomes


Notes

Reasons for post-randomisation drop-out: conversion to open cholecystectomy. Attempts were made to contact the authors in April 2008. Authors provided replies in April 2008

Risk of bias Bias




Quote: “Computer generated” (author replies).


Quote: “Held by a third party; syringes were prepared by the pharmacy” (author replies)

Low risk






High risk



High risk


For-profit bias

Unclear risk



60

Kallel 2011 Methods


Participants

Country: Tunisia. Sample size: 40. Post-randomisation drop-outs: not stated. Revised sample size: 40. Mean age: not stated. Females: 40 (100%). Inclusion criteria 1. People undergoing laparoscopic cholecystectomy. 2. Females aged between 20 and 60 years weighing > 50 kg with ASA physical status I or II.

Interventions

The participants were randomised to the following groups. Group 1: lignocaine 1% 40 mL (n = 20). Group 2: normal saline (n = 20).

Outcomes


Notes


Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk



61

Karaaslan 2006 Methods


Participants

Country: Turkey. Sample size: 80. Post-randomisation drop-outs: 15 (18.8%). Revised sample size: 65. Mean age: 52 years. Females: 41 (63.1%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Allergy to local anaesthetics. 2. Requiring fentanyl in the last 30 minutes of operation. 3. Requiring naloxone at the end of operation. 4. Required pethidine after operation.

Interventions

The participants were randomly assigned to the following groups. Group 1: bupivacaine 0.5% 20 mL before pneumoperitoneum (n = 16). Group 2: bupivacaine 0.5% 20 mL just after creation of pneumoperitoneum (n = 18) Group 3: bupivacaine 0.5% 20 mL at the end of surgery (n = 16) Group 4: no intervention (n = 15).

Outcomes


Notes

Reasons for post-randomisation drop-out: required opiates intraoperatively (n = 10) and post-operatively (n = 5). Attempts were made to contact the authors in April 2008.

Risk of bias Bias







Unclear 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”


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”


62

Karaaslan 2006

(Continued)


High risk



High risk


For-profit bias

Unclear risk


Karadeniz 2003 Methods


Participants

Country: Turkey. Sample size: 67. Post-randomisation drop-outs: 7 (10.4%). Revised sample size: 60. Mean age: 29 years. Females: 47 (78.3%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. Aged 25 to 65 years. 3. ASA I or II. Exclusion criteria 1. Allergy to local anaesthetics. 2. Acute cholecystitis.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 20 mL just after creation of pneumoperitoneum (n = 15) Group 2: bupivacaine 0.5% 20 mL end of surgery (n = 15). Group 3: bupivacaine 0.5% 20 mL after end of surgery (n = 15). Group 4: placebo (further details not available) (n = 15).

Outcomes


Notes

Reasons for post-randomisation drop-out: conversion to open cholecystectomy (n = 3) and requirement for drain insertion (n = 4). Attempts were made to contact the authors in April 2008. Authors provided replies in April 2008

Risk of bias Bias




Quote: “We used random number table”.


Quote: “It was held by third party”.

Low risk


63

Karadeniz 2003

(Continued)






High risk



Low risk


For-profit bias

Unclear risk


Kilic 1996 Methods


Participants

Country: Turkey. Sample size: 40. Post-randomisation drop-outs: not stated. Revised sample size: 40. Mean age: 49 years. Females: 33 (82.5%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II.

Interventions


Outcomes


Notes


Risk of bias Bias







Unclear risk


64

Kilic 1996

(Continued)






Unclear risk



High risk


For-profit bias

Unclear risk


Kim 2010 Methods


Participants

Country: Korea. Sample size: 40. Post-randomisation drop-outs: not stated. Revised sample size: 40. Mean age: 50 years. Females: 24 (60%). Inclusion criteria 1. Aged 18 to 65 years. 2. Uncomplicated symptomatic cholecystitis with cholelithiasis. Exclusion criteria 1. Weigh < 45 kg or > 100 kg. 2. Severe underlying cardiovascular, hepatic, or renal disease. 3. Allergy to local anaesthetics.

Interventions

The participants were randomised to the following groups. Group 1: ropivacaine 2 mg/kg diluted in 100 mL saline (n = 20). Group 2: normal saline (n = 20).

Outcomes

Intraoperative complications and pain.

Notes Risk of bias Bias



Support for judgement Quote: “Randomization…were based on Excel random number generation”


65

Kim 2010

(Continued)


Low risk

Quote: “The detail of series were unknown to investigators and contained in a set of sealed envelope, each bearing only the outside number”


Quote: “The operator entered the room after instillation preparation and performed procedure without information”


Quote: “The postoperative pain data was collected by blinded investigators”


Low risk



High risk


For-profit bias

Unclear risk

Quote: “This research was supported by the Chung-Ang University Research Grants in 2009”

Kolsi 2000 Methods


Participants

Country: Tunisia. Sample size: 42. Post-randomisation drop-outs: 2 (4.8%). Revised sample size: 40. Mean age: 43 years. Females: 40 (100%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. 3. Aged between 20 and 60 years. Exclusion criteria 1. History of chronic pain. 2. Regular intake of analgesic drugs (NSAIDs). 3. Allergy to local anaesthetic agents. 4. Psychiatric disease.

Interventions

The participants were randomised to the following groups. Group 1: lignocaine 1% 400 mg (n = 20). Group 2: normal saline (n = 20).

Outcomes


Notes

Reasons for post-randomisation drop-out: conversion to open cholecystectomy (n = 1) and lack of standardisation of anaesthetic technique (n = 1).


66

Kolsi 2000

(Continued)

Attempts were made to contact the authors in April 2008. Risk of bias Bias






Unclear risk





Quote: “Patients were transferred to a post-anaesthesia care unit where they were monitored and questioned by an independent observer who was not involved in the patient randomisation or anaesthesia administration”


High risk



High risk


For-profit bias

Unclear risk


Kucuk 2007 Methods


Participants

Country: Turkey. Sample size: 80. Post-randomisation drop-outs: not stated. Revised sample size: 80. Mean age: 50 years. Females: 69 (86.3%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Morbid obesity. 2. Severe chronic disease. 3. Allergic reactions to NSAIDs or local anaesthetics. 4. Chronic opioid treatment. 5. Acute cholecystitis. 6. Conversion to an open procedure.


67

Kucuk 2007

(Continued)

Interventions

The participants were randomised to the following groups. Group 1: ropivacaine 1.5% 10 mL (n = 20). Group 2: ropivacaine 0.5% 10 mL (n = 20). Group 3: bupivacaine 0.5% 10 mL (n = 20). Group 2: normal saline (n = 20).

Outcomes


Notes


Risk of bias Bias







Unclear risk


Comment: This was a placebo-controlled trial. However, the groups that were blinded to the drug were not reported


Comment: This was a placebo-controlled trial. However, the groups that were blinded to the drug were not reported


Unclear risk



High risk


For-profit bias

Unclear risk


Labaille 2002 Methods


Participants

Country: France. Sample size: 42. Post-randomisation drop-outs: 5 (11.9%). Revised sample size: 37. Mean age: 49 years. Females: 24 (64.9%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria


68

Labaille 2002

(Continued)

1. 2. 3. 4. 5.

Allergic to local anaesthetics. History of cardiac disease. Acute cholecystitis. Conversion to open procedure. Requiring rescue analgesia.

Interventions

The participants were randomised to the following groups. Group 1: ropivacaine 0.75% 40 mL (n = 11). Group 1: ropivacaine 0.25% 40 mL (n = 14). Group 2: normal saline (n = 12).

Outcomes


Notes

Reasons for post-randomisation drop-out: required rescue NSAIDs (n = 2); conversion to open cholecystectomy (n = 2); protocol violation (n = 1). Attempts were made to contact the authors in April 2008.

Risk of bias Bias







Unclear risk


Quote: “The surgeon was not informed of the contents of the solution” Comment: It was not clear whether the participants and other healthcare professionals involved in patient care were blinded




High risk



High risk


For-profit bias

Unclear risk



69

Lee 2001 Methods


Participants

Country: South Korea. Sample size: 88. Post-randomisation drop-outs: 6 (6.8%). Revised sample size: 82. Mean age: 47 years. Females: 36 (43.9%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Allergic to local anaesthetics. 2. Severe systemic disease. 3. Chronic pain diseases other than gallstone disease were excluded. 4. Acute cholecystitis before the operation.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.25% 40 mL just after creation of pneumoperitoneum (n = 20) Group 2: bupivacaine 0.25% 40 mL at end of surgery (n = 19). Group 3: normal saline just after creation of pneumoperitoneum (n = 22) Group 4: normal saline at end of surgery (n = 21).

Outcomes

Mortality and morbidity.

Notes

Reasons for post-randomisation drop-out: not stated. Attempts were made to contact the authors in April 2008.

Risk of bias Bias







Unclear risk


Quote: “No patients or observers were informed of the treatment group (preoperative or postoperative)”


Quote: “No patients or observers were informed of the treatment group (preoperative or postoperative)”


High risk



Low risk



70

Lee 2001

(Continued)

For-profit bias

Unclear risk


Lepner 2003 Methods


Participants

Country: Estonia. Sample size: 40. Post-randomisation drop-outs: 0 (0%). Revised sample size: 40. Mean age: 52 years. Females: 35 (87.5%). Inclusion criteria 1. Elective laparoscopic cholecystectomy for gallstone disease. 2. ASA I to III. Exclusion criteria 1. Acute cholecystitis. 2. Inability to understand and use the VAS. 3. History of allergy to NSAIDs, local anaesthetics, or both.

Interventions

The participants were randomised to the following groups. Group 1: lignocaine 0.15% 200 mL (n = 20). Group 2: normal saline (n = 20).

Outcomes

Mortality and morbidity.

Notes

Authors provided information on post-randomisation drop-outs in April 2008

Risk of bias Bias






Quote: “The patients were modernised prospectively, using a blind envelope system, into four groups of 20 persons each” Comment: Further details were not available.

Unclear risk


Quote: “The patients were blinded to the methods of analgesia used. The investigators, who were blinded to the patients’ division into groups and to the method of postoperative analgesia, assessed the patients’ postoperative abdominal pain and shoulder pain at rest”


71

Lepner 2003

(Continued)


Quote: “The patients were blinded to the methods of analgesia used. The investigators, who were blinded to the patients’ division into groups and to the method of postoperative analgesia, assessed the patients’ postoperative abdominal pain and shoulder pain at rest”


Low risk



Low risk


For-profit bias

Unclear risk


Louizos 2005 Methods


Participants

Country: Greece. Sample size: 108. Post-randomisation drop-outs: 4 (3.7%). Revised sample size: 104. Mean age: 49 years. Females: 56 (53.8%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. 3. Aged between 25 and 70 years. Exclusion criteria 1. Allergy to local anaesthetics. 2. Acute cholecystitis. 3. History of severe systemic disease. 4. Chronic pain diseases other than gallstone disease.

Interventions

The participants were randomised to the following groups. Group 1: levobupivacaine 0.25% 20 mL (n = 26). Group 2: normal saline (n = 25). Group 3: same as group 1 with local anaesthetic wound infiltration (n = 28) Group 4: same as group 2 with local anaesthetic wound infiltration (n = 25)

Outcomes


Notes

Reasons for post-randomisation drop-out: surgical complication (n = 2); protocol violation (n = 2). Authors provided information on allocation sequence generation and allocation concealment in March 2008

Risk of bias


72

Louizos 2005

(Continued)

Bias




Quote: “The random sequence was computer generated” (author replies)


Unclear risk

Quote: “We used sealed envelopes for the allocation” (author replies) Comment: Further details were not available.


Quote: “The surgeon performing both the preincisional local in ltration and the intraperitoneal instillation was not aware of the solution administered. Furthermore the anesthetist following up the pain score of the patients was not aware of the kind of solution administered to each patient” Comment: Not clear whether the participants were blinded.


Quote: “The surgeon performing both the preincisional local in ltration and the intraperitoneal instillation was not aware of the solution administered. Furthermore the anesthetist following up the pain score of the patients was not aware of the kind of solution administered to each patient”


High risk



High risk


For-profit bias

Unclear risk


Maestroni 2002 Methods


Participants

Country: Italy. Sample size: 61. Post-randomisation drop-outs: 1 (1.6%). Revised sample size: 60. Mean age: 54 years. Females: 33 (55%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Allergy to local anaesthetic. 2. Acute cholecystitis. 3. Surgery time > 90 minutes.


73

Maestroni 2002

(Continued)

Interventions

The participants were randomised to the following groups. Group 1: ropivacaine 5 mg/kg diluted in 200 mL saline (n = 30). Group 2: normal saline (n = 30).

Outcomes


Notes

Reasons for post-randomisation drop-out: duration of surgery > 90 minutes. Attempts were made to contact the authors in April 2008.

Risk of bias Bias






Unclear risk







High risk



High risk


For-profit bias

Unclear risk


Mraovic 1997 Methods


Participants

Country: Croatia. Sample size: 82. Post-randomisation drop-outs: 2 (2.4%). Revised sample size: 80. Mean age: 54 years. Females: 66 (82.5%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II.


74

Mraovic 1997

(Continued)

Interventions


Outcomes


Notes

Reasons for post-randomisation drop-out: conversion to open cholecystectomy (n = 1) and lost VAS (n = 1). Attempts were made to contact the authors in April 2008.

Risk of bias Bias




Quote: “Solutions were prepared by a nurse using computer-generated randomised numbers”



Unclear risk


Quote: “All clinical personnel were blinded to the treatment” Comment: Not clear if the participants were blinded.


Quote: “All clinical personnel were blinded to the treatment”


High risk



High risk


For-profit bias

Unclear risk


Ng 2004 Methods


Participants

Country: UK. Sample size: 48. Post-randomisation drop-outs: 5 (10.4%). Revised sample size: 43. Mean age: 46 years. Females: not stated. Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I or II.


75

Ng 2004

(Continued)

Exclusion criteria 1. Chronic pain syndrome. 2. Used analgesics regularly. Interventions


Outcomes


Notes

Reasons for post-randomisation drop-out: intraperitoneal solution not administered (n = 1), protocol violation (n = 2), haemorrhage precluding standard laparoscopic technique (n = 1); declined to participate (n = 1). The dose of adrenaline in the control group was half that of the intervention group. We do not consider that adrenaline in the absence of any local anaesthetic has any analgesic property on its own and included this trial. Attempts were made to contact the authors in April 2008.

Risk of bias Bias






Low risk

Quote: “This allocation was done randomly by computer in blocks of six and from instructions in envelopes that were sealed and opaque so that they could not be viewed, e.g. by shining a light”


Quote: “The treatment solution was prepared by the anaesthetist who was not involved further in the study”


Quote: “The treatment solution was prepared by the anaesthetist who was not involved further in the study”


High risk



High risk


For-profit bias

Unclear risk



76

Nicolau 2008 Methods


Participants

Country: Romania. Sample size: 60. Post-randomisation drop-outs: not stated. Revised sample size: 60. Mean age: 50 years. Females: 53 (88.3%). Inclusion criteria 1. People scheduled for laparoscopic cholecystectomy Exclusion criteria 1. Acute cholecystitis. 2. Conversion to open cholecystectomy. 3. Post-operative complication. 4. Allergy to local anaesthesia.

Interventions

The participants were randomised to the following groups. Group 1: ropivacaine 0.25% 20 mL (n = 15). Group 2: normal saline (n = 15). Group 3: same as group 1 with peri-portal local anaesthetic infiltration (n = 15) Group 4: same as group 2 with peri-portal local anaesthetic infiltration (n = 15)

Outcomes


Notes

Attempts were made contact the author in October 2009.

Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk



77

Pasqualucci 1994 Methods


Participants

Country: Italy. Sample size: 42. Post-randomisation drop-outs: 5 (11.9%). Revised sample size: 37. Mean age: 47 years. Females: 26 (70.3%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Allergy to local anaesthetics. 2. History of severe pulmonary or hormonal diseases. 3. Acute cholecystitis.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 20 mL just after creation of pneumoperitoneum (n = 12) Group 2: bupivacaine 0.5% 20 mL each just after creation of pneumoperitoneum and end of surgery (n = 14). Group 3: normal saline (n = 11).

Outcomes


Notes

Reasons for post-randomisation drop-out: received glucose (n = 3), received opiates (n = 3), conversion to open cholecystectomy (n = 1). Attempts were made to contact the author in April 2008. Although authors replied, no additional information was provided

Risk of bias Bias






Unclear risk








High risk


78

Pasqualucci 1994

(Continued)


High risk


For-profit bias

Unclear risk


Pasqualucci 1996 Methods


Participants

Country: Italy. Sample size: 120. Post-randomisation drop-outs: 11 (9.2%). Revised sample size: 109. Mean age: 47 years. Females: 61 (56%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. Exclusion criteria 1. Allergy to local anaesthetics. 2. History of severe pulmonary or hormonal diseases. 3. Acute cholecystitis.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 20 mL just after creation of pneumoperitoneum (n = 26) Group 2: bupivacaine 0.5% 20 mL at end of surgery (n = 28). Group 3: bupivacaine 0.5% 20 mL each just after creation of pneumoperitoneum and end of surgery (n = 28). Group 4: normal saline (n = 27).

Outcomes


Notes

Reasons for post-randomisation drop-out: received glucose (n = 1), received opiates (n = 3), intraoperative complications (n = 2), insufficient data (n = 5). Attempts were made to contact the author in April 2008. Although authors replied, no additional information was provided

Risk of bias Bias






Unclear risk


Blinding of participants and personnel Unclear risk (performance bias)



79

Pasqualucci 1996

(Continued)

All outcomes Blinding of outcome assessment (detection Unclear risk bias) All outcomes



High risk



High risk


For-profit bias

Unclear risk


Paulson 2003 Methods


Participants

Country: USA. Sample size: 77. Post-randomisation drop-outs: 11 (14.3%). Revised sample size: 66. Mean age: 42 years. Females: 53 (80.3%). Inclusion criteria 1. Elective laparoscopic cholecystectomy starting before noon. 2. ASA I or II. 3. Aged > 18 years. Exclusion criteria 1. Allergy to study medications.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 15 mL just after creation of pneumoperitoneum (n = 18) Group 2: bupivacaine 0.5% 15 mL at end of surgery (n = 15). Group 3: bupivacaine 0.5% 15 mL each just after creation of pneumoperitoneum and end of surgery (n = 19) Group 4: normal saline (n = 14).

Outcomes

Local anaesthetic-related complications and hospital stay.

Notes

Attempts were made to contact the authors in April 2008. Reasons for post-randomisation drop-outs: conversion to open procedure or drain use or liver pathology (n = 4), deviation from protocol (n = 2), loss of participants’ chart (n = 1), intraoperative cancellation without documentation (n = 4)

Risk of bias Bias




80

Paulson 2003

(Continued)




Low risk

Quote: “The pharmacy randomized the patients to one of four study groups” (only 2 groups were included for this review)


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


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


High risk



High risk


For-profit bias

Unclear risk


Rademaker 1994 Methods


Participants

Country: the Netherlands. Sample size: 45. Post-randomisation drop-outs: not stated. Revised sample size: 45. Mean age: 47 years. Females: 35 (77.8%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.25% 20 mL (n = 15). Group 2: lignocaine 0.5% 20 mL (n = 15). Group 2: normal saline (n = 15).

Outcomes



81

Rademaker 1994

(Continued)

Notes


Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk


Raetzell 1995a Methods


Participants

Country: Germany. Sample size: 30. Post-randomisation drop-outs: not stated. Revised sample size: 30. Mean age: not stated. Females: not stated. Inclusion criteria 1. Laparoscopic cholecystectomy.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.125% 50 mL (n = not stated). Group 1: bupivacaine 0.25% 50 mL (n = not stated). Group 2: normal saline (n = not stated).

Outcomes



82

Raetzell 1995a

(Continued)

Notes

Attempts were made to contact the authors in April 2008. The number of participants in each group was not reported. Bupivacaine 0.125% developed 1 complication (thrombophlebitis) and the control group developed 1 complication (umbilical abscess) There was no significant differences in the pain scores between the groups

Risk of bias Bias







Unclear risk


Quote: “Blinded solutions were prepared by our pharmacy department and were given intraperitoneally at the end of the operation through the trocars”




Unclear risk



Low risk


For-profit bias

Unclear risk


Raetzell 1995b Methods


Participants

Country: Germany. Sample size: 24. Post-randomisation drop-outs: not stated. Revised sample size: 24. Mean age: not stated. Females: not stated. Inclusion criteria 1. Laparoscopic cholecystectomy.

Interventions



83

Raetzell 1995b

(Continued)

Outcomes


Notes


Risk of bias Bias







Unclear risk






Unclear risk



Low risk


For-profit bias

Unclear risk


Razek 2003 Methods


Participants

Country: UK. Sample size: 40. Post-randomisation drop-outs: 0 (0%). Revised sample size: 40. Mean age: 43 years. Females: 36 (90%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. 2. ASA I or II. 3. Aged between 20 and 60 years. Exclusion criteria 1. History of chronic pain. 2. Contraindication for analgesic drugs (NSAIDs). 3. Allergy to local anaesthetic agents. 4. History of psychiatric disease.


84

Razek 2003

(Continued)

Interventions


Outcomes


Notes


Risk of bias Bias






Unclear risk





Quote: “Patients were transferred to the recovery room where they were monitored and questioned about their postoperative pain at rest by an independent observer who was not involved in patient randomisation or anaesthesia administration”


Low risk



High risk


For-profit bias

Unclear risk


Razman 2010 Methods


Participants

Country: Malaysia. Sample size: 60. Post-randomisation drop-outs: not stated. Revised sample size: 60. Mean age: not stated. Females: not stated. Inclusion criteria 1. People undergoing laparoscopic cholecystectomy.


85

Razman 2010

(Continued)

Interventions


Outcomes

None of the outcomes of interest for this review were reported in this trial

Notes


Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk


Roberts 2011 Methods


Participants

Country: UK. Sample size: 128. Post-randomisation drop-outs: 2 (1.6%). Revised sample size: 126. Mean age: 52 years. Females: 98 (77.8%). Inclusion criteria 1. Adults undergoing elective laparoscopic cholecystectomy. Exclusion criteria 1. Emergency laparoscopic cholecystectomy. 2. Undergoing additional planned procedures intraoperatively.


86

Roberts 2011

(Continued)

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.25% 20 mL in the subdiaphragmatic area (n = 42) Group 2: bupivacaine 0.25% 20 mL in the gallbladder bed (n = 41). Group 2: normal saline (n = 43).

Outcomes


Notes

Reasons for post-randomisation drop-outs: converted to open procedure (n = 1); acidosis following anaesthesia (n = 1)

Risk of bias Bias




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” Comment: This information was not available.


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.

Unclear risk


Quote: “Patients, anaesthetists, operating surgeons, recovery nursing, ward medical, and nursing staff were all blinded to the study”


Quote: “Patients, anaesthetists, operating surgeons, recovery nursing, ward medical, and nursing staff were all blinded to the study”


High risk



High risk


For-profit bias

Unclear risk



87

Rudra 2002 Methods


Participants

Country: India. Sample size: 60. Post-randomisation drop-outs: not stated. Revised sample size: 60. Mean age: 36 years. Females: 60 (100%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I. Exclusion criteria 1. Allergic to bupivacaine.

Interventions


Outcomes


Notes


Risk of bias Bias







Unclear risk


Quote: “The test solutions were drawn into two coded syringes by a postgraduate to the investigators, who did not know their contents”


Quote: “The test solutions were drawn into two coded syringes by a postgraduate to the investigators, who did not know their contents”


Unclear risk



High risk


For-profit bias

Unclear risk



88

Scheinin 1995 Methods


Participants

Country: Finland. Sample size: 60. Post-randomisation drop-outs: not stated. Revised sample size: 60. Mean age: 49 years. Females: 48 (80%). Inclusion criteria 1. Laparoscopic cholecystectomy. 2. ASA I or II.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.15% 100 mL (n = 20). Group 2: same as group 1 with adrenaline (n = 20). Group 3: normal saline (n = 20).

Outcomes

Local anaesthetic-related complications and hospital stay.

Notes


Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk



89

Szem 1996 Methods


Participants

Country: USA. Sample size: 75. Post-randomisation drop-outs: 20 (26.7%). Revised sample size: 55. Mean age: 45 years. Females: not stated. Inclusion criteria 1. Elective laparoscopic cholecystectomy for chronic calculous cholecystitis. 2. Aged between 18 and 80 years. Exclusion criteria 1. Acute cholecystitis. 2. Planned exploration of the common bile duct.

Interventions


Outcomes

Pain.

Notes

Reasons for post-randomisation drop-out: conversion to open procedure (n = 17), stroke (n = 1), suspected intraoperative pulmonary embolism (n = 1), and did not receive the study drug (n = 1). Attempts were made to contact the authors in April 2008.

Risk of bias Bias







Low risk


Quote: “Prior to the operation, only the scrub nurse was informed as to what substance would be used by the surgeon” Comment: Not clear whether the participants and other healthcare personnel were blinded




High risk



High risk



90

Szem 1996

(Continued)

For-profit bias

Unclear risk


Todorov 2009 Methods


Participants

Country: Bulgaria. Number randomised: 40. Post-randomisation drop-outs: 0 (0%). Revised sample size: 40. Mean age: 50 years. Females: 33 (82.5%). Inclusion criteria 1. People undergoing laparoscopic cholecystectomy. Exclusion criteria 1. Lack of informed consent on behalf of the patient. 2. Allergy to local anaesthetic. 3. Conversion to open procedure. 4. Unsuccessful application of local anaesthetic (there were no such cases).

Interventions


Outcomes


Notes

Attempts were made to contact the authors in December 2010. The authors provided replies

Risk of bias Bias






Quote: ”Sequentially-numbered sealed envelopes“ (author replies)

Unclear risk


Quote: ”Only researchers were “unblinded”, they did not participate in questionnaires’ filling in“ (author replies)


Quote: ”Only researchers were “unblinded”, they did not participate in questionnaires’ filling in“ (author replies)


91

Todorov 2009

(Continued)


Low risk

Quote: ”There were no post-randomisation drop-outs“ (author replies)


High risk


For-profit bias

Low risk

Quote: ”There was no funding“ (author replies)”.

Tunca 2001 Methods


Participants

Country: Turkey. Sample size: 32. Post-randomisation drop-outs: 2 (6.3%). Revised sample size: 30. Mean age: 49 years. Females: 26 (86.7%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. Exclusion criteria 1. Liver disease. 2. Cardiovascular disease. 3. Allergy to local anaesthetics. 4. Sarcoidosis.

Interventions


Outcomes


Notes

Reasons for post-randomisation drop-out: conversion to open cholecystectomy. Attempts were made to contact the authors in April 2008.

Risk of bias Bias







Unclear risk


Quote: “Double blind”. Comment: Further details were not available.


92

Tunca 2001

(Continued)




High risk



High risk


For-profit bias

Unclear risk


Verma 2006 Methods


Participants

Country: India. Sample size: 30. Post-randomisation drop-outs: 0 (0%). Revised sample size: 30. Mean age: not stated. Females: not stated. Inclusion criteria 1. Elective laparoscopic cholecystectomy for chronic cholecystitis. 2. ASA I or II. Exclusion criteria 1. History of major upper abdominal surgeries. 2. Choledocholithiasis. 3. Acute cholecystitis. 4. Conversion to open cholecystectomy.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 2 mg/kg in absorbable cellulose strips (n = 15). Group 2: normal saline soaked cellulose strips (n = 15).

Outcomes

Pain.

Notes


Risk of bias Bias




Quote: “The patients were divided into four groups of 15 patients each with the help of computer-generated randomization numbers”



Unclear risk


93

Verma 2006

(Continued)






Low risk



High risk


For-profit bias

Unclear risk


Weber 1997 Methods


Participants

Country: Mexico. Sample size: 150. Post-randomisation drop-outs: not stated. Revised sample size: 150. Mean age: 47 years. Females: 119 (79.3%). Inclusion criteria 1. People undergoing laparoscopic cholecystectomy.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.25% 40 mL (n = 50). Group 2: normal saline (n = 50). Group 3: no intervention (n = 50).

Outcomes

Local anaesthetic-related complications pain.

Notes


Risk of bias Bias







Unclear risk


94

Weber 1997

(Continued)






Unclear risk



Unclear risk


For-profit bias

Unclear risk


Zimmer 2010 Methods


Participants

Country: USA. Number randomised: 50. Post-randomisation drop-outs: 0 (0%). Revised sample size: 50. Mean age: 43 years. Females: 40 (80%). Inclusion criteria 1. Aged ≥ 18 years. Exclusion criteria 1. Pregnancy. 2. Previous upper abdominal surgery. 3. Known allergy to bupivacaine. 4. Suspected common bile duct stones. 5. Chronic pain syndrome or chronic narcotic use.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.5% 10 mL (n = 25). Group 2: water (n = 25).

Outcomes

Mortality, morbidity, hospital stay, and pain.

Notes


Risk of bias Bias



Support for judgement Comment: This information was not available.


95

Zimmer 2010

(Continued)


Low risk

Quote: “Fifty patients were randomized by the pharmacy. ..The agent was delivered to the operating room labeled as ”study drug“ for injection into the Insuflow device as routinely done”


Quote: “All operative and perioperative team members were blinded to the contents of the study drug”


Quote: “All operative and perioperative team members were blinded to the contents of the study drug”


Low risk



Low risk


For-profit bias

Low risk

Quote: “Appreciation is extended to the Penrose-St. Francis Health Foundation for their financial support of this study”

Zmora 2000 Methods


Participants

Country: USA. Sample size: 60. Post-randomisation drop-outs: 9 (15%). Revised sample size: 51. Mean age: 44 years. Females: 35 (68.6%). Inclusion criteria 1. Elective laparoscopic cholecystectomy. Exclusion criteria 1. Conversion to an open procedure. 2. Drain left in the peritoneal cavity.

Interventions

The participants were randomised to the following groups. Group 1: bupivacaine 0.2% 50 mL (n = 26). Group 2: normal saline soaked cellulose strips (n = 25).

Outcomes

Pain.

Notes

Reasons for post-randomisation drop-out: requiring conversion to open cholecystectomy or requiring drain. Attempts were made to contact the authors in April 2008.

Risk of bias Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

96

Zmora 2000

(Continued)

Bias







Unclear risk


Quote: “The patients, the surgeons, and the nursing staff were blinded to the randomization”


Quote: “The patients, the surgeons, and the nursing staff were blinded to the randomization”


High risk



High risk


For-profit bias

Unclear risk


ASA: American Society of Anesthesiologists; NSAID: non-steroidal anti-inflammatory drug; VAS: visual analogue scale.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Ahmed 2008

30 (15%) people had to be excluded because of various reasons. These participants were replaced by other people. We consider that this will result in inadequate randomisation

Alexander 1997

Letter to editor containing no information of any trial suitable for inclusion in this review

Bayar 1998

Not a randomised clinical trial.

Beqiri 2012

Not intraperitoneal local anaesthetic instillation.

Berven 1995


Bisgaard 1999

Intraperitoneal and wound infiltration of local anaesthetic in 1 group and no local anaesthetic in 1 group

Busley 1999

Only the control group received systemic opioids.

Celik 2000

No appropriate control group with normal saline or no intervention


97

(Continued)

Cha 2012

Excluded participants were replaced with other people. This might have introduced selection bias

Cunniffe 1998

No separate data available for people who underwent laparoscopic cholecystectomy

Di Pace 2009

No separate data available for laparoscopic cholecystectomy.

Elhakim 2000b

Lidocaine was combined with either intraperitoneal or intravenous tenoxicam and compared with control

Gharaibeh 2000

Quasi-randomised study (randomisation by alternation). This study did not report the adverse effects of the local anaesthetic

Gupta 2002

Intraperitoneal and wound infiltration of local anaesthetic in 1 group and no local anaesthetic in 1 group

Hernández-Palazón 2003

Only the local anaesthetic group received opiate analgesics.

Hilvering 2011

The local anaesthetic intraperitoneal group alone received peri-portal local anaesthetic wound infiltration

Inan 2004


Johnson 1999

Comparison of intraperitoneal bupivacaine and bupivacaine by wound infiltration

Lauwick 2008

Apart from the difference in the groups related to the administration of local anaesthetic, the doses of pre-operative fentanyl was also different in the 2 groups

Lindgren 1997

Editorial about an included trial.

Mack 1995

Letter to editor about an included trial.

Maharjan 2009

The local anaesthetic intraperitoneal group alone received peri-portal local anaesthetic wound infiltration

Memedov 2010

Only the intervention group (local anaesthetic intraperitoneal instillation group) received local anaesthetic wound infiltration

Michaloliakou 1996

Assessment of multilayered local anaesthetic infiltration. However, only the treatment group received pethidine and ketorolac as pre-medication

Moreira 2000


Newcomb 2007

Assessment of multimodal analgesia compared with control.

Ng 2002

Editorial; refers to identified trials.

Paech 2008

No separate data available for people who underwent laparoscopic cholecystectomy

Papadima 2009

Open allocation schedule.


98

(Continued)

Pappas-Gogos 2008

7 people (5.8%) were excluded post-randomisation. These participants were replaced by new participants to “maintain homogeneity”. This introduced selection bias

Rizzotti 2002


Schulte-Steinberg 1995


Sozbilen 2007

Comparison of different types of multimodal analgesia.

Stempin 2007

There was no appropriate control to assess the effectiveness of intraperitoneal bupivacaine

Tsimoyiannis 1998a

In this trial, participants who had to be excluded post-randomisation were replaced by selected participants

Tsimoyiannis 1998b


Tsimoyiannis 1998c


Wallace 1996

Compared intraperitoneal instillation with wound infiltration

Özkoçak 2002



99

DATA AND ANALYSES

Comparison 1. Local anaesthetic versus no local anaesthetic

Outcome or subgroup title 1 Mortality 2 Serious adverse events 3 Proportion discharged as day surgery 4 Hospital stay 5 Pain (4 to 8 hours) 6 Pain (9 to 24 hours)

No. of studies

No. of participants

8 8 3

446 446 242

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 3.0 [0.13, 67.06] 1.25 [0.99, 1.58]

5 32 29

335 2020 1787

Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

0.04 [-0.23, 0.32] -0.99 [-1.10, -0.88] -0.53 [-0.62, -0.44]

Statistical method

Effect size

Comparison 2. Sensitivity analysis

Outcome or subgroup title 1 Proportion discharged as day surgery 1.1 Best-best scenario 1.2 Best-worst scenario 1.3 Worst-best scenario 1.4 Worst-worst scenario 2 Hospital stay 3 Pain (4 to 8 hours) (studies with imputed values removed) 4 Pain (9 to 24 hours) (studies with imputed values removed)

No. of studies

No. of participants

3

Statistical method

Effect size

Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only

3 3 3 3 1 10

244 244 244 244 60 576

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

1.25 [0.99, 1.58] 1.21 [0.96, 1.53] 1.26 [1.00, 1.60] 1.23 [0.97, 1.55] 0.53 [-0.14, 1.21] -1.04 [-1.17, -0.90]

12

676

Mean Difference (IV, Fixed, 95% CI)

-0.38 [-0.48, -0.28]

Comparison 3. Subgroup analysis

Outcome or subgroup title 1 Pain (4 to 8 hours) by local anaesthetic 1.1 Bupivacaine 1.2 Levobupivacaine 1.3 Ropivacaine 1.4 Lignocaine 2 Pain (4 to 8 hours) by dose 2.1 Weight-based

No. of studies

No. of participants

32

2020

Mean Difference (IV, Random, 95% CI)

-1.22 [-1.52, -0.91]

25 2 5 2 32 7

1626 80 252 62 2020 385

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-1.38 [-1.77, -0.98] -0.99 [-1.69, -0.28] -0.71 [-1.03, -0.39] -1.37 [-2.37, -0.37] -1.22 [-1.52, -0.91] -1.11 [-1.26, -0.96]

Statistical method

Effect size


100

2.2 Fixed dose 3 Pain (4 to 8 hours) by form 3.1 Liquid 3.2 Others 4 Pain (4 to 8 hours) by time 4.1 Before pneumoperitoneum 4.2 Just after creation of pneumoperitoneum 4.3 End of surgery 4.4 After end of surgery 4.5 Just after creation of pneumoperitoneum and end of surgery 5 Pain (4 to 8 hours) by location 5.1 Gallbladder bed 5.2 Subdiaphragmatic area 5.3 Subdiaphragmatic area and gallbladder bed 5.4 Diffuse 6 Pain (4 to 8 hours) by norepinephrine use 6.1 Norepinephrine used 6.2 Norepinephrine not used 7 Pain (4 to 8 hours) by control 7.1 Normal saline 7.2 No intervention 7.3 Others 8 Pain (4 to 8 hours) by wound infiltration 8.1 Wound infiltration used 8.2 Wound infiltration not used 9 Pain (4 to 8 hours) by routine supplemental analgesia 9.1 Routine supplemental analgesia 9.2 No routine supplemental analgesia 10 Pain (9 to 24 hours) by local anaesthetic 10.1 Bupivacaine 10.2 Levobupivacaine 10.3 Ropivacaine 10.4 Lignocaine 11 Pain (9 to 24 hours) by dose 11.1 Weight-based 11.2 Fixed dose 12 Pain (9 to 24 hours) by form 12.1 Liquid 12.2 Others 13 Pain (9 to 24 hours) by time

25 32 29 4 32 2

1635 2020 1880 140 2020 120

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-1.32 [-1.78, -0.87] -1.22 [-1.52, -0.91] -0.96 [-1.16, -0.75] -3.03 [-6.58, 0.51] -1.22 [-1.52, -0.91] -1.01 [-1.23, -0.79]

8

382


-1.30 [-1.74, -0.86]

24 1 3

1361 20 137

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-1.17 [-1.70, -0.64] -1.68 [-4.07, 0.71] -1.49 [-2.87, -0.12]

32 9 4 18

2020 445 358 997

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-1.22 [-1.52, -0.91] -0.87 [-1.23, -0.51] -1.55 [-2.97, -0.14] -0.92 [-1.21, -0.64]

3 32

220 2020

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-2.54 [-3.75, -1.33] -1.22 [-1.52, -0.91]

6 26 32 26 3 5 8

395 1625 2020 1619 145 256 574

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-1.33 [-1.98, -0.68] -1.19 [-1.54, -0.83] -1.22 [-1.52, -0.91] -1.23 [-1.57, -0.89] -1.15 [-2.42, 0.11] -1.11 [-1.80, -0.43] -1.22 [-1.79, -0.66]

5 4

405 169


-1.81 [-2.66, -0.96] -0.53 [-0.89, -0.18]

28

1720


-0.99 [-1.10, -0.88]

8

495


-1.53 [-1.88, -1.19]

20

1225


-0.93 [-1.05, -0.81]

29

1787


-0.81 [-1.11, -0.51]

22 2 5 1 29 7 22 29 25 5 29

1415 80 252 40 1787 385 1402 1787 1597 190 1787

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-0.94 [-1.33, -0.55] -0.47 [-1.48, 0.54] -0.34 [-0.62, -0.06] -1.1 [-2.12, -0.08] -0.81 [-1.11, -0.51] -0.41 [-0.53, -0.30] -0.91 [-1.36, -0.45] -0.81 [-1.11, -0.51] -0.63 [-0.89, -0.38] -1.93 [-4.10, 0.24] -0.81 [-1.11, -0.51]


101

13.1 Before pneumoperitoneum 13.2 Just after creation of pneumoperitoneum 13.3 End of surgery 13.4 After end of surgery 13.5 Just after creation of pneumoperitoneum and end of surgery 14 Pain (9 to 24 hours) by location 14.1 Gallbladder bed 14.2 Subdiaphragmatic area 14.3 Subdiaphragmatic area and gallbladder bed 14.4 Diffuse 15 Pain (9 to 24 hours) by norepinephrine use 15.1 Norepinephrine used 15.2 Norepinephrine not used 16 Pain (9 to 24 hours) by control 16.1 Normal saline 16.2 No intervention 16.3 Others 17 Pain (9 to 24 hours) by wound infiltration 17.1 Wound infiltration used 17.2 Wound infiltration not used 18 Pain (9 to 24 hours) by routine supplemental analgesia 18.1 Routine supplemental analgesia 18.2 No routine supplemental analgesia

2

120


-0.40 [-0.55, -0.25]

7

252


-1.08 [-1.95, -0.21]

22 1 3

1258 20 137

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-0.81 [-1.27, -0.35] 0.83 [-0.43, 2.09] -1.19 [-2.17, -0.20]

29 17 2 7

1787 942 250 325

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-0.81 [-1.11, -0.51] -0.58 [-0.99, -0.18] -3.33 [-6.66, -0.00] -0.57 [-0.90, -0.24]

4 29

270 1787


-1.55 [-2.44, -0.66] -0.81 [-1.11, -0.51]

6 23 29 22 3 6 8

395 1392 1787 1336 145 306 499

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-1.07 [-1.74, -0.41] -0.69 [-1.03, -0.35] -0.81 [-1.11, -0.51] -0.83 [-1.16, -0.50] -1.65 [-3.80, 0.51] -0.64 [-1.68, 0.39] -0.81 [-1.24, -0.38]

5 4

330 169


-1.27 [-1.98, -0.56] -0.32 [-0.59, -0.05]

26

1532


-0.54 [-0.63, -0.44]

6

315


-1.05 [-1.41, -0.69]

20

1217


-0.50 [-0.60, -0.40]

ADDITIONAL TABLES Table 1. Further details about intervention and co-interventions Study name

Local anaes- Time§ thetic

Abdel-Raouf 2004

bupivacaine

Ahmad 1998 Ahmad 1998

Location

Norepinephrine

Peri-portal local anaesthetic infiltration

Drain use

Other routine analgesia*

end of surgery subdiaphragmatic area

no

yes

no

none

bupivacaine

not stated

not stated

no

no

not stated

none

bupivacaine

not stated

not stated

no

yes

not stated

none


102

Table 1. Further details about intervention and co-interventions

Alagöl 2003

(Continued)

bupivacaine

end of surgery subdiaphrag- no matic area and gallbladder bed

not stated

not stated

none

Alagöl 2003 bupivacaine (intraperitoneal ondansetron administered in both groups)


not stated

not stated

none

Alkhamesi 2007

bupivacaine

end of surgery diffuse

no

yes

not stated

routine NSAID and opioid analgesics

Alkhamesi 2007

bupivacaine

end of surgery gallbladder bed

no

yes

not stated

routine NSAID and opioid analgesics

Alper 2009

levobupivacaine

just after creation of pneumoperitoneum

subdiaphrag- no matic area and gallbladder bed

yes

not stated

no

not stated

Alptekin 2010 bupivacaine


no

not stated

not stated

Alptekin 2010 bupivacaine

after end of gallbladder surgery bed

no

not stated

for the contin- not stated uous infusion group

Barczynski 2006

bupivacaine

before pneu- diffuse moperitoneum

no

yes

not stated

no

Barczynski 2006

bupivacaine

just after cre- diffuse ation of pneumoperitoneum

no

yes

not stated

no

Bhardwaj 2002

bupivacaine

end of surgery subdiaphrag- yes matic area and gallbladder bed

not stated

not stated

no


103


(Continued)

Castillo-Garza bupivacaine 2012


no

not stated

no

no

Chundrigar 1993

bupivacaine


no

not stated

no

no

Elfberg 2000

bupivacaine


no

not stated

no

not stated

Elhakim 2000 lignocaine


no

yes

yes

no

El-Labban 2011

levobupivacaine


no

no

routine NSAID

Feroci 2009

bupivacaine


no

no

not stated

no

Fornari 1996

bupivacaine


yes

not stated

no

no

Fu 2009

ropivacaine


no

not stated

not stated

no

Fuhrer 1996

bupivacaine


not stated

not stated

no

Garcia 2007

bupivacaine (s75-r25)


no

not stated

not stated

routine NSAID

Golubovic 2009

bupivacaine


not stated

not stated

no

Gvozdenovic 2011

bupivacaine

end of surgery not stated

no

not stated

not stated

not stated

Hasan 2007

bupivacaine

not stated

not stated

no

no

not stated

routine NSAID

Hasan 2007

bupivacaine

not stated

not stated

no

no

not stated

routine NSAID


104


(Continued)

bupivacaine


yes

not stated

no

bupivacaine


no

not stated

not stated

no

Jabbourbupivacaine Khoury 2005 (intravenous ketoprofen administered in both groups)


no

not stated

not stated

no

Jiranantarat 2002

bupivacaine


not stated

not stated

no

Joris 1995

bupivacaine


no

not stated

no

Kallel 2011

lignocaine


not stated

not stated

not stated

Karaaslan 2006

bupivacaine

before pneu- gallbladder moperibed toneum

no

not stated

not stated

no

Karaaslan 2006

bupivacaine

just after cre- gallbladder ation of pneu- bed moperitoneum

no

not stated

not stated

no

Karaaslan 2006

bupivacaine


no

not stated

not stated

no

Karadeniz 2003

bupivacaine



not stated

no

no

Karadeniz 2003

bupivacaine

end of surgery subdiaphrag- no matic area and gallbladder

not stated

no

no

Hazinedaroglu 2006

JabbourKhoury 2005

yes


105


(Continued)

bed Karadeniz 2003

bupivacaine

after end of subdiaphrag- no surgery matic area and gallbladder bed (by infusion pump)

not stated

possibly no for the continuous infusion group

Kilic 1996

bupivacaine


no

not stated

not stated

not stated

Kim 2010

ropivacaine



not stated

not stated

no

Kolsi 2000

lignocaine


not stated

not stated

no

Kucuk 2007

ropivacaine


no

not stated

no

Kucuk 2007

ropivacaine


no

not stated

no

Kucuk 2007

bupivacaine


no

not stated

no

Labaille 2002

ropivacaine

just after creation of pneumoperitoneum and end of surgery


no

not stated

no

Labaille 2002

ropivacaine



no

not stated

no


106


(Continued)

Lee 2001

bupivacaine


subdiaphrag- yes matic area and gallbladder bed

yes

not stated

routine NSAID

Lee 2001

bupivacaine


no

not stated

routine NSAID

Lepner 2003

lignocaine


no

yes

no

routine NSAID

Louizos 2005

levobupivacaine


no

no

not stated

no

Louizos 2005

levobupivacaine


no

yes

not stated

no

Maestroni 2002

ropivacaine

before pneu- diffuse moperitoneum

no

not stated

not stated

routine NSAID

Mraovic 1997

bupivacaine



not stated

not stated

no

Ng 2004

levobupivacaine


not stated

selecnot stated tively (reasons clearly not stated)

Nicolau 2008

ropivacaine


no

no

selectively (for routine patients NSAID with difficult haemostasis)

Nicolau 2008

ropivacaine


no

yes

selectively (for routine patients NSAID with difficult haemostasis)

Pasqualucci 1994

bupivacaine


not stated

not stated


no


107


(Continued)

Pasqualucci 1994

bupivacaine



not stated

not stated

no

Pasqualucci 1996

bupivacaine



not stated

not stated

no

Pasqualucci 1996

bupivacaine


not stated

not stated

no

Pasqualucci 1996

bupivacaine



not stated

not stated

no

Paulson 2003

bupivacaine



no

no

no

Paulson 2003

bupivacaine


no

no

no

Paulson 2003

bupivacaine


no

no

no

Rademaker 1994

bupivacaine


no

not stated

not stated

not stated

Rademaker 1994

lignocaine


no

not stated

not stated

not stated


not stated

not stated

routine NSAID

Raetzell 1995a bupivacaine



108


(Continued)

Raetzell 1995a bupivacaine


not stated

not stated

routine NSAID

Raetzell 1995b

bupivacaine


not stated

not stated

routine NSAID

Razek 2003

levobupivacaine


not stated

not stated

routine NSAID

Razman 2010

bupivacaine

not stated

yes

yes

not stated

not stated

Roberts 2011

bupivacaine

just after cre- subdiaphragation of pneu- matic area moperitoneum

no

yes

selecroutine tively (reasons NSAID and not stated) opioid analgesics

Roberts 2011

bupivacaine

just after cre- gallbladder ation of pneu- bed moperitoneum

no

yes

selecroutine tively (reasons NSAID and not stated) opioid analgesics

Rudra 2002

bupivacaine


not stated

not stated

no

Scheinin 1995 bupivacaine


no

not stated

no

no

Scheinin 1995 bupivacaine


yes

not stated

no

no

Szem 1996



not stated

not stated

routine opioid analgesic


not stated

not stated

not stated

bupivacaine

Todorov 2009 levobupivacaine

not stated


109


Tunca 2001

bupivacaine



Verma 2006

bupivacaine


Weber 1997

bupivacaine

Weber 1997

(Continued)

not stated

not stated

no

no

no

not stated

no


no

not stated

not stated

not stated

bupivacaine


no

not stated

not stated

not stated

Zimmer 2010

bupivacaine

just after cre- diffuse ation of pneumoperitoneum

no

yes

not stated

no

Zmora 2000

bupivacaine


not stated

no

routine NSAID and opioid analgesic

NSAID: non-steroidal anti-inflammatory drug. § ’End of surgery’ indicates instillation after removal of gallbladder usually before closure of the wounds but in all instances before the reversal of anaesthesia; ’after end of surgery’ indicates that the participant received the local anaesthetic by an infusion pump after reversal of anaesthesia. * refers to routine analgesia. Most trials allowed ’on-demand’ analgesia or analgesia was administered if the pain was above a certain threshold.

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. GP Guerrini, C Toon, 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.


110

DECLARATIONS OF INTEREST None known.

SOURCES OF SUPPORT Internal sources • None, Other.

External sources • None, Other.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW 1. We have revised the outcomes based on importance to the participants and not according to the expected treatment effect. As a result, we moved pain to a secondary outcome as we considered mortality 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 and SF-36 since using unvalidated other scales may be misleading. With regards to pain, we limited pain to four to eight hours and nine to 24 hours since this is the time period that most patients 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 a section on trial sequential analysis to control for random errors. 3. We considered non-randomised studies for treatment-related harms.

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. 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).

INDEX TERMS


111

Medical Subject Headings (MeSH) Ambulatory Surgical Procedures [statistics & numerical data]; Anesthesia, Local [methods]; Anesthetics, Local [∗ administration & dosage]; Bupivacaine [administration & dosage]; Cholecystectomy, Laparoscopic [∗ adverse effects; methods]; Gallstones [surgery]; Length of Stay [statistics & numerical data]; Randomized Controlled Trials as Topic

MeSH check words Humans


112

Intraperitoneal local anaesthetic for shoulder pain after day-case laparoscopy.

Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy.

Anaesthetic regimens for day-procedure laparoscopic cholecystectomy.

Pain relief from combined wound and intraperitoneal local anesthesia for patients who undergo laparoscopic cholecystectomy.

INTRAPERITONEAL INSTILLATION OF BUPIVACAINE FOR ANALGESIA AFTER LAPAROSCOPIC STERILISATION: A CASE CONTROL STUDY.

Effect of intraperitoneal local anesthetic on pain characteristics after laparoscopic cholecystectomy.

Effect of intraperitoneal curcumin instillation on postoperative peritoneal adhesions.

A dangerous local anaesthetic spray.

Cytoreduction with hyperthermic intraperitoneal chemotherapy: An anaesthetic challenge.

Phorbol dibutyrate enhances local anaesthetic action.

s Rectus Sheath Block for Postoperative Pain Relief Following Laparoscopic Cholecystectomy: A Prospective Study.

Lateral subcutaneous sphincterotomy: local or general anaesthetic?

Local anaesthetic activity of some substituted propiophenones.

Local anaesthetic creams and intradermal skin tests.

Use of labels on local anaesthetic syringes.

Re: Comment on: Comparison of Intraabdominal and Trocar Site Local Anaesthetic Infiltration on Postoperative Analgesia After Laparoscopic Cholecystectomy.

Comment on: Comparison of Intraabdominal and Trocar Site Local Anaesthetic Infiltration Efficacy on Postoperative Analgesia After Laparoscopic Cholecystectomy.

Comparative anaesthetic properties of various local anaesthetic agents in extradural block for labour.

Use of warm local anaesthetic solution for caudal blocks.

Aerosolized intraperitoneal local anesthetic for laparoscopic surgery: a randomized, double-blinded, placebo-controlled trial.

Surface anaesthetic properties of the new local anaesthetic amid etidocaine (Duranest): A laboratory evaluation.

Postoperative pain relief after laparoscopic cholecystectomy: intraperitoneal sodium bicarbonate versus normal saline.

Local Anaesthetic Drug Administration in Dentistry Using Computer Assisted Anaesthetic Delivery System: A Systematic Review.

Effects of Intraperitoneal Local Anaesthetics Bupivacaine and Ropivacaine versus Placebo on Postoperative Pain after Laparoscopic Cholecystectomy: A Randomised Double Blind Study.