Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy.

Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy (Review) Loizides S, Gurusamy KS, Nagendran M, Rossi M, Guerrini GP, 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

Wound infiltration with local anaesthetic agents 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. . . . . . . . . . . . . . . . . . . Figure 10. . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . 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 . .

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[Intervention Review]

Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy Sofronis Loizides1 , Kurinchi Selvan Gurusamy2 , Myura Nagendran3 , Michele Rossi4 , Gian Piero Guerrini5 , Brian R Davidson2 1 Department of General Surgery, St Richard’s Hospital Chichester, Chichester, UK. 2 Department of Surgery, Royal Free Campus, UCL Medical School, London, UK. 3 UCL Division of Surgery and Interventional Science, Department of Surgery, London, UK. 4 Endoscopia Chirurgica, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy. 5 Department of Surgery, Ravenna Hospital, Ravenna, Italy

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: 18 February 2013. Citation: Loizides S, Gurusamy KS, Nagendran M, Rossi M, Guerrini GP, Davidson BR. Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD007049. DOI: 10.1002/14651858.CD007049.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background While laparoscopic cholecystectomy is generally considered to be less painful than open surgery, pain is one of the important reasons for delayed discharge after day surgery resulting in overnight stay following laparoscopic cholecystectomy. The safety and effectiveness of local anaesthetic wound infiltration in people undergoing laparoscopic cholecystectomy is not known. Objectives To assess the benefits and harms of local anaesthetic wound infiltration in patients undergoing laparoscopic cholecystectomy and to identify the best method of local anaesthetic wound infiltration with regards to the type of local anaesthetic, dosage, and time of administration of the local anaesthetic. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded until February 2013 to identify studies of relevance to this review. We included randomised clinical trials for benefit and quasi-randomised and comparative non-randomised studies for treatment-related harms. Selection criteria Only randomised clinical trials (irrespective of language, blinding, or publication status) comparing local anaesthetic wound infiltration versus placebo, no intervention, or inactive control during laparoscopic cholecystectomy, trials comparing different local anaesthetic agents for local anaesthetic wound infiltration, and trials comparing the different times of local anaesthetic wound infiltration were considered for the review. Data collection and analysis Two review authors collected the data independently. We analysed the data with both fixed-effect and random-effects meta-analysis models using RevMan. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results Twenty-six trials fulfilled the inclusion criteria of the review. All the 26 trials except one trial of 30 participants were at high risk of bias. Nineteen of the trials with 1263 randomised participants provided data for this review. Ten of the 19 trials compared local anaesthetic wound infiltration versus inactive control. One of the 19 trials compared local anaesthetic wound infiltration with two inactive controls, normal saline and no intervention. Two of the 19 trials had four arms comparing local anaesthetic wound infiltration with inactive controls in the presence and absence of co-interventions to decrease pain after laparoscopic cholecystectomy. Four of the 19 trials had three or more arms that could be included for the comparison of local anaesthetic wound infiltration versus inactive control and different methods of local anaesthetic wound infiltration. The remaining two trials compared different methods of local anaesthetic wound infiltration. Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. Seventeen trials randomised a total of 1095 participants to local anaesthetic wound infiltration (587 participants) versus no local anaesthetic wound infiltration (508 participants). Various anaesthetic agents were used but bupivacaine was the commonest local anaesthetic used. There was no mortality in either group in the seven trials that reported mortality (0/280 (0%) in local anaesthetic infiltration group versus 0/259 (0%) in control group). The effect of local anaesthetic on the proportion of people who developed serious adverse events was imprecise and compatible with increase or no difference in serious adverse events (seven trials; 539 participants; 2/280 (0.8%) in local anaesthetic group versus 1/259 (0.4%) in control; RR 2.00; 95% CI 0.19 to 21.59; very low quality evidence). None of the serious adverse events were related to local anaesthetic wound infiltration. None of the trials reported patient quality of life. The proportion of participants who were discharged as day surgery patients was higher in the local anaesthetic infiltration group than in the no local anaesthetic infiltration group (one trial; 97 participants; 33/50 (66.0%) in the local anaesthetic group versus 20/47 (42.6%) in the control group; RR 1.55; 95% CI 1.05 to 2.28; very low quality evidence). The effect of local anaesthetic on the length of hospital stay was compatible with a decrease, increase, or no difference in the length of hospital stay between the two groups (four trials; 327 participants; MD 0.26 days; 95% CI -0.67 to 0.16; very low quality evidence). The pain scores as measured by the visual analogue scale (0 to 10 cm) were lower in the local anaesthetic infiltration group than the control group at 4 to 8 hours (13 trials; 806 participants; MD -1.33 cm on the VAS; 95% CI -1.54 to -1.12; very low quality evidence) and 9 to 24 hours (12 trials; 756 participants; MD -0.36 cm on the VAS; 95% CI -0.53 to -0.20; very low quality evidence). The effect of local anaesthetic on the time taken to return to normal activity between the two groups was imprecise and compatible with a decrease, increase, or no difference in the time taken to return to normal activity (two trials; 195 participants; MD 0.14 days; 95% CI -0.59 to 0.87; very low quality evidence). None of the trials reported on return to work. Four trials randomised a total of 149 participants to local anaesthetic wound infiltration prior to skin incision (74 participants) versus local anaesthetic wound infiltration at the end of surgery (75 participants). Two trials randomised a total of 176 participants to four different local anaesthetics (bupivacaine, levobupivacaine, ropivacaine, neosaxitoxin). Although there were differences between the groups in some outcomes the changes were not consistent. There was no evidence to support the preference of one local anaesthetic over another or to prefer administration of local anaesthetic at a specific time compared with another. Authors’ conclusions Serious adverse events were rare in studies evaluating local anaesthetic wound infiltration (very low quality evidence). There is very low quality evidence that infiltration 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. Further randomised clinical trials at 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 Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy (local anaesthetic administration into the surgical wound 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 United States alone. Laparoscopic cholecystectomy (removal of the gallbladder through a keyhole, also Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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known as a port) is now the preferred method of cholecystectomy. While laparoscopic cholecystectomy is generally considered to be 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 people from feeling pain) into the surgical wound (local anaesthetic wound infiltration) may be an effective way of decreasing pain after laparoscopic cholecystectomy. However, the benefits and harms of local anaesthetic wound infiltration is not known. We sought to answer these questions by reviewing the medical literature and obtaining information from randomised clinical trials on the benefits related to the treatment. When conducted well, such studies provide the most accurate information on the best treatment. We also considered comparative non-randomised studies for treatment-related harms. Two authors searched the literature until February 2013 and obtained information from the studies thereby minimising errors. Study characteristics We identified 19 randomised clinical trials in this review. Most participants in the trials were low anaesthetic risk people undergoing planned laparoscopic cholecystectomy. Key results A total of 1095 participants were randomised to local anaesthetic wound infiltration (587 participants) or no local anaesthetic wound infiltration (508 participants) in 17 trials. 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 were compared in groups of patients who were as similar as possible. There were no deaths in either group in the seven trials (539 participants) that reported deaths. The difference in serious complications between the groups was imprecise. There were no local anaesthetic-related complications in nearly 450 participants who received local anaesthetic wound infiltration in the different trials that reported complications. None of the trials reported quality of life or the time taken to return to work. The proportion of participants who were discharged as day surgery patients was higher in the local anaesthetic group than in the control group in the only trial that reported this information. The difference in the length of hospital stay or the time taken to return to normal activity was imprecise. Pain was lower in the participants who received intra-abdominal local anaesthetic administration compared with those in the control groups at four to eight hours and at nine to 24 hours, as measured by the visual analogue scale (a chart which rates the amount of pain on a scale of 1 to 10). In the comparisons of different methods of local anaesthetic infiltration, there were differences between the groups in some outcomes but the changes were not consistent. There is, therefore, no evidence to prefer any particular drug or method of administering local anaesthetics. Serious adverse events were rare in studies evaluating local anaesthetic wound infiltration. There is very low quality evidence that infiltration 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. Quality of evidence Most of the trials were at high risk of bias, that is there is a possibility of arriving at wrong conclusions by overestimating the benefits or underestimating the harms of one method over another because of the way a study was conducted. The overall quality of evidence was very low. Future research Further trials are necessary. Such trials should include outcomes such as quality of life, hospital stay, 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]

Local anaesthetic wound infiltration compared to no local anaesthetic wound infiltration for people undergoing laparoscopic cholecystectomy Patient or population: patients with people undergoing laparoscopic cholecystectomy. Settings: secondary or tertiary. Intervention: local anaesthetic wound infiltration. Comparison: no local anaesthetic wound infiltration. Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Relative effect (95% CI)

No of participants (trials)

Quality of the evidence (GRADE)

Corresponding risk

No local anaesthetic wound Local anaesthetic wound ininfiltration filtration Mortality

There was no mortality in either group.

Not estimable

539 (7 trials)

⊕

very low1,2

Serious adverse events

4 per 1000

8 per 1000 (1 to 83)

RR 2 (0.19 to 21.59)

539 (7 trials)

⊕

very low1,2

660 per 1000 (447 to 970)

RR 1.55 (1.05 to 2.28)

97 (1 trial)

⊕

very low1,3

Proportion discharged as day 426 per 1000 surgery Length of hospital stay

The mean length of hospital The mean length of hospital stay in the control groups was stay in the intervention groups 1.9 days was 0.26 lower (0.67 lower to 0.16 higher)

327 (4 trials)

⊕

very low1,4,5

Pain 4 to 8 hours

The mean pain 4 to 8 hours in The mean pain 4 to 8 hours in the control groups was the intervention groups was 3.61 cm VAS 1.33 lower (1.54 to 1.12 lower)

806 (13 trials)

⊕

very low1,4

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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 2.45 cm VAS 0.36 lower (0.53 to 0.2 lower)

756 (12 trials)

⊕⊕

low1

Return to normal activity

The mean return to normal ac- The mean return to normal activity in the control groups was tivity in the intervention groups 6.8 days was 0.14 higher (0.59 lower to 0.87 higher)

195 (2 trials)

⊕

very low1,5

*The basis for the assumed risk is the mean control group risk across studies. 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; VAS: visual analogue scale. 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 (downgraded by 2 points). 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 (downgraded by 2 points). 3 There were fewer than 300 events (downgraded by 1 point). 4 There was severe heterogeneity as noted by the I-square and the lack of overlap of confidence intervals (downgraded by 2 points). 5 There were fewer than 400 participants in both groups in total (downgraded by 1 point). 2

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BACKGROUND

(Butterworth 1990). Local anaesthetic wound infiltration might decrease incisional pain by decreasing the excitability of nerves transmitting pain.

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). Every year, 1.5 million cholecystectomies are performed in the US and 60,000 in the UK (Dolan 2009; HES 2011). Approximately 80% of the cholecystectomies are performed laparoscopically (keyhole surgery) (Ballal 2009). While laparoscopic cholecystectomy is generally considered to be less painful than open surgery, pain may affect the quality of life of people undergoing laparoscopic cholecystectomy and is one of the important reasons for delayed discharge after laparoscopic cholecystectomy (Gurusamy 2008; Gurusamy 2008a). The pain after laparoscopic cholecystectomy could be incisional pain, shoulder pain, or abdominal pain (Ng 2004). A cut in the skin and subcutaneous tissues during the surgical incision causes damage to the tissues which stimulates peripheral nociceptors resulting in pain sensation (Dubin 2010). In addition, inflammation of the wound can stimulate the nociceptors resulting in pain sensation (Clark 2006; Dubin 2010).

Description of the intervention Wound infiltration with local anaesthetic agents such as lignocaine or bupivacaine has been suggested as a way of reduction of incisional pain (Dath 1999). The wound infiltration can be performed before skin incision (at the beginning of surgery) or after skin incision (at the end of surgery) (Dath 1999; Cantore 2008). The wound infiltration is performed to involve at least the skin and subcutaneous tissue but can be performed until the parietal peritoneum (Lee 2001). The adverse events related to local anaesthetic wound infiltration include allergic reactions, fits (convulsions), cardiac arrhythmias, and cardiac arrest (Fuzier 2009). Alternative interventions to local anaesthetic wound infiltration for decreasing pain after laparoscopic cholecystectomy include intraperitoneal local anaesthetic instillation (Gurusamy 2013a) and pharmacological interventions such as non-steroidal anti-inflammatory drugs and opiate analgesics (Gurusamy 2013b).

Why it is important to do this review We were not able to identify any systematic review assessing the benefits and harms of local anaesthetic wound infiltration in people undergoing laparoscopic cholecystectomy. A reduction in pain may improve quality of life and increase the proportion of people discharged as day surgery patients, and so may result in cost savings. The impact of wound infiltration on reduction of pain is different with different procedures (Joshi 2012; Kjaergaard 2012). So, it is important to assess the impact of local anaesthetic wound infiltration on pain after laparoscopic cholecystectomy.

OBJECTIVES The primary objective of this review was to assess the benefits and harms of local anaesthetic wound infiltration in people undergoing laparoscopic cholecystectomy. The secondary objectives was to identify the best method of local anaesthetic wound infiltration with regards to the type of local anaesthetic, dosage, and time of administration of the local anaesthetic.

METHODS

Criteria for considering studies for this review

Types of studies We considered all randomised clinical trials (irrespective of language, blinding, publication status, or sample size) for inclusion. We excluded quasi-randomised 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

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

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 the following comparisons. • Wound infiltration compared with no wound infiltration or wound infiltration with normal saline. • Different local anaesthetics used for wound infiltration (eg, bupivacaine versus lignocaine). • Different doses of the same local anaesthetic. • Different times of wound infiltration (eg, before incision compared with after incision). Co-interventions were allowed if carried out equally in the trial groups. Types of outcome measures Primary outcomes

1. Mortality. 2. Serious adverse events defined as any event that would increase mortality, is life-threatening, requires inpatient hospitalisation, results in a persistent or significant disability, or any important medical event that might have jeopardised the patient or required intervention to prevent it (ICH-GCP 1997). Complications such as bile duct injury; re-operations; intraabdominal collections requiring drainage (radiological or surgical); infected intra-abdominal collections; bile leaks requiring drainage, stent, or surgery; convulsions; cardiac arrhythmias which required additional monitoring and hence increased the hospital stay were classified as serious adverse events. Complications such as wound infections, bile leaks, or abdominal collections that did not require any treatment and settled spontaneously were not considered serious adverse events. 3. Patient quality of life (however defined by authors using a validated scale such as Euro-QoL or Short Form (SF)-36). Secondary outcomes

1. Hospital stay (length of hospital stay, proportion discharged as day surgery laparoscopic cholecystectomy patients). 2. Pain (overall pain) at different time points (4 to 8 hours and 9 to 24 hours) using a visual analogue scale. 3. Return to activity. 4. Return to work. We have reported all the outcomes with at least one trial in the 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), MEDLINE, EMBASE, Science Citation Index

Expanded (Royle 2003), and the World Health Organization International Clinical Trials Registry Platform portal (WHO ICTRP) (apps.who.int/trialsearch/) until February 2013. The WHO ICTRP portal allows searches of various trial registers including clinicaltrials.gov and ISRCTN among other registers. We have given the search strategies in Appendix 1 with the time spans for the searches. Searching other resources We also searched the references of the identified trials to identify further relevant trials.

Data collection and analysis We performed the systematic review according to the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2014). Selection of studies Two authors (SF and KG) identified the trials for inclusion independently of each other. We have also listed the excluded studies with the reasons for the exclusions. Data extraction and management Three authors (SF, KG, and MN) 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. Depth of infiltration (skin versus skin along with tissues until fascial layer). 11. Intraperitoneal instillation with local anaesthetic. 12. Other co-interventions. 13. Outcomes (mentioned above). 14. Risk of bias (described below). We sought any unclear or missing information by contacting the authors of the individual trials. If there was any doubt as to whether the trials shared the same patients, completely or partially (by identifying common authors and centres), we planned to contact the authors of the trials to clarify whether the trial report had been duplicated. We resolved any differences in opinion through discussion or arbitration by another author (KG).


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Assessment of risk of bias in included studies We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2014). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a), 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 was 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 was likely to be influenced by lack of blinding. Incomplete outcome data

• Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data. • Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results. • High risk of bias: the results were likely to be biased due to missing data. Selective outcome reporting

• Low risk of bias: all outcomes were predefined and reported, or all clinically relevant and reasonably expected outcomes were reported. • Uncertain risk of bias: it is unclear whether all predefined 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 for example, published in a paper journal. In the case where the trial was run and published in the years when trial registration was not required, we carefully scrutinised all publications reporting on the trial to identify the trial objectives and outcomes and to determine whether usable data were provided on all outcomes specified in the trial objectives in the results section of publications. For-profit bias

• Low risk of bias: the trial appears to be free of industry sponsorship or other kind of for-profit support that may manipulate the trial design, conduct, or results of the trial. • Uncertain risk of bias: the trial may or may not be free of for-profit bias as no information on clinical trial support or sponsorship is provided. • High risk of bias: the trial is sponsored by the industry or has received other kinds of for-profit support. We considered trials which were classified as low risk of bias in all the above domains as trials with low risk of bias and the remaining trials as trials with high risk of bias.


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Measures of treatment effect For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval. We also calculated the risk difference with 95% confidence interval. We planned to report the risk difference only if the conclusions were different from those of the risk ratio. Risk difference includes ’zero event trials’ (trials in which both groups have no events) for calculating the summary treatment effect, while such trials will not be taken into account when calculating the summary treatment effect in the case of RR. For continuous variables, we calculated the mean difference (MD) with 95% confidence interval for outcomes such as total hospital stay, or standardised mean difference (SMD) with 95% confidence interval for outcomes such as quality of life where different authors use different scales. Unit of analysis issues The unit of analysis was the person about to undergo laparoscopic cholecystectomy and randomised to local anaesthetic wound infiltration or control. Dealing with missing data We performed an intention-to-treat analysis (Newell 1992) whenever possible. 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 2014). For continuous outcomes, we used available case analysis. We imputed the standard deviation from P values according to the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and we used the median for the meta-analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the confidence interval, 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 the calculation of mean differences and bias the effect estimate to no effect in the case of standardised mean differences (Higgins 2011). Assessment of heterogeneity We explored heterogeneity by the Chi2 test with significance set at a P value less than 0.10, and measured the quantity of heterogeneity by the I2 statistic (Higgins 2002). We also used overlapping of confidence intervals on the forest plot to determine heterogeneity. Assessment of reporting biases We used visual asymmetry on a funnel plot to explore reporting bias as more than 10 trials were identified (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. Data synthesis We performed the meta-analyses using the software package Review Manager 5.2 (RevMan 2012) and following the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2014). We used both a random-effects model (DerSimonian 1986) and a fixedeffect model (DeMets 1987) for meta-analysis. In the case of a discrepancy between the two models we have reported both results; otherwise we have reported the results of the fixed-effect model. We planned to use the generic inverse method to combine the hazard ratios for time-to-event outcomes. Trial sequential analysis Traditional meta-analyses run the risk of random errors due to sparse data and repetitive testing on accumulating evidence. Trial sequential analysis can control such random errors (Wetterslev 2008; Thorlund 2011). 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 the trials are added alphabetically according to the last name of the first author. On the basis of the required information size, trial sequential monitoring boundaries are constructed. 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. On the other hand, 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 diversity-adjusted required sample size calculated from an alpha error of 0.05, a beta error of 0.20, a control event proportion obtained from the results, and a relative risk reduction of 20% for binary outcomes if there were two or more trials reporting the outcome to determine whether more trials are necessary on this topic (if the trial sequential alpha-spending monitoring boundary or the futility zone is crossed, then more trials may be unnecessary) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). As trial sequential analysis cannot be performed for SMD, we did not plan to perform the trial sequential analysis for quality of life. For pain, we calculated the required sample size from an alpha error of 0.05, a beta error of 0.20, the variance estimated from the meta-analysis results of low


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risk of bias trials (if possible), and a MD of 1 cm on the visual analogue scale (Todd 1996). For length of hospital stay, return to work, and return to activity, we planned to calculate the required sample size using a mean difference of one day with the remaining variables kept the same as for pain.

Subgroup analysis and investigation of heterogeneity 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 depths of wound infiltration. • Intraperitoneal local anaesthetic instillation. • Routine supplemental analgesia compared to no routine (’on-demand’) supplemental analgesia. We used the ’test for subgroup differences’ available through RevMan to identify the differences between subgroups. We used the random-effects model meta-analysis for this purpose.

Sensitivity analysis We performed a sensitivity analysis by imputing data for binary outcomes using various scenarios such as best-best scenario, best-worst scenario, worst-best scenario, and worst-worst scenario (Gurusamy 2009; Gluud 2014). We performed a sensitivity anal-

ysis by excluding the trials in which the means and the standard deviations were imputed. Summary of findings table We have summarised the results of all the reported outcomes in a summary of findings table prepared using GRADEPro 3.6 ( ims.cochrane.org/revman/gradepro).

RESULTS

Description of studies Results of the search We identified a total of 811 references through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (n = 316), MEDLINE (n = 60), EMBASE (n = 64), and Science Citation Index Expanded (n = 371). We did not identify any new trials from the trial registers. We excluded 273 duplicates and 495 clearly irrelevant references through reading the abstracts. Forty-three references were retrieved for further assessment. No references were identified through scanning reference lists of the identified randomised trials. We excluded 16 references (15 studies) for the reasons listed in the table ’Characteristics of excluded studies’. We did not identify any quasi-randomised or nonrandomised comparative studies that reported treatment-related harms. Twenty-seven references (26 trials) fulfilled the inclusion criteria. The reference flow diagram is shown in Figure 1.


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Figure 1. Study flow diagram.


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Included studies

Twenty-six trials fulfilled the inclusion criteria of the review. Of these, seven trials did not provide usable information for this systematic review (Shikano 1994; Ahmad 1998; Hasaniya 2001; Hasan 2007; Cantore 2008; Liang 2011; Beqiri 2012). These trials reported some specific aspects of pain for example, incisional pain, but did not report the pain scores or did not report the number of participants in each group. Thus, 1263 participants were included in the 19 trials that provided the data for the review. Ten of the 19 trials were two-armed trials that compared local anaesthetic wound infiltration versus inactive control (Ure 1993; Bilge 1997; Dath 1999; Noma 2001; Papaziogas 2001; Pavlidis 2003; Zajaczkowska 2004; Louizos 2005; Feroci 2009; Liu 2009) that is, although some of these trials randomised participants to more than two arms, only two arms were eligible for inclusion in this review. One trial was a three-armed trial that compared local anaesthetic wound infiltration with two inactive controls, normal saline and no intervention (Lepner 2003). Two trials had four arms comparing local anaesthetic wound infiltration with inactive controls in the presence and absence of oral rofecoxib (Newcomb 2007) or local anaesthetic intraperitoneal instillation (Nicolau 2008). Three trials had three or more arms that could be included for the comparison of local anaesthetic wound infiltration versus inactive control and comparison of the timing of administration of local anaesthetic (Sarac 1996; Lee 2001; Uzunkoy 2001). One trial had three arms which could be included for the comparison of local anaesthetic wound infiltration versus inactive control and comparison of different local anaesthetics for wound infiltration (Papagiannopoulou 2003). One trial had two arms which could be included for the comparison of the timing of local anaesthetic wound infiltration (Sozbilen 2007). One trial had two arms that compared different local anaesthetics for wound infiltration (Rodriguez-Navarro 2011). In summary, a total of 1095 participants were randomised to local anaesthetic wound infiltration (587 participants) versus no local anaesthetic wound infiltration (508 participants) in 17 trials (Ure 1993; Sarac 1996; Bilge 1997; Dath 1999; Lee 2001; Noma 2001; Papaziogas 2001; Uzunkoy 2001; Lepner 2003; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Louizos 2005; Newcomb 2007; Nicolau 2008; Feroci 2009; Liu 2009); a total of 149 participants were randomised to local anaesthetic wound infiltration prior to skin incision (74 participants) versus local anaesthetic wound infiltration at the end of surgery (75 participants) in four trials (Sarac 1996; Lee 2001; Uzunkoy 2001; Sozbilen 2007); and

a total of 176 participants were randomised to four different local anaesthetics (bupivacaine, levobupivacaine, ropivacaine, neosaxitoxin) in two trials (Papagiannopoulou 2003; Rodriguez-Navarro 2011). There were no trials comparing different doses of the same local anaesthetic.

Participant characteristics

Twelve trials clearly stated that they included participants undergoing elective laparoscopic cholecystectomy (Ure 1993; Dath 1999; Lee 2001; Papaziogas 2001; Lepner 2003; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Louizos 2005; Newcomb 2007; Nicolau 2008; Feroci 2009). The inclusion of people with acute cholecystitis was not reported in the remaining seven trials (Sarac 1996; Bilge 1997; Noma 2001; Uzunkoy 2001; Sozbilen 2007; Liu 2009; Rodriguez-Navarro 2011). Ten trials stated that they included only American Society of Anesthesiologists (ASA) status I or II people (Lee 2001; Noma 2001; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Louizos 2005; Newcomb 2007; Nicolau 2008; Feroci 2009; Rodriguez-Navarro 2011). In two trials, only people who were ASA status I to III were included (Papaziogas 2001; Lepner 2003). In the remaining seven trials, the ASA status of the participants was not reported (Ure 1993; Sarac 1996; Bilge 1997; Dath 1999; Uzunkoy 2001; Sozbilen 2007; Liu 2009).

Intervention

The details of the intervention and co-interventions in the different trials are summarised in Table 1.

Co-intervention

The details of the use of intraperitoneal local anaesthetic infiltration and routine supplemental analgesia are shown in Table 1. Further details about sample size, participant characteristics, the inclusion and exclusion criteria used in the trials, post-randomisation dropouts, intervention and control, comparisons, outcomes reported in the trials, and the risk of bias in the trials are shown in the table ’Characteristics of included studies’.

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).


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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Allocation Only four trials (4/26 (15.4%)) described random sequence generation and allocation concealment adequately (Bilge 1997; Feroci 2009; Liu 2009; Beqiri 2012). These trials were considered to be at low risk of selection bias. Blinding Five trials (5/26 (19.2%)) 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 (Ure 1993; Lepner 2003; Pavlidis 2003; Zajaczkowska 2004; Feroci 2009).

Other potential sources of bias Only one trial (1/26 (3.8%)) was considered to be at low risk of ’for-profit’ bias (Feroci 2009).

Effects of interventions See: Summary of findings for the main comparison Local anaesthetic wound infiltration compared to no local anaesthetic wound infiltration for people undergoing laparoscopic cholecystectomy; Summary of findings 2 Wound infiltration with different local anaesthetic agents for people undergoing laparoscopic cholecystectomy; Summary of findings 3 Local anaesthetic wound infiltration before incision compared to end of surgery for people undergoing laparoscopic cholecystectomy

Incomplete outcome data Six trials (6/26 (23.1%)) had no post-randomisation dropouts and were considered to be at low risk of attrition bias (Bilge 1997; Lepner 2003; Pavlidis 2003; Newcomb 2007; Feroci 2009; Liu 2009).

Local anaesthetic wound infiltration versus no local anaesthetic wound infiltration The main results are summarised in the Summary of findings for the main comparison.

Selective reporting Seven trials (7/26 (26.9%)) reported on mortality and morbidity and were considered to be at low risk of selective reporting bias (Dath 1999; Lee 2001; Lepner 2003; Pavlidis 2003; Newcomb 2007; Feroci 2009; Liu 2009).

Mortality

There was no mortality in either group in the seven trials that reported mortality (0/280 (0%) in local anaesthetic infiltration group versus 0/259 (0%) in control group) (Ure 1993; Dath 1999;


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Lee 2001; Lepner 2003; Pavlidis 2003; Feroci 2009; Liu 2009). There were no post-randomisation dropouts in four trials (Lepner 2003; Pavlidis 2003; Feroci 2009; Liu 2009). It was not clear whether there were post-randomisation dropouts in two trials (Ure 1993; Lee 2001). The other trial did not state the number of postrandomisation dropouts in each group (Dath 1999). So, we did not perform a sensitivity analysis imputing outcomes for different scenarios. 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 in the trial sequential analysis. Instead, we used a proportion of 0.2% in the control group based on data from approximately 30,000 patients included in a database in Switzerland (Giger 2011). The proportion of information accrued was only 0.15% 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.

Figure 4. Trial sequential analysis of mortality (local anaesthetic versus no local anaesthetic)The diversityadjusted required information size (DARIS) was calculated to 352,564 patients, based on the proportion of patients in the control group with the outcome of 0.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z-curve (blue line). After accruing a total of 539 participants in seven trials, only 0.15% 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 cumulative Z-curve do not even cross the conventional statistical boundaries (dotted red lines).

Morbidity

Seven trials (539 participants) reported serious adverse events (Ure 1993; Dath 1999; Lee 2001; Lepner 2003; Pavlidis 2003; Feroci 2009; Liu 2009). There was no significant difference between the two groups in the proportion of people who developed serious adverse events (RR 2.00; 95% CI 0.19 to 21.59) (Analysis 1.1). There were serious adverse events in only one trial and these were

not related to the local anaesthetic (Pavlidis 2003) (Analysis 1.1). Although the remaining trials did not report the overall morbidity, four trials (167 participants) reported that there were no drugrelated serious adverse events in any of the 167 participants who received the local anaesthetics (Sarac 1996; Papagiannopoulou 2003; Louizos 2005; Nicolau 2008). One trial reported that there were no intra-operative complications in any of the 40 participants included in the trial (Bilge 1997). The remaining trials did not


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report on the complications that participants developed. The same trials that reported mortality reported on serious adverse events. We did not perform a sensitivity analysis imputing outcomes for different scenarios for the same reasons mentioned under mortality. The trial sequential analysis revealed that the proportion of information accrued was only 0.29% of the diversityadjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 5). The cumulative Zcurve did not cross the conventional statistical boundaries. Figure 5. Trial sequential analysis of morbidity (local anaesthetic versus no local anaesthetic)The diversityadjusted required information size (DARIS) was calculated to 185,703 participants, based on the proportion of patients in the control group with the outcome of 0.42%, 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 a total of 539 participants in seven trials, only 0.29% 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, cumulative Z-curve do not even cross the conventional statistical boundaries (dotted red lines).

Patient quality of life

None of the trials reported patient quality of life. Hospital stay

Proportion discharged as day surgery patients

Only one trial (97 participants) reported the proportion of participants discharged as day surgery patients (Dath 1999). The proportion of participants who were discharged as day surgery patients was higher in the local anaesthetic infiltration group than the no local anaesthetic infiltration group (RR 1.55; 95% CI 1.05 to 2.28) (Analysis 1.2). This trial did not report the number of post-randomisation dropouts in each group and so we did not perform a sensitivity analysis. We did not perform the trial sequential


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analysis because of the presence of only one trial.

Length of hospital stay Four trials (327 participants) reported the length of hospital stay (Ure 1993; Pavlidis 2003; Newcomb 2007; Liu 2009). There were no differences in the length of hospital stay between the two groups (MD -0.26 days; 95% CI -0.67 to 0.16) (Analysis 1.3). There were no changes in the results using the random-effects model. Ei-

ther the mean or the standard deviation or both were not reported and had to be imputed in three trials (Ure 1993; Pavlidis 2003; Newcomb 2007). Exclusion of these trials resulted in a shorter hospital stay in the local anaesthetic group than the control group (MD -1.70 days; 95% CI -2.59 to -0.81) (Analysis 1.7). The trial sequential analysis suggested that further trials are required to identify benefits or harms of local anaesthetic wound infiltration compared with no local anaesthetic wound infiltration with regards to the length of hospital stay (Figure 6).

Figure 6. Trial sequential analysis of length of hospital stay (local anaesthetic versus no local anaesthetic)The diversity-adjusted required information size (DARIS) was 931 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 7.40, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 79.99%. After accruing a total of 327 participants in three trials, only 35.12% of the DARIS has been reached. Accordingly, the futility area has not been drawn. The cumulative Z-curve (blue line) has not crossed the trial sequential monitoring boundaries (red line) or the conventional statistical boundaries (dotted red line). This suggests that further trials are required to identify benefits or harms of local anaesthetic wound infiltration compared to no local anaesthetic wound infiltration with regards to the length of hospital stay.

Pain

Pain at four to eight hours Thirteen trials (806 participants) reported this outcome (Sarac 1996; Bilge 1997; Dath 1999; Noma 2001; Papaziogas 2001; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007; Nicolau 2008; Feroci 2009; Liu 2009). The pain

scores as measured by the visual analogue scale were lower in the local anaesthetic infiltration group than the control group (MD -1.33 cm on the VAS; 95% CI -1.54 to -1.12) (Analysis 1.4). There were no changes in the interpretation of results using a random-effects model meta-analysis. Either the mean or the standard deviation was imputed in six trials (Ure 1993; Sarac 1996; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007). Exclusion of these trials did not alter the results


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(MD -1.34 cm on the VAS; 95% CI -1.55 to -1.12) (Analysis 1.8). One trial contributed to nearly 45% of the weight of the analysis (Noma 2001). It was not clear whether the trial reported the standard deviation or standard error. Exclusion of this trial from the analysis in addition to the other trials where the standard deviation was imputed did not alter the results (MD -0.73 cm on the VAS; 95% CI -1.03 to -0.44). All the trial sequential monitoring boundaries were crossed by the cumulative Z-curve favouring local anaesthetic infiltration. The findings were consistent with local anaesthetic infiltration decreasing pain at between four and eight hours compared with no local anaesthetic infiltration with no risk of random errors (Figure 7). Figure 7. Trial sequential analysis of pain (4 to 8 hours) (local anaesthetic versus no local anaesthetic)The diversity-adjusted required information size (DARIS) was 789 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 4.68, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 81.38%. The conventional statistical boundary for benefit (dotted red line) is crossed by the cumulative Z-curve (blue line) after the fifth trial. The trial sequential monitoring boundaries (red line) are crossed by cumulative Z-curve after the sixth trial. The findings are consistent with local anaesthetic infiltration decreasing pain between 4 and 8 hours compared to no local anaesthetic infiltration with no risk of random errors.

Pain at nine to 24 hours Twelve trials (756 participants) reported this outcome (Sarac 1996; Bilge 1997; Dath 1999; Noma 2001; Papaziogas 2001; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007; Nicolau 2008; Feroci 2009; Liu 2009). The pain scores as measured by the visual analogue scale were lower in the

local anaesthetic infiltration group than the control group (MD 0.36 cm on the VAS; 95% CI -0.53 to -0.20) (Analysis 1.5). There were no changes in the interpretation of results by using a randomeffects model meta-analysis. Either the mean or the standard deviation was imputed in five trials (Sarac 1996; Papagiannopoulou


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2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007). Exclusion of these trials did not alter the results (MD -0.34 cm on the VAS; 95% CI -0.51 to -0.17) (Analysis 1.9). One trial contributed to nearly 45% of the weight of the analysis (Noma 2001). It was not clear whether the trial reported the standard deviation or standard error. Exclusion of this trial from the analysis in addition to the other trials where the standard deviation was imputed did not alter the results (MD -0.61 cm on the VAS; 95% CI 0.88 to -0.33). All the trial sequential monitoring boundaries were crossed by the cumulative Z-curve favouring local anaesthetic infiltration. The findings were consistent with local anaesthetic instillation decreasing pain at between nine and 24 hours compared with no local anaesthetic infiltration without the risk of random errors (Figure 8). Figure 8. Trial sequential analysis of pain (9 to 24 hours) (local anaesthetic versus no local anaesthetic)The diversity-adjusted required information size (DARIS) was 168 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 2.66, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 50.3%. The conventional statistical boundary for benefit (dotted red line) is crossed by the cumulative Z-curve (blue line) after the fifth trial. The findings are consistent with local anaesthetic infiltration decreasing pain between 9 and 24 hours compared with no local anaesthetic infiltration without the risk of random errors.


Two trials (195 participants) reported the return to normal activity (Uzunkoy 2001; Pavlidis 2003). There were no differences in the time taken to return to normal activity between the two groups

(MD 0.14 days; 95% CI -0.59 to 0.87) (Analysis 1.6). The standard deviation was not reported and had to be imputed in one trial (Pavlidis 2003). Exclusion of this trial did not result in a change in the results (MD 1.02 days; 95% CI -0.37 to 2.41) (Analysis


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1.10). The trial sequential analysis suggested that further trials are required to identify benefits or harms of local anaesthetic wound infiltration compared with no local anaesthetic wound infiltration with regards to the time taken to return to normal activity (Figure 9). Figure 9. Trial sequential analysis of return to normal activity (local anaesthetic versus no local anaesthetic)The diversity-adjusted required information size (DARIS) was 562 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 13.59, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 24.03%. After accruing a total of 195 participants in two trials, only 34.70% of the DARIS has been reached. Accordingly, the futility area has not been drawn. The cumulative Z-curve (blue line) has not crossed the trial sequential monitoring boundaries (red lines) or the conventional statistical boundaries (dotted red lines). This suggests that further trials are required to identify benefits or harms of local anaesthetic wound infiltration compared with no local anaesthetic wound infiltration with regards to the time taken to return to normal activity.

Return to work

None of the trials reported return to work.

Subgroup analysis

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 for the other outcomes. We did not perform the following subgroup analyses. • 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. • Different depths of wound infiltration: all the trials that reported the depth of wound infiltration reported that they infiltrated at least the fascia. • Maximum safe dose used (that is, whether the trials used the dose based on body weight): only one trial calculated the dose of the local anaesthetic based on weight (Feroci 2009). • Intraperitoneal local anaesthetic instillation: the information about whether intraperitoneal instillation was used


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was available for only two trials (Nicolau 2008; Feroci 2009). • Routine supplemental analgesia: routine supplemental analgesia was used in only one trial (Nicolau 2008). So, only two subgroup analyses were performed for each outcome. • Different local anaesthetic agents. ◦ Pain at four to eight hours: the test for subgroup differences was significant (P = 0.03). The effect seemed to be highest for levobupivacaine followed by bupivacaine and then ropivacaine (Analysis 1.11). • ◦ Pain at nine to 24 hours: the test for subgroup differences was significant (P = 0.006). The effect seemed to be highest for levobupivacaine followed by ropivacaine and then bupivacaine (Analysis 1.12). • Different timing of instillation. ◦ Pain at four to eight hours: the test for subgroup differences was significant (P < 0.00001). The effect seemed to be higher when the local anaesthetic was administered prior to incision than at the end of surgery (Analysis 1.13).

Morbidity

There were no serious adverse events in either group in the only trial that reported morbidity: 0/69 (0%) in the neosaxitoxin group versus 0/68 (0%) in the bupivacaine group (Rodriguez-Navarro 2011). We did not perform a sensitivity analysis or trial sequential analysis because of the same reasons as for mortality.

Patient quality of life

None of the trials reported patient quality of life.

Hospital stay

Proportion discharged as day surgery patients None of the trials reported the proportion discharged as day surgery patients.

Length of hospital stay ◦ Pain at nine to 24 hours: the test for subgroup differences was not significant (P = 0.24). The effect seemed to be highest for levobupivacaine followed by ropivacaine and then bupivacaine (Analysis 1.14).

Reporting and other bias

We explored reporting and other bias by funnel plots only for pain at four to eight hours and for pain at nine to 24 hours because of the presence of adequate number of trials for these two outcomes only. The funnel plots did not reveal any evidence of reporting bias. The Egger’s test did not reveal any evidence of reporting bias (P = 0.246 and P = 0.075 respectively).

Local anaesthetic wound infiltration: different local anaesthetics

One trial (137 participants) reported the length of hospital stay (Rodriguez-Navarro 2011). There was no significant difference in the length of hospital stay between the two groups (MD 0.00 days; 95% CI -0.65 to 0.65) (Analysis 2.1).

Pain

Pain at four to eight hours One trial (39 participants) reported this outcome (Papagiannopoulou 2003). The pain scores as measured by the visual analogue scale were significantly higher in the ropivacaine group than the levobupivacaine group (MD 2.30 cm on the VAS; 95% CI 0.23 to 4.37) (Analysis 2.2). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.

The main results are summarised in the Summary of findings 2. Pain at nine to 24 hours Mortality

There was no mortality in either group in the only trial that reported mortality: 0/69 (0%) in the neosaxitoxin group versus 0/68 (0%) in the bupivacaine group (Rodriguez-Navarro 2011). There were no post-randomisation dropouts in this trial. So, we did not perform a sensitivity analysis. We did not perform a trial sequential analysis because of the presence of only one trial for this outcome.

One trial (39 participants) reported this outcome (Papagiannopoulou 2003). The pain scores as measured by the visual analogue scale were significantly higher in the ropivacaine group than the levobupivacaine group (MD 1.90 cm on the VAS; 95% CI 1.00 to 2.80) (Analysis 2.3). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.


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One trial (137 participants) reported the return to normal activity (Rodriguez-Navarro 2011). The time taken to return to normal activity was significantly shorter in the neosaxitoxin group than the bupivacaine group (MD -1.90 days; 95% CI -2.71 to -1.09) (Analysis 2.4). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.

Return to work

2001). So, we did not perform a sensitivity analysis imputing outcomes for different scenarios. We did not perform a trial sequential analysis because of the presence of only one trial for this outcome.

Morbidity

There were no serious adverse events in either group in the only trial that reported morbidity: 0/22 (0%) in the pre-incisional group versus 0/21 (0%) in the post-surgical group (Lee 2001). We did not perform a sensitivity analysis or trial sequential analysis because of the same reasons as for mortality.

None of the trials reported return to work. Patient quality of life

None of the trials reported patient quality of life. Subgroup analysis

We did not perform any subgroup analysis because of the paucity of data.

Hospital stay

None of the trials reported the proportion discharged as day surgery patients or the length of hospital stay.

Reporting bias

We did not explore reporting bias because of the few trials included for this comparison.

Pain

Pain at four to eight hours Local anaesthetic wound infiltration: before skin incision versus end of surgery The main results are summarised in the Summary of findings 3.

Mortality

There was no mortality in either group in the only trial that reported mortality: 0/22 (0%) in the pre-incisional group versus 0/ 21 (0%) in the post-surgical group (Lee 2001). It was not clear whether there were post-randomisation dropouts in this trial (Lee

Two trials (76 participants) reported this outcome (Sarac 1996; Sozbilen 2007). There was no difference in the pain scores as measured by the visual analogue scale between the two groups (MD 0.18 cm on the VAS; 95% CI -1.90 to 2.26) (Analysis 3.1). There were no changes in the interpretation of results by using a randomeffects model meta-analysis. Either the mean or the standard deviation was imputed in both trials. So, we did not perform a sensitivity analysis. The trial sequential analysis suggested that further trials are necessary to show significant benefits or harms of local anaesthetic infiltration before incision versus local anaesthetic infiltration towards the end of surgery (Figure 10).


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Figure 10. Trial sequential analysis of pain (4 to 8 hours) (before incision versus after surgery)The diversityadjusted required information size (DARIS) was 1344 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 42.78, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. After accrual of 76 participants in two trials, only 5.65% of DARIS has been reached. Accordingly, the futility area was not drawn. The trial sequential boundaries (red lines) or the conventional statistical boundaries (dotted red lines) were not crossed by the cumulative Z-curve (blue line). This suggests that further trials are necessary to show significant benefits or harms of local anaesthetic infiltration before incision versus local anaesthetic infiltration towards the end of surgery.

Pain at nine to 24 hours One trial (40 participants) reported this outcome (Sarac 1996). There was no difference in the pain scores as measured by the visual analogue scale between the two groups (MD 0.10 cm on the VAS; 95% CI -2.53 to 2.73) (Analysis 3.2). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.

sitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome. Return to work

None of the trials reported on return to work. Subgroup analysis


One trial (30 participants) reported the return to normal activity (Uzunkoy 2001). There were no differences in the time taken to return to normal activity between the two groups (MD 0.50 days; 95% CI -1.05 to 2.05) (Analysis 3.3). We did not perform a sen-

We did not perform any subgroup analysis because of the paucity of data. Reporting bias

We did not explore reporting bias because of the few trials included for this comparison.


23


A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Wound infiltration with different local anaesthetic agents for people undergoing laparoscopic cholecystectomy Patient or population: people undergoing laparoscopic cholecystectomy. Settings: secondary or tertiary. Intervention: different local anaesthetic agents. Outcomes


Assumed risk

Corresponding risk

Control

Different local anaesthetic agents


No of participants (trials)


Neosaxitoxin versus bupivacaine Mortality

There was no mortality in either group

Not estimable

137 (1 trial)

⊕

very low1,2


There were no serious adverse events in either group

Not estimable

137 (1 trial)

⊕

very low1,2

Length of hospital stay

The mean length of hospital The mean length of hospital stay in the control groups was stay in the intervention groups 1 day was 0 higher (0.65 lower to 0.65 higher)

137 (1 trial)

⊕

very low1,3


The mean return to normal ac- The mean return to normal activity in the control groups was tivity in the intervention groups 5.7 days was 1.9 lower (2.71 to 1.09 lower)

137 (1 trial)

⊕

very low1,3

Ropivacaine versus levobupivacaine 24


Pain 4 to 8 hours

The mean pain 4 to 8 hours in The mean pain 4 to 8 hours in the control groups was the intervention groups was 1.1 cm VAS 2.3 higher (0.23 to 4.37 higher)

39 (1 trial)

⊕

very low1,3

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 0.6 cm VAS 1.9 higher (1 to 2.8 higher)

39 (1 trial)

⊕

very low1,3

*The basis for the assumed risk was the control group risk. 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; VAS: visual analogue scale. 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 was of high risk of bias (downgraded by 2 points). 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 (downgraded by 2 points). 3 There were fewer than 400 participants included in total (downgraded by 1 point). 2

25


Local anaesthetic wound infiltration before incision compared to end of surgery for people undergoing laparoscopic cholecystectomy Patient or population: patients with people undergoing laparoscopic cholecystectomy Settings: secondary or tertiary Intervention: before incision Comparison: end of surgery Outcomes


Assumed risk

Corresponding risk

End of surgery

Before incision


No of participants (studies)


Mortality

There was no mortality in either group

Not estimable

43 (1 trial)

⊕

very low1,2


There were no serious adverse events in either group Not estimable

43 (1 trial)

⊕

very low1,2

Pain 4 to 8 hours

The mean pain 4 to The mean pain 4 to 8 8 hours in the control hours in the intervention groups was groups was 3 cm VAS 0.18 higher (1.9 lower to 2.26 higher)

76 (2 trials)

⊕

very low1,3

Pain 9 to 24 hours

The mean pain 9 to The mean pain 9 to 24 24 hours in the control hours in the intervention groups was groups was 2.7 cm VAS 0.1 higher (2.53 lower to 2.73 higher)

40 (1 trial)

⊕

very low1,3

Comments

26


Return to normal activity The mean return to normal activity in the control groups was 7.6 days

The mean return to normal activity in the intervention groups was 0.5 higher (1.05 lower to 2.05 higher)

30 (1 trial)

⊕

very low1,3

*The basis for the assumed risk is the mean control group risk. 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; VAS: visual analogue scale. 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 (downgraded by 2 points). 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 (downgraded by 2 points). 3 The confidence intervals overlapped 0 and minimal clinically important difference. The total number of patients in the intervention and control group was fewer than 400 (downgraded by 2 points). 2

27

DISCUSSION Summary of main results In this review, we have compared local anaesthetic wound infiltration with no wound infiltration with local anaesthetic agents to reduce pain during laparoscopic cholecystectomy. We included a total of 17 randomised clinical trials involving 1095 participants randomised to local anaesthetic infiltration (587 participants) or control (508 participants) which contributed to one or more of the outcomes. We also compared different local anaesthetics and different times of administration of local anaesthetics. There were no significant differences in mortality or morbidity between the compared groups. The overall mortality after laparoscopic cholecystectomy is low (0.2%) (Giger 2011). In this review, the trials excluded high risk patients 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 were no local anaesthetic-related serious adverse events in any of the participants included in the trials that reported this information. 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 laparoscopic cholecystectomy is performed under general anaesthesia with patients likely to be monitored because of the use of other anaesthetic agents, one can conclude that local anaesthetics are generally safe to use in patients undergoing laparoscopic cholecystectomy who are without an allergy to local anaesthetic. None of the trials reported quality of life or return to work. Only three trials reported return to normal activity (Uzunkoy 2001; Pavlidis 2003; Rodriguez-Navarro 2011). The main purpose of the local anaesthetic is to decrease pain, enabling the patients 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 for the state-funded health system. While quality of life is the outcome that is used for assessing the costeffectiveness 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. Only one trial reported the proportion of participants discharged as day surgery patients (Dath 1999). The proportion of participants who were discharged as day surgery patients was significantly higher after local anaesthetic wound infiltration than an inactive control (Analysis 1.2). The trial had a significant number of dropouts and one cannot rely upon the results from this single trial. However, if the effect was real, this may be due to the reduction in the overall pain at four to eight hours, which is generally the time at which discharges are performed in the day surgery setting. It does not appear from the

description in the trials that day surgery was attempted in most of the remaining trials. Future trials should investigate the role of local anaesthetic wound infiltration in the day surgery laparoscopic cholecystectomy setting. There were no significant differences in the length of hospital stay in the comparisons that reported these outcomes. These outcomes are important for the patients both in a private health setting and in a state-funded health system because of the costs associated with hospital stay. However, only five trials reported this important outcome (Ure 1993; Pavlidis 2003; Newcomb 2007; Liu 2009; Rodriguez-Navarro 2011). The pain at four to eight hours and at nine to 24 hours was significantly reduced in the local anaesthetic wound infiltration group compared with no active intervention. The findings were robust to sensitivity analysis. The trial sequential analysis also confirmed that the risk of random errors in concluding that local anaesthetic wound infiltration decreased pain is low. Although some subgroup analyses and some direct comparisons between local anaesthetics showed the significant influence of some factors, such as the local anaesthetic agent used and the time at which the local anaesthetic is administered, on the amount of pain reduction, these were not consistent. Thus, there is no convincing evidence from this review to suggest that one method of local anaesthetic wound infiltration is better than another method. The mean reduction in pain was about 1 cm on the 0 to 10 cm visual analogue scale at four to eight hours and about 0.4 cm at 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 local anaesthetic wound infiltration may have a role in increasing the proportion of laparoscopic cholecystectomies performed as day surgery cases, as mentioned earlier, since patients undergoing day surgery laparoscopic cholecystectomy are discharged at between four and eight hours.

Overall completeness and applicability of evidence Most of the trials included in this review included mainly patients undergoing elective laparoscopic cholecystectomy (Included studies; Characteristics of included studies). Most trials included only low anaesthetic risk patients undergoing laparoscopic cholecystectomy (Included studies; Characteristics of included studies). The findings of this review are applicable only to such patients.

Quality of the evidence The overall quality of evidence is low to 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.


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Potential biases in the review process

Implications for practice

We performed a thorough search of the literature. However, we included ’pain’ as one of the components 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 the data, thus minimising errors. We imputed the mean and standard deviation when these were not available. We performed a sensitivity analysis excluding such trials. While most analyses were robust to such sensitivity analyses, the results changed significantly for length of hospital stay in the comparison between local anaesthetic wound infiltration and inactive control. Thus, the imputations may have altered the interpretation of data.

Serious adverse events were rare in studies evaluating local anaesthetic wound infiltration (very low quality evidence). There is very low quality evidence that infiltration 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.

Agreements and disagreements with other studies or reviews This is the first systematic review of local anaesthetic wound infiltration in people undergoing laparoscopic cholecystectomy. We agree with many of the authors of the trials included in this review that wound infiltration with local anaesthetic decreases pain after laparoscopic cholecystectomy.

AUTHORS’ CONCLUSIONS

Implications for research • Further randomised clinical trials are necessary to evaluate the role of local anaesthetic wound filtration in the emergency setting and in the elective setting, particularly for day surgery elective laparoscopic cholecystectomies. • Future trials should include quality of life, hospital stay, return to normal activity, and return to work as outcomes. • Future trials need to be designed according to the SPIRIT guidelines (www.spirit-statement.org/) and conducted and reported according to the CONSORT statement (www.consortstatement.org).

ACKNOWLEDGEMENTS To the Cochrane Hepato-Biliary Group for the support that they have provided. Peer Reviewers: Shao Peng, Canada; Pablo L Ingelmo, Canada. Contact Editor: 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 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. Beqiri 2012 {published data only} Beqiri AI, Domi RQ, Sula HH, Zaimi EQ, Petrela EY. The combination of infiltrative bupivacaine with low-pressure laparoscopy reduces postcholecystectomy pain A prospective

randomized controlled study. Saudi Medical Journal 2012; 33(2):134–8. Bilge 1997 {published data only} Bilge O, Tekant Y, Yavru A, Acarli K, Gulbaba G. The effect of post-incisional injection of bupivacaine on post-operative pain in laparoscopic cholecystectomy: A prospective randomized study. Turkish Journal of Surgery 1997;13(5): 349–53. Cantore 2008 {published data only} Cantore F, Boni L, Di Giuseppe M, Giavarini L, Rovera F, Dionigi G. Pre-incision local infiltration with


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levobupivacaine reduces pain and analgesic consumption after laparoscopic cholecystectomy: a new device for daycase procedure. International Journal of Surgery 2008;6 Suppl 1:S89–S92. Dath 1999 {published data only} Dath D, Park AE. Randomized, controlled trial of bupivacaine injection to decrease pain after laparoscopic cholecystectomy. Canadian Journal of Surgery 1999;42(4): 284–8. Feroci 2009 {published data only} Feroci F, Kroning KC, Scatizzi M. Effectiveness for pain after laparoscopic cholecystectomy of 0.5% bupivacaine-soaked Tabotamp placed in the gallbladder bed: a prospective, randomized, clinical trial. Surgical Endoscopy 2009;23(10): 2214–20. Hasan 2007 {published data only} Hasan S, Lauwers M, Hoeij Van Nieuwenhove Y, Camu F. Postoperative vain relief after laparoscopic cholecystectomy. 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. Hasaniya 2001 {published data only} Hasaniya N, Zayed F, Faiz H, Severino R. Preinsertion local anesthesia at the trocar site improves perioperative pain and decreases costs of laparoscopic cholecystectomy. Surgical Endoscopy 2001;15(9):962–4. 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, Samarutel J. Postoperative pain relief after laparoscopic cholecystectomy: a randomised prospective double-blind clinical trial. Scandinavian Journal of Surgery 2003;92(2):121–4. Liang 2011 {published data only} Liang HS, Feng Y, Liu YZ, An HY, Yang BX. Effect of flurbiprofen combined different concentrations of ropivacaine local infiltration on postoperative analgesia after laparoscopic cholecystectomy. Beijing Da Xue Xue Bao 2011;43(5):753–6. Liu 2009 {published data only} Liu YY, Yeh CN, Lee HL, Wang SY, Tsai CY, Lin CC, et al.Local anesthesia with ropivacaine for patients undergoing laparoscopic cholecystectomy. World Journal of Gastroenterology 2009; Vol. 15, issue 19:2376–80. 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; Vol. 19, issue 11:1503–6.

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. American Surgeon 2007; Vol. 73, issue 6:618-24; discussion 624-5. 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 controlled trial. Chirurgia (Bucharest, Romania) 2008;103(5):547–51. Noma 2001 {published data only} Noma H, Kakiuchi H, Nojiri K, Izumi R, Tashiro C. Evaluation of postoperative pain relief by infiltration of bupivacaine or epidural block after laparoscopic cholecystectomy. Masui 2001;50(11):1201–4. Papagiannopoulou 2003 {published data only} Papagiannopoulou P, Argiriadou H, Georgiou M, Papaziogas B, Sfyra E, Kanakoudis F. Preincisional local infiltration of levobupivacaine vs ropivacaine for pain control after laparoscopic cholecystectomy. Surgical Endoscopy 2003;17(12):1961–4. Papaziogas 2001 {published data only} Papaziogas B, Argiriadou H, Papagiannopoulou P, Pavlidis T, Georgiou M, Sfyra E, et al.Preincisional intravenous lowdose ketamine and local infiltration with ropivacaine reduces postoperative pain after laparoscopic cholecystectomy. Surgical Endoscopy 2001;15(9):1030–3. Pavlidis 2003 {published data only} Pavlidis TE, Atmatzidis KS, Papaziogas BT, Makris JG, Lazaridis CN, Papaziogas TB. The effect of preincisional periportal infiltration with ropivacaine in pain relief after laparoscopic procedures: a prospective, randomized controlled trial. Journal of the Society of Laparoendoscopic Surgeons 2003;7(4):305–10. Rodriguez-Navarro 2011 {published data only} Rodriguez-Navarro A, Berde C, Wiedmaier G, Mercado A, Iglesias V, Garcia C. Neosaxitoxin for postoperative analgesia in laparoscopic cholecystectomy. A randomized double blind controlled trial with 250 patients. Regional Anesthesia and Pain Medicine 2010;35(5):E54. ∗ Rodriguez-Navarro AJ, Berde CB, Wiedmaier G, Mercado A, Garcia C, Iglesias V, et al.Comparison of neosaxitoxin versus bupivacaine via port infiltration for postoperative analgesia following laparoscopic cholecystectomy: a randomized, double-blind trial. Regional Anesthesia and Pain Medicine 2011;36(2):103–9. Sarac 1996 {published data only} Sarac AM, Aktan AO, Baykan N, Yegen C, Yalin R. The effect and timing of local anesthesia in laparoscopic cholecystectomy. Surgical Laparoscopy and Endoscopy 1996; Vol. 6, issue 5:362–6. Shikano 1994 {published data only} Shikano S, Yamashita H, Kawahara M, Shimizu N, Nomura S, Nobusawa S, et al.Effect of wound infiltration


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with bupivacaine for postoperative pain after laparoscopic cholecystectomy. Surgical Laparoscopy and Endoscopy 1994; 4(6):500. 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;24(2):247–57. Ure 1993 {published data only} Ure BM, Troidl H, Spangenberger W, Neugebauer E, Lefering R, Ullmann K, et al.Preincisional local anesthesia with bupivacaine and pain after laparoscopic cholecystectomy. A double-blind randomized clinical trial. Surgical Endoscopy 1993;7(6):482–8. Uzunkoy 2001 {published data only} Uzunkoy A, Coskun A, Akinci OF. The value of preemptive analgesia in the treatment of postoperative pain after laparoscopic cholecystectomy. European Surgical Research 2001; Vol. 33, issue 1:39–41. Zajaczkowska 2004 {published data only} Zajaczkowska R, Wnek W, Wordliczek J, Dobrogowski J. Peripheral opioid analgesia in laparoscopic cholecystectomy. Regional Anesthesia and Pain Medicine 2004;29(5):424–9.

References to studies excluded from this review Alexander 1996 {published data only} Alexander DJ, Ngoi SS, Lee L, So J, Mak K, Chan S, et al.Randomized trial of periportal peritoneal bupivacaine for pain relief after laparoscopic cholecystectomy. British Journal of Surgery 1996;83(9):1223–5. 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. 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. 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 and Advanced Surgical Techniques 2009;19(6):821–5. Futier 2011 {published data only} Futier E, Petit A, Pezet D. Authors’ Reply: Randomized clinical trial of combined preincisional infiltration and intraperitoneal instillation of levobupivacaine for postoperative pain after laparoscopic cholecystectomy

(British Journal of Surgery 2011;98:784-9). British Journal of Surgery 2011;98(8):1179. Hilvering 2011 {published data only} Hilvering B, Draaisma WA, van der Bilt JDW, Valk RM, Kofman KE, Consten ECJ. Authors’ reply: Randomized clinical trial of combined preincisional infiltration and intraperitoneal instillation of levobupivacaine for postoperative pain after laparoscopic cholecystectomy (British Journal of Surgery 2011;98:784-9). British Journal of Surgery 2011;98(8):1179–80. ∗ Hilvering B, Draaisma WA, van der Bilt JDW, Valk RM, Kofman KE, Consten ECJ. Randomized clinical trial of combined preincisional infiltration and intraperitoneal instillation of levobupivacaine for postoperative pain after laparoscopic cholecystectomy. British Journal of Surgery 2011; Vol. 98, issue 6:784–9. Karadeniz 1998 {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. British Journal of Anaesthesia 1998;80 Suppl 1:A597. Lopez-Maya 2011 {published data only} Lopez-Maya L, Lina-Manjarrez F, Diaz-Peralta A, Lina-Lopez LM. Reduction of postoperative pain in cholecystectomy laparoscopy. Cutaneous and intraperitoneal ropivacaine (before vs after) the incision and pneumoperitoneum. Revista Mexicana de Anestesiologia 2011;34(4):251–9. Lotz 1997 {published data only} Lotz JC. Randomized trial of periportal peritoneal bupivacaine for pain relief after laparoscopic cholecystectomy. British Journal of Surgery 1997;84(5):730. 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. 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;82(1):44–51. 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 2006;20(10):1560–4.


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anaesthetic instillation versus no intra-peritoneal local anaesthetic instillation for laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews Under editorial, issue Under editorial. Gurusamy 2013b Gurusamy KS, Vaughan J, Toon CD, Davidson BR. Pharmacological interventions for prevention or treatment of post-operative pain in patients undergoing laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews Under editorial, issue Under editorial. 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. HES 2011 HESonline. Hospital Episode Statistics. Main procedures and interventions: 3 character. www.hscic.gov.uk/ catalogue/PUB08288 2011 (accessed on 3 September 2013). Higgins 2002 Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539–58. 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 1997 CFR & ICH Guidelines1. Vol. 1, PA 19063-2043, USA: Barnett International/PAREXEL, 1997. Joshi 2012 Joshi GP, Rawal N, Kehlet H, Bonnet F, Camu F, Fischer HB, et al.Evidence-based management of postoperative pain in adults undergoing open inguinal hernia surgery. British Journal of Surgery 2012;99(2):168–85. Kjaergaard 2012 Kjaergaard M, Moiniche S, Olsen KS. Wound infiltration with local anesthetics for post-operative pain relief in lumbar spine surgery: a systematic review. Acta Anaesthesiologica Scandinavica 2012;56(3):282–90. 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]

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. 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. Ng 2004 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. NIH 1992 NIH. NIH consensus statement on gallstones and laparoscopic cholecystectomy. consensus.nih.gov/1992/ 1992GallstonesLaparoscopy090html.htm 1992 (accessed 3 September 2013). 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 2012 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 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. 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. 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


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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 22 February 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]

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


34

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Ahmad 1998 Methods

Randomised clinical trial

Participants

Country: UK. Number randomised: 20. Post-randomisation dropouts: not stated. Revised sample size: 20. Average age: not stated. Females: not stated. Inclusion criteria: People undergoing laparoscopic cholecystectomy.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 10). Further details: 20 ml of 0.25% bupivacaine. Group 2: No local anaesthetic (n = 10). Further details: normal saline.

Outcomes

The outcome reported was pain.

Notes

Attempts were made to contact the authors in March 2013. The pain scores were not provided. The pain was significantly lower in the local anaesthetic group than control group

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


Incomplete outcome data (attrition bias) All outcomes

Unclear risk


Selective reporting (reporting bias)

High risk

Comment: Mortality and morbidity were not reported.


35

Ahmad 1998

For-profit bias

(Continued)

Unclear risk


Beqiri 2012 Methods


Participants

Country: Albania. Number randomised: 500. Post-randomisation dropouts: 27 (5.4%). Revised sample size: 473. Average age: 44 years. Females: 293 (61.9%). Inclusion criteria: 1. ASA I-II. 2. Scheduled laparoscopic cholecystectomy. Exclusion criteria: 1. Pre-existing pulmonary and cardiac disease. 2. Intracranial lesions. 3. Spinal and peridural anaesthesia. 4. Local anaesthetic hypersensitivity. 5. Paediatric patients.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 121). Further details: 5 ml of 0.5% bupivacaine was infiltrated pre-incisionally in all port sites. Intrabdominal insufflation pressure of under 10 mm Hg was used Group 2: No local anaesthetic (n = 110). Further details: No local anaesthetic was used. Intra-abdominal insufflation pressure of under 10 mm Hg was used Group 3: Local anaesthetic (n=122). Further details: 5 ml of 0.5 % bupivacaine was infiltrated pre-incisionally in all port sites. Intra-abdominal insufflation pressure of 15 mm Hg was used Group 4: No local anaesthetic (n= 120). Further details: No Local anaesthetic was used. Intra-abdominal insufflation pressure of 15 mm Hg was used

Outcomes

None of the outcomes of interest were reported.

Notes

Reasons for post-randomisation dropouts: Conversion to an open procedure due to complications

Risk of bias Bias


Random sequence generation (selection Low risk bias)

Support for judgement Quote: “4 coloured balls in a non-transparent vase were used to randomise patients between groups”


36

Beqiri 2012

(Continued)


Low risk

Quote: “4 coloured balls in a non-transparent vase were used to randomise patients between groups”






High risk

Comment: There were post-randomisation dropouts.


High risk


For-profit bias

Unclear risk


Bilge 1997 Methods


Participants

Country: Turkey. Number randomised: 40. Post-randomisation dropouts: 0 (0%). Revised sample size: 40. Average age: 51 years. Females: 31 (77.5%). Inclusion criteria: 1. Laparoscopic cholecystectomy for symptomatic gallbladder stones

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 20). Further details: 10 ml of 0.2% bupivacaine infiltrated at the subcutaneous layer and fascia of the ports at the end of the operation. Group 2: No local anaesthetic (n = 20). Further details: No local anaesthetic was used.

Outcomes

The outcomes reported were intraoperative complications and pain

Notes

Attempts were made to contact the authors in February 2008 and August 2010. Authors provided information in February 2008

Risk of bias Bias




37

Bilge 1997

(Continued)


Quote: “The random sequence was generated by drawing one of the sealed envelopes in the operating theatre before the operation. Forty of such envelopes were prepared (20 for each treatment) and mixed-up” (author replies)


Quote: “The random sequence was generated by drawing one of the sealed envelopes in the operating theatre before the operation. Forty of such envelopes were prepared (20 for each treatment) and mixed-up” (author replies)

Low risk



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

Quote: “The person evaluating post-operative pain did not know which group the patients belonged to”


Low risk

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


High risk


For-profit bias

Unclear risk


Cantore 2008 Methods


Participants

Country: Italy. Number randomised: 50. Post-randomisation dropouts: not stated. Revised sample size: 50. Average age: 59 years. Females: 32 (64%). Inclusion criteria: 1. ASA I. 2. Symptomatic cholelithiasis. Exclusion criteria: 1. Acute cholecystitis. 2. If a subxiphoid incision was applied for gallbladder extraction. 3. Serious cardiovascular, renal, haematologic or hepatic diseases. 4. History of drugs or alcohol abuse.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic pre-incision (n = 25). Further details: Levobupivacaine 1% 100 ml was administered prior skin incision in the subumbilical site blindly on the muscular fascia, while in the other three sites levobupi-


38

Cantore 2008

(Continued)

vacaine was infiltrated under visual control. Group 2: Local anaesthetic pre-closure (n = 25). Further details: Levobuivacaine 1% 100 ml was instilled at the end of surgery after trocar removal in the same fashion Outcomes


Notes

Attempts were made to contact the authors in March 2013.

Risk of bias Bias






Unclear risk





Quote: “The nurses in surgical department were trained to monitor the VAS pain scores and to administer analgesic. The nurses were blinded the patients status concerning perioperative local anaesthetics”


Unclear risk



High risk


For-profit bias

Unclear risk


Dath 1999 Methods


Participants

Country: USA. Number randomised: 124. Post-randomisation dropouts: 27 (21.8%). Revised sample size: 97. Average age: 46 years. Females: 81 (83.5%). Inclusion criteria: 1. Elective laparoscopic cholecystectomy. 2. Ultrasound proof of gallstones or sludge. 3. More than 16 years old.


39

Dath 1999

(Continued)

4. Eligibility for a standard anaesthesia protocol developed by anaesthesia department. Exclusion criteria: 1. Lack of compliance in completing pain assessments. 2. Placement of a drain intra-operatively. 3. The presence of acute pancreatitis. 4. Prolonged hospitalisation to facilitate endoscopy. 5. Repair of incidental umbilical hernia. 6. Documented recent narcotic abuse. Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 50). Further details: 20 ml of 0.5% bupivacaine with epinephrine 1:200000 given just before closure. 6 ml on each of the midline port sites and 4 ml on each of the lateral port sites. Group 2: No local anaesthetic (n = 47). Further details: No local anaesthetic was used.

Outcomes

The outcomes reported were mortality, morbidity, proportion discharged as day surgery, and pain

Notes

Reasons for post-randomisation dropouts: Patients were withdrew from study after randomisation because it was ’too much of a nuisance’, 2 patients and ’25 early patients were excluded because pain scores were inappropriately culled from charts before review’

Risk of bias Bias




Quote: “envelopes containing randomly generated instructions”. Comment: Further details were not available.


Quote: “an envelope”’. Comment: Further details were not available.

Unclear risk


Quote: “The operative control sheet was included in the chart in the event that it needed to be referenced…The patients were thoroughly blinded to the intervention as was the surgeon”. Comment: Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken


Quote: “Neither the PACU or the ward nurses knew the information was available”. Comment: Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken



High risk


40

Dath 1999

(Continued)


Low risk

Comment: Mortality and morbidity were reported.

For-profit bias

Unclear risk


Feroci 2009 Methods


Participants

Country: Italy. Number randomised: 30. Post-randomisation dropouts: 0 (0%). Revised sample size: 30. Average age: 52 years. Females: 21 (70%). Inclusion criteria: 1. Age older than 18 years. 2. ASA I and II. 3. Gallbladder calculosis with no clinical, biochemical, or instrumental signs of acute cholecystitis at time of intervention. Exclusion criteria: 1. Pregnant women. 2. Patients who had previous supra-mesocolic major surgery. 3. Affected by cholecystocholedochal calculosis, acute pancreatitis, or acute cholecystitis at time of interventions. 4. Those who underwent laparotomy conversion were excluded from the study

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 15). Further details: 0.5% bupivacaine (2 mg/kg) infiltrated in the muscular fasciae of the trocar sites before suturing surgical incisions. Group 2: No local anaesthetic (n = 15). Further details: No local anaesthetic used.

Outcomes

The outcomes reported were mortality, morbidity, and pain.

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)


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’

Low risk


41

Feroci 2009

(Continued)

assistance. The envelopes were opaque and sealed” (author replies) Blinding of participants and personnel Low risk (performance bias) All outcomes

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

Comment: There were no post-randomisation dropouts.


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)

Hasan 2007 Methods


Participants

Country: Belgium. Number randomised: 36. Post-randomisation dropouts: not stated. Revised sample size: 36. Average age: not stated. Females: not stated. Inclusion criteria: 1. People undergoing laparoscopic cholecystectomy. 2. ASA physical status I or II.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = not stated). Further details: 20 ml bupivacaine 0.25% incisional infiltration. Group 2: No local anaesthetic (n = not stated). Further details: 20 ml normal saline incisional infiltration. Group 3: Local anaesthetic (n = not stated). Further details: same as group 1 but with intraperitoneal local anaesthetic. Group 4: No local anaesthetic (n = not stated). Further details: same as group 2 but with intraperitoneal local anaesthetic

Outcomes

The outcomes reported were drug-related serious adverse events and pain


42

Hasan 2007

(Continued)

Notes

Attempts were made to contact the authors in March 2013. There were no serious drug-related adverse events in any of the groups There was a significant reduction in pain in group 1 compared to group 2. There was no significant difference in the pain between group 3 and group 4

Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk


Hasaniya 2001 Methods

Randomised clinical trial.

Participants

Country: USA. Number randomised: 100. Post-randomisation dropouts: 16 (16%). Revised sample size: 84. Average age: not stated. Females: not stated. Inclusion criteria: Patients with symptomatic cholelithiasis undergoing laparoscopic cholecystectomy

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 43). Further details: The trocar site was infiltrated with 0.5% bupivacaine 20 ml before the skin incision was made and before insertion of the trocars into the abdomen. Group 2: No local anaesthetic (n = 41). Further details: No local anaesthetic was used.


43

Hasaniya 2001

(Continued)

Outcomes

No outcomes of interest for this review were reported.

Notes

Reasons for post-randomisation dropouts: ’Inability to communicate with patients due to their altered mental status, or because of conversion to open technique or due to performance of other surgical procedures’ - 13 patients. ’Because patients had left the hospital the night after surgery at their request’ - three patients

Risk of bias Bias







Unclear risk


Quote: “All were blinded concerning the group to which they had been randomized” Comment: Not clear whether the healthcare personnel were blinded




High risk



High risk


For-profit bias

Unclear risk


Lee 2001 Methods


Participants

Country: Korea. Number randomised: 123. Post-randomisation dropouts: not stated. Revised sample size: 123. Average age: 47 years. Females: 57 (46.3%). Inclusion criteria: 1. Elective laparoscopic cholecystectomy. Exclusion criteria: 1. Patients allergic to local anaesthetics. 2. Those with a history of severe systemic disease.


44

Lee 2001

(Continued)

3. Patients with chronic pain diseases other than gallstone disease. 4. Patients ASA physical status III or greater. 5. Patients who had acute cholecystitis before the operation Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 20). Further details: Pre-operative peri-portal 0.25% bupivacaine (20 ml) 15 minutes before incision and intraperitoneal 0.25% bupivacaine (40 ml with 1:200,000 epinephrine) immediately after the creation of pneumoperitoneum.. Group 2: No local anaesthetic (n = 20). Further details: intraperitoneal 0.25% bupivacaine (40 mL with 1:200,000 epinephrine) immediately after the creation of pneumoperitoneum. Group 3: Local anaesthetic (n = 19). Further details: Postoperative periportal 0.25% bupivacaine (20 ml) 15 min before closure and intraperitoneal 0.25% bupivacaine (40 ml with 1:200,000 epinephrine) immediately after removal of trocars at the end of the operation. Group 4: No local anaesthetic (n = 21). Further details: 0.25% bupivacaine (40 mL with 1:200,000 epinephrine) immediately after removal of trocars at the end of the operation. Group 5: Local anaesthetic (n = 22). Further details: Preoperative periportal 0.25% bupivacaine (20 ml) 15 min before incision. Group 6: No local anaesthetic (n = 25). Further details: No local anaesthetic was used. The fascia, muscle, pre-peritoneal space, and the parietal peritoneum were infiltrated (infiltration of four port sites in total, seven ml each for two 10 mm sites, 3 ml each for the other two 5 mm sites)

Outcomes

The outcomes reported were mortality and morbidity.

Notes

Attempts were made to contact the authors in February 2008.

Risk of bias Bias






Unclear risk





Quote: “No patients or observers were informed of the treatment group (preoperative or postoperative)”. Comment: Further details were not available.


45

Lee 2001

(Continued)


Low risk



Low risk


For-profit bias

Unclear risk


Lepner 2003 Methods


Participants

Country: Estonia. Number randomised: 60. Post-randomisation dropouts: 0 (0%). Revised sample size: 60. Average age: 53 years. Females: 48 (80%). Inclusion criteria: 1. ASA 1-3 patients. 2. Scheduled for laparoscopic cholecystectomy for gallstone disease Exclusion criteria: 1. Acute cholecystitis. 2. Inability to understand and use VAS. 3. History of allergy to NSAIDS and/or local anaesthetic.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 20). Further details: At the end of the operation all wounds were infiltrated with 80 ml 0.125% bupivacaine containing 5mg of phenylephrine. Pre-peritoneal, muscle, subcutaneous fat and skin were infiltrated. Group 2: No local anaesthetic (n = 20). Further details: No local anaesthetic used. Group 3: No local anaesthetic (n = 20). Further details: Wounds infiltrated with normal saline. Pre-peritoneal, muscle, subcutaneous fat and skin were infiltrated

Outcomes

The outcomes reported were mortality and morbidity.

Notes

Authors provided information on post-randomisation dropouts in April 2008

Risk of bias Bias



Support for judgement Comment: This information was not available.


46

Lepner 2003

(Continued)


Unclear risk

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

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

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”


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


Liang 2011 Methods


Participants

Country: China. Number randomised: 60. Post-randomisation dropouts: not stated. Revised sample size: 60. Average age: 56 years. Females: 29 (48.3%). Inclusion criteria: 1. Patients between the ages of 45 and 65 years. 2. ASA of I or II. 3. Undergoing laparoscopic cholecystectomy. 4. No allergies to the drugs used in the study. Exclusion criteria: 1. Not taking warfarin and other anticoagulants. 2. No gastrointestinal bleeding tendency. 3. No history of serious heart/respiratory/liver disease. 4. Abnormal kidney function.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 20). Further details: 6 ml 0.5% ropivacaine incision infiltration at the end of surgery. Group 2: Local anaesthetic (n = 20).


47

Liang 2011

(Continued)

Further details: 6 ml 0.25% ropivacaine incision infiltration at the end of surgery Group 3: No local anaesthetic (n = 20). Further details: No local anaesthetic. Outcomes


Notes

Reasons for post-randomisation dropouts: not stated.

Risk of bias Bias




This information was not available.


Unclear risk





Quote: “The person evaluating postoperative pain was not aware of group allocations”


Unclear risk



High risk


For-profit bias

Unclear risk


Liu 2009 Methods


Participants

Country: China. Number randomised: 72. Post-randomisation dropouts: 0 (0%). Revised sample size: 72. Average age: 50 years. Females: 53 (73.6%). Inclusion criteria: 1. Aged 20 to 85 years. 2. Not pregnant. 3. Adequate hematological, hepatic and renal function. Exclusion criteria: 1.Immunosuppressive drug therapy within the previous six months.


48

Liu 2009

(Continued)

2. An immunosuppressive condition, including AIDS. 3. Autoimmune disorders. 4. Organ transplantation. 5. Radiotherapy or chemotherapy within the previous six months. 6. Insulin-dependent diabetes mellitus (type 1). Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 36). Further details: 1.0% ropivacaine 20 ml at the port site after wound closure. The solution was applied to the skin, subcutis, fascia, and parietal peritoneum through the port sites at the end of surgery. 20 ml were applied at the port sites after wound closure (6 ml for epigastric port, 6 ml for umbilical port, and 4 ml for each working port). Group 2: No local anaesthetic (n = 36). Further details: The control group received 0.9% normal saline after wound closure in the same fashion and volume as Group 1

Outcomes

The outcomes reported were mortality, morbidity, hospital stay, and pain

Notes

Attempts were made to contact the author in August 2010.

Risk of bias Bias




Quote: “The randomization was centralized and used a random permuted block design”


Quote: “The randomization was centralized and used a random permuted block design”

Low risk






Low risk



Low risk

Comment: All important outcomes were reported.

For-profit bias

Unclear risk



49

Louizos 2005 Methods


Participants

Country: Greece. Number randomised: 108. Post-randomisation dropouts: 4 (3.7%). Revised sample size: 104. Average age: 49 years. Females: 56 (54%). Inclusion criteria: 1. ASA I and II. 2. Aged 25-70 years. 3. Elective laparoscopic cholecystectomy under general anaesthesia. Exclusion criteria: 1. Patients allergic to local anaesthetics. 2. Acute cholecystitis. 3. A history of severe systemic disease. 4. Chronic pain diseases other than gallstone disease.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 25). Further details: Received pre-incisional local infiltration (trocar sites) of 20 ml levobupivacaine 0.25%. Group 2: No local anaesthetic (n = 25). Further details: Received pre-incisional local infiltration of 20 ml normal saline at the trocar sites. Group 3: Local anaesthetic (n = 28). Further details: Same as group 1 but received 20 ml levobupivacaine 0.25% intraperitoneally. Group 4: No local anaesthetic (n = 26). Further details: Same as group 2 but received 20 ml levobupivacaine 0.25% intraperitoneally In all groups the fascia, muscle and preperitoneal space were infiltrated using 5 ml (infiltration of four trocar sites, thus using a total of 20 ml solution)

Outcomes

The outcomes reported were local anaesthetic related complications

Notes

Reasons for post-randomisation dropouts: Two patients due to surgical complications and two patients due to protocol violation Authors provided additional information in February 2010. Further information was sought but could not be obtained in August 2010

Risk of bias Bias



Support for judgement Quote: “The answer to your first question is that the random sequence was computer generated” (author replies)


50

Louizos 2005

(Continued)


Unclear risk

Quote: “Regarding the second question we used sealed envelopes for the allocation.” Comment: Further details of the sealed envelope method were not available


Quote: “The surgeon performing both the preincisional local infiltration and the intraperitoneal instillation was not aware of the solution administered”. Comment: Further details about patient blinding were not available


Quote: “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


Newcomb 2007 Methods


Participants

Country: USA. Number randomised: 55. Post-randomisation dropouts: 0 (0%). Revised sample size: 55. Average age: not stated. Females: not stated. Inclusion criteria: 1. At least 18 years old. 2. Elective laparoscopic cholecystectomy. Exclusion criteria: 1. Weight less than 40 kg. 2. ASA greater than III. 3. Documented allergy or contraindication to rofecoxib, COX-2 inhibitors, NSAIDS , morphine or bupivacaine. 4. Pregnant. 5. Renal insufficiency. 6. Peptic ulcer. 7. Bleeding diathesis. 8. Not able to operate PCA. 9. Patients that received any analgesic for acute or chronic pain within 72h of surgery


51

Newcomb 2007

(Continued)

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 12). Further details: Pre-incisional 0.25% bupivacaine. No further information given. Group 2: No local anaesthetic (n = 15). Further details: Oral placebo. Group 3: Local anaesthetic (n = 13). Further details: Rofecoxib and pre-incisional 0.25% bupivacaine. Group 4: No local anaesthetic (n = 15). Further details: Rofecoxib.

Outcomes

The outcomes reported were length of hospital stay and pain.

Notes


Risk of bias Bias







Unclear risk


Quote: “Neither the patients not the staff measuring the outcomes knew which group a participant was included”. Comment: Further details about healthcare personnel blinding were not available


Quote: “Neither the patients not the staff measuring the outcomes knew which group a participant was included”


Low risk



High risk


For-profit bias

Unclear risk


Nicolau 2008 Methods


Participants

Country: Romania. Number randomised: 60. Post-randomisation dropouts: 0 (0%). Revised sample size: 60. Average age: 50 years.


52

Nicolau 2008

(Continued)

Females: 53 (88.3%). Exclusion criteria: 1. Acute cholecystitis. 2. Conversion to open procedure, the abdominal. 3. Post-operative complications. 4. Known allergy to local anaesthetic. Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 15). Further details: 20 ml 0.25% ropivacaine wound infiltration. Group 2: No local anaesthetic (n = 15). Further details: 20 ml of normal saline wound infiltration. Group 3: Local anaesthetic (n = 15). Further details: Same as group 1 but 20 ml 0.25% ropivacaine intraperitoneally in addition. Group 4: No local anaesthetic (n = 15). Further details: Same as group 2 but 20 ml 0.25% ropivacaine intraperitoneally in addition In all groups the abdominal wall was infiltrated with 20 ml at each port at the fascia, muscle and preperitoneal layers after pneumoperitoneum

Outcomes

The outcomes reported were local anaesthetic-related complications and pain

Notes

Attempts were made to contact the author in October 2009.

Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk



53

Noma 2001 Methods


Participants

Country: Japan. Number randomised: 30. Post-randomisation dropouts: not stated. Revised sample size: 30. Average age: 53 years. Females: 16 (53.3%). Inclusion criteria: 1. Laparoscopic cholecystectomy. 2. ASA I-II.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 15). Further details: 0.5% bupivacaine 20 ml into the surgical wound before surgery. Group 2: No local anaesthetic (n = 15). Further details: No local anaesthetic was used. Muscular and pre-peritoneal layers infiltrated.

Outcomes

The outcome reported were pain.

Notes


Risk of bias Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk



54

Papagiannopoulou 2003 Methods


Participants

Country: Greece. Number randomised: 60. Post-randomisation dropouts: 3 (3.4%). Revised sample size: 57. Average age: 44 years. Females: 34 (57.6%). Inclusion criteria: 1. ASA I-II. 2. Elective laparoscopic cholecystectomy. Exclusion criteria: 1. Contraindications to any of the drugs used in the study. 2. Age 65 years. 3. Weight 110 kg. 4. Evidence of severe cardiovascular, renal, haematologic, or hepatic disease. 5. American Society of Anaesthesiology >III. 6. Pre-existing neurological or psychiatric illness. 7. Chronic pain syndrome. 8. History of alcohol or drug abuse.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 20). Further details: ropivacaine 1%, 20 ml, divided proportionally according to the length of the skin incision (7 ml for the 10 mm trocar and 3 ml for the 5 mm trocars). Preincisional administration. Group 2: Local anaesthetic (n = 19). Further details: levobupivacaine 0.5%, 20 ml, divided proportionally according to the length of the skin incision (7 ml for the 10 mm trocar and 3 ml for the 5 mm trocars). Pre-incisional administration Group 3: No local anaesthetic (n = 18). Further details: Normal saline was infiltrated, 20 ml, divided proportionally according to the length of the skin incision (7 ml for the 10 mm trocar and 3 ml for the 5 mm trocars). Pre-incisional administration

Outcomes


Notes

Reasons for post-randomisation dropouts: Protocol violation for two patients Attempts were made to contact the authors in February 2008.

Risk of bias Bias




Quote: “randomized”. Comment: Further details were not available.



Unclear risk


55

Papagiannopoulou 2003

(Continued)


Quote: “double-blinded”. Comment: Further details were not available.




High risk



High risk


For-profit bias

Unclear risk


Papaziogas 2001 Methods


Participants

Country: Greece. Number randomised: 37. Post-randomisation dropouts: 2 (5.4%). Revised sample size: 35. Average age: 46 years. Females: 26 (74.3%). Inclusion criteria: Patients undergoing elective laparoscopic cholecystectomy under general anaesthesia. Exclusion criteria: 1. Contraindications to any of anaesthetic or study drugs used. 2. Age < 18 years or > 75 years. 3. Weight < 45 kg or > 120 kg. 4. Evidence of severe cardiovascular, renal, haematologic or hepatic disease. 5. ASA > lII. 6. Pre-existing neurological or psychiatric illnesses. 7. Chronic pain syndromes. 8. Alcohol or drug abuse. 9. Difficulties in communication and cooperation between doctor and patient

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 17). Further details: Received local infiltration with 20 ml 1% ropivacaine. Before skin incision, all trocar insertion sites were infiltrated with ropivacaine to a total of 20 ml, which was divided proportionally according to the length of the skin incision (7 ml for the 10 mm trocars and 3 ml for the 5 mm trocars). Group 2: No local anaesthetic (n = 18). Further details: Received pre-incisional placebos. No more details given


56

Papaziogas 2001

(Continued)

Outcomes

The outcomes reported were operating time, VAS pain four to eight hours and VAS pain nine to 24 hours

Notes

Reasons for post-randomisation dropouts: Difficulties in communication between patient and doctor in the post-operative period for two patients Attempts were made to contact the author in August 2010.

Risk of bias Bias




Comment: Further details were not available.


Unclear risk







High risk



High risk


For-profit bias

Unclear risk


Pavlidis 2003 Methods


Participants

Country: Greece. Number randomised: 150. Post-randomisation dropouts: not stated. Revised sample size: 150. Average age: 56 years. Females: 120 (80%). Inclusion criteria: 1. ASA I-II. Exclusion criteria: 1. Patients with a previous upper abdominal operation. 2. Suspected bile duct stones by ultrasonography and liver function tests


57

Pavlidis 2003

(Continued)

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 75). Further details: Before the skin incision and trocar placement, local infiltration of the port sites throughout all layers with 20 ml 1% ropivacaine. The local anaesthetic or saline was equally allocated according to the diameter of the trocar 7 ml for 10 to 12 mm and 3 ml for 5 mm. Group 2: No local anaesthetic (n = 75). Further details: Normal saline was infiltrated at wound sites

Outcomes

The outcomes reported were mortality, morbidity, hospital stay, return to activity, and pain

Notes


Risk of bias Bias




Quote: “Patients were randomly allocated into 2 groups”. Comment: Further details were not available.



Unclear risk


Quote: “An independent surgeon was responsible for the randomization as well as for the preparation of an unmarked syringe containing 20 mL of ropivacaine or saline. The operating surgeon, the staff, and the patients were blinded to this procedure.”


Quote: “An independent nurse recorded the postoperative pain at the 3rd, 6th, 12th, and 24th hour after the operation according to patient’s perception. The randomization was blind to both of them.”


Low risk



Low risk


For-profit bias

Unclear risk



58

Rodriguez-Navarro 2011 Methods


Participants

Country: Chile. Number randomised: 150. Post-randomisation drop-outs: 13 (8.7%). Revised sample size: 137. Average age: 46 years. Females: 123 (89.8%). Inclusion criteria: 1. Patients 18 to 80 years of age. 2. Cholelithiasis or gallbladder polyps. 3. Scheduled for laparoscopic cholecystectomy. Exclusion criteria: 1. ASA III or IV. 2. Having previous abdominal surgery. 3 Pregnancy or lactation. 4. Renal or hepatic disease. 5. Having known choledocholithiasis. 6. Severe psychiatric illness, or known drug or alcohol dependency

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 69). Further details: Neosaxitoxin 100 mcg per patient, divided to give 35 mcg in the two 10 mm ports and 15 mcg in each of the two 5 mm ports. Group 2: Local anaesthetic (n = 68). Further details: Bupivacaine 50 mg infiltrated in the same fashion. Infiltration was approximately at 3 depths: peritoneum, muscle or aponeurosis, and skin and subcutaneous tissues. Port sites were marked and infiltrated after induction of general anaesthesia and before placement of the instruments

Outcomes

The outcomes reported were mortality, morbidity, return to activity, and hospital stay

Notes

Reasons for post-randomisation dropouts: Five patients converted to open surgery; one patient, surgery not performed; six patients lost to follow-up; one patient early re-operation Attempts were made to contact the authors in March 2013.

Risk of bias Bias




Quote: “Treatments were assigned using a computer-generated randomisation table in blocks of 10”


Quote: “Treatments were assigned using a computer-generated randomisation table in blocks of 10” Comment: No further details were available

Unclear risk


59

Rodriguez-Navarro 2011

(Continued)


Quote: “The assistant transporting solutions to the operation room, the surgeons, the anesthesiologist all remained blinded” Comment: Not clear if the patients were blinded.


Quote: “Investigators who conducted the postoperative assessments all remained blinded to the treatment assignments.”


High risk



Low risk


For-profit bias

Unclear risk


Sarac 1996 Methods


Participants

Country: Turkey. Number randomised: 70. Post-randomisation dropouts: not stated. Revised sample size: 70. Average age: 53 years. Females: 56 (80%). Inclusion criteria: 1. Patients with symptomatic cholelithiasis. Exclusion criteria: 1. Patients requiring open surgery.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 20). Further details: 3 ml 0.5% bupivacaine subcutaneously around 5 mm trocars and 4 ml around 10 mm trocars just before incision. Group 2: Local anaesthetic (n = 25). Further details: 3 ml 0.5% bupivacaine subcutaneously around 5 mm trocars and 4 ml around 10 mm trocars after closure of wounds at the end of the operation Group 3: No local anaesthetic (n = 25). Further details: 3 ml 0.9% normal saline subcutaneously around 5 mm trocar sites and 4 ml around 10 mm trocar sites

Outcomes


Notes


Risk of bias


60

Sarac 1996

(Continued)

Bias






Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk


Shikano 1994 Methods


Participants

Country: Japan. Number randomised: 50. Post-randomisation dropouts: not stated. Revised sample size: 50. Average age: not stated. Females: not stated. Inclusion criteria: 1. Laparoscopic cholecystectomy

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 25). Further details: 20 to 30 ml of 0.255 % bupivacaine. Group 2: No local anaesthetic (n = 25).

Outcomes


Notes


Risk of bias Bias




61

Shikano 1994

(Continued)




Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk


Sozbilen 2007 Methods


Participants

Country: Turkey. Number randomised: 31. Post-randomisation dropouts: not stated. Revised sample size: 31. Average age: 49 years. Females: 16 (51.6%). Inclusion criteria: 1. Consecutive patients undergoing laparoscopic cholecystectomy

Interventions

Participants were randomly assigned to the following groups. Group 1: LA pre-incision (n = 17). Further details: Each trocar site was pre-incisionally infiltrated (into skin, subcutaneous tissue, and fascia) with 5 ml of 3.75% ropivacaine. Group 2: LA pre-closure (n = 14). Further details: at the end of the procedure, just before desufflation, each trocar site was infiltrated (into skin, subcutaneous tissue, and fascia) with 5 ml of 3.75% ropivacaine

Outcomes


Notes

Reasons for post-randomisation dropouts: not stated.

Risk of bias Bias




62

Sozbilen 2007

(Continued)




Unclear risk







Unclear risk



High risk


For-profit bias

Unclear risk


Ure 1993 Methods


Participants

Country: Germany. Number randomised: 50. Post-randomisation dropouts: not stated. Revised sample size: 50. Average age: 48 years. Females: 34 (68%). Inclusion criteria: 1. Elective laparoscopic cholecystectomy. 2. Symptomatic gallstone disease. 3. All patients had gallstones on ultrasound examination. Exclusion criteria: 1. Less than 18 years old. 2. Previous abdominal operation. 3. Acute cholecystitis. 4. Suffered from cardiovascular, hepatic, renal, or neurological disease or diabetes. 5. Patients taking analgesics for non-biliary complaints.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 25). Further details: 32 ml bupivacaine 0.5%. Group 2: No local anaesthetic (n = 25). Further details: 32 ml normal saline. Pre-incisional infiltration of all abdominal wall layers was performed. The final infiltration of the peritoneum was visualised from the abdominal cavity to ensure that all


63

Ure 1993

(Continued)

abdominal wall layers were anaesthetised Outcomes

The outcomes reported were mortality, morbidity, hospital stay, and pain

Notes


Risk of bias Bias




Comment: Further details were not available.



Unclear risk


Quote: “The operating surgeon, the investigator, the patients, and all staff at the postoperative ward were blinded to the patient groups.”


Quote: “The operating surgeon, the investigator, the patients, and all staff at the postoperative ward were blinded to the patient groups.”


Unclear risk



High risk


For-profit bias

Unclear risk


Uzunkoy 2001 Methods


Participants

Country: Turkey. Number randomised: 45. Post-randomisation dropouts: not stated. Revised sample size: 45. Average age: 43 years. Females: not stated. Inclusion criteria: 1. Patients undergoing laparoscopic cholecystectomy.

Interventions

Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 15). Further details: received 30 ml 0.25% solution of bupivacaine at the trocar sites before incision. 5 ml local anaesthetic solution was used for a 5 mm trocar and 10 ml for a 10 mm trocar.


64

Uzunkoy 2001

(Continued)

Group 2: Local anaesthetic (n = 15). Further details: received 30 ml 0.25% bupivacaine infiltrated after the trocar was removed.5 ml local anaesthetic solution was used for a 5 mm trocar and 10 ml for a 10 mm trocar Group 3: No local anaesthetic (n = 15). Further details: No local anaesthetic was used. During infiltration skin, subcutaneous tissue and muscles through the peritoneum were infiltrated Outcomes

The outcome reported was return to activity.

Notes


Risk of bias Bias






Unclear risk





Quote: “Pain that the patients experienced was evaluated by surgery nurses who were unaware of the groups”


Unclear risk



High risk


For-profit bias

Unclear risk


Zajaczkowska 2004 Methods


Participants

Country: Poland. Sample size: 60. Post-randomisation dropout(s): not stated. Revised sample size: 60. Average age: 49 years. Females: 48 (80%). Inclusion criteria:


65

Zajaczkowska 2004

(Continued)

1. Elective laparoscopic cholecystectomy for symptomatic gallstones. 2. ASA I or II. 3. > 18 years of age. Exclusion criteria: 1. Acute cholecystitis. 2. Significant cardiac, respiratory, hepatic, renal, or neurologic disease. 3. Local anaesthetic and morphine allergies. 4. Analgesics for non-biliary complaints. Interventions

The patients were randomised to the following groups. Group 1: local anaesthetic (n = 30). Further details: 20 ml of 0.5% bupivacaine before incision. Group 2: control (n = 30). Further details: 20 ml of normal saline before incision.

Outcomes


Notes

Attempts were made to contact the authors in August 2010.

Risk of bias Bias




Quote: “Using sealed envelopes that had been prepared according to a computer-generated random-number table, we assigned the patients to one of the following 5 groups.”


Quote: “Using sealed envelopes that had been prepared according to a computer-generated random-number table, we assigned the patients to one of the following 5 groups.” Comment: Further information on the sealed envelopes was not available

Unclear risk


Comment: “The surgeons, the investigator, the patients, and all staff at the postoperative ward were blinded to the patients’ groups”


Comment: “The surgeons, the investigator, the patients, and all staff at the postoperative ward were blinded to the patients’ groups”


High risk



Low risk


For-profit bias

Unclear risk



66

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Alexander 1996

Not clear whether intraperitoneal bupivacaine was administered in the intervention group

Bisgaard 1999

This trial was a comparison of periportal and intraperitoneal ropivacaine versus normal saline

Cha 2012

Five patients were excluded after randomisation. These patients were replaced with other patients. The method of selection of the replacements was not stated. The randomisation in this trial may have been lost

Di Pace 2009

This trial was performed on patients undergoing various laparoscopic procedures. Results for laparoscopic cholecystectomy not given individually

Futier 2011

Not a randomised clinical trial.

Hilvering 2011


Karadeniz 1998

This trial involved intraperitoneal bupivacaine injection and no wound infiltration

Lopez-Maya 2011

This trial compared periportal and intraperitoneal ropivacaine at different timings

Lotz 1997


Maharjan 2009

This trial compared periportal and intraperitoneal bupivacaine versus control

Memedov 2010

This trial compared multi-regional and periportal ropivacaine versus lornoxicam versus placebo

Michaloliakou 1996

This trial compared multimodal analgesia (intramuscular meperidine and ketorolac and periportal bupivacaine) versus control

Verma 2006

In this trial no control group available to match periportal bupivacaine group

Wallace 1996

In this trial wound infiltration with local anaesthetic was combined with intraperitoneal instillation of local anaesthetic

Wong 1997



67

DATA AND ANALYSES

Comparison 1. Local anaesthetic versus no local anaesthetic

Outcome or subgroup title 1 Serious adverse events 2 Proportion discharged as day surgery 3 Length of hospital stay 4 Pain 4 to 8 hours 5 Pain 9 to 24 hours 6 Return to normal activity 7 Length of hospital stay (sensitivity analysis) 8 Pain 4 to 8 hours (sensitivity analysis) 9 Pain 9 to 24 hours (sensitivity analysis) 10 Return to normal activity (sensitivity analysis) 11 Pain 4 to 8 hours (stratified by local anaesthetic agent) 11.1 Bupivacaine 11.2 Levobupivacaine 11.3 Ropivacaine 12 Pain 9 to 24 hours (stratified by local anaesthetic agent) 12.1 Bupivacaine 12.2 Levobupivacaine 12.3 Ropivacaine 13 Pain 4 to 8 hours (stratified by time of administration) 13.1 Before incision 13.2 End of surgery 14 Pain 9 to 24 hours (stratified by time of administration) 14.1 Before incision 14.2 End of surgery

No. of studies

No. of participants

7 1

539 97

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

2.0 [0.19, 21.59] 1.55 [1.05, 2.28]

4 13 12 2 1

327 806 756 195

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

-0.26 [-0.67, 0.16] -1.33 [-1.54, -1.12] -0.36 [-0.53, -0.20] 0.14 [-0.59, 0.87] Totals not selected

7

364

Mean Difference (IV, Fixed, 95% CI)

-1.34 [-1.55, -1.12]

7

364


-0.34 [-0.51, -0.17]

1

45


1.02 [-0.37, 2.41]

12

756


-1.33 [-1.55, -1.12]

10 1 2 12

543 28 185 756

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

-1.42 [-1.66, -1.18] -3.90 [-6.52, -1.28] -0.93 [-1.39, -0.47] -0.36 [-0.53, -0.20]

10 1 2 12

543 28 185 756


-0.29 [-0.46, -0.11] -1.70 [-2.84, -0.56] -1.07 [-1.74, -0.39] -1.33 [-1.55, -1.12]

7 6 12

419 337 756

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

-1.69 [-1.95, -1.43] -0.63 [1.00, -0.27] -0.36 [-0.53, -0.20]

7 6

419 337

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

-0.29 [-0.49, -0.10] -0.51 [-0.80, -0.22]

Statistical method


Effect size

68

Comparison 2. Comparison of different local anaesthetics

Outcome or subgroup title

No. of studies

No. of participants

1 Length of hospital stay 2 Pain 4 to 8 hours 3 Pain 9 to 24 hours 4 Return to normal activity

1 1 1 1

137 39 39 137

Statistical method

Effect size


0.0 [-0.65, 0.65] 2.3 [0.23, 4.37] 1.90 [1.00, 2.80] -1.90 [-2.71, -1.09]

Comparison 3. Before incision versus end of surgery

Outcome or subgroup title

No. of studies

No. of participants

1 Pain 4 to 8 hours 2 Pain 9 to 24 hours 3 Return to normal activity

2 1 1

76 40 30

Statistical method

Effect size

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

0.18 [-1.90, 2.26] 0.10 [-2.53, 2.73] 0.5 [-1.05, 2.05]

ADDITIONAL TABLES Table 1. Details of intervention and co-interventions Study

Comparison

AddiLoConcentional in- cal anaes- tration formation thetic

Dose

Time

Depth

Intraperitoneal LA

Routine supplemental analgesia*

Bilge 1997 LA versus none

bupivacaine

0.20%

10 ml

end of fascia surgery

not stated

no

Dath 1999 LA versus none

bupivacaine

0.50%

20 ml

end of not stated surgery

not stated

no

Feroci 2009

LA versus none

bupivacaine

2 mg/kg

not stated

end of fascia surgery

no

no

Lee 2001

LA versus no bupivanone intrapericaine toneal instillation

0.25%

20 ml

preincisional

until pari- yes etal peritoneum

routine NSAID

Lee 2001

LA versus intraperibupivanone toneal in- caine stillation

0.25%

20 ml

end of until pari- yes surgery etal peritoneum

routine NSAID


69

Table 1. Details of intervention and co-interventions

(Continued)

Lee 2001

LA versus LA (timing)

bupivacaine

0.25%

20 ml

pre-inciuntil pari- yes sional ver- etal perisus end of toneum surgery

routine NSAID

Lepner 2003

LA versus no inter- bupivanone vention as caine control

0.13%

80 ml

end of presurgery peritoneal space

no

routine NSAID

Lepner 2003

LA versus norbupivanone mal saline caine as control

0.13%

80 ml


no

routine NSAID

Liu 2009

LA versus none

ropivacaine

1.00%

20 ml

end of until pari- not stated surgery etal peritoneum

not stated

Louizos 2005

LA versus none

levobupivacaine

0.25%

20 ml

preincisional

preperitoneal space

yes and no

no

Newcomb 2007

LA versus no none rofecoxib

bupivacaine

0.25%

not stated

preincisional

not stated

not stated

no

Newcomb 2007

LA versus rofecoxib none

bupivacaine

0.25%

not stated

preincisional

not stated

not stated

no

Nicolau 2008

LA versus no ropivanone intrapericaine toneal instillation

0.25%

20 ml


no

routine NSAID

Nicolau 2008

LA versus intraperiropivanone toneal in- caine stillation

0.25%

20 ml


yes

routine NSAID

Noma 2001

LA versus none

bupivacaine

0.50%

20 ml

preincisional

preperitoneal space

not stated

no

PapaLA versus ropivagiannopoulounone caine 2003

ropivacaine

1.00%

20 ml

preincisional

not stated

not stated

no

PapaLA versus levobupigiannopoulounone vacaine 2003

levobupivacaine

0.50%

20 ml

preincisional

not stated

not stated

no


70


(Continued)

PapaLA versus giannopoulouLA (drug) 2003

ropiva1% and 0. 20 ml caine ver- 5% respecsus levop- tively bupivacaine

preincisional

not stated

not stated

no

Papaziogas 2001

LA versus none

ropivacaine

1.00%

20 ml

preincisional

not stated

not stated

no

Pavlidis 2003

LA versus none

ropivacaine

1.00%

20 ml

preincisional

until pari- not stated etal peritoneum

no

RodriguezNavarro 2011

LA versus LA (drug)

neosax100 not stated itoxin ver- mcg versus sus bupiva- 50 mg caine

preincisional


no

Sarac 1996 LA versus none

bupivacaine

0.50%

14 ml

preincisional

not stated

not stated

no

Sarac 1996 LA versus none

bupivacaine

0.50%

14 ml

end of not stated surgery

not stated

no

Sarac 1996 LA versus LA (timing)

bupivacaine

0.50%

14 ml

pre-incinot stated sional versus end of surgery

not stated

no

Sozbilen 2007


ropivacaine

3.75%

5 ml

pre-incifascia sional versus end of surgery

yes

no

Ure 1993

LA versus none

bupivacaine

0.50%

32 ml

pre-incipresional ver- peritoneal sus end of space surgery

not stated

no

Uzunkoy 2001

LA versus none

bupivacaine

0.25%

30 ml

preincisional


no

Uzunkoy 2001

LA versus none

bupivacaine

0.25%

30 ml

end of until pari- not stated surgery etal peritoneum

no


71


Uzunkoy 2001

(Continued)


bupivacaine

0.25%

30 ml

pre-inciuntil pari- not stated sional ver- etal perisus end of toneum surgery

no

LA versus Zajaczkowska none 2004

bupivacaine

0.50%

20 ml

preincisional

no

not stated

not stated

LA = local anaesthetic. * 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 S Loizides assessed the trials for inclusion, performed the data extraction, performed data analysis, and wrote the first draft. KS Gurusamy assessed the trials for inclusion, extracted the data for some studies, performed the analysis, interpreted the information, and wrote sections of the review. M Nagendaran extracted the data for the included trials. M Rossi and GP Guerrini extracted some data for the trials which had to be updated in line with the revisions of the Cochrane Handbook for Systematic Reviews of Interventions. BR Davidson critically commented on the review. All authors agreed on the final version of the review.

DECLARATIONS OF INTEREST None known.

SOURCES OF SUPPORT Internal sources • None, Other.

External sources • National Institute of Health Research, UK.


72

DIFFERENCES BETWEEN PROTOCOL AND REVIEW 1. The outcomes have been revised based on importance to the patients and not according to the expected treatment effect. As a result, pain was moved to a secondary outcome as mortality was considered to be more important than pain. With regards to quality of life, we accepted only validated scales of quality of life such as Euro-QoL and SF-36 since using unvalidated 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 when most patients are discharged. We also included only trials that reported pain on the visual analogue scale. Even this is difficult to interpret (please 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.


73

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

Wound infiltration of local anaesthetic after lower segment caesarean section.

Anaesthetic regimens for day-procedure laparoscopic cholecystectomy.

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.

Local anaesthetic wound infiltration used for caesarean section pain relief: a meta-analysis.

Intraoperative wound infiltration with bupivacaine in patients undergoing elective cholecystectomy.

Epidural versus local anaesthetic infiltration via wound catheters in open liver resection: a meta-analysis.

Does EMLA reduce the discomfort associated with local-anaesthetic infiltration?

Local Anaesthetic Infiltration and Indwelling Postoperative Wound Catheters for Patients with Hip Fracture Reduce Death Rates and Length of Stay.

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

Transversus abdominis plane block versus local anaesthetic wound infiltration for postoperative analgesia: A systematic review and meta-analysis.

Comparison between analgesic effect of bupivacaine thoracic epidural and ketamine infusion plus wound infiltration with local anesthetics in open cholecystectomy.

Anaesthetic management for laparoscopic cholecystectomy in patient with situs inversus totalis.

Wound infiltration with 0.25% bupivacaine not effective for postoperative analgesia after cholecystectomy.

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

Open cholecystectomy: a control group for comparison with laparoscopic cholecystectomy.

Evaluation of the toxicity of local anaesthetic agents in man.

Scarless cholecystectomy: laparoscopic cholecystectomy with abdominoplasty.

Local analgesia for infant pyloromyotomy. Does wound infiltration with bupivacaine affect postoperative behaviour?

Preemptive analgesia with Ketamine for Laparoscopic cholecystectomy.

Anesthesia for pediatric laparoscopic cholecystectomy.

Laparoscopic cholecystectomy: evaluation with sonography.

Laparoscopic cholecystectomy.