Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy
Abstract
Background
While laparoscopic cholecystectomy is generally considered less painful than open surgery, pain is one of the important reasons for delayed discharge after day surgery and overnight stay laparoscopic cholecystectomy. The safety and effectiveness of intraperitoneal local anaesthetic instillation in people undergoing laparoscopic cholecystectomy is unknown.
Objectives
To assess the benefits and harms of intraperitoneal instillation of local anaesthetic agents in people undergoing laparoscopic cholecystectomy.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded to March 2013 to identify randomised clinical trials of relevance to this review.
Selection criteria
We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing local anaesthetic intraperitoneal instillation versus placebo, no intervention, or inactive control during laparoscopic cholecystectomy for the review with regards to benefits while we considered quasi‐randomised studies and non‐randomised studies for treatment‐related harms.
Data collection and analysis
Two review authors collected the data independently. We analysed the data with both fixed‐effect and random‐effects models using Review Manager 5 analysis. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).
Main results
We included 58 trials, of which 48 trials with 2849 participants randomised to intraperitoneal local anaesthetic instillation (1558 participants) versus control (1291 participants) contributed data to one or more of the outcomes. All the trials except one trial with 30 participants were at high risk of bias. Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. Various intraperitoneal local anaesthetic agents were used but bupivacaine in the liquid form was the most common local anaesthetic used. There were considerable differences in the methods of local anaesthetic instillation including the location (subdiaphragmatic, gallbladder bed, or both locations) and timing (before or after the removal of gallbladder) between the trials. There was no mortality in either group in the eight trials that reported mortality (0/236 (0%) in local anaesthetic instillation versus 0/210 (0%) in control group; very low quality evidence). One participant experienced the outcome of serious morbidity (eight trials; 446 participants; 1/236 (0.4%) in local anaesthetic instillation group versus 0/210 (0%) in the control group; RR 3.00; 95% CI 0.13 to 67.06; very low quality evidence). Although the remaining trials did not report the overall morbidity, three trials (190 participants) reported that there were no intra‐operative complications. Twenty trials reported that there were no serious adverse events in any of the 715 participants who received local anaesthetic instillation. None of the trials reported participant quality of life, return to normal activity, or return to work.
The effect of local anaesthetic instillation on the proportion of participants discharged as day surgery between the two groups was imprecise and compatible with benefit and no difference of intervention (three trials; 242 participants; 89/160 (adjusted proportion 61.0%) in local anaesthetic instillation group versus 40/82 (48.8%) in control group; RR 1.25; 95% CI 0.99 to 1.58; very low quality evidence). The MD in length of hospital stay was 0.04 days (95% CI ‐0.23 to 0.32; five trials; 335 participants; low quality evidence). The pain scores as measured by the visual analogue scale (VAS) were significantly lower in the local anaesthetic instillation group than the control group at four to eight hours (32 trials; 2020 participants; MD ‐0.99 cm; 95% CI ‐1.10 to ‐0.88 on a VAS scale of 0 to 10 cm; very low quality evidence) and at nine to 24 hours (29 trials; 1787 participants; MD ‐0.53 cm; 95% CI ‐0.62 to ‐0.44; very low quality evidence). Various subgroup analyses and meta‐regressions to investigate the influence of the different local anaesthetic agents, different methods of local anaesthetic instillation, and different controls on the effectiveness of local anaesthetic intraperitoneal instillation were inconsistent.
Authors' conclusions
Serious adverse events were rare in studies evaluating local anaesthetic intraperitoneal instillation (very low quality evidence). There is very low quality evidence that it reduces pain in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is unknown and likely to be small. Further randomised clinical trials of low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment.
PICOs
Plain language summary
Intra‐abdominal local anaesthetic administration in people undergoing laparoscopic cholecystectomy
Background
About 10% to 15% of the adult western population have gallstones. Between 1% and 4% become symptomatic each year. Removal of the gallbladder (cholecystectomy) is the mainstay treatment for symptomatic gallstones. More than half a million cholecystectomies are performed per year in the US alone. Laparoscopic cholecystectomy (removal of gallbladder through a keyhole incision, also known as a port) is now the preferred method of cholecystectomy. While laparoscopic cholecystectomy is generally considered less painful than open surgery, pain is one the major reasons for delayed hospital discharge after laparoscopic cholecystectomy. Administration of local anaesthetics (drugs that numb part of the body, similar to the ones used by the dentist to prevent the people from feeling pain) into the tummy (abdomen) may be an effective way of decreasing the pain after laparoscopic cholecystectomy. However, the benefits and harms of intra‐abdominal administration of local anaesthetics is unknown. We sought to answer these questions by reviewing the medical literature and obtaining information from randomised clinical trials with regards to benefits and other comparative study designs for treatment‐related harms. When conducted correctly, randomised clinical studies provide the most accurate information on the best treatment. Two review authors searched the literature and obtained information from the studies thereby minimising errors.
Study characteristics
We identified 58 trials, of which 48 randomised clinical trials involving 2849 people undergoing laparoscopic cholecystectomy contributed data to one or more of the outcomes. Most participants in the trials were low anaesthetic risk people undergoing planned laparoscopic cholecystectomy. The choice of whether the participants received local anaesthetic agents (or not) was determined by a method similar to the toss of a coin so that the treatments compared were conducted in people who were as similar as possible.
Key results
There were no deaths in either group in eight trials (446 participants) that reported deaths. The studies reported very few or no serious complications in the groups. There were no local anaesthetic‐related complications in nearly 1000 participants who received intra‐abdominal local anaesthetic administration in the different trials that reported complications. None of the trials reported quality of life, the time taken to return to normal activity, or the time taken to return to work. The small differences in hospital stay between the two groups were imprecise. Pain scores were lower in the participants who received intra‐abdominal local anaesthetic administration compared with those who received controls at four to eight hours and at nine to 24 hours as measured by the visual analogue scale (a chart that rates the amount of pain on a scale of 1 to 10).
Quality of evidence
Most of the trials were of high risk of bias, that means that there is possibility of arriving at wrong conclusions overestimating benefits or underestimating harms of one method or the other because of the way that the study was conducted. Overall, the quality of evidence was very low.
Conclusions
Serious adverse event rates were low in studies evaluating local anaesthetic intra‐abdominal administration (very low quality evidence). There is very low quality evidence that local anaesthetic intra‐abdominal administration reduces pain in low anaesthetic risk people undergoing planned laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is likely to be small.
Future research
Further trials are necessary. Such trials should include outcomes such as quality of life, the time taken to return to normal activity, and the time taken to return to work, which are important for the person undergoing laparoscopic cholecystectomy and the people who provide funds for the treatment.
Authors' conclusions
Summary of findings
| Intraperitoneal local anaesthetic instillation compared with control for people undergoing laparoscopic cholecystectomy | |||||
| Patient or population: people undergoing laparoscopic cholecystectomy. | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Intraperitoneallocal anaesthetic instillation | ||||
| Mortality | No mortality in either group | Not estimable | 446 | ⊕⊝⊝⊝ | |
| Serious adverse events | Moderate | RR 3 | 446 | ⊕⊝⊝⊝ | |
| 20 per 1000 | 60 per 1000 | ||||
| Proportion discharged as day surgery | 488 per 1000 | 610 per 1000 | RR 1.25 (0.99 to 1.58) | 242 | ⊕⊝⊝⊝ |
| Hospital stay | The mean hospital stay in the control groups was | The mean hospital stay in the intervention groups was | ‐ | 335 | ⊕⊕⊝⊝ |
| Pain (4 to 8 hours) | The mean pain (4 to 8 hours) in the control groups was | The mean pain (4 to 8 hours) in the intervention groups was | ‐ | 2020 | ⊕⊝⊝⊝ |
| Pain (9 to 24 hours) | The mean pain (9 to 24 hours) in the control groups was | The mean pain (9 to 24 hours) in the intervention groups was | ‐ | 1787 | ⊕⊝⊝⊝ |
| *The basis for the assumed risk was the mean control group risk across studies for day‐surgery proportion. Since there were no events in the control group in the trials included for serious adverse events, the control group proportion used was 2%. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The trial(s) was (were) of high risk of bias. | |||||
Background
Description of the condition
About 5% to 25% of the adult western population have gallstones (GREPCO 1984; GREPCO 1988; Bates 1992; Halldestam 2004). The annual incidence of gallstones is about 1 in 200 people (NIH 1992). Only 2% to 4% of people with gallstones become symptomatic with biliary colic (pain), acute cholecystitis (inflammation), obstructive jaundice, or gallstone pancreatitis in a year (Attili 1995; Halldestam 2004). Cholecystectomy (removal of gallstones) is the preferred option in the treatment of symptomatic gallstones (Strasberg 1993) and every year, 0.5 million cholecystectomies are performed in the US and 70,000 in the UK (CDC 2013; HES 2013). Approximately 80% to 90% of the cholecystectomies are performed laparoscopically (keyhole surgery) (Ballal 2009; NHS Reference Costs 2013).
While laparoscopic cholecystectomy is generally considered less painful than open surgery, pain is one of the important reasons for delayed discharge after laparoscopic cholecystectomy (Gurusamy 2008; Vaughan 2013). The pain after laparoscopic cholecystectomy could be incisional pain, shoulder pain, or abdominal pain (Ng 2004). The aetiology of abdominal pain and shoulder pain after laparoscopic cholecystectomy is unclear. Peritoneal irritation, caused by carbonic acid and creation of space between diaphragm and liver, leading to loss of suction support of the heavy liver have been suggested as possible mechanisms of pain (Alexander 1987). However, use of an overnight drain to let out the gas on the presumption that carbon dioxide in the subdiaphragmatic space is the reason for the pain has not been effective in the reduction of pain (Gurusamy 2013b).
Description of the intervention
Intraperitoneal instillation of local anaesthetic agents, such as bupivacaine (Alkhamesi 2007), levobupivacaine (Ng 2004; Louizos 2005), lidocaine (Elhakim 2000), and ropivacaine (Gupta 2002), has been suggested as a way of reduction of abdominal and shoulder pain after laparoscopic cholecystectomy. The instillation can be performed either before or after the development of the pneumoperitoneum (Barczynski 2006) or towards the end of the surgery (Louizos 2005; Alkhamesi 2007). The intraperitoneal instillation of the local anaesthetic could be by washing the gallbladder bed of the liver with the local anaesthetic (Alkhamesi 2007), instillation under the diaphragm (Abdel‐Raouf 2004), or as an aerolised spray in the general peritoneum (Alkhamesi 2007). The instillation can be performed either as a bolus or as a continuous infusion (Bayar 1998).
How the intervention might work
Local anaesthetics inhibit voltage‐gated sodium channels. This results in decreased excitability of nerves transmitting pain (Butterworth 1990).
Why it is important to do this review
A review by Boddy 2006 et al. revealed that intraperitoneal instillation of local anaesthetic resulted in a reduction of the mean pain score although no reduction in analgesic requirement was noted). There were no adverse effects attributable to local anaesthetic. Another review reported similar results, although the meta‐analysis in the review included only three trials and found no significant difference between local anaesthetic intraperitoneal instillation and placebo (Gupta 2005). In another review of randomised clinical trials, Bisgaard did not recommend routine use of intraperitoneal local anaesthetics because of conflicting results (Bisgaard 2006).
We found no Cochrane systematic reviews assessing the benefits and harms of local anaesthetic agents in people undergoing laparoscopic cholecystectomy.
Objectives
To assess the benefits and harms of intraperitoneal instillation of local anaesthetic agents in people undergoing laparoscopic cholecystectomy.
Methods
Criteria for considering studies for this review
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 non‐randomised studies regarding assessment of benefit, but planned to include these studies regarding assessment of treatment‐related harms.
Types of participants
People undergoing laparoscopic cholecystectomy irrespective of age, elective or emergency surgery, and the reason why the laparoscopic cholecystectomy was performed.
Types of interventions
We included only trials comparing intraperitoneal instillation of local anaesthetic agent (irrespective of the local anaesthetic agent used, timing of delivery, and the method of delivery) with no intraperitoneal instillation of local anaesthetic agent. We accepted any of the following control groups: normal saline, another placebo, or no instillation of any drug or fluid.
Co‐interventions were allowed if carried out equally in the trial groups.
Types of outcome measures
Primary outcomes
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Mortality.
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Serious adverse events defined as any event that would increase mortality, was life‐threatening, required inpatient hospitalisation, resulted in a persistent or significant disability, or any important medical event that might have jeopardised the person or required intervention to prevent it (ICH‐GCP 1997). We classified complications such as bile duct injury; re‐operations; intra‐abdominal collections requiring drainage (radiological or surgical); infected intra‐abdominal collections; bile leaks requiring drainage, stent, or surgery; convulsions; cardiac arrhythmias that required additional monitoring and hence increased the hospital stay as serious adverse events. We classified complications such as wound infections, bile leaks, or abdominal collections that did not require any treatment and settled spontaneously as non‐serious adverse events.
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Patient quality of life (however defined by study authors using a validated scale such as Euro‐QoL or 36‐item Short‐Form (SF‐36)).
Secondary outcomes
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Hospital stay (length of hospital stay, proportion discharged as day‐surgery laparoscopic cholecystectomy).
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Pain (overall pain) at different time points (4 to 8 hours and 9 to 24 hours) using visual analogue scale (VAS).
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Return to activity.
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Return to work.
We have reported all the outcomes that have at least one trial in the summary of findings Table for the main comparison.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2013), MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003), and the World Health Organization International Clinical Trials Registry Platform portal (WHO ICTRP) (apps.who.int/trialsearch/) to March 2013. The WHO ICTRP portal allows search of various trial registers including clinicaltrials.gov and International Standard Randomised Controlled Trial Number (ISRCTN). We have given the search strategies in Appendix 1 with the time span for the searches.
Searching other resources
We also searched the references of the identified trials to identify further relevant trials.
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 2013).
Selection of studies
Two review authors (KSG and CT, GPG, or MZ) identified the trials for inclusion independently of each other. We have also listed the excluded studies with the reasons for the exclusion (Characteristics of excluded studies).
Data extraction and management
Two review authors (KSG, MN, CT, GPG, or MZ) extracted the following data independently of each other.
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Year and language of publication.
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Country in which the trial was conducted.
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Year of trial.
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Inclusion and exclusion criteria.
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Sample size.
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Elective surgery or acute cholecystitis.
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Local anaesthetic agent used.
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Dose of local anaesthetic agent (per kilogram body weight or total dose however reported by authors).
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Timing of administration.
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Location where instilled.
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Physical form of local anaesthetic agent (aerosol, liquid).
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Duration of administration (bolus/infusion period).
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Drain or no drain.
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Peri‐laparoscopic‐portal infiltration with local anaesthetic.
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Other co‐interventions.
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Outcomes (see Primary outcomes; Secondary outcomes).
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Risk of bias (see Assessment of risk of bias in included studies).
We sought any unclear or missing information by contacting the authors of the individual trials. If there was any doubt whether the trials shared the same participants ‐ completely or partially (by identifying common authors and centres) ‐ we planned to contact the authors of the trials to clarify whether the trial report had been duplicated.
We resolved any differences in opinion through discussion or arbitration of the third review author (BRD).
Assessment of risk of bias in included studies
We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2013). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012a; Savovic 2012b), the risk of bias of the trials was assessed based on the following bias risk domains.
Allocation sequence generation
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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.
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Uncertain risk of bias: the method of sequence generation was not specified.
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High risk of bias: the sequence generation method was not random.
Allocation concealment
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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).
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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.
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High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.
Blinding of participants and personnel
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Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
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Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to introduce bias on the results.
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High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.
Blinding of outcome assessors
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Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
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Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.
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High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.
Incomplete outcome data
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Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, have been employed to handle missing data.
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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.
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High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting
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Low risk of bias: all outcomes were pre‐defined and reported, or all clinically relevant and reasonably expected outcomes were reported.
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Uncertain risk of bias: it is unclear whether all pre‐defined and clinically relevant (mortality and morbidity) and reasonably expected outcomes were reported.
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High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.
For this purpose, the trial should have been registered either on the www.clinicaltrials.gov website or a similar register with sufficient evidence that the protocol had not been revised during the update, or there should be a protocol (eg, published in a paper journal). In the case when the trial was run and published in the years when trial registration was not required, we carefully scrutinized all publications reporting on the trial to identify the trial objectives and outcomes, and determine whether usable data were provided in the publication's results section on all outcomes specified in the trial objectives.
For‐profit bias
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Low risk of bias: the trial appeared to be free of industry sponsorship or other type of for‐profit support that may manipulate the trial design, conductance, or results of the trial.
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Uncertain risk of bias: the trial may or may not have been free of for‐profit bias as no information on clinical trial support or sponsorship was provided.
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High risk of bias: the trial was sponsored by the industry or received other type of for‐profit support.
We considered trials that were classified as low risk of bias in all the above domains as trials with low risk of bias and the remaining as trials with high risk of bias.
Measures of treatment effect
For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval (CI). We also calculated the risk difference (RD) with 95% CI. We planned to report the RD only if the conclusions were different from those of the RR. RD includes 'zero event trials' (trials in which both groups had no events) for calculating the summary treatment effect, while such trials will not be taken into account while calculating the summary treatment effect in the case of the RR. For continuous variables, we calculated the mean difference (MD) with 95% CI for outcomes such as total hospital stay or standardised mean difference (SMD) with 95% CI for outcomes such as quality of life, where different study authors use different scales of quality of life.
Unit of analysis issues
The units of analysis was the person about to undergo laparoscopic cholecystectomy and randomised to the intraperitoneal local anaesthetic instillation or control.
Dealing with missing data
We performed an intention‐to‐treat analysis whenever possible (Newell 1992). We imputed data for binary outcomes using various scenarios such as best‐best scenario, best‐worst scenario, worst‐best scenario, and worst‐worst scenario (Gurusamy 2009; Gluud 2013).
For continuous outcomes, we used an available‐case analysis. We imputed the standard deviation from P values according to the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and we used the median for the meta‐analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the CI, we planned to impute the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation would decrease the weight of the study for calculation of MDs and bias the effect estimate to no effect in the case of SMD (Higgins 2011).
Assessment of heterogeneity
We explored heterogeneity using the Chi2 test with significance set at a P value less than 0.10, and measured the quantity of heterogeneity using the I2 statistic (Higgins 2002). We also used overlapping of CIs on the forest plot to determine heterogeneity.
Assessment of reporting biases
We used visual asymmetry on a funnel plot to explore reporting bias since we identified more than 10 trials (Egger 1997; Macaskill 2001). We performed the linear regression approach described by Egger 1997 to determine the funnel plot asymmetry. Selective reporting was also considered as evidence for reporting bias.
Data synthesis
We performed the meta‐analyses using the software package Review Manager 5 (RevMan 2012), and following the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2013). We used both a random‐effects model (DerSimonian 1986), and a fixed‐effect model (DeMets 1987), meta‐analysis. In the case of discrepancy between the two models, we have reported both results; otherwise, we have reported the results of the fixed‐effect model. We planned to use the generic inverse method to combine the hazard ratios for time‐to‐event outcomes.
Trial sequential analysis
The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We will add the trials according to the year of publication, and, if more than one trial was published in a year, we will add the trials alphabetically according to the last name of the first author. On the basis of the required information size, we will construct trial sequential monitoring boundaries. These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. In contrast, if the boundaries are not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).
We applied trial sequential analysis (CTU 2011; Thorlund 2011) using a required sample size calculated from an alpha error of 0.05, a beta error of 0.20, a control event proportion obtained from the results, and a relative risk reduction of 20% for binary outcomes if there were two or more trials reporting the outcome to determine whether more trials are necessary on this topic (if the trial sequential monitoring boundary or the futility zone is crossed, then more trials may be unnecessary) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). Since trial sequential analysis cannot be performed for SMDs, we did not plan to perform the trial sequential analysis for quality of life. For pain, we calculated the required sample size from an alpha error of 0.05, a beta error of 0.20, the variance estimated from the meta‐analysis results of low risk of bias trials, and an MD of 1 cm on the VAS (Todd 1996). For length of hospital stay, return to work, and return to activity, we planned to calculate the required sample size using an MD of one day with the remaining parameters kept the same as that for pain.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses.
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Trials with low bias risk compared to trials with high bias risk.
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Elective compared to emergency laparoscopic cholecystectomy.
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Different local anaesthetic agents.
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Maximum safe dose used (ie, whether the trials used the dose based on body weight).
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Different timing of instillation.
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Different locations of instillation.
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Physical forms of local anaesthetic agent.
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Bolus and continuous infusion.
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Drain or no drain.
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Peri‐laparoscopic‐portal infiltration with local anaesthetic.
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Routine supplemental analgesia compared to no routine ('on‐demand') supplemental analgesia.
We used the 'test for subgroup differences' available through Review Manager 5 (RevMan 2012) to identify the differences between subgroups. We used the random‐effects model for this purpose. We also used meta‐regression (in the presence of adequate number of trials) to determine the influence of the above factors on the effect estimate. We performed this for pain at four to eight hours and pain at nine to 24 hours (as these are the times at which day‐procedure laparoscopic cholecystectomy and overnight stay laparoscopic cholecystectomy patients are discharged) using the 'metareg' command of Stata/IC 11 (StataCorp LP).
Sensitivity analysis
We performed a sensitivity analysis by imputing data for binary outcomes using various scenarios such as best‐best scenario, best‐worst scenario, worst‐best scenario, and worst‐worst scenario (Gurusamy 2009; Gluud 2013). We performed a sensitivity analysis by excluding the trials in which the mean and the standard deviation were imputed.
'Summary of findings' table
We have summarised the results of all the reported outcomes in summary of findings Table for the main comparison, which was prepared using GRADEPro 3.6 (ims.cochrane.org/revman/gradepro).
Results
Description of studies
Results of the search
We identified 474 references through electronic searches of CENTRAL (85 references), MEDLINE (127 references), EMBASE (105 references), and Science Citation Index Expanded (157 references). We did not identify any new trials from the trial registers. We excluded 84 duplicates and 289 clearly irrelevant references through reading abstracts. We retrieved 101 references for further assessment. We found no references through scanning reference lists of the identified randomised trials. We excluded 39 references for the reasons listed in the Characteristics of excluded studies table. Sixty‐two references fulfilled the inclusion criteria. Of these 62 references, five were duplicate reports of the same trial (Joris 1995; Fuhrer 1996; Karadeniz 2003; Feroci 2009; Kim 2010). One report contained two trials (Raetzell 1995a; Raetzell 1995b). Thus, 58 randomised clinical trials were reported in the 62 included references. We did not identify any quasi‐randomised studies or comparative non‐randomised studies that reported treatment‐related harms. The reference flow is shown in Figure 1.
Study flow diagram.
Included studies
Of the 58 randomised clinical trials that fulfilled the inclusion criteria, nine trials did not provide any information for this systematic review (Joris 1995; Kilic 1996; Elhakim 2000; Abdel‐Raouf 2004; Ng 2004; Jabbour‐Khoury 2005; Hasan 2007; Razman 2010; El‐Labban 2011). These trials reported some specific aspects of pain, for example, shoulder pain or abdominal pain, used other scales of pain or reported other outcomes such as stress response. One other trial did not report the number of participants randomised to the local anaesthetic and control groups (Raetzell 1995a). Thus, 48 randomised clinical trials including 2849 participants randomised to intraperitoneal local anaesthetic instillation (1558 participants) and control (1291 participants) were included in this review. In 28 trials, two arms were included for this review (Chundrigar 1993; Raetzell 1995b; Fornari 1996; Fuhrer 1996; Szem 1996; Mraovic 1997; Kolsi 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Maestroni 2002; Rudra 2002; Lepner 2003; Razek 2003; Hazinedaroglu 2006; Verma 2006; Garcia 2007; Alper 2009; Feroci 2009; Fu 2009; Golubovic 2009; Todorov 2009; Kim 2010; Zimmer 2010; Gvozdenovic 2011; Kallel 2011; Castillo‐Garza 2012), that is, although some of these trials randomised participants to more than two arms, only two arms were eligible for inclusion in this review. In 20 trials, multiple arms were included for this review (Pasqualucci 1994; Rademaker 1994; Scheinin 1995; Pasqualucci 1996; Weber 1997; Ahmad 1998; Elfberg 2000; Lee 2001; Labaille 2002; Alagöl 2003; Karadeniz 2003; Paulson 2003; Louizos 2005; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Kucuk 2007; Nicolau 2008; Alptekin 2010; Roberts 2011). Thus, 72 comparisons were possible in the 48 randomised clinical trials that contributed data for this review.
Participant characteristics
Forty‐one trials clearly stated that they included participants undergoing elective laparoscopic cholecystectomy (Chundrigar 1993; Pasqualucci 1994; Rademaker 1994; Fornari 1996; Fuhrer 1996; Pasqualucci 1996; Szem 1996; Mraovic 1997; Elfberg 2000; Kolsi 2000; Zmora 2000; Lee 2001; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Labaille 2002; Maestroni 2002; Rudra 2002; Karadeniz 2003; Lepner 2003; Paulson 2003; Razek 2003; Louizos 2005; Barczynski 2006; Hazinedaroglu 2006; Karaaslan 2006; Verma 2006; Alkhamesi 2007; Garcia 2007; Kucuk 2007; Nicolau 2008; Alper 2009; Feroci 2009; Fu 2009; Golubovic 2009; Alptekin 2010; Kim 2010; Zimmer 2010; Gvozdenovic 2011; Roberts 2011; Castillo‐Garza 2012). In one trial, it was clear from the characteristics tables that people with acute cholecystitis were included (Todorov 2009). The inclusion of people with acute cholecystitis was not reported in the remaining six trials (Raetzell 1995b; Scheinin 1995; Weber 1997; Ahmad 1998; Alagöl 2003; Kallel 2011). Thirty‐three trials stated that they included only American Society of Anesthesiologists (ASA) status I or II (Pasqualucci 1994; Rademaker 1994; Scheinin 1995; Fornari 1996; Fuhrer 1996; Pasqualucci 1996; Mraovic 1997; Elfberg 2000; Kolsi 2000; Lee 2001; Bhardwaj 2002; Jiranantarat 2002; Labaille 2002; Maestroni 2002; Alagöl 2003; Karadeniz 2003; Paulson 2003; Razek 2003; Louizos 2005; Barczynski 2006; Hazinedaroglu 2006; Karaaslan 2006; Verma 2006; Alkhamesi 2007; Garcia 2007; Kucuk 2007; Alper 2009; Feroci 2009; Fu 2009; Golubovic 2009; Zimmer 2010; Kallel 2011; Roberts 2011). In one trial, only people who were ASA status I were included (Rudra 2002). In two trials, only people who were ASA status I to III were included (Lepner 2003; Kim 2010). In the remaining 12 trials, the ASA status of the participants was not reported (Chundrigar 1993; Raetzell 1995b; Szem 1996; Weber 1997; Ahmad 1998; Zmora 2000; Tunca 2001; Nicolau 2008; Todorov 2009; Alptekin 2010; Gvozdenovic 2011; Castillo‐Garza 2012).
Intervention
The details of the intervention in the different trials are summarised in the Characteristics of included studies table and Table 1.
| Study name | Local anaesthetic | Time§ | Location | Norepinephrine | Peri‐portal local anaesthetic infiltration | Drain use | Other routine analgesia* |
| bupivacaine | end of surgery | subdiaphragmatic area | no | yes | no | none | |
| bupivacaine | not stated | not stated | no | no | not stated | none | |
| bupivacaine | not stated | not stated | no | yes | not stated | none | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | none | |
| Alagöl 2003 (intraperitoneal ondansetron administered in both groups) | bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | none |
| bupivacaine | end of surgery | diffuse | no | yes | not stated | routine NSAID and opioid analgesics | |
| bupivacaine | end of surgery | gallbladder bed | no | yes | not stated | routine NSAID and opioid analgesics | |
| levobupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | yes | not stated | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | not stated | not stated | |
| bupivacaine | after end of surgery | gallbladder bed | no | not stated | for the continuous infusion group | not stated | |
| bupivacaine | before pneumoperitoneum | diffuse | no | yes | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | diffuse | no | yes | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | no | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | no | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | no | not stated | |
| lignocaine | end of surgery | subdiaphragmatic area | no | yes | yes | no | |
| levobupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | no | no | routine NSAID | |
| bupivacaine | end of surgery | gallbladder bed | no | no | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | yes | not stated | no | no | |
| ropivacaine | end of surgery | gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| bupivacaine (s75‐r25) | end of surgery | subdiaphragmatic area | no | not stated | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | not stated | no | not stated | not stated | not stated | |
| bupivacaine | not stated | not stated | no | no | not stated | routine NSAID | |
| bupivacaine | not stated | not stated | no | no | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | yes | not stated | no | |
| bupivacaine | end of surgery | not stated | no | not stated | not stated | no | |
| Jabbour‐Khoury 2005 (intravenous ketoprofen administered in both groups) | bupivacaine | end of surgery | not stated | no | not stated | not stated | no |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | yes | no | not stated | no | |
| lignocaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | not stated | |
| bupivacaine | before pneumoperitoneum | gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | not stated | no | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | no | no | |
| bupivacaine | after end of surgery | subdiaphragmatic area and gallbladder bed (by infusion pump) | no | not stated | possibly for the continuous infusion group | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| ropivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| lignocaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| ropivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | no | not stated | no | |
| ropivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | no | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | no | not stated | no | |
| ropivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | no | no | not stated | no | |
| ropivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | no | no | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | yes | yes | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | no | not stated | routine NSAID | |
| lignocaine | end of surgery | subdiaphragmatic area | no | yes | no | routine NSAID | |
| levobupivacaine | end of surgery | gallbladder bed | no | no | not stated | no | |
| levobupivacaine | end of surgery | gallbladder bed | no | yes | not stated | no | |
| ropivacaine | before pneumoperitoneum | diffuse | no | not stated | not stated | routine NSAID | |
| bupivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| levobupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | selectively (reasons not stated) | not stated clearly | |
| ropivacaine | end of surgery | gallbladder bed | no | no | selectively (for patients with difficult haemostasis) | routine NSAID | |
| ropivacaine | end of surgery | gallbladder bed | no | yes | selectively (for patients with difficult haemostasis) | routine NSAID | |
| bupivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | no | no | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | no | no | no | |
| bupivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | no | no | no | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| lignocaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine NSAID | |
| levobupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine NSAID | |
| bupivacaine | not stated | not stated | yes | yes | not stated | not stated | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area | no | yes | selectively (reasons not stated) | routine NSAID and opioid analgesics | |
| bupivacaine | just after creation of pneumoperitoneum | gallbladder bed | no | yes | selectively (reasons not stated) | routine NSAID and opioid analgesics | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | no | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | yes | not stated | no | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine opioid analgesic | |
| levobupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | not stated | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | end of surgery | gallbladder bed | no | no | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| bupivacaine | just after creation of pneumoperitoneum | diffuse | no | yes | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | no | routine NSAID and opioid analgesic |
NSAID: non‐steroidal anti‐inflammatory drug.
§ 'End of surgery' indicates instillation after removal of gallbladder usually before closure of the wounds but in all instances before the reversal of anaesthesia; 'after end of surgery' indicates that the participant received the local anaesthetic by an infusion pump after reversal of anaesthesia.
* refers to routine analgesia. Most trials allowed 'on‐demand' analgesia or analgesia was administered if the pain was above a certain threshold.
Control
In 38 trials, intraperitoneal normal saline (of equivalent volume as the intervention) was used for the control group (Chundrigar 1993; Pasqualucci 1994; Rademaker 1994; Raetzell 1995b; Scheinin 1995; Fornari 1996; Fuhrer 1996; Pasqualucci 1996; Szem 1996; Mraovic 1997; Ahmad 1998; Elfberg 2000; Kolsi 2000; Lee 2001; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Labaille 2002; Maestroni 2002; Rudra 2002; Alagöl 2003; Lepner 2003; Paulson 2003; Razek 2003; Louizos 2005; Barczynski 2006; Hazinedaroglu 2006; Garcia 2007; Kucuk 2007; Nicolau 2008; Alper 2009; Golubovic 2009; Todorov 2009; Kim 2010; Gvozdenovic 2011; Kallel 2011; Roberts 2011; Castillo‐Garza 2012). In three trials, no intervention was used for the control (Karaaslan 2006; Feroci 2009; Alptekin 2010). In three trials, other controls such as fibrin sealant (Fu 2009) and normal saline‐soaked cellulose strips (Zmora 2000; Verma 2006) were used. In these trials, local anaesthetic mixed with fibrin sealant (Fu 2009) or local anaesthetic‐soaked cellulose strips were used as interventions (Zmora 2000; Verma 2006). One trial stated that a placebo was used without providing further information as to what the placebo solution was (Karadeniz 2003). In one trial, sterile water was used for the control (Zimmer 2010). In one four‐armed trial, the control used was normal saline and normal saline aerosol (Alkhamesi 2007). In one three‐armed trial, the control used was sterile water and no intervention (Weber 1997).
Co‐intervention
The details of norepinephrine (noradrenaline) use, the use of peri‐laparoscopic portal local anaesthetic wound infiltration, drain use, whether routine analgesia was used for supplemental analgesia in both groups are shown in Table 1.
Further details about sample size, participant characteristics, the inclusion and exclusion criteria used in the trials, post‐randomisation drop‐outs, intervention and control, comparisons, outcomes reported in the trials, and the risk of bias in the trials are shown in the Characteristics of included studies table and Table 1.
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).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Only six trials (6/58 (10.3%)) described random sequence generation and allocation concealment adequately (Joris 1995; Fornari 1996; Szem 1996; Barczynski 2006; Feroci 2009; Kim 2010). These six trials were considered to be at low risk of selection bias.
Blinding
Twenty‐one trials (21/58 (36.2%)) reported that the participants, healthcare personnel involved in patient care, and outcome assessors were blinded and were considered to be at low risk of performance and detection bias (Chundrigar 1993; Raetzell 1995a; Raetzell 1995b; Elfberg 2000; Zmora 2000; Lee 2001; Tunca 2001; Rudra 2002; Lepner 2003; Paulson 2003; Ng 2004; Hazinedaroglu 2006; Karaaslan 2006; Alkhamesi 2007; Garcia 2007; Alper 2009; Feroci 2009; Golubovic 2009; Kim 2010; Zimmer 2010; Roberts 2011).
Incomplete outcome data
Fourteen trials (14/58 (24.1%)) had no post‐randomisation drop‐outs and was considered to be at low risk of attrition bias (Lepner 2003; Razek 2003; Barczynski 2006; Hazinedaroglu 2006; Alper 2009; Feroci 2009; Fu 2009; Golubovic 2009; Todorov 2009; Kim 2010; Zimmer 2010; El‐Labban 2011; Castillo‐Garza 2012).
Selective reporting
Nine trials (9/58 (15.5%)) reported mortality and morbidity and were considered to be at low risk of selective reporting bias (Raetzell 1995a; Raetzell 1995b; Fornari 1996; Lee 2001; Karadeniz 2003; Lepner 2003; Feroci 2009; Zimmer 2010; Castillo‐Garza 2012).
Other potential sources of bias
Four trials (4/58 (6.9%)) were considered to be at low risk of 'for‐profit' bias (Feroci 2009; Todorov 2009; Zimmer 2010; El‐Labban 2011).
Effects of interventions
The main results are summarised in the summary of findings Table for the main comparison.
Mortality
There was no mortality in either group in the eight trials that reported mortality (0/236 (0%) in local anaesthetic instillation versus 0/210 (0%) in control group) (Raetzell 1995b; Fornari 1996; Lee 2001; Lepner 2003; Karadeniz 2003; Feroci 2009; Zimmer 2010; Castillo‐Garza 2012). Since there was no mortality in either group, we were unable to use the control group proportion for the calculation of the required information size of the trial sequential analysis. Instead, we used a proportion of 0.2% in the control group based on data from approximately 30,000 people included in a database in Switzerland (Giger 2011). The proportion of information accrued was only 0.13% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 4). The cumulative Z curve did not cross the conventional statistical boundaries.
Trial sequential analysis of mortality
The diversity‐adjusted required information size (DARIS) was calculated to 352,564 participants, based on the proportion of participants in the control group with the outcome of 0.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 446 participants in eight trials, only 0.13% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Morbidity
Eight trials reported serious adverse events (Raetzell 1995b; Fornari 1996; Lee 2001; Karadeniz 2003; Lepner 2003; Feroci 2009; Zimmer 2010; Castillo‐Garza 2012). There was no significant difference in the proportion of people who developed the serious adverse events between intraperitoneal local anaesthetic instillation and inactive control groups (RR 3.00; 95% CI 0.13 to 67.06) (Analysis 1.2). There was only one serious adverse event in the local anaesthetic instillation group (1/236 (0.4%)) compared with no serious adverse events in the control group (0/210 (0%)) (Analysis 1.2). The serious adverse event was thrombophlebitis, which was unrelated to the local anaesthetic instillation. One trial did not report the complications adequately but stated that one person developed lactic acidosis but this was not considered to be due to the local anaesthetic since the person had developed a similar problem with previous anaesthesia (Roberts 2011). Bupivacaine was used in this trial.
Although the remaining trials did not report overall morbidity, three trials (190 participants; 100 participants received local anaesthetic and 90 participants received control) reported that there were no intra‐operative complications (Barczynski 2006; Alptekin 2010; Kim 2010). Twenty trials reported that there were no serious adverse events in any of the 715 participants who received local anaesthetic instillation (Scheinin 1995; Pasqualucci 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Tunca 2001; Labaille 2002; Maestroni 2002; Rudra 2002; Paulson 2003; Razek 2003; Louizos 2005; Hazinedaroglu 2006; Karaaslan 2006; Garcia 2007; Kucuk 2007; Nicolau 2008; Alper 2009; Kallel 2011). The remaining trials did not report about the complications that participants developed.
Since there was no serious adverse event in the control group in the meta‐analysis, we were unable to use the control group proportion for the calculation of the required information size of the trial sequential analysis as before. Laparoscopic cholecystectomy is generally considered to have low morbidity in people with low anaesthetic risk. We used a control group proportion of 2%. The proportion of information accrued was only 1.29% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 5). The cumulative Z‐curve did not cross the conventional statistical boundaries.
Trial sequential analysis of morbidity
The diversity‐adjusted required information size (DARIS) was calculated to 34,685 participants, based on the proportion of participants in the control group with the outcome of 2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 446 participants in eight trials, only 1.29% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
Proportion discharged as day surgery
Three trials (242 participants; 160 participants received local anaesthetic and 82 participants received control) reported the proportion of participants discharged as day surgery (Paulson 2003; Zimmer 2010; Roberts 2011). There were no significant differences between the two groups (RR 1.25; 95% CI 0.99 to 1.58) (Analysis 1.3). There was no change in the results by using random‐effects model. There were no changes in the results by imputing missing outcome data using various scenarios (Analysis 2.1). However, when RD was used, the proportion of participants who were discharged as day surgery was significantly higher in the local anaesthetic instillation group than the control group using the fixed‐effect model (RD 0.11; 95% CI 0.01 to 0.22) but not by the random‐effects model (RD 0.11; 95% CI ‐0.05 to 0.28). The trial sequential analysis revealed that the proportion of information accrued was only 0.02% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 6). The cumulative Z curve did not cross the conventional statistical boundaries.
Trial sequential analysis of proportion discharged as day surgery
The diversity‐adjusted required information size (DARIS) was calculated to 1,419,571 participants, based on the proportion of participants in the control group with the outcome of 48.78%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 99.94%. To account for zero event groups (or groups in which all the participants were discharged as day surgery), a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 242 participants in three trials, only 0.02% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Length of hospital stay
Five trials (335 participants; 175 participants received local anaesthetic and 160 participants received control) reported the length of hospital stay (Scheinin 1995; Fornari 1996; Szem 1996; Jiranantarat 2002; Todorov 2009). There were no significant differences between the two groups (MD 0.04 days; 95% CI ‐0.23 to 0.32) (Analysis 1.4). Either the mean or the standard deviation or both were not reported and had to be imputed in three trials (Fornari 1996; Szem 1996; Jiranantarat 2002). The standard deviation was zero in the control group as all participants were discharged on the first postoperative day in one of the trials (Todorov 2009). To include this trial in the analysis, we imputed the standard deviation in this trial also. Exclusion of these trials did not result in change in the conclusions (MD 0.53 days; 95% CI ‐0.14 to 1.21) (Analysis 2.2). The trial sequential analysis suggested that it is unlikely that future trials are likely to demonstrate any significant difference in the length of hospital stay between local anaesthetic instillation and no local anaesthetic instillation since the cumulative Z‐curve had entered the futility area and did not cross the conventional statistical boundaries (Figure 7).
Trial sequential analysis of length of hospital stay
The diversity‐adjusted required information size (DARIS) was 107 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 3.39, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. After accruing 335 participants in five trials, the cumulative Z‐curve (blue line) has crossed the trial sequential monitoring boundaries (red line) but lies within the futility area and the conventional statistical boundaries (dotted red line). This suggests that it is unlikely that future trials are likely to demonstrate any significant difference in the length of hospital stay between local anaesthetic instillation and no local anaesthetic instillation.
Pain
Pain at four to eight hours
Thirty‐two trials (2020 participants; 1081 participants received local anaesthetic and 939 participants received control) reported this outcome (Chundrigar 1993; Pasqualucci 1994; Rademaker 1994; Raetzell 1995b; Fornari 1996; Pasqualucci 1996; Szem 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Maestroni 2002; Alagöl 2003; Karadeniz 2003; Razek 2003; Barczynski 2006; Hazinedaroglu 2006; Verma 2006; Alkhamesi 2007; Kucuk 2007; Nicolau 2008; Feroci 2009; Fu 2009; Golubovic 2009; Todorov 2009; Kim 2010; Roberts 2011; Castillo‐Garza 2012). The pain scores as measured by the VAS were significantly lower in the local anaesthetic instillation group than the control group (MD ‐0.99 cm VAS; 95% CI ‐1.10 to ‐0.88) (Analysis 1.5). There were no changes in the interpretation of results by using a random‐effects meta‐analysis. Either the mean or the standard deviation was imputed in 22 trials (Chundrigar 1993; Rademaker 1994; Raetzell 1995b; Fornari 1996; Pasqualucci 1996; Szem 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Maestroni 2002; Alagöl 2003; Razek 2003; Hazinedaroglu 2006; Alkhamesi 2007; Fu 2009; Golubovic 2009; Roberts 2011; Castillo‐Garza 2012). Exclusion of these trials did not alter the results (MD ‐1.04 cm VAS; 95% CI ‐1.17 to ‐0.90) (Analysis 2.3). One trial contributed to more than 50% of the weight of the analysis (Barczynski 2006). It was not clear whether the values were standard deviation or standard error. Therefore, we performed another sensitivity analysis excluding this trial along with the other trials where mean or standard deviation was imputed. There was no change in the results by excluding this trial also (MD ‐0.76 cm VAS; 95% CI ‐1.01 to ‐0.51). All the trial sequential monitoring boundaries were crossed by cumulative Z‐curve favouring local anaesthetic instillation. The findings were consistent with local anaesthetic instillation decreasing pain between four and eight hours compared with no local anaesthetic instillation without the risk of random errors (Figure 8).
Trial sequential analysis of pain (4 to 8 hours)
The diversity‐adjusted required information size (DARIS) was 796 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 3.19, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 87.32%. The conventional statistical boundaries (dotted red line) are crossed by the cumulative Z‐curve (blue line) after the second trial. All the trial sequential monitoring boundaries (red line) are crossed by cumulative Z‐curve after the seventeenth trial. The findings are consistent with local anaesthetic instillation decreasing pain between 4 and 8 hours compared with no local anaesthetic instillation without the risk of random errors.
Pain at nine to 24 hours
Twenty‐nine trials (1787 participants; 940 participants received local anaesthetic and 847 participants received control) reported this outcome (Pasqualucci 1994; Raetzell 1995b; Fornari 1996; Pasqualucci 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Jiranantarat 2002; Maestroni 2002; Alagöl 2003; Karadeniz 2003; Razek 2003; Barczynski 2006; Hazinedaroglu 2006; Verma 2006; Alkhamesi 2007; Kucuk 2007; Nicolau 2008; Feroci 2009; Fu 2009; Golubovic 2009; Todorov 2009; Kim 2010; Zimmer 2010; Castillo‐Garza 2012). The pain scores as measured by the VAS were significantly lower in the local anaesthetic instillation group than the control group (MD ‐0.53 cm VAS; 95% CI ‐0.62 to ‐0.44) (Analysis 1.6). There were no changes in the interpretation of results by using a random‐effects meta‐analysis. Either the mean or the standard deviation was imputed in 17 trials (Raetzell 1995b; Fornari 1996; Pasqualucci 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Zmora 2000; Tunca 2001; Bhardwaj 2002; Maestroni 2002; Alagöl 2003; Razek 2003; Hazinedaroglu 2006; Alkhamesi 2007; Fu 2009; Golubovic 2009; Zimmer 2010). Exclusion of these trials did not alter the results (MD ‐0.38 cm VAS; 95% CI ‐0.48 to ‐0.28) (Analysis 2.4). One trial contributed to more than 50% of the weight of the analysis (Barczynski 2006). It was not clear whether the values were standard deviation or standard error. Therefore, we performed another sensitivity analysis excluding this trial along with the other trials where mean or standard deviation was imputed. There was also no change in the results by excluding this trial (MD ‐0.34 cm VAS; 95% CI ‐0.52 to ‐0.16). All the trial sequential monitoring boundaries were crossed by cumulative Z‐curve favouring local anaesthetic instillation. The findings were consistent with local anaesthetic instillation decreasing pain between nine and 24 hours compared with no local anaesthetic instillation without the risk of random errors (Figure 9).
Trial sequential analysis of pain (9 to 24 hours)
The diversity‐adjusted required information size (DARIS) was 580 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 2.06, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 88.81%. The conventional statistical boundaries (dotted red line) are crossed by the cumulative Z‐curve (blue line) after the fifth trial . All the trial sequential monitoring boundaries (red line) are crossed by cumulative Z‐curve after the twelfth trial. The findings are consistent with local anaesthetic instillation decreasing pain between 9 and 24 hours compared to no local anaesthetic instillation without the risk of random errors.
Return to normal activity
None of the trials reported return to normal activity.
Return to work
None of the trials reported return to work.
Subgroup analysis and meta‐regression
Only pain at four to eight hours and pain at nine to 24 hours were suitable for various subgroup analyses because of the paucity of data in the other outcomes. We did not perform the following subgroup analysis or meta‐regression.
-
Trials with low bias risk compared to trials with high bias risk: only one trial was at low risk of bias (Feroci 2009).
-
Elective compared to emergency laparoscopic cholecystectomy: none of the trials reported data for emergency laparoscopic cholecystectomy separately.
-
Drain or no drain. The only trial that reported drain use in all the participants did not report any of the outcomes of interest for this review (El‐Labban 2011). The remaining trials in which drain use was reported in some participants and provided data for this review did not report the data separately for participants in whom the drain was used (Nicolau 2008; Roberts 2011).
We included all the other variables except peri‐portal local anaesthetic infiltration and routine supplemental analgesia in the meta‐regression because of missing information for these two variables. Therefore, these two variables were used alone in two other meta‐regression models. Therefore, there were three meta‐regression models for each of pain at four to eight hours and pain at nine to 24 hours.
Pain at four to eight hours
The test for subgroup differences was significant only for peri‐portal infiltration with local anaesthetic (P value = 0.007) (Analysis 3.8) and for routine supplemental analgesia (P value < 0.0001) (Analysis 3.9). The intraperitoneal local anaesthetic instillation was more effective in participants who did not have peri‐portal infiltration with local anaesthetic than those who had peri‐portal local anaesthetic infiltration. The intraperitoneal local anaesthetic instillation was more effective in participants who received routine supplemental analgesia than those who received on‐demand supplemental analgesia.
The tests for subgroup differences were not significant for the following subgroup analyses.
-
Different local anaesthetic agents (Analysis 3.1).
-
Maximum safe dose used (ie, whether the trials used the dose based on body weight) (Analysis 3.2).
-
Different physical forms of instillation (Analysis 3.3).
-
Different timing of instillation (Analysis 3.4).
-
Different locations of instillation (Analysis 3.5).
-
Norepinephrine use (Analysis 3.6).
-
Control used (Analysis 3.7).
The findings of the meta‐regression were as follows.
Ropivacaine was associated with a lower treatment effect than other local anaesthetics. The form of local anaesthetic delivered in terms of liquid or other forms significantly affected the effect estimates. Other forms of local anaesthetic, such as aerosol or soaked in cellulose strips, were more effective than liquid form. Local anaesthetic delivery at the end of surgery was less effective than other times of drug delivery, such as just after creation of pneumoperitoneum or delivered twice ‐ just after pneumoperitoneum and end of surgery. Meta‐regression also revealed that the local anaesthetics were more effective when norepinephrine was added to the local anaesthetic. None of the other factors influenced the effect estimate significantly.
Pain at nine to 24 hours
The test for subgroup differences was significant for the following subgroups.
-
Dose of local anaesthetic used (P value = 0.04). The local anaesthetics were more effective when a fixed dose of local anaesthetic rather than a dose based on body weight was used (Analysis 3.11).
-
Time of administration (P value = 0.04). Local anaesthetic delivery at the end of surgery was less effective than other times of drug delivery, such as just after creation of pneumoperitoneum or delivered twice ‐ just after pneumoperitoneum and end of surgery (Analysis 3.13).
-
Peri‐portal infiltration with local anaesthetic (P value = 0.01). The intraperitoneal local anaesthetic instillation was more effective in participants who did not have peri‐portal infiltration with local anaesthetic than those who had peri‐portal local anaesthetic infiltration (Analysis 3.17).
-
Routine supplemental analgesia (P value = 0.004). The intraperitoneal local anaesthetic instillation was more effective in participants who received routine supplemental analgesia than those who received on‐demand supplemental analgesia.
The tests for subgroup differences were not significant for the following subgroup analyses for pain between nine and 24 hours.
-
Different local anaesthetic agents (Analysis 3.10).
-
Different physical forms of instillation (Analysis 3.12).
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Different locations of instillation (Analysis 3.14).
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Norepinephrine use (Analysis 3.15).
-
Control used (Analysis 3.16).
The findings of the meta‐regression were as follows.
Other forms of local anaesthetic administration such as aerosol or soaked in cellulose strips were more effective than liquid form. None of the other factors influenced the effect estimate significantly.
Reporting bias
We explored reporting bias only for pain at four to eight hours and for pain at nine to 24 hours by funnel plots because of the presence of adequate number of trials for these two outcomes only. The funnel plots did not reveal any evidence of reporting bias (P value = 0.227). The Egger's test did not reveal any evidence of reporting bias (P value = 0.099).
Discussion
Summary of main results
In this review, we have compared the intraperitoneal instillation of local anaesthetic agents versus no installation of local anaesthetic agents to reduce pain during laparoscopic cholecystectomy. We included 48 randomised clinical trials including 2849 participants randomised to intraperitoneal local anaesthetic instillation (1558 participants) and control (1291 participants) that contributed to one or more of the outcomes. There were no significant differences in mortality or morbidity between intraperitoneal instillation of local anaesthetic and no intraperitoneal instillation. The overall mortality after laparoscopic cholecystectomy is low (0.2%) (Giger 2011). In this review, the trials excluded high‐risk participants and we would anticipate that mortality would be even lower in these studies. To detect a 20% relative risk difference in mortality, more than 350,000 people are necessary. It is unlikely that trials will be powered to measure differences in mortality during laparoscopic cholecystectomy. Major complications during laparoscopic cholecystectomy are also rare. There was only one serious adverse event in the local anaesthetic instillation group (1/236 (0.4%)) compared with no serious adverse events in the control group (0/210 (0%)) (Analysis 1.2). The serious adverse event was thrombophlebitis, which was unrelated to the local anaesthetic instillation. One trial did not report the complications adequately but stated that one person developed lactic acidosis (Roberts 2011). Lactic acidosis has not been reported as a complication of local anaesthetic use (Martindale 2013). Although the remaining trials did not report the overall morbidity, three trials (190 participants) reported that there were no intra‐operative complications (Barczynski 2006; Alptekin 2010; Kim 2010). In addition, 20 trials reported that there were no serious adverse events in any of the 715 participants who received local anaesthetic instillation (Scheinin 1995; Pasqualucci 1996; Mraovic 1997; Weber 1997; Elfberg 2000; Kolsi 2000; Tunca 2001; Labaille 2002; Maestroni 2002; Rudra 2002; Paulson 2003; Razek 2003; Louizos 2005; Hazinedaroglu 2006; Karaaslan 2006; Garcia 2007; Kucuk 2007; Nicolau 2008; Alper 2009; Kallel 2011). Overall, there were no serious adverse events related to local anaesthetics in the participants included in this review. The morbidity associated with local anaesthetics is very low with a reporting rate of approximately five adverse drug reactions per one million ampoules sold (Fuzier 2009). About 45% of these adverse drug reactions were serious (Fuzier 2009). Given this low morbidity associated with local anaesthetics and considering that the laparoscopic cholecystectomy is performed under general anaesthesia with people likely to be monitored because of the use of the general anaesthetic agent, one can conclude that local anaesthetics are generally safe to use in people undergoing laparoscopic cholecystectomy without allergy to local anaesthetic.
None of the trials reported quality of life, return to normal activity, and return to work. The main purpose of the local anaesthetic is to decrease pain enabling the people to be discharged from hospital and to return to normal activity and work as early as possible. These outcomes are not only important for the patients but also important for the state‐funded health system. While quality of life is the outcome that is used for assessing the cost‐effectiveness of an intervention, return to normal activity and return to work may also have relevance to the state in terms of lack of productivity of the individual. There were no significant differences in the hospital stay either in terms of proportion discharged as day‐surgery or in terms of the length of the hospital stay in the comparisons that reported these outcomes (Analysis 1.3; Analysis 1.4). These outcomes are important for the patients in a private health setting and for the state in a state‐funded health system because of the costs associated with hospital stay. However, only eight trials reported this important outcome (Scheinin 1995; Fornari 1996; Szem 1996; Jiranantarat 2002; Paulson 2003; Todorov 2009; Zimmer 2010; Roberts 2011). Future trials on this topic should include these outcomes.
The pain at four to eight hours and at nine to 24 hours were significantly reduced in the intraperitoneal local anaesthetic instillation. The findings were robust to different sensitivity analysis. The trial sequential analysis also confirmed the risk of random errors in concluding that intraperitoneal instillation decreased pain is low. Although some subgroup analyses and meta‐regression showed significant influence of some factors over the effect estimates, these were not consistent. Thus, there is no evidence from this review to suggest that one method of local anaesthetic intraperitoneal instillation is better than another method. These findings are consistent with our findings in a systematic review comparing different methods of local anaesthetic intraperitoneal instillation, which concluded that there is no evidence to suggest that one method of local anaesthetic intraperitoneal instillation is better than another method (Gurusamy 2013a). The mean reduction in pain was about 1 cm on the 0 to 10 cm VAS for four to eight hours and about 0.5 cm for nine to 24 hours. Differences in pain scores of between 0.9 and 1.8 cm are generally considered clinically significant (Todd 1996). Thus, it appears that intraperitoneal local anaesthetic instillation may have a role in increasing the proportion of laparoscopic cholecystectomies performed as day‐surgery since patients undergoing day‐surgery laparoscopic cholecystectomy are discharged between four and eight hours after surgery. There was no significant difference in the proportion of participants who were discharged as day surgery in this review. It does not appear from the description in the trials that day surgery was attempted in most trials. Future trials should investigate the role of intraperitoneal local anaesthetic instillation in the day‐surgery laparoscopic cholecystectomy setting.
Overall completeness and applicability of evidence
Most of the trials in this review involved mainly people undergoing elective laparoscopic cholecystectomy (Included studies; Characteristics of included studies). Most trials included only low anaesthetic‐risk participants undergoing laparoscopic cholecystectomy (Included studies; Characteristics of included studies). The findings of this review are applicable only to such people. A number of local anaesthetic agents were used in different doses, time with relation to surgery, and locations. Although there were some differences noted in the subgroup analysis, another review that compared different methods of intraperitoneal instillation did not find any significant difference between different methods of intraperitoneal local anaesthetic instillation (Gurusamy 2013a). A safe dose of local anaesthetic that takes into account any local anaesthetic administered for wound infiltration is recommended. For bupivacaine, the most common local anaesthetic used in the trials included in this review, this is approximately 2 mg/kg (Martindale 2013).
Quality of the evidence
The overall quality of evidence was very low. Although it is difficult to blind many interventions in surgery, this is one of the few interventions in which adequate blinding can be achieved and high quality evidence is possible. Nevertheless, this is the best evidence that is currently available.
Potential biases in the review process
We performed a thorough search of the literature. However, we included 'pain' as one of the domains in this search strategy. Considering that reduction in pain is the main reason for the use of intraperitoneal local anaesthetic instillation, we expected that all the trials related to the topic would be identified and given the number of trials included in this review, it is likely that most of the trials on this topic have been identified, However, it is possible that trials did not mention pain or words related to pain, and such trials might have been missed by this search strategy. The impact of this is likely to be small since it is likely that most trials would have mentioned the purpose of the use of the intervention. At least two review authors independently identified trials for inclusion and extracted data, thus minimising errors. However, we imputed the mean and standard deviation when these were not available. We performed a sensitivity analysis excluding such trials but this did not change the results significantly thus demonstrating the minimal impact of missing mean or standard deviation.
Agreements and disagreements with other studies or reviews
A review by Boddy et al. revealed that intraperitoneal instillation of local anaesthetic resulted in a reduction of the mean pain score although no reduction in analgesic requirement was noted (Boddy 2006). There were no adverse effects attributable to local anaesthetic. Another review reported similar results, although the meta‐analysis in the review included only three trials and found no significant difference between local anaesthetic instillation and placebo (Gupta 2005). In another review of randomised clinical trials, Bisgaard did not recommend routine use of intraperitoneal local anaesthetics because of conflicting results (Bisgaard 2006). In another review, Kahokehr et al. concluded that intraperitoneal local anaesthetic instillation reduced pain and no further trials were necessary (Kahokehr 2010).
Our conclusions are similar in some aspects to some of the above reviews in that we have found that the rate of adverse events in studies of local anaesthetic intraperitoneal instillation are low and reduces pain in low anaesthetic‐risk people undergoing elective laparoscopic cholecystectomy. However, we have concluded that more trials are necessary to investigate the clinical impact of this reduction in pain.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Trial sequential analysis of mortality
The diversity‐adjusted required information size (DARIS) was calculated to 352,564 participants, based on the proportion of participants in the control group with the outcome of 0.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 446 participants in eight trials, only 0.13% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of morbidity
The diversity‐adjusted required information size (DARIS) was calculated to 34,685 participants, based on the proportion of participants in the control group with the outcome of 2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 446 participants in eight trials, only 1.29% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of proportion discharged as day surgery
The diversity‐adjusted required information size (DARIS) was calculated to 1,419,571 participants, based on the proportion of participants in the control group with the outcome of 48.78%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 99.94%. To account for zero event groups (or groups in which all the participants were discharged as day surgery), a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 242 participants in three trials, only 0.02% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of length of hospital stay
The diversity‐adjusted required information size (DARIS) was 107 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 3.39, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. After accruing 335 participants in five trials, the cumulative Z‐curve (blue line) has crossed the trial sequential monitoring boundaries (red line) but lies within the futility area and the conventional statistical boundaries (dotted red line). This suggests that it is unlikely that future trials are likely to demonstrate any significant difference in the length of hospital stay between local anaesthetic instillation and no local anaesthetic instillation.
Trial sequential analysis of pain (4 to 8 hours)
The diversity‐adjusted required information size (DARIS) was 796 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 3.19, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 87.32%. The conventional statistical boundaries (dotted red line) are crossed by the cumulative Z‐curve (blue line) after the second trial. All the trial sequential monitoring boundaries (red line) are crossed by cumulative Z‐curve after the seventeenth trial. The findings are consistent with local anaesthetic instillation decreasing pain between 4 and 8 hours compared with no local anaesthetic instillation without the risk of random errors.
Trial sequential analysis of pain (9 to 24 hours)
The diversity‐adjusted required information size (DARIS) was 580 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 2.06, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 88.81%. The conventional statistical boundaries (dotted red line) are crossed by the cumulative Z‐curve (blue line) after the fifth trial . All the trial sequential monitoring boundaries (red line) are crossed by cumulative Z‐curve after the twelfth trial. The findings are consistent with local anaesthetic instillation decreasing pain between 9 and 24 hours compared to no local anaesthetic instillation without the risk of random errors.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 1 Mortality.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 2 Serious adverse events.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 3 Proportion discharged as day surgery.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 4 Hospital stay.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 5 Pain (4 to 8 hours).
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 6 Pain (9 to 24 hours).
Comparison 2 Sensitivity analysis, Outcome 1 Proportion discharged as day surgery.
Comparison 2 Sensitivity analysis, Outcome 2 Hospital stay.
Comparison 2 Sensitivity analysis, Outcome 3 Pain (4 to 8 hours) (studies with imputed values removed).
Comparison 2 Sensitivity analysis, Outcome 4 Pain (9 to 24 hours) (studies with imputed values removed).
Comparison 3 Subgroup analysis, Outcome 1 Pain (4 to 8 hours) by local anaesthetic.
Comparison 3 Subgroup analysis, Outcome 2 Pain (4 to 8 hours) by dose.
Comparison 3 Subgroup analysis, Outcome 3 Pain (4 to 8 hours) by form.
Comparison 3 Subgroup analysis, Outcome 4 Pain (4 to 8 hours) by time.
Comparison 3 Subgroup analysis, Outcome 5 Pain (4 to 8 hours) by location.
Comparison 3 Subgroup analysis, Outcome 6 Pain (4 to 8 hours) by norepinephrine use.
Comparison 3 Subgroup analysis, Outcome 7 Pain (4 to 8 hours) by control.
Comparison 3 Subgroup analysis, Outcome 8 Pain (4 to 8 hours) by wound infiltration.
Comparison 3 Subgroup analysis, Outcome 9 Pain (4 to 8 hours) by routine supplemental analgesia.
Comparison 3 Subgroup analysis, Outcome 10 Pain (9 to 24 hours) by local anaesthetic.
Comparison 3 Subgroup analysis, Outcome 11 Pain (9 to 24 hours) by dose.
Comparison 3 Subgroup analysis, Outcome 12 Pain (9 to 24 hours) by form.
Comparison 3 Subgroup analysis, Outcome 13 Pain (9 to 24 hours) by time.
Comparison 3 Subgroup analysis, Outcome 14 Pain (9 to 24 hours) by location.
Comparison 3 Subgroup analysis, Outcome 15 Pain (9 to 24 hours) by norepinephrine use.
Comparison 3 Subgroup analysis, Outcome 16 Pain (9 to 24 hours) by control.
Comparison 3 Subgroup analysis, Outcome 17 Pain (9 to 24 hours) by wound infiltration.
Comparison 3 Subgroup analysis, Outcome 18 Pain (9 to 24 hours) by routine supplemental analgesia.
| Intraperitoneal local anaesthetic instillation compared with control for people undergoing laparoscopic cholecystectomy | |||||
| Patient or population: people undergoing laparoscopic cholecystectomy. | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Intraperitoneallocal anaesthetic instillation | ||||
| Mortality | No mortality in either group | Not estimable | 446 | ⊕⊝⊝⊝ | |
| Serious adverse events | Moderate | RR 3 | 446 | ⊕⊝⊝⊝ | |
| 20 per 1000 | 60 per 1000 | ||||
| Proportion discharged as day surgery | 488 per 1000 | 610 per 1000 | RR 1.25 (0.99 to 1.58) | 242 | ⊕⊝⊝⊝ |
| Hospital stay | The mean hospital stay in the control groups was | The mean hospital stay in the intervention groups was | ‐ | 335 | ⊕⊕⊝⊝ |
| Pain (4 to 8 hours) | The mean pain (4 to 8 hours) in the control groups was | The mean pain (4 to 8 hours) in the intervention groups was | ‐ | 2020 | ⊕⊝⊝⊝ |
| Pain (9 to 24 hours) | The mean pain (9 to 24 hours) in the control groups was | The mean pain (9 to 24 hours) in the intervention groups was | ‐ | 1787 | ⊕⊝⊝⊝ |
| *The basis for the assumed risk was the mean control group risk across studies for day‐surgery proportion. Since there were no events in the control group in the trials included for serious adverse events, the control group proportion used was 2%. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The trial(s) was (were) of high risk of bias. | |||||
| Study name | Local anaesthetic | Time§ | Location | Norepinephrine | Peri‐portal local anaesthetic infiltration | Drain use | Other routine analgesia* |
| bupivacaine | end of surgery | subdiaphragmatic area | no | yes | no | none | |
| bupivacaine | not stated | not stated | no | no | not stated | none | |
| bupivacaine | not stated | not stated | no | yes | not stated | none | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | none | |
| Alagöl 2003 (intraperitoneal ondansetron administered in both groups) | bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | none |
| bupivacaine | end of surgery | diffuse | no | yes | not stated | routine NSAID and opioid analgesics | |
| bupivacaine | end of surgery | gallbladder bed | no | yes | not stated | routine NSAID and opioid analgesics | |
| levobupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | yes | not stated | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | not stated | not stated | |
| bupivacaine | after end of surgery | gallbladder bed | no | not stated | for the continuous infusion group | not stated | |
| bupivacaine | before pneumoperitoneum | diffuse | no | yes | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | diffuse | no | yes | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | no | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | no | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | no | not stated | |
| lignocaine | end of surgery | subdiaphragmatic area | no | yes | yes | no | |
| levobupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | no | no | routine NSAID | |
| bupivacaine | end of surgery | gallbladder bed | no | no | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | yes | not stated | no | no | |
| ropivacaine | end of surgery | gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| bupivacaine (s75‐r25) | end of surgery | subdiaphragmatic area | no | not stated | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | not stated | no | not stated | not stated | not stated | |
| bupivacaine | not stated | not stated | no | no | not stated | routine NSAID | |
| bupivacaine | not stated | not stated | no | no | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | yes | not stated | no | |
| bupivacaine | end of surgery | not stated | no | not stated | not stated | no | |
| Jabbour‐Khoury 2005 (intravenous ketoprofen administered in both groups) | bupivacaine | end of surgery | not stated | no | not stated | not stated | no |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | yes | no | not stated | no | |
| lignocaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | not stated | |
| bupivacaine | before pneumoperitoneum | gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | not stated | no | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | no | no | |
| bupivacaine | after end of surgery | subdiaphragmatic area and gallbladder bed (by infusion pump) | no | not stated | possibly for the continuous infusion group | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| ropivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| lignocaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| ropivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | no | not stated | no | |
| ropivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | no | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | no | not stated | no | |
| ropivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | no | no | not stated | no | |
| ropivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | no | no | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | yes | yes | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | no | not stated | routine NSAID | |
| lignocaine | end of surgery | subdiaphragmatic area | no | yes | no | routine NSAID | |
| levobupivacaine | end of surgery | gallbladder bed | no | no | not stated | no | |
| levobupivacaine | end of surgery | gallbladder bed | no | yes | not stated | no | |
| ropivacaine | before pneumoperitoneum | diffuse | no | not stated | not stated | routine NSAID | |
| bupivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| levobupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | selectively (reasons not stated) | not stated clearly | |
| ropivacaine | end of surgery | gallbladder bed | no | no | selectively (for patients with difficult haemostasis) | routine NSAID | |
| ropivacaine | end of surgery | gallbladder bed | no | yes | selectively (for patients with difficult haemostasis) | routine NSAID | |
| bupivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | no | no | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | no | no | no | |
| bupivacaine | just after creation of pneumoperitoneum and end of surgery | subdiaphragmatic area and gallbladder bed | no | no | no | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| lignocaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine NSAID | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine NSAID | |
| levobupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine NSAID | |
| bupivacaine | not stated | not stated | yes | yes | not stated | not stated | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area | no | yes | selectively (reasons not stated) | routine NSAID and opioid analgesics | |
| bupivacaine | just after creation of pneumoperitoneum | gallbladder bed | no | yes | selectively (reasons not stated) | routine NSAID and opioid analgesics | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | no | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | yes | not stated | no | no | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | routine opioid analgesic | |
| levobupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | not stated | not stated | |
| bupivacaine | just after creation of pneumoperitoneum | subdiaphragmatic area and gallbladder bed | yes | not stated | not stated | no | |
| bupivacaine | end of surgery | gallbladder bed | no | no | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| bupivacaine | end of surgery | subdiaphragmatic area | no | not stated | not stated | not stated | |
| bupivacaine | just after creation of pneumoperitoneum | diffuse | no | yes | not stated | no | |
| bupivacaine | end of surgery | subdiaphragmatic area and gallbladder bed | no | not stated | no | routine NSAID and opioid analgesic | |
| NSAID: non‐steroidal anti‐inflammatory drug. § 'End of surgery' indicates instillation after removal of gallbladder usually before closure of the wounds but in all instances before the reversal of anaesthesia; 'after end of surgery' indicates that the participant received the local anaesthetic by an infusion pump after reversal of anaesthesia. * refers to routine analgesia. Most trials allowed 'on‐demand' analgesia or analgesia was administered if the pain was above a certain threshold. | |||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality Show forest plot | 8 | 446 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Serious adverse events Show forest plot | 8 | 446 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.13, 67.06] |
| 3 Proportion discharged as day surgery Show forest plot | 3 | 242 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.99, 1.58] |
| 4 Hospital stay Show forest plot | 5 | 335 | Mean Difference (IV, Fixed, 95% CI) | 0.04 [‐0.23, 0.32] |
| 5 Pain (4 to 8 hours) Show forest plot | 32 | 2020 | Mean Difference (IV, Fixed, 95% CI) | ‐0.99 [‐1.10, ‐0.88] |
| 6 Pain (9 to 24 hours) Show forest plot | 29 | 1787 | Mean Difference (IV, Fixed, 95% CI) | ‐0.53 [‐0.62, ‐0.44] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Proportion discharged as day surgery Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Best‐best scenario | 3 | 244 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.25 [0.99, 1.58] |
| 1.2 Best‐worst scenario | 3 | 244 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.21 [0.96, 1.53] |
| 1.3 Worst‐best scenario | 3 | 244 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [1.00, 1.60] |
| 1.4 Worst‐worst scenario | 3 | 244 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.23 [0.97, 1.55] |
| 2 Hospital stay Show forest plot | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.53 [‐0.14, 1.21] |
| 3 Pain (4 to 8 hours) (studies with imputed values removed) Show forest plot | 10 | 576 | Mean Difference (IV, Fixed, 95% CI) | ‐1.04 [‐1.17, ‐0.90] |
| 4 Pain (9 to 24 hours) (studies with imputed values removed) Show forest plot | 12 | 676 | Mean Difference (IV, Fixed, 95% CI) | ‐0.38 [‐0.48, ‐0.28] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain (4 to 8 hours) by local anaesthetic Show forest plot | 32 | 2020 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.52, ‐0.91] |
| 1.1 Bupivacaine | 25 | 1626 | Mean Difference (IV, Random, 95% CI) | ‐1.38 [‐1.77, ‐0.98] |
| 1.2 Levobupivacaine | 2 | 80 | Mean Difference (IV, Random, 95% CI) | ‐0.99 [‐1.69, ‐0.28] |
| 1.3 Ropivacaine | 5 | 252 | Mean Difference (IV, Random, 95% CI) | ‐0.71 [‐1.03, ‐0.39] |
| 1.4 Lignocaine | 2 | 62 | Mean Difference (IV, Random, 95% CI) | ‐1.37 [‐2.37, ‐0.37] |
| 2 Pain (4 to 8 hours) by dose Show forest plot | 32 | 2020 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.52, ‐0.91] |
| 2.1 Weight‐based | 7 | 385 | Mean Difference (IV, Random, 95% CI) | ‐1.11 [‐1.26, ‐0.96] |
| 2.2 Fixed dose | 25 | 1635 | Mean Difference (IV, Random, 95% CI) | ‐1.32 [‐1.78, ‐0.87] |
| 3 Pain (4 to 8 hours) by form Show forest plot | 32 | 2020 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.52, ‐0.91] |
| 3.1 Liquid | 29 | 1880 | Mean Difference (IV, Random, 95% CI) | ‐0.96 [‐1.16, ‐0.75] |
| 3.2 Others | 4 | 140 | Mean Difference (IV, Random, 95% CI) | ‐3.03 [‐6.58, 0.51] |
| 4 Pain (4 to 8 hours) by time Show forest plot | 32 | 2020 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.52, ‐0.91] |
| 4.1 Before pneumoperitoneum | 2 | 120 | Mean Difference (IV, Random, 95% CI) | ‐1.01 [‐1.23, ‐0.79] |
| 4.2 Just after creation of pneumoperitoneum | 8 | 382 | Mean Difference (IV, Random, 95% CI) | ‐1.30 [‐1.74, ‐0.86] |
| 4.3 End of surgery | 24 | 1361 | Mean Difference (IV, Random, 95% CI) | ‐1.17 [‐1.70, ‐0.64] |
| 4.4 After end of surgery | 1 | 20 | Mean Difference (IV, Random, 95% CI) | ‐1.68 [‐4.07, 0.71] |
| 4.5 Just after creation of pneumoperitoneum and end of surgery | 3 | 137 | Mean Difference (IV, Random, 95% CI) | ‐1.49 [‐2.87, ‐0.12] |
| 5 Pain (4 to 8 hours) by location Show forest plot | 32 | 2020 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.52, ‐0.91] |
| 5.1 Gallbladder bed | 9 | 445 | Mean Difference (IV, Random, 95% CI) | ‐0.87 [‐1.23, ‐0.51] |
| 5.2 Subdiaphragmatic area | 4 | 358 | Mean Difference (IV, Random, 95% CI) | ‐1.55 [‐2.97, ‐0.14] |
| 5.3 Subdiaphragmatic area and gallbladder bed | 18 | 997 | Mean Difference (IV, Random, 95% CI) | ‐0.92 [‐1.21, ‐0.64] |
| 5.4 Diffuse | 3 | 220 | Mean Difference (IV, Random, 95% CI) | ‐2.54 [‐3.75, ‐1.33] |
| 6 Pain (4 to 8 hours) by norepinephrine use Show forest plot | 32 | 2020 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.52, ‐0.91] |
| 6.1 Norepinephrine used | 6 | 395 | Mean Difference (IV, Random, 95% CI) | ‐1.33 [‐1.98, ‐0.68] |
| 6.2 Norepinephrine not used | 26 | 1625 | Mean Difference (IV, Random, 95% CI) | ‐1.19 [‐1.54, ‐0.83] |
| 7 Pain (4 to 8 hours) by control Show forest plot | 32 | 2020 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.52, ‐0.91] |
| 7.1 Normal saline | 26 | 1619 | Mean Difference (IV, Random, 95% CI) | ‐1.23 [‐1.57, ‐0.89] |
| 7.2 No intervention | 3 | 145 | Mean Difference (IV, Random, 95% CI) | ‐1.15 [‐2.42, 0.11] |
| 7.3 Others | 5 | 256 | Mean Difference (IV, Random, 95% CI) | ‐1.11 [‐1.80, ‐0.43] |
| 8 Pain (4 to 8 hours) by wound infiltration Show forest plot | 8 | 574 | Mean Difference (IV, Random, 95% CI) | ‐1.22 [‐1.79, ‐0.66] |
| 8.1 Wound infiltration used | 5 | 405 | Mean Difference (IV, Random, 95% CI) | ‐1.81 [‐2.66, ‐0.96] |
| 8.2 Wound infiltration not used | 4 | 169 | Mean Difference (IV, Random, 95% CI) | ‐0.53 [‐0.89, ‐0.18] |
| 9 Pain (4 to 8 hours) by routine supplemental analgesia Show forest plot | 28 | 1720 | Mean Difference (IV, Fixed, 95% CI) | ‐0.99 [‐1.10, ‐0.88] |
| 9.1 Routine supplemental analgesia | 8 | 495 | Mean Difference (IV, Fixed, 95% CI) | ‐1.53 [‐1.88, ‐1.19] |
| 9.2 No routine supplemental analgesia | 20 | 1225 | Mean Difference (IV, Fixed, 95% CI) | ‐0.93 [‐1.05, ‐0.81] |
| 10 Pain (9 to 24 hours) by local anaesthetic Show forest plot | 29 | 1787 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.11, ‐0.51] |
| 10.1 Bupivacaine | 22 | 1415 | Mean Difference (IV, Random, 95% CI) | ‐0.94 [‐1.33, ‐0.55] |
| 10.2 Levobupivacaine | 2 | 80 | Mean Difference (IV, Random, 95% CI) | ‐0.47 [‐1.48, 0.54] |
| 10.3 Ropivacaine | 5 | 252 | Mean Difference (IV, Random, 95% CI) | ‐0.34 [‐0.62, ‐0.06] |
| 10.4 Lignocaine | 1 | 40 | Mean Difference (IV, Random, 95% CI) | ‐1.1 [‐2.12, ‐0.08] |
| 11 Pain (9 to 24 hours) by dose Show forest plot | 29 | 1787 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.11, ‐0.51] |
| 11.1 Weight‐based | 7 | 385 | Mean Difference (IV, Random, 95% CI) | ‐0.41 [‐0.53, ‐0.30] |
| 11.2 Fixed dose | 22 | 1402 | Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.36, ‐0.45] |
| 12 Pain (9 to 24 hours) by form Show forest plot | 29 | 1787 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.11, ‐0.51] |
| 12.1 Liquid | 25 | 1597 | Mean Difference (IV, Random, 95% CI) | ‐0.63 [‐0.89, ‐0.38] |
| 12.2 Others | 5 | 190 | Mean Difference (IV, Random, 95% CI) | ‐1.93 [‐4.10, 0.24] |
| 13 Pain (9 to 24 hours) by time Show forest plot | 29 | 1787 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.11, ‐0.51] |
| 13.1 Before pneumoperitoneum | 2 | 120 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐0.55, ‐0.25] |
| 13.2 Just after creation of pneumoperitoneum | 7 | 252 | Mean Difference (IV, Random, 95% CI) | ‐1.08 [‐1.95, ‐0.21] |
| 13.3 End of surgery | 22 | 1258 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.27, ‐0.35] |
| 13.4 After end of surgery | 1 | 20 | Mean Difference (IV, Random, 95% CI) | 0.83 [‐0.43, 2.09] |
| 13.5 Just after creation of pneumoperitoneum and end of surgery | 3 | 137 | Mean Difference (IV, Random, 95% CI) | ‐1.19 [‐2.17, ‐0.20] |
| 14 Pain (9 to 24 hours) by location Show forest plot | 29 | 1787 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.11, ‐0.51] |
| 14.1 Gallbladder bed | 17 | 942 | Mean Difference (IV, Random, 95% CI) | ‐0.58 [‐0.99, ‐0.18] |
| 14.2 Subdiaphragmatic area | 2 | 250 | Mean Difference (IV, Random, 95% CI) | ‐3.33 [‐6.66, ‐0.00] |
| 14.3 Subdiaphragmatic area and gallbladder bed | 7 | 325 | Mean Difference (IV, Random, 95% CI) | ‐0.57 [‐0.90, ‐0.24] |
| 14.4 Diffuse | 4 | 270 | Mean Difference (IV, Random, 95% CI) | ‐1.55 [‐2.44, ‐0.66] |
| 15 Pain (9 to 24 hours) by norepinephrine use Show forest plot | 29 | 1787 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.11, ‐0.51] |
| 15.1 Norepinephrine used | 6 | 395 | Mean Difference (IV, Random, 95% CI) | ‐1.07 [‐1.74, ‐0.41] |
| 15.2 Norepinephrine not used | 23 | 1392 | Mean Difference (IV, Random, 95% CI) | ‐0.69 [‐1.03, ‐0.35] |
| 16 Pain (9 to 24 hours) by control Show forest plot | 29 | 1787 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.11, ‐0.51] |
| 16.1 Normal saline | 22 | 1336 | Mean Difference (IV, Random, 95% CI) | ‐0.83 [‐1.16, ‐0.50] |
| 16.2 No intervention | 3 | 145 | Mean Difference (IV, Random, 95% CI) | ‐1.65 [‐3.80, 0.51] |
| 16.3 Others | 6 | 306 | Mean Difference (IV, Random, 95% CI) | ‐0.64 [‐1.68, 0.39] |
| 17 Pain (9 to 24 hours) by wound infiltration Show forest plot | 8 | 499 | Mean Difference (IV, Random, 95% CI) | ‐0.81 [‐1.24, ‐0.38] |
| 17.1 Wound infiltration used | 5 | 330 | Mean Difference (IV, Random, 95% CI) | ‐1.27 [‐1.98, ‐0.56] |
| 17.2 Wound infiltration not used | 4 | 169 | Mean Difference (IV, Random, 95% CI) | ‐0.32 [‐0.59, ‐0.05] |
| 18 Pain (9 to 24 hours) by routine supplemental analgesia Show forest plot | 26 | 1532 | Mean Difference (IV, Fixed, 95% CI) | ‐0.54 [‐0.63, ‐0.44] |
| 18.1 Routine supplemental analgesia | 6 | 315 | Mean Difference (IV, Fixed, 95% CI) | ‐1.05 [‐1.41, ‐0.69] |
| 18.2 No routine supplemental analgesia | 20 | 1217 | Mean Difference (IV, Fixed, 95% CI) | ‐0.50 [‐0.60, ‐0.40] |
