Abstract
Background
While laparoscopic cholecystectomy is generally considered to be less painful than open surgery, pain is one of the important reasons for delayed discharge after day surgery resulting in overnight stay following laparoscopic cholecystectomy. The safety and effectiveness of local anaesthetic wound infiltration in people undergoing laparoscopic cholecystectomy is not known.
Objectives
To assess the benefits and harms of local anaesthetic wound infiltration in patients undergoing laparoscopic cholecystectomy and to identify the best method of local anaesthetic wound infiltration with regards to the type of local anaesthetic, dosage, and time of administration of the local anaesthetic.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded until February 2013 to identify studies of relevance to this review. We included randomised clinical trials for benefit and quasi‐randomised and comparative non‐randomised studies for treatment‐related harms.
Selection criteria
Only randomised clinical trials (irrespective of language, blinding, or publication status) comparing local anaesthetic wound infiltration versus placebo, no intervention, or inactive control during laparoscopic cholecystectomy, trials comparing different local anaesthetic agents for local anaesthetic wound infiltration, and trials comparing the different times of local anaesthetic wound infiltration were considered for the review.
Data collection and analysis
Two review authors collected the data independently. We analysed the data with both fixed‐effect and random‐effects meta‐analysis models using RevMan. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI).
Main results
Twenty‐six trials fulfilled the inclusion criteria of the review. All the 26 trials except one trial of 30 participants were at high risk of bias. Nineteen of the trials with 1263 randomised participants provided data for this review. Ten of the 19 trials compared local anaesthetic wound infiltration versus inactive control. One of the 19 trials compared local anaesthetic wound infiltration with two inactive controls, normal saline and no intervention. Two of the 19 trials had four arms comparing local anaesthetic wound infiltration with inactive controls in the presence and absence of co‐interventions to decrease pain after laparoscopic cholecystectomy. Four of the 19 trials had three or more arms that could be included for the comparison of local anaesthetic wound infiltration versus inactive control and different methods of local anaesthetic wound infiltration. The remaining two trials compared different methods of local anaesthetic wound infiltration.
Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. Seventeen trials randomised a total of 1095 participants to local anaesthetic wound infiltration (587 participants) versus no local anaesthetic wound infiltration (508 participants). Various anaesthetic agents were used but bupivacaine was the commonest local anaesthetic used. There was no mortality in either group in the seven trials that reported mortality (0/280 (0%) in local anaesthetic infiltration group versus 0/259 (0%) in control group). The effect of local anaesthetic on the proportion of people who developed serious adverse events was imprecise and compatible with increase or no difference in serious adverse events (seven trials; 539 participants; 2/280 (0.8%) in local anaesthetic group versus 1/259 (0.4%) in control; RR 2.00; 95% CI 0.19 to 21.59; very low quality evidence). None of the serious adverse events were related to local anaesthetic wound infiltration. None of the trials reported patient quality of life. The proportion of participants who were discharged as day surgery patients was higher in the local anaesthetic infiltration group than in the no local anaesthetic infiltration group (one trial; 97 participants; 33/50 (66.0%) in the local anaesthetic group versus 20/47 (42.6%) in the control group; RR 1.55; 95% CI 1.05 to 2.28; very low quality evidence). The effect of local anaesthetic on the length of hospital stay was compatible with a decrease, increase, or no difference in the length of hospital stay between the two groups (four trials; 327 participants; MD ‐0.26 days; 95% CI ‐0.67 to 0.16; very low quality evidence). The pain scores as measured by the visual analogue scale (0 to 10 cm) were lower in the local anaesthetic infiltration group than the control group at 4 to 8 hours (13 trials; 806 participants; MD ‐1.33 cm on the VAS; 95% CI ‐1.54 to ‐1.12; very low quality evidence) and 9 to 24 hours (12 trials; 756 participants; MD ‐0.36 cm on the VAS; 95% CI ‐0.53 to ‐0.20; very low quality evidence). The effect of local anaesthetic on the time taken to return to normal activity between the two groups was imprecise and compatible with a decrease, increase, or no difference in the time taken to return to normal activity (two trials; 195 participants; MD 0.14 days; 95% CI ‐0.59 to 0.87; very low quality evidence). None of the trials reported on return to work.
Four trials randomised a total of 149 participants to local anaesthetic wound infiltration prior to skin incision (74 participants) versus local anaesthetic wound infiltration at the end of surgery (75 participants). Two trials randomised a total of 176 participants to four different local anaesthetics (bupivacaine, levobupivacaine, ropivacaine, neosaxitoxin). Although there were differences between the groups in some outcomes the changes were not consistent. There was no evidence to support the preference of one local anaesthetic over another or to prefer administration of local anaesthetic at a specific time compared with another.
Authors' conclusions
Serious adverse events were rare in studies evaluating local anaesthetic wound infiltration (very low quality evidence). There is very low quality evidence that infiltration reduces pain in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is likely to be small. Further randomised clinical trials at low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment.
Keywords: Humans; Ambulatory Surgical Procedures; Anesthesia, Local; Anesthesia, Local/methods; Anesthetics, Local; Anesthetics, Local/administration & dosage; Bupivacaine; Bupivacaine/administration & dosage; Cholecystectomy, Laparoscopic; Cholecystectomy, Laparoscopic/adverse effects; Cholecystectomy, Laparoscopic/methods; Length of Stay; Pain, Postoperative; Pain, Postoperative/prevention & control; Randomized Controlled Trials as Topic; Sodium Chloride; Sodium Chloride/administration & dosage
Plain language summary
Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy (local anaesthetic administration into the surgical wound in people undergoing laparoscopic cholecystectomy)
Background About 10% to 15% of the adult western population have gallstones. Between 1% and 4% become symptomatic each year. Removal of the gallbladder (cholecystectomy) is the mainstay treatment for symptomatic gallstones. More than half a million cholecystectomies are performed per year in the United States alone. Laparoscopic cholecystectomy (removal of the gallbladder through a keyhole, also known as a port) is now the preferred method of cholecystectomy. While laparoscopic cholecystectomy is generally considered to be less painful than open surgery, pain is one the major reasons for delayed hospital discharge after laparoscopic cholecystectomy. Administration of local anaesthetics (drugs that numb part of the body, similar to the ones used by the dentist to prevent people from feeling pain) into the surgical wound (local anaesthetic wound infiltration) may be an effective way of decreasing pain after laparoscopic cholecystectomy. However, the benefits and harms of local anaesthetic wound infiltration is not known. We sought to answer these questions by reviewing the medical literature and obtaining information from randomised clinical trials on the benefits related to the treatment. When conducted well, such studies provide the most accurate information on the best treatment. We also considered comparative non‐randomised studies for treatment‐related harms. Two authors searched the literature until February 2013 and obtained information from the studies thereby minimising errors.
Study characteristics We identified 19 randomised clinical trials in this review. Most participants in the trials were low anaesthetic risk people undergoing planned laparoscopic cholecystectomy.
Key results A total of 1095 participants were randomised to local anaesthetic wound infiltration (587 participants) or no local anaesthetic wound infiltration (508 participants) in 17 trials. The choice of whether the participants received local anaesthetic agents (or not) was determined by a method similar to the toss of a coin so that the treatments were compared in groups of patients who were as similar as possible. There were no deaths in either group in the seven trials (539 participants) that reported deaths. The difference in serious complications between the groups was imprecise. There were no local anaesthetic‐related complications in nearly 450 participants who received local anaesthetic wound infiltration in the different trials that reported complications. None of the trials reported quality of life or the time taken to return to work. The proportion of participants who were discharged as day surgery patients was higher in the local anaesthetic group than in the control group in the only trial that reported this information. The difference in the length of hospital stay or the time taken to return to normal activity was imprecise. Pain was lower in the participants who received intra‐abdominal local anaesthetic administration compared with those in the control groups at four to eight hours and at nine to 24 hours, as measured by the visual analogue scale (a chart which rates the amount of pain on a scale of 1 to 10). In the comparisons of different methods of local anaesthetic infiltration, there were differences between the groups in some outcomes but the changes were not consistent. There is, therefore, no evidence to prefer any particular drug or method of administering local anaesthetics. Serious adverse events were rare in studies evaluating local anaesthetic wound infiltration. There is very low quality evidence that infiltration reduces pain in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is likely to be small.
Quality of evidence Most of the trials were at high risk of bias, that is there is a possibility of arriving at wrong conclusions by overestimating the benefits or underestimating the harms of one method over another because of the way a study was conducted. The overall quality of evidence was very low.
Future research Further trials are necessary. Such trials should include outcomes such as quality of life, hospital stay, the time taken to return to normal activity, and the time taken to return to work, which are important for the person undergoing laparoscopic cholecystectomy and the people who provide funds for the treatment.
Summary of findings
Summary of findings for the main comparison. Local anaesthetic wound infiltration compared to no local anaesthetic wound infiltration for people undergoing laparoscopic cholecystectomy.
| Local anaesthetic wound infiltration compared to no local anaesthetic wound infiltration for people undergoing laparoscopic cholecystectomy | |||||
| Patient or population: patients with people undergoing laparoscopic cholecystectomy. Settings: secondary or tertiary. Intervention: local anaesthetic wound infiltration. Comparison: no local anaesthetic wound infiltration. | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Quality of the evidence (GRADE) | |
| Assumed risk | Corresponding risk | ||||
| No local anaesthetic wound infiltration | Local anaesthetic wound infiltration | ||||
| Mortality | There was no mortality in either group. | Not estimable | 539 (7 trials) | ⊕⊝⊝⊝ very low1,2 | |
| Serious adverse events | 4 per 1000 | 8 per 1000 (1 to 83) | RR 2 (0.19 to 21.59) | 539 (7 trials) | ⊕⊝⊝⊝ very low1,2 |
| Proportion discharged as day surgery | 426 per 1000 | 660 per 1000 (447 to 970) | RR 1.55 (1.05 to 2.28) | 97 (1 trial) | ⊕⊝⊝⊝ very low1,3 |
| Length of hospital stay | The mean length of hospital stay in the control groups was 1.9 days | The mean length of hospital stay in the intervention groups was 0.26 lower (0.67 lower to 0.16 higher) | 327 (4 trials) | ⊕⊝⊝⊝ very low1,4,5 | |
| Pain 4 to 8 hours | The mean pain 4 to 8 hours in the control groups was 3.61 cm VAS | The mean pain 4 to 8 hours in the intervention groups was 1.33 lower (1.54 to 1.12 lower) | 806 (13 trials) | ⊕⊝⊝⊝ very low1,4 | |
| Pain 9 to 24 hours | The mean pain 9 to 24 hours in the control groups was 2.45 cm VAS | The mean pain 9 to 24 hours in the intervention groups was 0.36 lower (0.53 to 0.2 lower) | 756 (12 trials) | ⊕⊕⊝⊝ low1 | |
| Return to normal activity | The mean return to normal activity in the control groups was 6.8 days | The mean return to normal activity in the intervention groups was 0.14 higher (0.59 lower to 0.87 higher) | 195 (2 trials) | ⊕⊝⊝⊝ very low1,5 | |
| *The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; VAS: visual analogue scale. | |||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | |||||
1 The trial(s) was (were) of high risk of bias (downgraded by 2 points). 2 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both. The number of events in the intervention and control group was fewer than 300 (downgraded by 2 points). 3 There were fewer than 300 events (downgraded by 1 point). 4 There was severe heterogeneity as noted by the I‐square and the lack of overlap of confidence intervals (downgraded by 2 points). 5 There were fewer than 400 participants in both groups in total (downgraded by 1 point).
Summary of findings 2. Wound infiltration with different local anaesthetic agents for people undergoing laparoscopic cholecystectomy.
| Wound infiltration with different local anaesthetic agents for people undergoing laparoscopic cholecystectomy | |||||
| Patient or population: people undergoing laparoscopic cholecystectomy. Settings: secondary or tertiary. Intervention: different local anaesthetic agents. | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (trials) | Quality of the evidence (GRADE) | |
| Assumed risk | Corresponding risk | ||||
| Control | Different local anaesthetic agents | ||||
| Neosaxitoxin versus bupivacaine | |||||
| Mortality | There was no mortality in either group | Not estimable | 137 (1 trial) | ⊕⊝⊝⊝ very low1,2 | |
| Serious adverse events | There were no serious adverse events in either group | Not estimable | 137 (1 trial) | ⊕⊝⊝⊝ very low1,2 | |
| Length of hospital stay | The mean length of hospital stay in the control groups was 1 day | The mean length of hospital stay in the intervention groups was 0 higher (0.65 lower to 0.65 higher) | 137 (1 trial) | ⊕⊝⊝⊝ very low1,3 | |
| Return to normal activity | The mean return to normal activity in the control groups was 5.7 days | The mean return to normal activity in the intervention groups was 1.9 lower (2.71 to 1.09 lower) | 137 (1 trial) | ⊕⊝⊝⊝ very low1,3 | |
| Ropivacaine versus levobupivacaine | |||||
| Pain 4 to 8 hours | The mean pain 4 to 8 hours in the control groups was 1.1 cm VAS | The mean pain 4 to 8 hours in the intervention groups was 2.3 higher (0.23 to 4.37 higher) | 39 (1 trial) | ⊕⊝⊝⊝ very low1,3 | |
| Pain 9 to 24 hours | The mean pain 9 to 24 hours in the control groups was 0.6 cm VAS | The mean pain 9 to 24 hours in the intervention groups was 1.9 higher (1 to 2.8 higher) | 39 (1 trial) | ⊕⊝⊝⊝ very low1,3 | |
| *The basis for the assumed risk was the control group risk. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; VAS: visual analogue scale. | |||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | |||||
1 The trial was of high risk of bias (downgraded by 2 points). 2 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both. The number of events in the intervention and control group was fewer than 300 (downgraded by 2 points). 3 There were fewer than 400 participants included in total (downgraded by 1 point).
Summary of findings 3. Local anaesthetic wound infiltration before incision compared to end of surgery for people undergoing laparoscopic cholecystectomy.
| Local anaesthetic wound infiltration before incision compared to end of surgery for people undergoing laparoscopic cholecystectomy | ||||||
| Patient or population: patients with people undergoing laparoscopic cholecystectomy Settings: secondary or tertiary Intervention: before incision Comparison: end of surgery | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| End of surgery | Before incision | |||||
| Mortality | There was no mortality in either group | Not estimable | 43 (1 trial) | ⊕⊝⊝⊝ very low1,2 | ||
| Serious adverse events | There were no serious adverse events in either group | Not estimable | 43 (1 trial) | ⊕⊝⊝⊝ very low1,2 | ||
| Pain 4 to 8 hours | The mean pain 4 to 8 hours in the control groups was 3 cm VAS | The mean pain 4 to 8 hours in the intervention groups was 0.18 higher (1.9 lower to 2.26 higher) | 76 (2 trials) | ⊕⊝⊝⊝ very low1,3 | ||
| Pain 9 to 24 hours | The mean pain 9 to 24 hours in the control groups was 2.7 cm VAS | The mean pain 9 to 24 hours in the intervention groups was 0.1 higher (2.53 lower to 2.73 higher) | 40 (1 trial) | ⊕⊝⊝⊝ very low1,3 | ||
| Return to normal activity | The mean return to normal activity in the control groups was 7.6 days | The mean return to normal activity in the intervention groups was 0.5 higher (1.05 lower to 2.05 higher) | 30 (1 trial) | ⊕⊝⊝⊝ very low1,3 | ||
| *The basis for the assumed risk is the mean control group risk. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; VAS: visual analogue scale. | ||||||
| GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. | ||||||
1 The trial(s) was (were) of high risk of bias (downgraded by 2 points). 2 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both. The number of events in the intervention and control group was fewer than 300 (downgraded by 2 points). 3 The confidence intervals overlapped 0 and minimal clinically important difference. The total number of patients in the intervention and control group was fewer than 400 (downgraded by 2 points).
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). Every year, 1.5 million cholecystectomies are performed in the US and 60,000 in the UK (Dolan 2009; HES 2011). Approximately 80% of the cholecystectomies are performed laparoscopically (keyhole surgery) (Ballal 2009).
While laparoscopic cholecystectomy is generally considered to be less painful than open surgery, pain may affect the quality of life of people undergoing laparoscopic cholecystectomy and is one of the important reasons for delayed discharge after laparoscopic cholecystectomy (Gurusamy 2008; Gurusamy 2008a). The pain after laparoscopic cholecystectomy could be incisional pain, shoulder pain, or abdominal pain (Ng 2004). A cut in the skin and subcutaneous tissues during the surgical incision causes damage to the tissues which stimulates peripheral nociceptors resulting in pain sensation (Dubin 2010). In addition, inflammation of the wound can stimulate the nociceptors resulting in pain sensation (Clark 2006; Dubin 2010).
Description of the intervention
Wound infiltration with local anaesthetic agents such as lignocaine or bupivacaine has been suggested as a way of reduction of incisional pain (Dath 1999). The wound infiltration can be performed before skin incision (at the beginning of surgery) or after skin incision (at the end of surgery) (Dath 1999; Cantore 2008). The wound infiltration is performed to involve at least the skin and subcutaneous tissue but can be performed until the parietal peritoneum (Lee 2001). The adverse events related to local anaesthetic wound infiltration include allergic reactions, fits (convulsions), cardiac arrhythmias, and cardiac arrest (Fuzier 2009).
Alternative interventions to local anaesthetic wound infiltration for decreasing pain after laparoscopic cholecystectomy include intraperitoneal local anaesthetic instillation (Gurusamy 2013a) and pharmacological interventions such as non‐steroidal anti‐inflammatory drugs and opiate analgesics (Gurusamy 2013b).
How the intervention might work
Local anaesthetics inhibit the voltage‐gated sodium channels. This results in decreased excitability of nerves transmitting pain (Butterworth 1990). Local anaesthetic wound infiltration might decrease incisional pain by decreasing the excitability of nerves transmitting pain.
Why it is important to do this review
We were not able to identify any systematic review assessing the benefits and harms of local anaesthetic wound infiltration in people undergoing laparoscopic cholecystectomy. A reduction in pain may improve quality of life and increase the proportion of people discharged as day surgery patients, and so may result in cost savings. The impact of wound infiltration on reduction of pain is different with different procedures (Joshi 2012; Kjaergaard 2012). So, it is important to assess the impact of local anaesthetic wound infiltration on pain after laparoscopic cholecystectomy.
Objectives
The primary objective of this review was to assess the benefits and harms of local anaesthetic wound infiltration in people undergoing laparoscopic cholecystectomy. The secondary objectives was to identify the best method of local anaesthetic wound infiltration with regards to the type of local anaesthetic, dosage, and time of administration of the local anaesthetic.
Methods
Criteria for considering studies for this review
Types of studies
We considered all randomised clinical trials (irrespective of language, blinding, publication status, or sample size) for inclusion. We excluded quasi‐randomised studies (where the method of allocating participants to a treatment are not strictly random, for example, date of birth, hospital record number, alternation) and 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 the following comparisons.
Wound infiltration compared with no wound infiltration or wound infiltration with normal saline.
Different local anaesthetics used for wound infiltration (eg, bupivacaine versus lignocaine).
Different doses of the same local anaesthetic.
Different times of wound infiltration (eg, before incision compared with after incision).
Co‐interventions were allowed if carried out equally in the trial groups.
Types of outcome measures
Primary outcomes
Mortality.
Serious adverse events defined as any event that would increase mortality, is life‐threatening, requires inpatient hospitalisation, results in a persistent or significant disability, or any important medical event that might have jeopardised the patient or required intervention to prevent it (ICH‐GCP 1997). Complications such as bile duct injury; re‐operations; intra‐abdominal collections requiring drainage (radiological or surgical); infected intra‐abdominal collections; bile leaks requiring drainage, stent, or surgery; convulsions; cardiac arrhythmias which required additional monitoring and hence increased the hospital stay were classified as serious adverse events. Complications such as wound infections, bile leaks, or abdominal collections that did not require any treatment and settled spontaneously were not considered serious adverse events.
Patient quality of life (however defined by authors using a validated scale such as Euro‐QoL or Short Form (SF)‐36).
Secondary outcomes
Hospital stay (length of hospital stay, proportion discharged as day surgery laparoscopic cholecystectomy patients).
Pain (overall pain) at different time points (4 to 8 hours and 9 to 24 hours) using a visual analogue scale.
Return to activity.
Return to work.
We have reported all the outcomes with at least one trial in the Table 1.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003), and the World Health Organization International Clinical Trials Registry Platform portal (WHO ICTRP) (apps.who.int/trialsearch/) until February 2013. The WHO ICTRP portal allows searches of various trial registers including clinicaltrials.gov and ISRCTN among other registers. We have given the search strategies in Appendix 1 with the time spans for the searches.
Searching other resources
We also searched the references of the identified trials to identify further relevant trials.
Data collection and analysis
We performed the systematic review according to the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2014).
Selection of studies
Two authors (SF and KG) identified the trials for inclusion independently of each other. We have also listed the excluded studies with the reasons for the exclusions.
Data extraction and management
Three authors (SF, KG, and MN) extracted the following data independently of each other.
Year and language of publication.
Country in which the trial was conducted.
Year of trial.
Inclusion and exclusion criteria.
Sample size.
Elective surgery or acute cholecystitis.
Local anaesthetic agent used.
Dose of local anaesthetic agent (per kilogram body weight or total dose, however reported by authors).
Timing of administration.
Depth of infiltration (skin versus skin along with tissues until fascial layer).
Intraperitoneal instillation with local anaesthetic.
Other co‐interventions.
Outcomes (mentioned above).
Risk of bias (described below).
We sought any unclear or missing information by contacting the authors of the individual trials. If there was any doubt as to whether the trials shared the same patients, completely or partially (by identifying common authors and centres), we planned to contact the authors of the trials to clarify whether the trial report had been duplicated.
We resolved any differences in opinion through discussion or arbitration by another author (KG).
Assessment of risk of bias in included studies
We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2014). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a), the risk of bias of the trials was assessed based on the following bias risk domains.
Allocation sequence generation
Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial.
Uncertain risk of bias: the method of sequence generation was not specified.
High risk of bias: the sequence generation method was not random.
Allocation concealment
Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (eg, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.
Blinding of participants and personnel
Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to introduce bias on the results.
High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes was likely to be influenced by lack of blinding.
Blinding of outcome assessors
Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.
High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes was likely to be influenced by lack of blinding.
Incomplete outcome data
Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data.
Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting
Low risk of bias: all outcomes were predefined and reported, or all clinically relevant and reasonably expected outcomes were reported.
Uncertain risk of bias: it is unclear whether all predefined and clinically relevant (mortality and morbidity) and reasonably expected outcomes were reported.
High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.
For this purpose, the trial should have been registered either on the www.clinicaltrials.gov website or a similar register with sufficient evidence that the protocol had not been revised during the update, or there should be a protocol for example, published in a paper journal. In the case where the trial was run and published in the years when trial registration was not required, we carefully scrutinised all publications reporting on the trial to identify the trial objectives and outcomes and to determine whether usable data were provided on all outcomes specified in the trial objectives in the results section of publications.
For‐profit bias
Low risk of bias: the trial appears to be free of industry sponsorship or other kind of for‐profit support that may manipulate the trial design, conduct, or results of the trial.
Uncertain risk of bias: the trial may or may not be free of for‐profit bias as no information on clinical trial support or sponsorship is provided.
High risk of bias: the trial is sponsored by the industry or has received other kinds of for‐profit support.
We considered trials which were classified as low risk of bias in all the above domains as trials with low risk of bias and the remaining trials as trials with high risk of bias.
Measures of treatment effect
For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval. We also calculated the risk difference with 95% confidence interval. We planned to report the risk difference only if the conclusions were different from those of the risk ratio. Risk difference includes 'zero event trials' (trials in which both groups have no events) for calculating the summary treatment effect, while such trials will not be taken into account when calculating the summary treatment effect in the case of RR. For continuous variables, we calculated the mean difference (MD) with 95% confidence interval for outcomes such as total hospital stay, or standardised mean difference (SMD) with 95% confidence interval for outcomes such as quality of life where different authors use different scales.
Unit of analysis issues
The unit of analysis was the person about to undergo laparoscopic cholecystectomy and randomised to local anaesthetic wound infiltration or control.
Dealing with missing data
We performed an intention‐to‐treat analysis (Newell 1992) whenever possible. We imputed data for binary outcomes using various scenarios such as best‐best scenario, best‐worst scenario, worst‐best scenario, and worst‐worst scenario (Gurusamy 2009; Gluud 2014).
For continuous outcomes, we used available case analysis. We imputed the standard deviation from P values according to the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and we used the median for the meta‐analysis when the mean was not available. If it was not possible to calculate the standard deviation from the P value or the confidence interval, we planned to impute the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation would decrease the weight of the study for the calculation of mean differences and bias the effect estimate to no effect in the case of standardised mean differences (Higgins 2011).
Assessment of heterogeneity
We explored heterogeneity by the Chi2 test with significance set at a P value less than 0.10, and measured the quantity of heterogeneity by the I2 statistic (Higgins 2002). We also used overlapping of confidence intervals on the forest plot to determine heterogeneity.
Assessment of reporting biases
We used visual asymmetry on a funnel plot to explore reporting bias as more than 10 trials were identified (Egger 1997; Macaskill 2001). We performed the linear regression approach described by Egger 1997 to determine the funnel plot asymmetry. Selective reporting was also considered as evidence for reporting bias.
Data synthesis
We performed the meta‐analyses using the software package Review Manager 5.2 (RevMan 2012) and following the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2014). We used both a random‐effects model (DerSimonian 1986) and a fixed‐effect model (DeMets 1987) for meta‐analysis. In the case of a discrepancy between the two models we have reported both results; otherwise we have reported the results of the fixed‐effect model. We planned to use the generic inverse method to combine the hazard ratios for time‐to‐event outcomes.
Trial sequential analysis
Traditional meta‐analyses run the risk of random errors due to sparse data and repetitive testing on accumulating evidence. Trial sequential analysis can control such random errors (Wetterslev 2008; Thorlund 2011).
The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We will add the trials according to the year of publication, and if more than one trial was published in a year the trials are added alphabetically according to the last name of the first author. On the basis of the required information size, trial sequential monitoring boundaries are constructed. These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. On the other hand, if the boundaries are not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).
We applied trial sequential analysis (CTU 2011; Thorlund 2011) using a diversity‐adjusted required sample size calculated from an alpha error of 0.05, a beta error of 0.20, a control event proportion obtained from the results, and a relative risk reduction of 20% for binary outcomes if there were two or more trials reporting the outcome to determine whether more trials are necessary on this topic (if the trial sequential alpha‐spending monitoring boundary or the futility zone is crossed, then more trials may be unnecessary) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). As trial sequential analysis cannot be performed for SMD, we did not plan to perform the trial sequential analysis for quality of life. For pain, we calculated the required sample size from an alpha error of 0.05, a beta error of 0.20, the variance estimated from the meta‐analysis results of low risk of bias trials (if possible), and a MD of 1 cm on the visual analogue scale (Todd 1996). For length of hospital stay, return to work, and return to activity, we planned to calculate the required sample size using a mean difference of one day with the remaining variables kept the same as for pain.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses.
Trials with low bias risk compared to trials with high bias risk.
Elective compared to emergency laparoscopic cholecystectomy.
Different local anaesthetic agents.
Maximum safe dose used (ie, whether the trials used the dose based on body weight).
Different timing of instillation.
Different depths of wound infiltration.
Intraperitoneal local anaesthetic instillation.
Routine supplemental analgesia compared to no routine ('on‐demand') supplemental analgesia.
We used the 'test for subgroup differences' available through RevMan to identify the differences between subgroups. We used the random‐effects model meta‐analysis for this purpose.
Sensitivity analysis
We performed a sensitivity analysis by imputing data for binary outcomes using various scenarios such as best‐best scenario, best‐worst scenario, worst‐best scenario, and worst‐worst scenario (Gurusamy 2009; Gluud 2014). We performed a sensitivity analysis by excluding the trials in which the means and the standard deviations were imputed.
Summary of findings table
We have summarised the results of all the reported outcomes in a summary of findings table prepared using GRADEPro 3.6 (ims.cochrane.org/revman/gradepro).
Results
Description of studies
Results of the search
We identified a total of 811 references through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (n = 316), MEDLINE (n = 60), EMBASE (n = 64), and Science Citation Index Expanded (n = 371). We did not identify any new trials from the trial registers. We excluded 273 duplicates and 495 clearly irrelevant references through reading the abstracts. Forty‐three references were retrieved for further assessment. No references were identified through scanning reference lists of the identified randomised trials. We excluded 16 references (15 studies) for the reasons listed in the table 'Characteristics of excluded studies'. We did not identify any quasi‐randomised or non‐randomised comparative studies that reported treatment‐related harms. Twenty‐seven references (26 trials) fulfilled the inclusion criteria. The reference flow diagram is shown in Figure 1.
1.
Study flow diagram.
Included studies
Twenty‐six trials fulfilled the inclusion criteria of the review. Of these, seven trials did not provide usable information for this systematic review (Shikano 1994; Ahmad 1998; Hasaniya 2001; Hasan 2007; Cantore 2008; Liang 2011; Beqiri 2012). These trials reported some specific aspects of pain for example, incisional pain, but did not report the pain scores or did not report the number of participants in each group. Thus, 1263 participants were included in the 19 trials that provided the data for the review.
Ten of the 19 trials were two‐armed trials that compared local anaesthetic wound infiltration versus inactive control (Ure 1993; Bilge 1997; Dath 1999; Noma 2001; Papaziogas 2001; Pavlidis 2003; Zajaczkowska 2004; Louizos 2005; Feroci 2009; Liu 2009) that is, although some of these trials randomised participants to more than two arms, only two arms were eligible for inclusion in this review. One trial was a three‐armed trial that compared local anaesthetic wound infiltration with two inactive controls, normal saline and no intervention (Lepner 2003). Two trials had four arms comparing local anaesthetic wound infiltration with inactive controls in the presence and absence of oral rofecoxib (Newcomb 2007) or local anaesthetic intraperitoneal instillation (Nicolau 2008). Three trials had three or more arms that could be included for the comparison of local anaesthetic wound infiltration versus inactive control and comparison of the timing of administration of local anaesthetic (Sarac 1996; Lee 2001; Uzunkoy 2001). One trial had three arms which could be included for the comparison of local anaesthetic wound infiltration versus inactive control and comparison of different local anaesthetics for wound infiltration (Papagiannopoulou 2003). One trial had two arms which could be included for the comparison of the timing of local anaesthetic wound infiltration (Sozbilen 2007). One trial had two arms that compared different local anaesthetics for wound infiltration (Rodriguez‐Navarro 2011). In summary, a total of 1095 participants were randomised to local anaesthetic wound infiltration (587 participants) versus no local anaesthetic wound infiltration (508 participants) in 17 trials (Ure 1993; Sarac 1996; Bilge 1997; Dath 1999; Lee 2001; Noma 2001; Papaziogas 2001; Uzunkoy 2001; Lepner 2003; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Louizos 2005; Newcomb 2007; Nicolau 2008; Feroci 2009; Liu 2009); a total of 149 participants were randomised to local anaesthetic wound infiltration prior to skin incision (74 participants) versus local anaesthetic wound infiltration at the end of surgery (75 participants) in four trials (Sarac 1996; Lee 2001; Uzunkoy 2001; Sozbilen 2007); and a total of 176 participants were randomised to four different local anaesthetics (bupivacaine, levobupivacaine, ropivacaine, neosaxitoxin) in two trials (Papagiannopoulou 2003; Rodriguez‐Navarro 2011). There were no trials comparing different doses of the same local anaesthetic.
Participant characteristics
Twelve trials clearly stated that they included participants undergoing elective laparoscopic cholecystectomy (Ure 1993; Dath 1999; Lee 2001; Papaziogas 2001; Lepner 2003; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Louizos 2005; Newcomb 2007; Nicolau 2008; Feroci 2009). The inclusion of people with acute cholecystitis was not reported in the remaining seven trials (Sarac 1996; Bilge 1997; Noma 2001; Uzunkoy 2001; Sozbilen 2007; Liu 2009; Rodriguez‐Navarro 2011). Ten trials stated that they included only American Society of Anesthesiologists (ASA) status I or II people (Lee 2001; Noma 2001; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Louizos 2005; Newcomb 2007; Nicolau 2008; Feroci 2009; Rodriguez‐Navarro 2011). In two trials, only people who were ASA status I to III were included (Papaziogas 2001; Lepner 2003). In the remaining seven trials, the ASA status of the participants was not reported (Ure 1993; Sarac 1996; Bilge 1997; Dath 1999; Uzunkoy 2001; Sozbilen 2007; Liu 2009).
Intervention
The details of the intervention and co‐interventions in the different trials are summarised in Table 4.
1. Details of intervention and co‐interventions.
| Study | Comparison | Additional information | Local anaesthetic | Concentration | Dose | Time | Depth | Intraperitoneal LA | Routine supplemental analgesia* |
| Bilge 1997 | LA versus none | ‐ | bupivacaine | 0.20% | 10 ml | end of surgery | fascia | not stated | no |
| Dath 1999 | LA versus none | ‐ | bupivacaine | 0.50% | 20 ml | end of surgery | not stated | not stated | no |
| Feroci 2009 | LA versus none | ‐ | bupivacaine | 2 mg/kg | not stated | end of surgery | fascia | no | no |
| Lee 2001 | LA versus none | no intraperitoneal instillation | bupivacaine | 0.25% | 20 ml | pre‐incisional | until parietal peritoneum | yes | routine NSAID |
| Lee 2001 | LA versus none | intraperitoneal instillation | bupivacaine | 0.25% | 20 ml | end of surgery | until parietal peritoneum | yes | routine NSAID |
| Lee 2001 | LA versus LA (timing) | ‐ | bupivacaine | 0.25% | 20 ml | pre‐incisional versus end of surgery | until parietal peritoneum | yes | routine NSAID |
| Lepner 2003 | LA versus none | no intervention as control | bupivacaine | 0.13% | 80 ml | end of surgery | pre‐peritoneal space | no | routine NSAID |
| Lepner 2003 | LA versus none | normal saline as control | bupivacaine | 0.13% | 80 ml | end of surgery | pre‐peritoneal space | no | routine NSAID |
| Liu 2009 | LA versus none | ‐ | ropivacaine | 1.00% | 20 ml | end of surgery | until parietal peritoneum | not stated | not stated |
| Louizos 2005 | LA versus none | ‐ | levobupivacaine | 0.25% | 20 ml | pre‐incisional | pre‐peritoneal space | yes and no | no |
| Newcomb 2007 | LA versus none | no rofecoxib | bupivacaine | 0.25% | not stated | pre‐incisional | not stated | not stated | no |
| Newcomb 2007 | LA versus none | rofecoxib | bupivacaine | 0.25% | not stated | pre‐incisional | not stated | not stated | no |
| Nicolau 2008 | LA versus none | no intraperitoneal instillation | ropivacaine | 0.25% | 20 ml | end of surgery | pre‐peritoneal space | no | routine NSAID |
| Nicolau 2008 | LA versus none | intraperitoneal instillation | ropivacaine | 0.25% | 20 ml | end of surgery | pre‐peritoneal space | yes | routine NSAID |
| Noma 2001 | LA versus none | ‐ | bupivacaine | 0.50% | 20 ml | pre‐incisional | pre‐peritoneal space | not stated | no |
| Papagiannopoulou 2003 | LA versus none | ropivacaine | ropivacaine | 1.00% | 20 ml | pre‐incisional | not stated | not stated | no |
| Papagiannopoulou 2003 | LA versus none | levobupivacaine | levobupivacaine | 0.50% | 20 ml | pre‐incisional | not stated | not stated | no |
| Papagiannopoulou 2003 | LA versus LA (drug) | ‐ | ropivacaine versus levopbupivacaine | 1% and 0.5% respectively | 20 ml | pre‐incisional | not stated | not stated | no |
| Papaziogas 2001 | LA versus none | ‐ | ropivacaine | 1.00% | 20 ml | pre‐incisional | not stated | not stated | no |
| Pavlidis 2003 | LA versus none | ‐ | ropivacaine | 1.00% | 20 ml | pre‐incisional | until parietal peritoneum | not stated | no |
| Rodriguez‐Navarro 2011 | LA versus LA (drug) | ‐ | neosaxitoxin versus bupivacaine | 100 mcg versus 50 mg | not stated | pre‐incisional | until parietal peritoneum | not stated | no |
| Sarac 1996 | LA versus none | ‐ | bupivacaine | 0.50% | 14 ml | pre‐incisional | not stated | not stated | no |
| Sarac 1996 | LA versus none | ‐ | bupivacaine | 0.50% | 14 ml | end of surgery | not stated | not stated | no |
| Sarac 1996 | LA versus LA (timing) | ‐ | bupivacaine | 0.50% | 14 ml | pre‐incisional versus end of surgery | not stated | not stated | no |
| Sozbilen 2007 | LA versus LA (timing) | ‐ | ropivacaine | 3.75% | 5 ml | pre‐incisional versus end of surgery | fascia | yes | no |
| Ure 1993 | LA versus none | ‐ | bupivacaine | 0.50% | 32 ml | pre‐incisional versus end of surgery | pre‐peritoneal space | not stated | no |
| Uzunkoy 2001 | LA versus none | ‐ | bupivacaine | 0.25% | 30 ml | pre‐incisional | until parietal peritoneum | not stated | no |
| Uzunkoy 2001 | LA versus none | ‐ | bupivacaine | 0.25% | 30 ml | end of surgery | until parietal peritoneum | not stated | no |
| Uzunkoy 2001 | LA versus LA (timing) | ‐ | bupivacaine | 0.25% | 30 ml | pre‐incisional versus end of surgery | until parietal peritoneum | not stated | no |
| Zajaczkowska 2004 | LA versus none | ‐ | bupivacaine | 0.50% | 20 ml | pre‐incisional | not stated | not stated | no |
LA = local anaesthetic.
* Refers to routine analgesia. Most trials allowed 'on‐demand' analgesia or analgesia was administered if the pain was above a certain threshold.
Co‐intervention
The details of the use of intraperitoneal local anaesthetic infiltration and routine supplemental analgesia are shown in Table 4.
Further details about sample size, participant characteristics, the inclusion and exclusion criteria used in the trials, post‐randomisation dropouts, intervention and control, comparisons, outcomes reported in the trials, and the risk of bias in the trials are shown in the table 'Characteristics of included studies'.
Risk of bias in included studies
One trial was at low risk of bias (Feroci 2009). All the remaining trials were at high risk of bias. The risk of bias in the included trials is summarised in the risk of bias graph (Figure 2) and risk of bias summary (Figure 3).
2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Only four trials (4/26 (15.4%)) described random sequence generation and allocation concealment adequately (Bilge 1997; Feroci 2009; Liu 2009; Beqiri 2012). These trials were considered to be at low risk of selection bias.
Blinding
Five trials (5/26 (19.2%)) reported that the participants, healthcare personnel involved in patient care, and outcome assessors were blinded and were considered to be at low risk of performance and detection bias (Ure 1993; Lepner 2003; Pavlidis 2003; Zajaczkowska 2004; Feroci 2009).
Incomplete outcome data
Six trials (6/26 (23.1%)) had no post‐randomisation dropouts and were considered to be at low risk of attrition bias (Bilge 1997; Lepner 2003; Pavlidis 2003; Newcomb 2007; Feroci 2009; Liu 2009).
Selective reporting
Seven trials (7/26 (26.9%)) reported on mortality and morbidity and were considered to be at low risk of selective reporting bias (Dath 1999; Lee 2001; Lepner 2003; Pavlidis 2003; Newcomb 2007; Feroci 2009; Liu 2009).
Other potential sources of bias
Only one trial (1/26 (3.8%)) was considered to be at low risk of 'for‐profit' bias (Feroci 2009).
Effects of interventions
See: Table 1; Table 2; Table 3
Local anaesthetic wound infiltration versus no local anaesthetic wound infiltration
The main results are summarised in the Table 1.
Mortality
There was no mortality in either group in the seven trials that reported mortality (0/280 (0%) in local anaesthetic infiltration group versus 0/259 (0%) in control group) (Ure 1993; Dath 1999; Lee 2001; Lepner 2003; Pavlidis 2003; Feroci 2009; Liu 2009). There were no post‐randomisation dropouts in four trials (Lepner 2003; Pavlidis 2003; Feroci 2009; Liu 2009). It was not clear whether there were post‐randomisation dropouts in two trials (Ure 1993; Lee 2001). The other trial did not state the number of post‐randomisation dropouts in each group (Dath 1999). So, we did not perform a sensitivity analysis imputing outcomes for different scenarios. Since there was no mortality in either group, we were unable to use the control group proportion for the calculation of the required information size in the trial sequential analysis. Instead, we used a proportion of 0.2% in the control group based on data from approximately 30,000 patients included in a database in Switzerland (Giger 2011). The proportion of information accrued was only 0.15% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 4). The cumulative Z‐curve did not cross the conventional statistical boundaries.
4.
Trial sequential analysis of mortality (local anaesthetic versus no local anaesthetic) The diversity‐adjusted required information size (DARIS) was calculated to 352,564 patients, based on the proportion of patients in the control group with the outcome of 0.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing a total of 539 participants in seven trials, only 0.15% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the cumulative Z‐curve do not even cross the conventional statistical boundaries (dotted red lines).
Morbidity
Seven trials (539 participants) reported serious adverse events (Ure 1993; Dath 1999; Lee 2001; Lepner 2003; Pavlidis 2003; Feroci 2009; Liu 2009). There was no significant difference between the two groups in the proportion of people who developed serious adverse events (RR 2.00; 95% CI 0.19 to 21.59) (Analysis 1.1). There were serious adverse events in only one trial and these were not related to the local anaesthetic (Pavlidis 2003) (Analysis 1.1). Although the remaining trials did not report the overall morbidity, four trials (167 participants) reported that there were no drug‐related serious adverse events in any of the 167 participants who received the local anaesthetics (Sarac 1996; Papagiannopoulou 2003; Louizos 2005; Nicolau 2008). One trial reported that there were no intra‐operative complications in any of the 40 participants included in the trial (Bilge 1997). The remaining trials did not report on the complications that participants developed.
1.1. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 1 Serious adverse events.
The same trials that reported mortality reported on serious adverse events. We did not perform a sensitivity analysis imputing outcomes for different scenarios for the same reasons mentioned under mortality. The trial sequential analysis revealed that the proportion of information accrued was only 0.29% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 5). The cumulative Z‐curve did not cross the conventional statistical boundaries.
5.
Trial sequential analysis of morbidity (local anaesthetic versus no local anaesthetic) The diversity‐adjusted required information size (DARIS) was calculated to 185,703 participants, based on the proportion of patients in the control group with the outcome of 0.42%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing a total of 539 participants in seven trials, only 0.29% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, cumulative Z‐curve do not even cross the conventional statistical boundaries (dotted red lines).
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
Proportion discharged as day surgery patients
Only one trial (97 participants) reported the proportion of participants discharged as day surgery patients (Dath 1999). The proportion of participants who were discharged as day surgery patients was higher in the local anaesthetic infiltration group than the no local anaesthetic infiltration group (RR 1.55; 95% CI 1.05 to 2.28) (Analysis 1.2). This trial did not report the number of post‐randomisation dropouts in each group and so we did not perform a sensitivity analysis. We did not perform the trial sequential analysis because of the presence of only one trial.
1.2. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 2 Proportion discharged as day surgery.
Length of hospital stay
Four trials (327 participants) reported the length of hospital stay (Ure 1993; Pavlidis 2003; Newcomb 2007; Liu 2009). There were no differences in the length of hospital stay between the two groups (MD ‐0.26 days; 95% CI ‐0.67 to 0.16) (Analysis 1.3). There were no changes in the results using the random‐effects model. Either the mean or the standard deviation or both were not reported and had to be imputed in three trials (Ure 1993; Pavlidis 2003; Newcomb 2007). Exclusion of these trials resulted in a shorter hospital stay in the local anaesthetic group than the control group (MD ‐1.70 days; 95% CI ‐2.59 to ‐0.81) (Analysis 1.7). The trial sequential analysis suggested that further trials are required to identify benefits or harms of local anaesthetic wound infiltration compared with no local anaesthetic wound infiltration with regards to the length of hospital stay (Figure 6).
1.3. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 3 Length of hospital stay.
1.7. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 7 Length of hospital stay (sensitivity analysis).
6.
Trial sequential analysis of length of hospital stay (local anaesthetic versus no local anaesthetic) The diversity‐adjusted required information size (DARIS) was 931 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 7.40, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 79.99%. After accruing a total of 327 participants in three trials, only 35.12% of the DARIS has been reached. Accordingly, the futility area has not been drawn. The cumulative Z‐curve (blue line) has not crossed the trial sequential monitoring boundaries (red line) or the conventional statistical boundaries (dotted red line). This suggests that further trials are required to identify benefits or harms of local anaesthetic wound infiltration compared to no local anaesthetic wound infiltration with regards to the length of hospital stay.
Pain
Pain at four to eight hours
Thirteen trials (806 participants) reported this outcome (Sarac 1996; Bilge 1997; Dath 1999; Noma 2001; Papaziogas 2001; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007; Nicolau 2008; Feroci 2009; Liu 2009). The pain scores as measured by the visual analogue scale were lower in the local anaesthetic infiltration group than the control group (MD ‐1.33 cm on the VAS; 95% CI ‐1.54 to ‐1.12) (Analysis 1.4). There were no changes in the interpretation of results using a random‐effects model meta‐analysis. Either the mean or the standard deviation was imputed in six trials (Ure 1993; Sarac 1996; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007). Exclusion of these trials did not alter the results (MD ‐1.34 cm on the VAS; 95% CI ‐1.55 to ‐1.12) (Analysis 1.8). One trial contributed to nearly 45% of the weight of the analysis (Noma 2001). It was not clear whether the trial reported the standard deviation or standard error. Exclusion of this trial from the analysis in addition to the other trials where the standard deviation was imputed did not alter the results (MD ‐0.73 cm on the VAS; 95% CI ‐1.03 to ‐0.44). All the trial sequential monitoring boundaries were crossed by the cumulative Z‐curve favouring local anaesthetic infiltration. The findings were consistent with local anaesthetic infiltration decreasing pain at between four and eight hours compared with no local anaesthetic infiltration with no risk of random errors (Figure 7).
1.4. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 4 Pain 4 to 8 hours.
1.8. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 8 Pain 4 to 8 hours (sensitivity analysis).
7.
Trial sequential analysis of pain (4 to 8 hours) (local anaesthetic versus no local anaesthetic) The diversity‐adjusted required information size (DARIS) was 789 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 4.68, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 81.38%. The conventional statistical boundary for benefit (dotted red line) is crossed by the cumulative Z‐curve (blue line) after the fifth trial. The trial sequential monitoring boundaries (red line) are crossed by cumulative Z‐curve after the sixth trial. The findings are consistent with local anaesthetic infiltration decreasing pain between 4 and 8 hours compared to no local anaesthetic infiltration with no risk of random errors.
Pain at nine to 24 hours
Twelve trials (756 participants) reported this outcome (Sarac 1996; Bilge 1997; Dath 1999; Noma 2001; Papaziogas 2001; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007; Nicolau 2008; Feroci 2009; Liu 2009). The pain scores as measured by the visual analogue scale were lower in the local anaesthetic infiltration group than the control group (MD ‐0.36 cm on the VAS; 95% CI ‐0.53 to ‐0.20) (Analysis 1.5). There were no changes in the interpretation of results by using a random‐effects model meta‐analysis. Either the mean or the standard deviation was imputed in five trials (Sarac 1996; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007). Exclusion of these trials did not alter the results (MD ‐0.34 cm on the VAS; 95% CI ‐0.51 to ‐0.17) (Analysis 1.9). One trial contributed to nearly 45% of the weight of the analysis (Noma 2001). It was not clear whether the trial reported the standard deviation or standard error. Exclusion of this trial from the analysis in addition to the other trials where the standard deviation was imputed did not alter the results (MD ‐0.61 cm on the VAS; 95% CI ‐0.88 to ‐0.33). All the trial sequential monitoring boundaries were crossed by the cumulative Z‐curve favouring local anaesthetic infiltration. The findings were consistent with local anaesthetic instillation decreasing pain at between nine and 24 hours compared with no local anaesthetic infiltration without the risk of random errors (Figure 8).
1.5. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 5 Pain 9 to 24 hours.
1.9. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 9 Pain 9 to 24 hours (sensitivity analysis).
8.
Trial sequential analysis of pain (9 to 24 hours) (local anaesthetic versus no local anaesthetic) The diversity‐adjusted required information size (DARIS) was 168 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 2.66, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 50.3%. The conventional statistical boundary for benefit (dotted red line) is crossed by the cumulative Z‐curve (blue line) after the fifth trial. The findings are consistent with local anaesthetic infiltration decreasing pain between 9 and 24 hours compared with no local anaesthetic infiltration without the risk of random errors.
Return to normal activity
Two trials (195 participants) reported the return to normal activity (Uzunkoy 2001; Pavlidis 2003). There were no differences in the time taken to return to normal activity between the two groups (MD 0.14 days; 95% CI ‐0.59 to 0.87) (Analysis 1.6). The standard deviation was not reported and had to be imputed in one trial (Pavlidis 2003). Exclusion of this trial did not result in a change in the results (MD 1.02 days; 95% CI ‐0.37 to 2.41) (Analysis 1.10). The trial sequential analysis suggested that further trials are required to identify benefits or harms of local anaesthetic wound infiltration compared with no local anaesthetic wound infiltration with regards to the time taken to return to normal activity (Figure 9).
1.6. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 6 Return to normal activity.
1.10. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 10 Return to normal activity (sensitivity analysis).
9.
Trial sequential analysis of return to normal activity (local anaesthetic versus no local anaesthetic) The diversity‐adjusted required information size (DARIS) was 562 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 13.59, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 24.03%. After accruing a total of 195 participants in two trials, only 34.70% of the DARIS has been reached. Accordingly, the futility area has not been drawn. The cumulative Z‐curve (blue line) has not crossed the trial sequential monitoring boundaries (red lines) or the conventional statistical boundaries (dotted red lines). This suggests that further trials are required to identify benefits or harms of local anaesthetic wound infiltration compared with no local anaesthetic wound infiltration with regards to the time taken to return to normal activity.
Return to work
None of the trials reported return to work.
Subgroup analysis
Only pain at four to eight hours and pain at nine to 24 hours were suitable for various subgroup analyses because of the paucity of data for the other outcomes. We did not perform the following subgroup analyses.
Trials with low bias risk compared to trials with high bias risk: only one trial was at low risk of bias (Feroci 2009).
Elective compared to emergency laparoscopic cholecystectomy: none of the trials reported data for emergency laparoscopic cholecystectomy separately.
Different depths of wound infiltration: all the trials that reported the depth of wound infiltration reported that they infiltrated at least the fascia.
Maximum safe dose used (that is, whether the trials used the dose based on body weight): only one trial calculated the dose of the local anaesthetic based on weight (Feroci 2009).
Intraperitoneal local anaesthetic instillation: the information about whether intraperitoneal instillation was used was available for only two trials (Nicolau 2008; Feroci 2009).
Routine supplemental analgesia: routine supplemental analgesia was used in only one trial (Nicolau 2008).
So, only two subgroup analyses were performed for each outcome.
Different local anaesthetic agents.
Pain at four to eight hours: the test for subgroup differences was significant (P = 0.03). The effect seemed to be highest for levobupivacaine followed by bupivacaine and then ropivacaine (Analysis 1.11).
Pain at nine to 24 hours: the test for subgroup differences was significant (P = 0.006). The effect seemed to be highest for levobupivacaine followed by ropivacaine and then bupivacaine (Analysis 1.12).
Different timing of instillation.
Pain at four to eight hours: the test for subgroup differences was significant (P < 0.00001). The effect seemed to be higher when the local anaesthetic was administered prior to incision than at the end of surgery (Analysis 1.13).
Pain at nine to 24 hours: the test for subgroup differences was not significant (P = 0.24). The effect seemed to be highest for levobupivacaine followed by ropivacaine and then bupivacaine (Analysis 1.14).
1.11. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 11 Pain 4 to 8 hours (stratified by local anaesthetic agent).
1.12. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 12 Pain 9 to 24 hours (stratified by local anaesthetic agent).
1.13. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 13 Pain 4 to 8 hours (stratified by time of administration).
1.14. Analysis.
Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 14 Pain 9 to 24 hours (stratified by time of administration).
Reporting and other bias
We explored reporting and other bias by funnel plots only for pain at four to eight hours and for pain at nine to 24 hours because of the presence of adequate number of trials for these two outcomes only. The funnel plots did not reveal any evidence of reporting bias. The Egger's test did not reveal any evidence of reporting bias (P = 0.246 and P = 0.075 respectively).
Local anaesthetic wound infiltration: different local anaesthetics
The main results are summarised in the Table 2.
Mortality
There was no mortality in either group in the only trial that reported mortality: 0/69 (0%) in the neosaxitoxin group versus 0/68 (0%) in the bupivacaine group (Rodriguez‐Navarro 2011). There were no post‐randomisation dropouts in this trial. So, we did not perform a sensitivity analysis. We did not perform a trial sequential analysis because of the presence of only one trial for this outcome.
Morbidity
There were no serious adverse events in either group in the only trial that reported morbidity: 0/69 (0%) in the neosaxitoxin group versus 0/68 (0%) in the bupivacaine group (Rodriguez‐Navarro 2011). We did not perform a sensitivity analysis or trial sequential analysis because of the same reasons as for mortality.
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
Proportion discharged as day surgery patients
None of the trials reported the proportion discharged as day surgery patients.
Length of hospital stay
One trial (137 participants) reported the length of hospital stay (Rodriguez‐Navarro 2011). There was no significant difference in the length of hospital stay between the two groups (MD 0.00 days; 95% CI ‐0.65 to 0.65) (Analysis 2.1).
2.1. Analysis.
Comparison 2 Comparison of different local anaesthetics, Outcome 1 Length of hospital stay.
Pain
Pain at four to eight hours
One trial (39 participants) reported this outcome (Papagiannopoulou 2003). The pain scores as measured by the visual analogue scale were significantly higher in the ropivacaine group than the levobupivacaine group (MD 2.30 cm on the VAS; 95% CI 0.23 to 4.37) (Analysis 2.2). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.
2.2. Analysis.
Comparison 2 Comparison of different local anaesthetics, Outcome 2 Pain 4 to 8 hours.
Pain at nine to 24 hours
One trial (39 participants) reported this outcome (Papagiannopoulou 2003). The pain scores as measured by the visual analogue scale were significantly higher in the ropivacaine group than the levobupivacaine group (MD 1.90 cm on the VAS; 95% CI 1.00 to 2.80) (Analysis 2.3). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.
2.3. Analysis.
Comparison 2 Comparison of different local anaesthetics, Outcome 3 Pain 9 to 24 hours.
Return to normal activity
One trial (137 participants) reported the return to normal activity (Rodriguez‐Navarro 2011). The time taken to return to normal activity was significantly shorter in the neosaxitoxin group than the bupivacaine group (MD ‐1.90 days; 95% CI ‐2.71 to ‐1.09) (Analysis 2.4). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.
2.4. Analysis.
Comparison 2 Comparison of different local anaesthetics, Outcome 4 Return to normal activity.
Return to work
None of the trials reported return to work.
Subgroup analysis
We did not perform any subgroup analysis because of the paucity of data.
Reporting bias
We did not explore reporting bias because of the few trials included for this comparison.
Local anaesthetic wound infiltration: before skin incision versus end of surgery
The main results are summarised in the Table 3.
Mortality
There was no mortality in either group in the only trial that reported mortality: 0/22 (0%) in the pre‐incisional group versus 0/21 (0%) in the post‐surgical group (Lee 2001). It was not clear whether there were post‐randomisation dropouts in this trial (Lee 2001). So, we did not perform a sensitivity analysis imputing outcomes for different scenarios. We did not perform a trial sequential analysis because of the presence of only one trial for this outcome.
Morbidity
There were no serious adverse events in either group in the only trial that reported morbidity: 0/22 (0%) in the pre‐incisional group versus 0/21 (0%) in the post‐surgical group (Lee 2001). We did not perform a sensitivity analysis or trial sequential analysis because of the same reasons as for mortality.
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
None of the trials reported the proportion discharged as day surgery patients or the length of hospital stay.
Pain
Pain at four to eight hours
Two trials (76 participants) reported this outcome (Sarac 1996; Sozbilen 2007). There was no difference in the pain scores as measured by the visual analogue scale between the two groups (MD 0.18 cm on the VAS; 95% CI ‐1.90 to 2.26) (Analysis 3.1). There were no changes in the interpretation of results by using a random‐effects model meta‐analysis. Either the mean or the standard deviation was imputed in both trials. So, we did not perform a sensitivity analysis. The trial sequential analysis suggested that further trials are necessary to show significant benefits or harms of local anaesthetic infiltration before incision versus local anaesthetic infiltration towards the end of surgery (Figure 10).
3.1. Analysis.
Comparison 3 Before incision versus end of surgery, Outcome 1 Pain 4 to 8 hours.
10.
Trial sequential analysis of pain (4 to 8 hours) (before incision versus after surgery) The diversity‐adjusted required information size (DARIS) was 1344 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 42.78, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. After accrual of 76 participants in two trials, only 5.65% of DARIS has been reached. Accordingly, the futility area was not drawn. The trial sequential boundaries (red lines) or the conventional statistical boundaries (dotted red lines) were not crossed by the cumulative Z‐curve (blue line). This suggests that further trials are necessary to show significant benefits or harms of local anaesthetic infiltration before incision versus local anaesthetic infiltration towards the end of surgery.
Pain at nine to 24 hours
One trial (40 participants) reported this outcome (Sarac 1996). There was no difference in the pain scores as measured by the visual analogue scale between the two groups (MD 0.10 cm on the VAS; 95% CI ‐2.53 to 2.73) (Analysis 3.2). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.
3.2. Analysis.
Comparison 3 Before incision versus end of surgery, Outcome 2 Pain 9 to 24 hours.
Return to normal activity
One trial (30 participants) reported the return to normal activity (Uzunkoy 2001). There were no differences in the time taken to return to normal activity between the two groups (MD 0.50 days; 95% CI ‐1.05 to 2.05) (Analysis 3.3). We did not perform a sensitivity analysis or trial sequential analysis because of the presence of only one trial for this outcome.
3.3. Analysis.
Comparison 3 Before incision versus end of surgery, Outcome 3 Return to normal activity.
Return to work
None of the trials reported on return to work.
Subgroup analysis
We did not perform any subgroup analysis because of the paucity of data.
Reporting bias
We did not explore reporting bias because of the few trials included for this comparison.
Discussion
Summary of main results
In this review, we have compared local anaesthetic wound infiltration with no wound infiltration with local anaesthetic agents to reduce pain during laparoscopic cholecystectomy. We included a total of 17 randomised clinical trials involving 1095 participants randomised to local anaesthetic infiltration (587 participants) or control (508 participants) which contributed to one or more of the outcomes. We also compared different local anaesthetics and different times of administration of local anaesthetics. There were no significant differences in mortality or morbidity between the compared groups. The overall mortality after laparoscopic cholecystectomy is low (0.2%) (Giger 2011). In this review, the trials excluded high risk patients and we would anticipate that mortality would be even lower in these studies. To detect a 20% relative risk difference in mortality, more than 350,000 people are necessary. It is unlikely that trials will be powered to measure differences in mortality during laparoscopic cholecystectomy. Major complications during laparoscopic cholecystectomy are also rare. There were no local anaesthetic‐related serious adverse events in any of the participants included in the trials that reported this information. The morbidity associated with local anaesthetics is very low, with a reporting rate of approximately five adverse drug reactions per one million ampoules sold (Fuzier 2009). About 45% of these adverse drug reactions were serious (Fuzier 2009). Given this low morbidity associated with local anaesthetics and considering that laparoscopic cholecystectomy is performed under general anaesthesia with patients likely to be monitored because of the use of other anaesthetic agents, one can conclude that local anaesthetics are generally safe to use in patients undergoing laparoscopic cholecystectomy who are without an allergy to local anaesthetic.
None of the trials reported quality of life or return to work. Only three trials reported return to normal activity (Uzunkoy 2001; Pavlidis 2003; Rodriguez‐Navarro 2011). The main purpose of the local anaesthetic is to decrease pain, enabling the patients to be discharged from hospital and to return to normal activity and work as early as possible. These outcomes are not only important for the patients but also for the state‐funded health system. While quality of life is the outcome that is used for assessing the 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. Only one trial reported the proportion of participants discharged as day surgery patients (Dath 1999). The proportion of participants who were discharged as day surgery patients was significantly higher after local anaesthetic wound infiltration than an inactive control (Analysis 1.2). The trial had a significant number of dropouts and one cannot rely upon the results from this single trial. However, if the effect was real, this may be due to the reduction in the overall pain at four to eight hours, which is generally the time at which discharges are performed in the day surgery setting. It does not appear from the description in the trials that day surgery was attempted in most of the remaining trials. Future trials should investigate the role of local anaesthetic wound infiltration in the day surgery laparoscopic cholecystectomy setting. There were no significant differences in the length of hospital stay in the comparisons that reported these outcomes. These outcomes are important for the patients both in a private health setting and in a state‐funded health system because of the costs associated with hospital stay. However, only five trials reported this important outcome (Ure 1993; Pavlidis 2003; Newcomb 2007; Liu 2009; Rodriguez‐Navarro 2011).
The pain at four to eight hours and at nine to 24 hours was significantly reduced in the local anaesthetic wound infiltration group compared with no active intervention. The findings were robust to sensitivity analysis. The trial sequential analysis also confirmed that the risk of random errors in concluding that local anaesthetic wound infiltration decreased pain is low. Although some subgroup analyses and some direct comparisons between local anaesthetics showed the significant influence of some factors, such as the local anaesthetic agent used and the time at which the local anaesthetic is administered, on the amount of pain reduction, these were not consistent. Thus, there is no convincing evidence from this review to suggest that one method of local anaesthetic wound infiltration is better than another method. The mean reduction in pain was about 1 cm on the 0 to 10 cm visual analogue scale at four to eight hours and about 0.4 cm at nine to 24 hours. Differences in pain scores of between 0.9 and 1.8 cm are generally considered clinically significant (Todd 1996). Thus it appears that local anaesthetic wound infiltration may have a role in increasing the proportion of laparoscopic cholecystectomies performed as day surgery cases, as mentioned earlier, since patients undergoing day surgery laparoscopic cholecystectomy are discharged at between four and eight hours.
Overall completeness and applicability of evidence
Most of the trials included in this review included mainly patients undergoing elective laparoscopic cholecystectomy (Included studies; Characteristics of included studies). Most trials included only low anaesthetic risk patients undergoing laparoscopic cholecystectomy (Included studies; Characteristics of included studies). The findings of this review are applicable only to such patients.
Quality of the evidence
The overall quality of evidence is low to very low. Although it is difficult to blind many interventions in surgery, this is one of the few interventions in which adequate blinding can be achieved and high quality evidence is possible. Nevertheless, this is the best evidence that is currently available.
Potential biases in the review process
We performed a thorough search of the literature. However, we included 'pain' as one of the components in this search strategy. Considering that reduction in pain is the main reason for the use of intraperitoneal local anaesthetic instillation, we expected that all the trials related to the topic would be identified and, given the number of trials included in this review, it is likely that most of the trials on this topic have been identified. However, it is possible that trials did not mention pain or words related to pain and such trials might have been missed by this search strategy. The impact of this is likely to be small since it is likely that most trials would have mentioned the purpose of the use of the intervention. At least two review authors independently identified trials for inclusion and extracted the data, thus minimising errors. We imputed the mean and standard deviation when these were not available. We performed a sensitivity analysis excluding such trials. While most analyses were robust to such sensitivity analyses, the results changed significantly for length of hospital stay in the comparison between local anaesthetic wound infiltration and inactive control. Thus, the imputations may have altered the interpretation of data.
Agreements and disagreements with other studies or reviews
This is the first systematic review of local anaesthetic wound infiltration in people undergoing laparoscopic cholecystectomy. We agree with many of the authors of the trials included in this review that wound infiltration with local anaesthetic decreases pain after laparoscopic cholecystectomy.
Authors' conclusions
Implications for practice.
Serious adverse events were rare in studies evaluating local anaesthetic wound infiltration (very low quality evidence). There is very low quality evidence that infiltration reduces pain in low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. However, the clinical importance of this reduction in pain is likely to be small.
Implications for research.
Further randomised clinical trials are necessary to evaluate the role of local anaesthetic wound filtration in the emergency setting and in the elective setting, particularly for day surgery elective laparoscopic cholecystectomies.
Future trials should include quality of life, hospital stay, return to normal activity, and return to work as outcomes.
Future trials need to be designed according to the SPIRIT guidelines (www.spirit‐statement.org/) and conducted and reported according to the CONSORT statement (www.consort‐statement.org).
Acknowledgements
To the Cochrane Hepato‐Biliary Group for the support that they have provided.
Peer Reviewers: Shao Peng, Canada; Pablo L Ingelmo, Canada. Contact Editor: Christian Gluud, Denmark.
This project was funded by the National Institute for Health Research. Disclaimer of the Department of Health: 'The views and opinions expressed in the review are those of the authors and do not necessarily reflect those of the National Institute for Health Research (NIHR), National Health Services (NHS), or the Department of Health'.
Appendices
Appendix 1. Search strategies
| Database | Period | Search strategy used |
| Cochrane Central Register of Controlled Trials (CENTRAL) | Issue 1 of 12, 2013. | #1 laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop* #2 cholecystectom* #3 MeSH descriptor Cholecystectomy, Laparoscopic explode all trees #4 (( #1 AND #2 ) OR #3) #5 (incision OR port* OR (surg* AND wound)) #6 MeSH descriptor Anesthetics, Local explode all trees #7 MeSH descriptor Anesthesia, Local explode all trees #8 MeSH descriptor Amides explode all trees #9 anaesthesia OR anesthesia OR anaesthetic OR anesthetic OR "Huneke neural therapy" OR "Neural therapy of Huneke" OR benzocaine OR bensokain OR "Aminobenzoic Acid" OR "Aminobenzoate" OR bupivacain* OR buvacaina OR sensorcaine OR marcain* OR svedocain* OR levobupivacaine OR carticain* OR articain* OR dibucaine OR cinchocaine OR Cincain OR Nupercain* OR Sovcaine OR etidocaine OR duranest OR "W19053" OR "W 19053" OR "W‐19053" OR Lidocaine OR Lignocaine OR Octocaine OR Xylesthesin OR Xylocaine OR Dalcaine OR Xylocitin OR Xyloneural OR Mepivacain* OR Carbocaine OR Polocaine OR isocaine OR isogaine OR Scandicain* OR prilocaine OR Propitocaine OR Tetracaine OR Tetrakain OR Amethocaine OR Dicaine OR Pantocaine OR Pontocaine OR Trimecaine OR Mesocaine OR ropivacaine #10 (#6 OR #7 OR #8 OR #9) #11 MeSH descriptor Pain explode all trees #12 pain OR ache* OR suffering* #13 (#11 OR #12) #14 (#4 AND #5 AND #10 AND #13) |
| MEDLINE (OvidSP) | January 1987 to February 2013 | (((laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*) AND (cholecystectom*)) OR “cholecystectomy, laparoscopic” [MeSH])) AND (incision OR port* OR (surg* AND wound)) AND ("Anesthetics, Local"[Mesh] OR "Anesthesia, Local"[Mesh] OR "Anesthetics, Local "[Pharmacological Action] OR "Amides"[Mesh] OR anaesthesia OR anesthesia OR anaesthetic OR anesthetic OR “Huneke neural therapy” OR “Neural therapy of Huneke” OR benzocaine OR bensokain OR ”Aminobenzoic Acid” OR “Aminobenzoate” OR bupivacain* OR buvacaina OR sensorcaine OR marcain* OR svedocain* OR levobupivacaine OR carticain* OR articain* OR dibucaine OR cinchocaine OR Cincain OR Nupercain* OR Sovcaine OR etidocaine OR duranest OR “W19053” OR “W 19053” OR “W‐19053” OR Lidocaine OR Lignocaine OR Octocaine OR Xylesthesin OR Xylocaine OR Dalcaine OR Xylocitin OR Xyloneural OR Mepivacain* OR Carbocaine OR Polocaine OR isocaine OR isogaine OR Scandicain* OR prilocaine OR Propitocaine OR Tetracaine OR Tetrakain OR Amethocaine OR Dicaine OR Pantocaine OR Pontocaine OR Trimecaine OR Mesocaine OR ropivacaine) AND ("Pain"[Mesh] OR pain OR ache* OR suffering*) AND ((randomised controlled trial [pt] OR controlled clinical trial [pt] OR randomised [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])) |
| EMBASE (OvidSP) | January 1987 to February 2013 | 1 exp crossover‐procedure/ or exp double‐blind procedure/ or exp randomised controlled trial/ or single‐blind procedure/ 2 (random* or factorial* or crossover* or placebo*).af. 3 1 or 2 4 (laparoscop* or coelioscop* or celioscop* or peritoneoscop*).af. 5 exp laparoscopic surgery/ 6 4 or 5 7 cholecystectom*.af. 8 exp cholecystectomy/ 9 7 or 8 10 (incision or port* or (surg* and wound)).af. 11 exp Local Anesthetic Agent/ 12 (anaesthesia or anesthesia or anaesthetic or anesthetic or Huneke neural therapy or Neural therapy of Huneke or benzocaine or bensokain or Aminobenzoic Acid or Aminobenzoate or bupivacain* or buvacaina or sensorcaine or marcain* or svedocain* or levobupivacaine or carticain* or articain* or dibucaine or cinchocaine or Cincain or Nupercain* or Sovcaine or etidocaine or duranest or W19053 or W '19053' or W‐19053).af. 13 (Lidocaine or Lignocaine or Octocaine or Xylesthesin or Xylocaine or Dalcaine or Xylocitin or Xyloneural or Mepivacain* or Carbocaine or Polocaine or isocaine or isogaine or Scandicain* or prilocaine or Propitocaine or Tetracaine or Tetrakain or Amethocaine or Dicaine or Pantocaine or Pontocaine or Trimecaine or Mesocaine or ropivacaine).af. 14 11 or 12 or 13 15 exp pain/ 16 (pain or ache* or suffering*).af. 17 15 or 16 18 3 and 6 and 9 and 10 and 14 and 17 |
| Science Citation Index Expanded (apps.isiknowledge.com) | January 1987 to February 2013 | #1 TS=(laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*) #2 TS=(cholecystectom*) #3 TS=(incision OR port* OR (surg* AND wound)) #4 TS=(anaesthesia OR anesthesia OR anaesthetic OR anesthetic OR (Huneke neural therapy) OR (Neural therapy of Huneke) OR benzocaine OR bensokain OR (Aminobenzoic Acid) OR Aminobenzoate OR bupivacain* OR buvacaina OR sensorcaine OR marcain* OR svedocain* OR levobupivacaine OR carticain* OR articain* OR dibucaine OR cinchocaine OR Cincain OR Nupercain* OR Sovcaine OR etidocaine OR duranest OR W19053 OR (W 19053) OR (W‐19053)) #5 TS=( Lidocaine OR Lignocaine OR Octocaine OR Xylesthesin OR Xylocaine OR Dalcaine OR Xylocitin OR Xyloneural OR Mepivacain* OR Carbocaine OR Polocaine OR isocaine OR isogaine OR Scandicain* OR prilocaine OR Propitocaine OR Tetracaine OR Tetrakain OR Amethocaine OR Dicaine OR Pantocaine OR Pontocaine OR Trimecaine OR Mesocaine OR ropivacaine) #6 #5 OR #4 #7 TS=(pain OR ache* OR suffering*) #8 #7 AND #6 AND #3 AND #2 AND #1 |
Data and analyses
Comparison 1. Local anaesthetic versus no local anaesthetic.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Serious adverse events | 7 | 539 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.19, 21.59] |
| 2 Proportion discharged as day surgery | 1 | 97 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.55 [1.05, 2.28] |
| 3 Length of hospital stay | 4 | 327 | Mean Difference (IV, Fixed, 95% CI) | ‐0.26 [‐0.67, 0.16] |
| 4 Pain 4 to 8 hours | 13 | 806 | Mean Difference (IV, Fixed, 95% CI) | ‐1.33 [‐1.54, ‐1.12] |
| 5 Pain 9 to 24 hours | 12 | 756 | Mean Difference (IV, Fixed, 95% CI) | ‐0.36 [‐0.53, ‐0.20] |
| 6 Return to normal activity | 2 | 195 | Mean Difference (IV, Fixed, 95% CI) | 0.14 [‐0.59, 0.87] |
| 7 Length of hospital stay (sensitivity analysis) | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 8 Pain 4 to 8 hours (sensitivity analysis) | 7 | 364 | Mean Difference (IV, Fixed, 95% CI) | ‐1.34 [‐1.55, ‐1.12] |
| 9 Pain 9 to 24 hours (sensitivity analysis) | 7 | 364 | Mean Difference (IV, Fixed, 95% CI) | ‐0.34 [‐0.51, ‐0.17] |
| 10 Return to normal activity (sensitivity analysis) | 1 | 45 | Mean Difference (IV, Fixed, 95% CI) | 1.02 [‐0.37, 2.41] |
| 11 Pain 4 to 8 hours (stratified by local anaesthetic agent) | 12 | 756 | Mean Difference (IV, Fixed, 95% CI) | ‐1.33 [‐1.55, ‐1.12] |
| 11.1 Bupivacaine | 10 | 543 | Mean Difference (IV, Fixed, 95% CI) | ‐1.42 [‐1.66, ‐1.18] |
| 11.2 Levobupivacaine | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | ‐3.90 [‐6.52, ‐1.28] |
| 11.3 Ropivacaine | 2 | 185 | Mean Difference (IV, Fixed, 95% CI) | ‐0.93 [‐1.39, ‐0.47] |
| 12 Pain 9 to 24 hours (stratified by local anaesthetic agent) | 12 | 756 | Mean Difference (IV, Fixed, 95% CI) | ‐0.36 [‐0.53, ‐0.20] |
| 12.1 Bupivacaine | 10 | 543 | Mean Difference (IV, Fixed, 95% CI) | ‐0.29 [‐0.46, ‐0.11] |
| 12.2 Levobupivacaine | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | ‐1.70 [‐2.84, ‐0.56] |
| 12.3 Ropivacaine | 2 | 185 | Mean Difference (IV, Fixed, 95% CI) | ‐1.07 [‐1.74, ‐0.39] |
| 13 Pain 4 to 8 hours (stratified by time of administration) | 12 | 756 | Mean Difference (IV, Fixed, 95% CI) | ‐1.33 [‐1.55, ‐1.12] |
| 13.1 Before incision | 7 | 419 | Mean Difference (IV, Fixed, 95% CI) | ‐1.69 [‐1.95, ‐1.43] |
| 13.2 End of surgery | 6 | 337 | Mean Difference (IV, Fixed, 95% CI) | ‐0.63 [1.00, ‐0.27] |
| 14 Pain 9 to 24 hours (stratified by time of administration) | 12 | 756 | Mean Difference (IV, Fixed, 95% CI) | ‐0.36 [‐0.53, ‐0.20] |
| 14.1 Before incision | 7 | 419 | Mean Difference (IV, Fixed, 95% CI) | ‐0.29 [‐0.49, ‐0.10] |
| 14.2 End of surgery | 6 | 337 | Mean Difference (IV, Fixed, 95% CI) | ‐0.51 [‐0.80, ‐0.22] |
Comparison 2. Comparison of different local anaesthetics.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Length of hospital stay | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [‐0.65, 0.65] |
| 2 Pain 4 to 8 hours | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | 2.3 [0.23, 4.37] |
| 3 Pain 9 to 24 hours | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | 1.90 [1.00, 2.80] |
| 4 Return to normal activity | 1 | 137 | Mean Difference (IV, Fixed, 95% CI) | ‐1.90 [‐2.71, ‐1.09] |
Comparison 3. Before incision versus end of surgery.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Pain 4 to 8 hours | 2 | 76 | Mean Difference (IV, Fixed, 95% CI) | 0.18 [‐1.90, 2.26] |
| 2 Pain 9 to 24 hours | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐2.53, 2.73] |
| 3 Return to normal activity | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.5 [‐1.05, 2.05] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Ahmad 1998.
| Methods | Randomised clinical trial | |
| Participants | Country: UK.
Number randomised: 20. Post‐randomisation dropouts: not stated. Revised sample size: 20. Average age: not stated. Females: not stated. Inclusion criteria: People undergoing laparoscopic cholecystectomy. |
|
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 10). Further details: 20 ml of 0.25% bupivacaine. Group 2: No local anaesthetic (n = 10). Further details: normal saline. | |
| Outcomes | The outcome reported was pain. | |
| Notes | Attempts were made to contact the authors in March 2013. The pain scores were not provided. The pain was significantly lower in the local anaesthetic group than control group. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Beqiri 2012.
| Methods | Randomised clinical trial | |
| Participants | Country: Albania. Number randomised: 500. Post‐randomisation dropouts: 27 (5.4%). Revised sample size: 473. Average age: 44 years. Females: 293 (61.9%). Inclusion criteria: 1. ASA I‐II. 2. Scheduled laparoscopic cholecystectomy. Exclusion criteria: 1. Pre‐existing pulmonary and cardiac disease. 2. Intracranial lesions. 3. Spinal and peridural anaesthesia. 4. Local anaesthetic hypersensitivity. 5. Paediatric patients. | |
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 121).
Further details: 5 ml of 0.5% bupivacaine was infiltrated pre‐incisionally in all port sites. Intrabdominal insufflation pressure of under 10 mm Hg was used. Group 2: No local anaesthetic (n = 110). Further details: No local anaesthetic was used. Intra‐abdominal insufflation pressure of under 10 mm Hg was used. Group 3: Local anaesthetic (n=122). Further details: 5 ml of 0.5 % bupivacaine was infiltrated pre‐incisionally in all port sites. Intra‐abdominal insufflation pressure of 15 mm Hg was used. Group 4: No local anaesthetic (n= 120). Further details: No Local anaesthetic was used. Intra‐abdominal insufflation pressure of 15 mm Hg was used. |
|
| Outcomes | None of the outcomes of interest were reported. | |
| Notes | Reasons for post‐randomisation dropouts: Conversion to an open procedure due to complications. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "4 coloured balls in a non‐transparent vase were used to randomise patients between groups". |
| Allocation concealment (selection bias) | Low risk | Quote: "4 coloured balls in a non‐transparent vase were used to randomise patients between groups". |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: There were post‐randomisation dropouts. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Bilge 1997.
| Methods | Randomised clinical trial | |
| Participants | Country: Turkey. Number randomised: 40. Post‐randomisation dropouts: 0 (0%). Revised sample size: 40. Average age: 51 years. Females: 31 (77.5%). Inclusion criteria: 1. Laparoscopic cholecystectomy for symptomatic gallbladder stones. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 20). Further details: 10 ml of 0.2% bupivacaine infiltrated at the subcutaneous layer and fascia of the ports at the end of the operation. Group 2: No local anaesthetic (n = 20). Further details: No local anaesthetic was used. | |
| Outcomes | The outcomes reported were intraoperative complications and pain. | |
| Notes | Attempts were made to contact the authors in February 2008 and August 2010. Authors provided information in February 2008. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The random sequence was generated by drawing one of the sealed envelopes in the operating theatre before the operation. Forty of such envelopes were prepared (20 for each treatment) and mixed‐up" (author replies). |
| Allocation concealment (selection bias) | Low risk | Quote: "The random sequence was generated by drawing one of the sealed envelopes in the operating theatre before the operation. Forty of such envelopes were prepared (20 for each treatment) and mixed‐up" (author replies). |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The person evaluating post‐operative pain did not know which group the patients belonged to". |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Quote: "There were no post‐randomisation drop‐outs in any group" (author replies). |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Cantore 2008.
| Methods | Randomised clinical trial | |
| Participants | Country: Italy. Number randomised: 50. Post‐randomisation dropouts: not stated. Revised sample size: 50. Average age: 59 years. Females: 32 (64%). Inclusion criteria: 1. ASA I. 2. Symptomatic cholelithiasis. Exclusion criteria: 1. Acute cholecystitis. 2. If a subxiphoid incision was applied for gallbladder extraction. 3. Serious cardiovascular, renal, haematologic or hepatic diseases. 4. History of drugs or alcohol abuse. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic pre‐incision (n = 25). Further details: Levobupivacaine 1% 100 ml was administered prior skin incision in the subumbilical site blindly on the muscular fascia, while in the other three sites levobupivacaine was infiltrated under visual control. Group 2: Local anaesthetic pre‐closure (n = 25). Further details: Levobuivacaine 1% 100 ml was instilled at the end of surgery after trocar removal in the same fashion. | |
| Outcomes | None of the outcomes of interest were reported. | |
| Notes | Attempts were made to contact the authors in March 2013. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The nurses in surgical department were trained to monitor the VAS pain scores and to administer analgesic. The nurses were blinded the patients status concerning peri‐operative local anaesthetics". |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Dath 1999.
| Methods | Randomised clinical trial | |
| Participants | Country: USA. Number randomised: 124. Post‐randomisation dropouts: 27 (21.8%). Revised sample size: 97. Average age: 46 years. Females: 81 (83.5%). Inclusion criteria: 1. Elective laparoscopic cholecystectomy. 2. Ultrasound proof of gallstones or sludge. 3. More than 16 years old. 4. Eligibility for a standard anaesthesia protocol developed by anaesthesia department. Exclusion criteria: 1. Lack of compliance in completing pain assessments. 2. Placement of a drain intra‐operatively. 3. The presence of acute pancreatitis. 4. Prolonged hospitalisation to facilitate endoscopy. 5. Repair of incidental umbilical hernia. 6. Documented recent narcotic abuse. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 50). Further details: 20 ml of 0.5% bupivacaine with epinephrine 1:200000 given just before closure. 6 ml on each of the midline port sites and 4 ml on each of the lateral port sites. Group 2: No local anaesthetic (n = 47). Further details: No local anaesthetic was used. | |
| Outcomes | The outcomes reported were mortality, morbidity, proportion discharged as day surgery, and pain. | |
| Notes | Reasons for post‐randomisation dropouts: Patients were withdrew from study after randomisation because it was 'too much of a nuisance', 2 patients and '25 early patients were excluded because pain scores were inappropriately culled from charts before review’. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "envelopes containing randomly generated instructions". Comment: Further details were not available. |
| Allocation concealment (selection bias) | Unclear risk | Quote: "an envelope'". Comment: Further details were not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "The operative control sheet was included in the chart in the event that it needed to be referenced…The patients were thoroughly blinded to the intervention as was the surgeon". Comment: Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote: "Neither the PACU or the ward nurses knew the information was available". Comment: Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: There were post‐randomisation dropouts. |
| Selective reporting (reporting bias) | Low risk | Comment: Mortality and morbidity were reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Feroci 2009.
| Methods | Randomised clinical trial | |
| Participants | Country: Italy. Number randomised: 30. Post‐randomisation dropouts: 0 (0%). Revised sample size: 30. Average age: 52 years. Females: 21 (70%). Inclusion criteria: 1. Age older than 18 years. 2. ASA I and II. 3. Gallbladder calculosis with no clinical, biochemical, or instrumental signs of acute cholecystitis at time of intervention. Exclusion criteria: 1. Pregnant women. 2. Patients who had previous supra‐mesocolic major surgery. 3. Affected by cholecystocholedochal calculosis, acute pancreatitis, or acute cholecystitis at time of interventions. 4. Those who underwent laparotomy conversion were excluded from the study. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 15). Further details: 0.5% bupivacaine (2 mg/kg) infiltrated in the muscular fasciae of the trocar sites before suturing surgical incisions. Group 2: No local anaesthetic (n = 15). Further details: No local anaesthetic used. | |
| Outcomes | The outcomes reported were mortality, morbidity, and pain. | |
| Notes | Attempts were made to contact the authors in August 2010. Authors provided further information in August 2010. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The randomization was obtained through a computer‐generated program" (author replies). |
| Allocation concealment (selection bias) | Low risk | Quote: "It consisted with an ordered series of numbers with a corresponding letter for each group. This series of numbers … in closed envelopes by a secretary not involved in patients' assistance. The envelopes were opaque and sealed" (author replies). |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "The surgeon who performed the intervention was not included in the follow‐up. Neither the patients nor the investigating doctors were informed about the way in which bupivacaine was administered" (author replies). |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The surgeon who performed the intervention was not included in the follow‐up. Neither the patients nor the investigating doctors were informed about the way in which bupivacaine was administered" (author replies). |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: There were no post‐randomisation dropouts. |
| Selective reporting (reporting bias) | Low risk | Comment: Mortality and morbidity were reported. |
| For‐profit bias | Low risk | Quote: "For the study we didn't receive any fund from industry. All material used in the study (tabotamp and bupivacaine) was property of the hospital that authorized its use for the study" (author replies). |
Hasan 2007.
| Methods | Randomised clinical trial | |
| Participants | Country: Belgium.
Number randomised: 36.
Post‐randomisation dropouts: not stated.
Revised sample size: 36.
Average age: not stated.
Females: not stated.
Inclusion criteria:
1. People undergoing laparoscopic cholecystectomy. 2. ASA physical status I or II. |
|
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = not stated). Further details: 20 ml bupivacaine 0.25% incisional infiltration. Group 2: No local anaesthetic (n = not stated). Further details: 20 ml normal saline incisional infiltration. Group 3: Local anaesthetic (n = not stated). Further details: same as group 1 but with intraperitoneal local anaesthetic. Group 4: No local anaesthetic (n = not stated). Further details: same as group 2 but with intraperitoneal local anaesthetic. | |
| Outcomes | The outcomes reported were drug‐related serious adverse events and pain. | |
| Notes | Attempts were made to contact the authors in March 2013. There were no serious drug‐related adverse events in any of the groups. There was a significant reduction in pain in group 1 compared to group 2. There was no significant difference in the pain between group 3 and group 4. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Hasaniya 2001.
| Methods | Randomised clinical trial. | |
| Participants | Country: USA. Number randomised: 100. Post‐randomisation dropouts: 16 (16%). Revised sample size: 84. Average age: not stated. Females: not stated. Inclusion criteria: Patients with symptomatic cholelithiasis undergoing laparoscopic cholecystectomy. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 43). Further details: The trocar site was infiltrated with 0.5% bupivacaine 20 ml before the skin incision was made and before insertion of the trocars into the abdomen. Group 2: No local anaesthetic (n = 41). Further details: No local anaesthetic was used. | |
| Outcomes | No outcomes of interest for this review were reported. | |
| Notes | Reasons for post‐randomisation dropouts: 'Inability to communicate with patients due to their altered mental status, or because of conversion to open technique or due to performance of other surgical procedures' ‐ 13 patients. 'Because patients had left the hospital the night after surgery at their request' ‐ three patients. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "All were blinded concerning the group to which they had been randomized". Comment: Not clear whether the healthcare personnel were blinded. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: There were post‐randomisation dropouts. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Lee 2001.
| Methods | Randomised clinical trial | |
| Participants | Country: Korea. Number randomised: 123. Post‐randomisation dropouts: not stated. Revised sample size: 123. Average age: 47 years. Females: 57 (46.3%). Inclusion criteria: 1. Elective laparoscopic cholecystectomy. Exclusion criteria: 1. Patients allergic to local anaesthetics. 2. Those with a history of severe systemic disease. 3. Patients with chronic pain diseases other than gallstone disease. 4. Patients ASA physical status III or greater. 5. Patients who had acute cholecystitis before the operation. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 20). Further details: Pre‐operative peri‐portal 0.25% bupivacaine (20 ml) 15 minutes before incision and intraperitoneal 0.25% bupivacaine (40 ml with 1:200,000 epinephrine) immediately after the creation of pneumoperitoneum.. Group 2: No local anaesthetic (n = 20). Further details: intraperitoneal 0.25% bupivacaine (40 mL with 1:200,000 epinephrine) immediately after the creation of pneumoperitoneum. Group 3: Local anaesthetic (n = 19). Further details: Postoperative periportal 0.25% bupivacaine (20 ml) 15 min before closure and intraperitoneal 0.25% bupivacaine (40 ml with 1:200,000 epinephrine) immediately after removal of trocars at the end of the operation. Group 4: No local anaesthetic (n = 21). Further details: 0.25% bupivacaine (40 mL with 1:200,000 epinephrine) immediately after removal of trocars at the end of the operation. Group 5: Local anaesthetic (n = 22). Further details: Preoperative periportal 0.25% bupivacaine (20 ml) 15 min before incision. Group 6: No local anaesthetic (n = 25). Further details: No local anaesthetic was used. The fascia, muscle, pre‐peritoneal space, and the parietal peritoneum were infiltrated (infiltration of four port sites in total, seven ml each for two 10 mm sites, 3 ml each for the other two 5 mm sites). | |
| Outcomes | The outcomes reported were mortality and morbidity. | |
| Notes | Attempts were made to contact the authors in February 2008. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote: "No patients or observers were informed of the treatment group (preoperative or postoperative)". Comment: Further details were not available. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | Low risk | Comment: Mortality and morbidity were reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Lepner 2003.
| Methods | Randomised clinical trial | |
| Participants | Country: Estonia.
Number randomised: 60.
Post‐randomisation dropouts: 0 (0%).
Revised sample size: 60.
Average age: 53 years.
Females: 48 (80%).
Inclusion criteria:
1. ASA 1‐3 patients.
2. Scheduled for laparoscopic cholecystectomy for gallstone disease. Exclusion criteria: 1. Acute cholecystitis. 2. Inability to understand and use VAS. 3. History of allergy to NSAIDS and/or local anaesthetic. |
|
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 20).
Further details: At the end of the operation all wounds were infiltrated with 80 ml 0.125% bupivacaine containing 5mg of phenylephrine. Pre‐peritoneal, muscle, subcutaneous fat and skin were infiltrated.
Group 2: No local anaesthetic (n = 20).
Further details: No local anaesthetic used.
Group 3: No local anaesthetic (n = 20).
Further details: Wounds infiltrated with normal saline. Pre‐peritoneal, muscle, subcutaneous fat and skin were infiltrated. |
|
| Outcomes | The outcomes reported were mortality and morbidity. | |
| Notes | Authors provided information on post‐randomisation dropouts in April 2008. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Quote: 'The patients were modernised prospectively, using a blind envelope system, into four groups of 20 persons each'. Comment: Further details were not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "The patients were blinded to the methods of analgesia used. The investigators, who were blinded to the patients' division into groups and to the method of postoperative analgesia, assessed the patients' postoperative abdominal pain and shoulder pain at rest". |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The patients were blinded to the methods of analgesia used. The investigators, who were blinded to the patients' division into groups and to the method of postoperative analgesia, assessed the patients' postoperative abdominal pain and shoulder pain at rest". |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: There were no post‐randomisation dropouts. |
| Selective reporting (reporting bias) | Low risk | Comment: Mortality and morbidity were reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Liang 2011.
| Methods | Randomised clinical trial | |
| Participants | Country: China.
Number randomised: 60.
Post‐randomisation dropouts: not stated.
Revised sample size: 60.
Average age: 56 years.
Females: 29 (48.3%).
Inclusion criteria:
1. Patients between the ages of 45 and 65 years.
2. ASA of I or II.
3. Undergoing laparoscopic cholecystectomy.
4. No allergies to the drugs used in the study. Exclusion criteria: 1. Not taking warfarin and other anticoagulants. 2. No gastrointestinal bleeding tendency. 3. No history of serious heart/respiratory/liver disease. 4. Abnormal kidney function. |
|
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 20).
Further details: 6 ml 0.5% ropivacaine incision infiltration at the end of surgery.
Group 2: Local anaesthetic (n = 20).
Further details: 6 ml 0.25% ropivacaine incision infiltration at the end of surgery. Group 3: No local anaesthetic (n = 20). Further details: No local anaesthetic. |
|
| Outcomes | None of the outcomes of interest were reported. | |
| Notes | Reasons for post‐randomisation dropouts: not stated. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The person evaluating postoperative pain was not aware of group allocations". |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Liu 2009.
| Methods | Randomised clinical trial | |
| Participants | Country: China. Number randomised: 72. Post‐randomisation dropouts: 0 (0%). Revised sample size: 72. Average age: 50 years. Females: 53 (73.6%). Inclusion criteria: 1. Aged 20 to 85 years. 2. Not pregnant. 3. Adequate hematological, hepatic and renal function. Exclusion criteria: 1.Immunosuppressive drug therapy within the previous six months. 2. An immunosuppressive condition, including AIDS. 3. Autoimmune disorders. 4. Organ transplantation. 5. Radiotherapy or chemotherapy within the previous six months. 6. Insulin‐dependent diabetes mellitus (type 1). | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 36). Further details: 1.0% ropivacaine 20 ml at the port site after wound closure. The solution was applied to the skin, subcutis, fascia, and parietal peritoneum through the port sites at the end of surgery. 20 ml were applied at the port sites after wound closure (6 ml for epigastric port, 6 ml for umbilical port, and 4 ml for each working port). Group 2: No local anaesthetic (n = 36). Further details: The control group received 0.9% normal saline after wound closure in the same fashion and volume as Group 1. | |
| Outcomes | The outcomes reported were mortality, morbidity, hospital stay, and pain. | |
| Notes | Attempts were made to contact the author in August 2010. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The randomization was centralized and used a random permuted block design". |
| Allocation concealment (selection bias) | Low risk | Quote: "The randomization was centralized and used a random permuted block design". |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: There were no post‐randomisation dropouts. |
| Selective reporting (reporting bias) | Low risk | Comment: All important outcomes were reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Louizos 2005.
| Methods | Randomised clinical trial | |
| Participants | Country: Greece. Number randomised: 108. Post‐randomisation dropouts: 4 (3.7%). Revised sample size: 104. Average age: 49 years. Females: 56 (54%). Inclusion criteria: 1. ASA I and II. 2. Aged 25–70 years. 3. Elective laparoscopic cholecystectomy under general anaesthesia. Exclusion criteria: 1. Patients allergic to local anaesthetics. 2. Acute cholecystitis. 3. A history of severe systemic disease. 4. Chronic pain diseases other than gallstone disease. | |
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 25).
Further details: Received pre‐incisional local infiltration (trocar sites) of 20 ml levobupivacaine 0.25%.
Group 2: No local anaesthetic (n = 25).
Further details: Received pre‐incisional local infiltration of 20 ml normal saline at the trocar sites.
Group 3: Local anaesthetic (n = 28).
Further details: Same as group 1 but received 20 ml levobupivacaine 0.25% intraperitoneally.
Group 4: No local anaesthetic (n = 26). Further details: Same as group 2 but received 20 ml levobupivacaine 0.25% intraperitoneally. In all groups the fascia, muscle and preperitoneal space were infiltrated using 5 ml (infiltration of four trocar sites, thus using a total of 20 ml solution). |
|
| Outcomes | The outcomes reported were local anaesthetic related complications. | |
| Notes | Reasons for post‐randomisation dropouts: Two patients due to surgical complications and two patients due to protocol violation. Authors provided additional information in February 2010. Further information was sought but could not be obtained in August 2010. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "The answer to your first question is that the random sequence was computer generated" (author replies). |
| Allocation concealment (selection bias) | Unclear risk | Quote: "Regarding the second question we used sealed envelopes for the allocation." Comment: Further details of the sealed envelope method were not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "The surgeon performing both the preincisional local infiltration and the intraperitoneal instillation was not aware of the solution administered". Comment: Further details about patient blinding were not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "the anesthetist following up the pain score of the patients was not aware of the kind of solution administered to each patient". |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: There were post‐randomisation dropouts. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Newcomb 2007.
| Methods | Randomised clinical trial | |
| Participants | Country: USA. Number randomised: 55. Post‐randomisation dropouts: 0 (0%). Revised sample size: 55. Average age: not stated. Females: not stated. Inclusion criteria: 1. At least 18 years old. 2. Elective laparoscopic cholecystectomy. Exclusion criteria: 1. Weight less than 40 kg. 2. ASA greater than III. 3. Documented allergy or contraindication to rofecoxib, COX‐2 inhibitors, NSAIDS , morphine or bupivacaine. 4. Pregnant. 5. Renal insufficiency. 6. Peptic ulcer. 7. Bleeding diathesis. 8. Not able to operate PCA. 9. Patients that received any analgesic for acute or chronic pain within 72h of surgery. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 12). Further details: Pre‐incisional 0.25% bupivacaine. No further information given. Group 2: No local anaesthetic (n = 15). Further details: Oral placebo. Group 3: Local anaesthetic (n = 13). Further details: Rofecoxib and pre‐incisional 0.25% bupivacaine. Group 4: No local anaesthetic (n = 15). Further details: Rofecoxib. | |
| Outcomes | The outcomes reported were length of hospital stay and pain. | |
| Notes | Attempts were made to contact the authors in March 2013. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "Neither the patients not the staff measuring the outcomes knew which group a participant was included". Comment: Further details about healthcare personnel blinding were not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Neither the patients not the staff measuring the outcomes knew which group a participant was included". |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: There were no post‐randomisation dropouts. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Nicolau 2008.
| Methods | Randomised clinical trial | |
| Participants | Country: Romania. Number randomised: 60. Post‐randomisation dropouts: 0 (0%). Revised sample size: 60. Average age: 50 years. Females: 53 (88.3%). Exclusion criteria: 1. Acute cholecystitis. 2. Conversion to open procedure, the abdominal. 3. Post‐operative complications. 4. Known allergy to local anaesthetic. | |
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 15).
Further details: 20 ml 0.25% ropivacaine wound infiltration.
Group 2: No local anaesthetic (n = 15).
Further details: 20 ml of normal saline wound infiltration.
Group 3: Local anaesthetic (n = 15).
Further details: Same as group 1 but 20 ml 0.25% ropivacaine intraperitoneally in addition.
Group 4: No local anaesthetic (n = 15).
Further details: Same as group 2 but 20 ml 0.25% ropivacaine intraperitoneally in addition. In all groups the abdominal wall was infiltrated with 20 ml at each port at the fascia, muscle and preperitoneal layers after pneumoperitoneum. |
|
| Outcomes | The outcomes reported were local anaesthetic‐related complications and pain. | |
| Notes | Attempts were made to contact the author in October 2009. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Noma 2001.
| Methods | Randomised clinical trial | |
| Participants | Country: Japan. Number randomised: 30. Post‐randomisation dropouts: not stated. Revised sample size: 30. Average age: 53 years. Females: 16 (53.3%). Inclusion criteria: 1. Laparoscopic cholecystectomy. 2. ASA I‐II. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 15). Further details: 0.5% bupivacaine 20 ml into the surgical wound before surgery. Group 2: No local anaesthetic (n = 15). Further details: No local anaesthetic was used. Muscular and pre‐peritoneal layers infiltrated. | |
| Outcomes | The outcome reported were pain. | |
| Notes | Attempts were made to contact the authors in February 2008. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Papagiannopoulou 2003.
| Methods | Randomised clinical trial | |
| Participants | Country: Greece. Number randomised: 60. Post‐randomisation dropouts: 3 (3.4%). Revised sample size: 57. Average age: 44 years. Females: 34 (57.6%). Inclusion criteria: 1. ASA I‐II. 2. Elective laparoscopic cholecystectomy. Exclusion criteria: 1. Contraindications to any of the drugs used in the study. 2. Age <18 or >65 years. 3. Weight <45 or >110 kg. 4. Evidence of severe cardiovascular, renal, haematologic, or hepatic disease. 5. American Society of Anaesthesiology >III. 6. Pre‐existing neurological or psychiatric illness. 7. Chronic pain syndrome. 8. History of alcohol or drug abuse. | |
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 20).
Further details: ropivacaine 1%, 20 ml, divided proportionally according to the length of the skin incision (7 ml for the 10 mm trocar and 3 ml for the 5 mm trocars). Pre‐incisional administration.
Group 2: Local anaesthetic (n = 19).
Further details: levobupivacaine 0.5%, 20 ml, divided proportionally according to the length of the skin incision (7 ml for the 10 mm trocar and 3 ml for the 5 mm trocars). Pre‐incisional administration. Group 3: No local anaesthetic (n = 18). Further details: Normal saline was infiltrated, 20 ml, divided proportionally according to the length of the skin incision (7 ml for the 10 mm trocar and 3 ml for the 5 mm trocars). Pre‐incisional administration. |
|
| Outcomes | The outcomes reported were drug‐related serious adverse events and pain. | |
| Notes | Reasons for post‐randomisation dropouts: Protocol violation for two patients. Attempts were made to contact the authors in February 2008. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "randomized". Comment: Further details were not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "double‐blinded". Comment: Further details were not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: There were post‐randomisation dropouts. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Papaziogas 2001.
| Methods | Randomised clinical trial | |
| Participants | Country: Greece. Number randomised: 37. Post‐randomisation dropouts: 2 (5.4%). Revised sample size: 35. Average age: 46 years. Females: 26 (74.3%). Inclusion criteria: Patients undergoing elective laparoscopic cholecystectomy under general anaesthesia. Exclusion criteria: 1. Contraindications to any of anaesthetic or study drugs used. 2. Age < 18 years or > 75 years. 3. Weight < 45 kg or > 120 kg. 4. Evidence of severe cardiovascular, renal, haematologic or hepatic disease. 5. ASA > lII. 6. Pre‐existing neurological or psychiatric illnesses. 7. Chronic pain syndromes. 8. Alcohol or drug abuse. 9. Difficulties in communication and cooperation between doctor and patient. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 17). Further details: Received local infiltration with 20 ml 1% ropivacaine. Before skin incision, all trocar insertion sites were infiltrated with ropivacaine to a total of 20 ml, which was divided proportionally according to the length of the skin incision (7 ml for the 10 mm trocars and 3 ml for the 5 mm trocars). Group 2: No local anaesthetic (n = 18). Further details: Received pre‐incisional placebos. No more details given. | |
| Outcomes | The outcomes reported were operating time, VAS pain four to eight hours and VAS pain nine to 24 hours. | |
| Notes | Reasons for post‐randomisation dropouts: Difficulties in communication between patient and doctor in the post‐operative period for two patients. Attempts were made to contact the author in August 2010. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: Further details were not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: There were post‐randomisation dropouts. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Pavlidis 2003.
| Methods | Randomised clinical trial | |
| Participants | Country: Greece. Number randomised: 150. Post‐randomisation dropouts: not stated. Revised sample size: 150. Average age: 56 years. Females: 120 (80%). Inclusion criteria: 1. ASA I‐II. Exclusion criteria: 1. Patients with a previous upper abdominal operation. 2. Suspected bile duct stones by ultrasonography and liver function tests. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 75). Further details: Before the skin incision and trocar placement, local infiltration of the port sites throughout all layers with 20 ml 1% ropivacaine. The local anaesthetic or saline was equally allocated according to the diameter of the trocar 7 ml for 10 to 12 mm and 3 ml for 5 mm. Group 2: No local anaesthetic (n = 75). Further details: Normal saline was infiltrated at wound sites. | |
| Outcomes | The outcomes reported were mortality, morbidity, hospital stay, return to activity, and pain. | |
| Notes | Attempts were made to contact the authors in February 2008. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Quote: "Patients were randomly allocated into 2 groups". Comment: Further details were not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "An independent surgeon was responsible for the randomization as well as for the preparation of an unmarked syringe containing 20 mL of ropivacaine or saline. The operating surgeon, the staff, and the patients were blinded to this procedure." |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "An independent nurse recorded the postoperative pain at the 3rd, 6th, 12th, and 24th hour after the operation according to patient’s perception. The randomization was blind to both of them." |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: There were no post‐randomisation dropouts. |
| Selective reporting (reporting bias) | Low risk | Comment: Mortality and morbidity were reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Rodriguez‐Navarro 2011.
| Methods | Randomised clinical trial | |
| Participants | Country: Chile.
Number randomised: 150.
Post‐randomisation drop‐outs: 13 (8.7%).
Revised sample size: 137.
Average age: 46 years.
Females: 123 (89.8%).
Inclusion criteria:
1. Patients 18 to 80 years of age.
2. Cholelithiasis or gallbladder polyps.
3. Scheduled for laparoscopic cholecystectomy.
Exclusion criteria:
1. ASA III or IV.
2. Having previous abdominal surgery.
3 Pregnancy or lactation.
4. Renal or hepatic disease. 5. Having known choledocholithiasis. 6. Severe psychiatric illness, or known drug or alcohol dependency. |
|
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 69). Further details: Neosaxitoxin 100 mcg per patient, divided to give 35 mcg in the two 10 mm ports and 15 mcg in each of the two 5 mm ports. Group 2: Local anaesthetic (n = 68). Further details: Bupivacaine 50 mg infiltrated in the same fashion. Infiltration was approximately at 3 depths: peritoneum, muscle or aponeurosis, and skin and subcutaneous tissues. Port sites were marked and infiltrated after induction of general anaesthesia and before placement of the instruments. | |
| Outcomes | The outcomes reported were mortality, morbidity, return to activity, and hospital stay. | |
| Notes | Reasons for post‐randomisation dropouts: Five patients converted to open surgery; one patient, surgery not performed; six patients lost to follow‐up; one patient early re‐operation. Attempts were made to contact the authors in March 2013. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Treatments were assigned using a computer‐generated randomisation table in blocks of 10". |
| Allocation concealment (selection bias) | Unclear risk | Quote: "Treatments were assigned using a computer‐generated randomisation table in blocks of 10". Comment: No further details were available |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Quote: "The assistant transporting solutions to the operation room, the surgeons, the anesthesiologist all remained blinded". Comment: Not clear if the patients were blinded. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Investigators who conducted the postoperative assessments all remained blinded to the treatment assignments." |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: There were post‐randomisation dropouts. |
| Selective reporting (reporting bias) | Low risk | Comment: Mortality and morbidity were reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Sarac 1996.
| Methods | Randomised clinical trial. | |
| Participants | Country: Turkey. Number randomised: 70. Post‐randomisation dropouts: not stated. Revised sample size: 70. Average age: 53 years. Females: 56 (80%). Inclusion criteria: 1. Patients with symptomatic cholelithiasis. Exclusion criteria: 1. Patients requiring open surgery. | |
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 20).
Further details: 3 ml 0.5% bupivacaine subcutaneously around 5 mm trocars and 4 ml around 10 mm trocars just before incision.
Group 2: Local anaesthetic (n = 25).
Further details: 3 ml 0.5% bupivacaine subcutaneously around 5 mm trocars and 4 ml around 10 mm trocars after closure of wounds at the end of the operation. Group 3: No local anaesthetic (n = 25). Further details: 3 ml 0.9% normal saline subcutaneously around 5 mm trocar sites and 4 ml around 10 mm trocar sites. |
|
| Outcomes | The outcomes reported were drug‐related serious adverse events and pain. | |
| Notes | Attempts were made to contact the authors in February 2010. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Shikano 1994.
| Methods | Randomised clinical trial. | |
| Participants | Country: Japan. Number randomised: 50. Post‐randomisation dropouts: not stated. Revised sample size: 50. Average age: not stated. Females: not stated. Inclusion criteria: 1. Laparoscopic cholecystectomy | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: Local anaesthetic (n = 25). Further details: 20 to 30 ml of 0.255 % bupivacaine. Group 2: No local anaesthetic (n = 25). | |
| Outcomes | None of the outcomes of interest were reported. | |
| Notes | Attempts were made to contact the authors in March 2013. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Sozbilen 2007.
| Methods | Randomised clinical trial | |
| Participants | Country: Turkey. Number randomised: 31. Post‐randomisation dropouts: not stated. Revised sample size: 31. Average age: 49 years. Females: 16 (51.6%). Inclusion criteria: 1. Consecutive patients undergoing laparoscopic cholecystectomy. | |
| Interventions | Participants were randomly assigned to the following groups. Group 1: LA pre‐incision (n = 17). Further details: Each trocar site was pre‐incisionally infiltrated (into skin, subcutaneous tissue, and fascia) with 5 ml of 3.75% ropivacaine. Group 2: LA pre‐closure (n = 14). Further details: at the end of the procedure, just before desufflation, each trocar site was infiltrated (into skin, subcutaneous tissue, and fascia) with 5 ml of 3.75% ropivacaine. | |
| Outcomes | The outcome reported was pain. | |
| Notes | Reasons for post‐randomisation dropouts: not stated. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Ure 1993.
| Methods | Randomised clinical trial | |
| Participants | Country: Germany. Number randomised: 50. Post‐randomisation dropouts: not stated. Revised sample size: 50. Average age: 48 years. Females: 34 (68%). Inclusion criteria: 1. Elective laparoscopic cholecystectomy. 2. Symptomatic gallstone disease. 3. All patients had gallstones on ultrasound examination. Exclusion criteria: 1. Less than 18 years old. 2. Previous abdominal operation. 3. Acute cholecystitis. 4. Suffered from cardiovascular, hepatic, renal, or neurological disease or diabetes. 5. Patients taking analgesics for non‐biliary complaints. | |
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 25).
Further details: 32 ml bupivacaine 0.5%.
Group 2: No local anaesthetic (n = 25).
Further details: 32 ml normal saline. Pre‐incisional infiltration of all abdominal wall layers was performed. The final infiltration of the peritoneum was visualised from the abdominal cavity to ensure that all abdominal wall layers were anaesthetised. |
|
| Outcomes | The outcomes reported were mortality, morbidity, hospital stay, and pain. | |
| Notes | Attempts were made to contact the authors in February 2008. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: Further details were not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "The operating surgeon, the investigator, the patients, and all staff at the postoperative ward were blinded to the patient groups.". |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "The operating surgeon, the investigator, the patients, and all staff at the postoperative ward were blinded to the patient groups.". |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Uzunkoy 2001.
| Methods | Randomised clinical trial | |
| Participants | Country: Turkey.
Number randomised: 45.
Post‐randomisation dropouts: not stated.
Revised sample size: 45.
Average age: 43 years.
Females: not stated.
Inclusion criteria: 1. Patients undergoing laparoscopic cholecystectomy. |
|
| Interventions | Participants were randomly assigned to the following groups.
Group 1: Local anaesthetic (n = 15).
Further details: received 30 ml 0.25% solution of bupivacaine at the trocar sites before incision. 5 ml local anaesthetic solution was used for a 5 mm trocar and 10 ml for a 10 mm trocar.
Group 2: Local anaesthetic (n = 15).
Further details: received 30 ml 0.25% bupivacaine infiltrated after the trocar was removed.5 ml local anaesthetic solution was used for a 5 mm trocar and 10 ml for a 10 mm trocar. Group 3: No local anaesthetic (n = 15). Further details: No local anaesthetic was used. During infiltration skin, subcutaneous tissue and muscles through the peritoneum were infiltrated. |
|
| Outcomes | The outcome reported was return to activity. | |
| Notes | Attempts were made to contact the authors in February 2008. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Comment: This information was not available. |
| Allocation concealment (selection bias) | Unclear risk | Comment: This information was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Quote: "Pain that the patients experienced was evaluated by surgery nurses who were unaware of the groups". |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: This information was not available. |
| Selective reporting (reporting bias) | High risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Zajaczkowska 2004.
| Methods | Randomised clinical trial | |
| Participants | Country: Poland.
Sample size: 60.
Post‐randomisation dropout(s): not stated.
Revised sample size: 60.
Average age: 49 years. Females: 48 (80%). Inclusion criteria: 1. Elective laparoscopic cholecystectomy for symptomatic gallstones. 2. ASA I or II. 3. > 18 years of age. Exclusion criteria: 1. Acute cholecystitis. 2. Significant cardiac, respiratory, hepatic, renal, or neurologic disease. 3. Local anaesthetic and morphine allergies. 4. Analgesics for non‐biliary complaints. |
|
| Interventions | The patients were randomised to the following groups. Group 1: local anaesthetic (n = 30). Further details: 20 ml of 0.5% bupivacaine before incision. Group 2: control (n = 30). Further details: 20 ml of normal saline before incision. | |
| Outcomes | The outcome reported was pain. | |
| Notes | Attempts were made to contact the authors in August 2010. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Using sealed envelopes that had been prepared according to a computer‐generated random‐number table, we assigned the patients to one of the following 5 groups." |
| Allocation concealment (selection bias) | Unclear risk | Quote: "Using sealed envelopes that had been prepared according to a computer‐generated random‐number table, we assigned the patients to one of the following 5 groups." Comment: Further information on the sealed envelopes was not available. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Comment: "The surgeons, the investigator, the patients, and all staff at the postoperative ward were blinded to the patients’ groups". |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Comment: "The surgeons, the investigator, the patients, and all staff at the postoperative ward were blinded to the patients’ groups". |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Comment: There were post‐randomisation dropouts. |
| Selective reporting (reporting bias) | Low risk | Comment: Mortality and morbidity were not reported. |
| For‐profit bias | Unclear risk | Comment: This information was not available. |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Alexander 1996 | Not clear whether intraperitoneal bupivacaine was administered in the intervention group. |
| Bisgaard 1999 | This trial was a comparison of periportal and intraperitoneal ropivacaine versus normal saline. |
| Cha 2012 | Five patients were excluded after randomisation. These patients were replaced with other patients. The method of selection of the replacements was not stated. The randomisation in this trial may have been lost. |
| Di Pace 2009 | This trial was performed on patients undergoing various laparoscopic procedures. Results for laparoscopic cholecystectomy not given individually. |
| Futier 2011 | Not a randomised clinical trial. |
| Hilvering 2011 | Not a randomised clinical trial. |
| Karadeniz 1998 | This trial involved intraperitoneal bupivacaine injection and no wound infiltration. |
| Lopez‐Maya 2011 | This trial compared periportal and intraperitoneal ropivacaine at different timings. |
| Lotz 1997 | Not a randomised clinical trial. |
| Maharjan 2009 | This trial compared periportal and intraperitoneal bupivacaine versus control. |
| Memedov 2010 | This trial compared multi‐regional and periportal ropivacaine versus lornoxicam versus placebo. |
| Michaloliakou 1996 | This trial compared multimodal analgesia (intramuscular meperidine and ketorolac and periportal bupivacaine) versus control. |
| Verma 2006 | In this trial no control group available to match periportal bupivacaine group. |
| Wallace 1996 | In this trial wound infiltration with local anaesthetic was combined with intraperitoneal instillation of local anaesthetic. |
| Wong 1997 | Not a randomised clinical trial. |
Differences between protocol and review
The outcomes have been revised based on importance to the patients and not according to the expected treatment effect. As a result, pain was moved to a secondary outcome as mortality was considered to be more important than pain. With regards to quality of life, we accepted only validated scales of quality of life such as Euro‐QoL and SF‐36 since using unvalidated scales may be misleading. With regards to pain, we limited pain to four to eight hours and nine to 24 hours since this is the time period when most patients are discharged. We also included only trials that reported pain on the visual analogue scale. Even this is difficult to interpret (please see Discussion) but using other scales would make it even more difficult to interpret. We added other outcomes such as return to normal activity and return to work, which are very important to the patient. We have excluded analgesic requirement, which was considered a surrogate to pain. Any clinically significant differences in pain would be captured by quality of life, return to normal activity, and return to work. By altering the outcomes, we have harmonised the outcomes in this review with other reviews aimed at decreasing pain in people undergoing laparoscopic cholecystectomy.
We have added a section on trial sequential analysis to control for random errors.
Contributions of authors
S Loizides assessed the trials for inclusion, performed the data extraction, performed data analysis, and wrote the first draft. KS Gurusamy assessed the trials for inclusion, extracted the data for some studies, performed the analysis, interpreted the information, and wrote sections of the review. M Nagendaran extracted the data for the included trials. M Rossi and GP Guerrini extracted some data for the trials which had to be updated in line with the revisions of the Cochrane Handbook for Systematic Reviews of Interventions. BR Davidson critically commented on the review. All authors agreed on the final version of the review.
Sources of support
Internal sources
None, Other.
External sources
National Institute of Health Research, UK.
Declarations of interest
None known.
New
References
References to studies included in this review
Ahmad 1998 {published data only}
- Ahmad SM, Hassanally D, Harris G, Simson J. Is local and intraperitoneal instillation of bupivacaine after laparoscopic cholecystectomy effective for pain?. British Journal of Surgery 1998;85 Suppl 1:47. [Google Scholar]
Beqiri 2012 {published data only}
- Beqiri AI, Domi RQ, Sula HH, Zaimi EQ, Petrela EY. The combination of infiltrative bupivacaine with low‐pressure laparoscopy reduces postcholecystectomy pain A prospective randomized controlled study. Saudi Medical Journal 2012;33(2):134‐8. [PubMed] [Google Scholar]
Bilge 1997 {published data only}
- Bilge O, Tekant Y, Yavru A, Acarli K, Gulbaba G. The effect of post‐incisional injection of bupivacaine on post‐operative pain in laparoscopic cholecystectomy: A prospective randomized study. Turkish Journal of Surgery 1997;13(5):349‐53. [Google Scholar]
Cantore 2008 {published data only}
- Cantore F, Boni L, Giuseppe M, Giavarini L, Rovera F, Dionigi G. Pre‐incision local infiltration with levobupivacaine reduces pain and analgesic consumption after laparoscopic cholecystectomy: a new device for day‐case procedure. International Journal of Surgery 2008;6 Suppl 1:S89‐S92. [DOI] [PubMed] [Google Scholar]
Dath 1999 {published data only}
- Dath D, Park AE. Randomized, controlled trial of bupivacaine injection to decrease pain after laparoscopic cholecystectomy. Canadian Journal of Surgery 1999;42(4):284‐8. [PMC free article] [PubMed] [Google Scholar]
Feroci 2009 {published data only}
- Feroci F, Kroning KC, Scatizzi M. Effectiveness for pain after laparoscopic cholecystectomy of 0.5% bupivacaine‐soaked Tabotamp placed in the gallbladder bed: a prospective, randomized, clinical trial. Surgical Endoscopy 2009;23(10):2214‐20. [DOI] [PubMed] [Google Scholar]
Hasan 2007 {published data only}
- Hasan S, Lauwers M, Hoeij Van Nieuwenhove Y, Camu F. Postoperative vain relief after laparoscopic cholecystectomy. A placebo‐controlled randomized trial of local infiltration and intra peritoneal administration of ropivacaine 0.25%. Acta Anaesthesiologica Belgica 2007; Vol. 58, issue 2:150.
Hasaniya 2001 {published data only}
- Hasaniya N, Zayed F, Faiz H, Severino R. Preinsertion local anesthesia at the trocar site improves perioperative pain and decreases costs of laparoscopic cholecystectomy. Surgical Endoscopy 2001;15(9):962‐4. [DOI] [PubMed] [Google Scholar]
Lee 2001 {published data only}
- Lee IO, Kim SH, Kong MH, Lee MK, Kim NS, Choi YS, et al. Pain after laparoscopic cholecystectomy: the effect and timing of incisional and intraperitoneal bupivacaine. Canadian Journal of Anaesthesia 2001;48(6):545‐50. [DOI] [PubMed] [Google Scholar]
Lepner 2003 {published data only}
- Lepner U, Goroshina J, Samarutel J. Postoperative pain relief after laparoscopic cholecystectomy: a randomised prospective double‐blind clinical trial. Scandinavian Journal of Surgery 2003;92(2):121‐4. [PubMed] [Google Scholar]
Liang 2011 {published data only}
- Liang HS, Feng Y, Liu YZ, An HY, Yang BX. Effect of flurbiprofen combined different concentrations of ropivacaine local infiltration on postoperative analgesia after laparoscopic cholecystectomy. Beijing Da Xue Xue Bao 2011;43(5):753‐6. [PubMed] [Google Scholar]
Liu 2009 {published data only}
- Liu YY, Yeh CN, Lee HL, Wang SY, Tsai CY, Lin CC, et al. Local anesthesia with ropivacaine for patients undergoing laparoscopic cholecystectomy. World Journal of Gastroenterology 2009; Vol. 15, issue 19:2376‐80. [DOI] [PMC free article] [PubMed]
Louizos 2005 {published data only}
- Louizos AA, Hadzilia SJ, Leandros E, Kouroukli IK, Georgiou LG, Bramis JP. Postoperative pain relief after laparoscopic cholecystectomy: a placebo‐controlled double‐blind randomized trial of preincisional infiltration and intraperitoneal instillation of levobupivacaine 0.25%. Surgical Endoscopy 2005; Vol. 19, issue 11:1503‐6. [DOI] [PubMed]
Newcomb 2007 {published data only}
- Newcomb W, Lincourt A, Hope W, Schmelzer T, Sing R, Kercher K, et al. Prospective, double‐blinded, randomized, placebo‐controlled comparison of local anesthetic and nonsteroidal anti‐inflammatory drugs for postoperative pain management after laparoscopic surgery. American Surgeon 2007; Vol. 73, issue 6:618‐24; discussion 624‐5. [PubMed]
Nicolau 2008 {published data only}
- Nicolau AE, Merlan V, Grecu I, Nicolau M, Micu B. Multimodal analgesia in elective laparoscopic cholecystectomy. A double‐blind randomized controlled trial. Chirurgia (Bucharest, Romania) 2008;103(5):547‐51. [PubMed] [Google Scholar]
Noma 2001 {published data only}
- Noma H, Kakiuchi H, Nojiri K, Izumi R, Tashiro C. Evaluation of postoperative pain relief by infiltration of bupivacaine or epidural block after laparoscopic cholecystectomy. Masui 2001;50(11):1201‐4. [PubMed] [Google Scholar]
Papagiannopoulou 2003 {published data only}
- Papagiannopoulou P, Argiriadou H, Georgiou M, Papaziogas B, Sfyra E, Kanakoudis F. Preincisional local infiltration of levobupivacaine vs ropivacaine for pain control after laparoscopic cholecystectomy. Surgical Endoscopy 2003;17(12):1961‐4. [DOI] [PubMed] [Google Scholar]
Papaziogas 2001 {published data only}
- Papaziogas B, Argiriadou H, Papagiannopoulou P, Pavlidis T, Georgiou M, Sfyra E, et al. Preincisional intravenous low‐dose ketamine and local infiltration with ropivacaine reduces postoperative pain after laparoscopic cholecystectomy. Surgical Endoscopy 2001;15(9):1030‐3. [DOI] [PubMed] [Google Scholar]
Pavlidis 2003 {published data only}
- Pavlidis TE, Atmatzidis KS, Papaziogas BT, Makris JG, Lazaridis CN, Papaziogas TB. The effect of preincisional periportal infiltration with ropivacaine in pain relief after laparoscopic procedures: a prospective, randomized controlled trial. Journal of the Society of Laparoendoscopic Surgeons 2003;7(4):305‐10. [PMC free article] [PubMed] [Google Scholar]
Rodriguez‐Navarro 2011 {published data only}
- Rodriguez‐Navarro A, Berde C, Wiedmaier G, Mercado A, Iglesias V, Garcia C. Neosaxitoxin for postoperative analgesia in laparoscopic cholecystectomy. A randomized double blind controlled trial with 250 patients. Regional Anesthesia and Pain Medicine 2010;35(5):E54. [DOI] [PubMed] [Google Scholar]
- Rodriguez‐Navarro AJ, Berde CB, Wiedmaier G, Mercado A, Garcia C, Iglesias V, et al. Comparison of neosaxitoxin versus bupivacaine via port infiltration for postoperative analgesia following laparoscopic cholecystectomy: a randomized, double‐blind trial. Regional Anesthesia and Pain Medicine 2011;36(2):103‐9. [DOI] [PubMed] [Google Scholar]
Sarac 1996 {published data only}
- Sarac AM, Aktan AO, Baykan N, Yegen C, Yalin R. The effect and timing of local anesthesia in laparoscopic cholecystectomy. Surgical Laparoscopy and Endoscopy 1996; Vol. 6, issue 5:362‐6. [PubMed]
Shikano 1994 {published data only}
- Shikano S, Yamashita H, Kawahara M, Shimizu N, Nomura S, Nobusawa S, et al. Effect of wound infiltration with bupivacaine for postoperative pain after laparoscopic cholecystectomy. Surgical Laparoscopy and Endoscopy 1994;4(6):500. [Google Scholar]
Sozbilen 2007 {published data only}
- Sozbilen M, Yeniay L, Unalp M, Makay O, Pirim A, Ulukaya S, et al. Effects of ropivacaine on pain after laparoscopic cholecystectomy: a prospective, randomized study. Advances in Therapy 2007;24(2):247‐57. [DOI] [PubMed] [Google Scholar]
Ure 1993 {published data only}
- Ure BM, Troidl H, Spangenberger W, Neugebauer E, Lefering R, Ullmann K, et al. Preincisional local anesthesia with bupivacaine and pain after laparoscopic cholecystectomy. A double‐blind randomized clinical trial. Surgical Endoscopy 1993;7(6):482‐8. [DOI] [PubMed] [Google Scholar]
Uzunkoy 2001 {published data only}
Zajaczkowska 2004 {published data only}
- Zajaczkowska R, Wnek W, Wordliczek J, Dobrogowski J. Peripheral opioid analgesia in laparoscopic cholecystectomy. Regional Anesthesia and Pain Medicine 2004;29(5):424‐9. [DOI] [PubMed] [Google Scholar]
References to studies excluded from this review
Alexander 1996 {published data only}
- Alexander DJ, Ngoi SS, Lee L, So J, Mak K, Chan S, et al. Randomized trial of periportal peritoneal bupivacaine for pain relief after laparoscopic cholecystectomy. British Journal of Surgery 1996;83(9):1223‐5. [PubMed] [Google Scholar]
Bisgaard 1999 {published data only}
- Bisgaard T, Klarskov B, Kristiansen VB, Callesen T, Schulze S, Kehlet H, et al. Multi‐regional local anesthetic infiltration during laparoscopic cholecystectomy in patients receiving prophylactic multi‐modal analgesia: a randomized, double‐blinded, placebo‐controlled study. Anesthesia and Analgesia 1999;89(4):1017‐24. [DOI] [PubMed] [Google Scholar]
Cha 2012 {published data only}
- Cha SM, Kang H, Baek CW, Jung YH, Koo GH, Kim BG, et al. Peritrocal and intraperitoneal ropivacaine for laparoscopic cholecystectomy: A prospective, randomized, double‐blind controlled trial. Journal of Surgical Research 2012;175(2):251‐8. [DOI] [PubMed] [Google Scholar]
Di Pace 2009 {published data only}
- Pace MR, Cimador M, Catalano P, Caruso A, Sergio M, Casuccio A, et al. Efficacy of periportal infiltration and intraperitoneal instillation of ropivacaine after laparoscopic surgery in children. Journal of Laparoendoscopic and Advanced Surgical Techniques 2009;19(6):821‐5. [DOI] [PubMed] [Google Scholar]
Futier 2011 {published data only}
- Futier E, Petit A, Pezet D. Authors’ Reply: Randomized clinical trial of combined preincisional infiltration and intraperitoneal instillation of levobupivacaine for postoperative pain after laparoscopic cholecystectomy (British Journal of Surgery 2011;98:784‐9). British Journal of Surgery 2011;98(8):1179. [DOI] [PubMed] [Google Scholar]
Hilvering 2011 {published data only}
- Hilvering B, Draaisma WA, Bilt JDW, Valk RM, Kofman KE, Consten ECJ. Authors' reply: Randomized clinical trial of combined preincisional infiltration and intraperitoneal instillation of levobupivacaine for postoperative pain after laparoscopic cholecystectomy (British Journal of Surgery 2011;98:784‐9). British Journal of Surgery 2011;98(8):1179‐80. [DOI] [PubMed] [Google Scholar]
- Hilvering B, Draaisma WA, Bilt JDW, Valk RM, Kofman KE, Consten ECJ. Randomized clinical trial of combined preincisional infiltration and intraperitoneal instillation of levobupivacaine for postoperative pain after laparoscopic cholecystectomy. British Journal of Surgery 2011; Vol. 98, issue 6:784‐9. [DOI] [PubMed]
Karadeniz 1998 {published data only}
- Karadeniz U, Erdemli O, Unver S, Ayoglu H, Ayogu F, Ebil S. Intraperitoneal bupivacaine injection and infusion via subphrenic catheter for postoperative pain management in laparoscopic cholecystectomy. British Journal of Anaesthesia 1998;80 Suppl 1:A597. [Google Scholar]
Lopez‐Maya 2011 {published data only}
- Lopez‐Maya L, Lina‐Manjarrez F, Diaz‐Peralta A, Lina‐Lopez LM. Reduction of postoperative pain in cholecystectomy laparoscopy. Cutaneous and intraperitoneal ropivacaine (before vs after) the incision and pneumoperitoneum. Revista Mexicana de Anestesiologia 2011;34(4):251‐9. [Google Scholar]
Lotz 1997 {published data only}
- Lotz JC. Randomized trial of periportal peritoneal bupivacaine for pain relief after laparoscopic cholecystectomy. British Journal of Surgery 1997;84(5):730. [DOI] [PubMed] [Google Scholar]
Maharjan 2009 {published data only}
- Maharjan SK, Shrestha S. Intraperitoneal and periportal injection of bupivacaine for pain after laparoscopic cholecystectomy. Kathmandu University Medical Journal 2009;7(25):50‐3. [DOI] [PubMed] [Google Scholar]
Memedov 2010 {published data only}
- Memedov C, Mentes O, Simsek A, Kece C, Yagci G, Harlak A, et al. Comparison of analgesic effects of intraperitoneal lornoxicam and ropivacaine administration in laparoscopic cholecystectomy. Trakya Universitesi Tip Fakultesi Dergisi 2010;27(2):142‐9. [Google Scholar]
Michaloliakou 1996 {published data only}
- Michaloliakou C, Chung F, Sharma S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesthesia and Analgesia 1996;82(1):44‐51. [DOI] [PubMed] [Google Scholar]
Verma 2006 {published data only}
- Verma GR, Lyngdoh TS, Kaman L, Bala I. Placement of 0.5% bupivacaine‐soaked Surgicel in the gallbladder bed is effective for pain after laparoscopic cholecystectomy. Surgical Endoscopy 2006;20(10):1560‐4. [DOI] [PubMed] [Google Scholar]
Wallace 1996 {published data only}
- Wallace DH, Serpell MG, O'Dwyer PJ. Effect of bupivacaine on postoperative pain and pulmonary function after laparoscopic cholecystectomy. British Journal of Surgery 1996;83:1637. [DOI] [PubMed] [Google Scholar]
Wong 1997 {published data only}
- Wong C, Rees BI. Randomized trial of periportal peritoneal bupivacaine for pain relief after laparoscopic cholecystectomy. British Journal of Surgery 1997;84(1):138. [DOI] [PubMed] [Google Scholar]
Additional references
Attili 1995
- Attili AF, Santis A, Capri R, Repice AM, Maselli S. The natural history of gallstones: The GREPCO experience. The GREPCO group. Hepatology 1995;21(3):655‐60. [DOI] [PubMed] [Google Scholar]
Ballal 2009
- Ballal M, David G, Willmott S, Corless DJ, Deakin M, Slavin JP. Conversion after laparoscopic cholecystectomy in England. Surgical Endoscopy 2009;23(10):2338‐44. [DOI] [PubMed] [Google Scholar]
Bates 1992
- Bates T, Harrison M, Lowe D, Lawson C, Padley N. Longitudinal study of gall stone prevalence at necropsy. Gut 1992;33(1):103‐7. [DOI] [PMC free article] [PubMed] [Google Scholar]
Brok 2008
- Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta‐analyses. Journal of Clinical Epidemiology 2008;61(8):763‐9. [DOI] [PubMed] [Google Scholar]
Brok 2009
- Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta‐analyses may be inconclusive ‐ trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta‐analyses. International Journal of Epidemiology 2009;38(1):287‐98. [DOI] [PubMed] [Google Scholar]
Butterworth 1990
- Butterworth JF 4th, Strichartz GR. Molecular mechanisms of local anesthesia: a review. Anesthesiology 1990;72(4):711‐34. [DOI] [PubMed] [Google Scholar]
Clark 2006
- Clark JD, Qiao Y, Li X, Shi X, Angst MS, Yeomans DC. Blockade of the complement C5a receptor reduces incisional allodynia, edema, and cytokine expression. Anesthesiology 2006;104(6):1274‐82. [DOI] [PubMed] [Google Scholar]
CTU 2011
- Copenhagen Trial Unit. TSA ‐ Trial Sequential Analysis. ctu.dk/tsa/ 2011 (accessed 22 February 2014).
DeMets 1987
- DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341‐50. [DOI] [PubMed] [Google Scholar]
DerSimonian 1986
- DerSimonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177‐88. [DOI] [PubMed] [Google Scholar]
Dolan 2009
- Dolan JP, Diggs BS, Sheppard BC, Hunter JG. The national mortality burden and significant factors associated with open and laparoscopic cholecystectomy: 1997‐2006. Journal of Gastrointestinal Surgery 2009;13(12):2292‐301. [DOI] [PubMed] [Google Scholar]
Dubin 2010
- Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. Journal of Clinical Investigation 2010;120(11):3760‐72. [DOI] [PMC free article] [PubMed] [Google Scholar]
Egger 1997
- Egger M, Davey SG, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ (Clinical Research Ed) 1997;315(7109):629‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]
Fuzier 2009
- Fuzier R, Lapeyre‐Mestre M, Samii K, Montastruc JL. Adverse drug reactions to local anaesthetics: a review of the French pharmacovigilance database. Drug Safety 2009;32(4):345‐56. [DOI] [PubMed] [Google Scholar]
Giger 2011
- Giger U, Ouaissi M, Schmitz SF, Krahenbuhl S, Krahenbuhl L. Bile duct injury and use of cholangiography during laparoscopic cholecystectomy. British Journal of Surgery 2011;98(3):391‐6. [DOI] [PubMed] [Google Scholar]
Gluud 2014
- Gluud C, Nikolova D, Klingenberg SL, Alexakis N, Als‐Nielsen B, Colli A, et al. Cochrane Hepato‐Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)). 2014, Issue 1. Art. No.: LIVER.
GREPCO 1984
- GREPCO. Prevalence of gallstone disease in an Italian adult female population. Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO). American Journal of Epidemiology 1984;119(5):796‐805. [PubMed] [Google Scholar]
GREPCO 1988
- GREPCO. The epidemiology of gallstone disease in Rome, Italy. Part i. Prevalence data in men. The Rome Group for Epidemiology and Prevention of Cholelithiasis (GREPCO). Hepatology 1988;8(4):904‐6. [PubMed] [Google Scholar]
Gurusamy 2008
- Gurusamy KS, Junnarkar S, Farouk M, Davidson BR. Day‐case versus overnight stay in laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2008, Issue 1. [DOI: 10.1002/14651858.CD006798.pub2] [DOI] [PubMed] [Google Scholar]
Gurusamy 2008a
- Gurusamy K, Junnarkar S, Farouk M, Davidson BR. Meta‐analysis of randomized controlled trials on the safety and effectiveness of day‐case laparoscopic cholecystectomy. British Journal of Surgery 2008;95(2):161‐8. [DOI] [PubMed] [Google Scholar]
Gurusamy 2009
- Gurusamy KS, Gluud C, Nikolova D, Davidson BR. Assessment of risk of bias in randomized clinical trials in surgery. British Journal of Surgery 2009;96(4):342‐9. [DOI] [PubMed] [Google Scholar]
Gurusamy 2013a
- Gurusamy KS, Nagendran M, Guerrini GP, Toon CD, Zinnuroglu M, Davidson BR. Intra‐peritoneal local anaesthetic instillation versus no intra‐peritoneal local anaesthetic instillation for laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews Under editorial, issue Under editorial. [DOI] [PubMed]
Gurusamy 2013b
- Gurusamy KS, Vaughan J, Toon CD, Davidson BR. Pharmacological interventions for prevention or treatment of post‐operative pain in patients undergoing laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews Under editorial, issue Under editorial. [DOI] [PMC free article] [PubMed]
Halldestam 2004
- Halldestam I, Enell EL, Kullman E, Borch K. Development of symptoms and complications in individuals with asymptomatic gallstones. British Journal of Surgery 2004;91(6):734‐8. [DOI] [PubMed] [Google Scholar]
HES 2011
- HESonline. Hospital Episode Statistics. Main procedures and interventions: 3 character. www.hscic.gov.uk/catalogue/PUB08288 2011 (accessed on 3 September 2013).
Higgins 2002
- Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta‐analysis. Statistics in Medicine 2002;21(11):1539‐58. [DOI] [PubMed] [Google Scholar]
Higgins 2011
- Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Colloboration, 2011. Available from www.cochrane‐handbook.org.
ICH‐GCP 1997
- International Conference on Harmonisation Expert Working Group. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Guideline for good clinical practice 1997 CFR & ICH Guidelines1. Vol. 1, PA 19063‐2043, USA: Barnett International/PAREXEL, 1997. [Google Scholar]
Joshi 2012
- Joshi GP, Rawal N, Kehlet H, Bonnet F, Camu F, Fischer HB, et al. Evidence‐based management of postoperative pain in adults undergoing open inguinal hernia surgery. British Journal of Surgery 2012;99(2):168‐85. [DOI] [PubMed] [Google Scholar]
Kjaergaard 2012
- Kjaergaard M, Moiniche S, Olsen KS. Wound infiltration with local anesthetics for post‐operative pain relief in lumbar spine surgery: a systematic review. Acta Anaesthesiologica Scandinavica 2012;56(3):282‐90. [DOI] [PubMed] [Google Scholar]
Kjaergard 2001
- Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta‐analyses. Annals of Internal Medicine 2001;135(11):982‐9. [DOI] [PubMed] [Google Scholar]
Lundh 2012
- Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2012, Issue 12. [DOI: 10.1002/14651858.MR000033.pub2] [DOI] [PubMed] [Google Scholar]
Macaskill 2001
- Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta‐analysis. Statistics in Medicine 2001;20(4):641‐54. [DOI] [PubMed] [Google Scholar]
Moher 1998
- Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. Lancet 1998;352(9128):609‐13. [DOI] [PubMed] [Google Scholar]
Newell 1992
- Newell DJ. Intention‐to‐treat analysis: implications for quantitative and qualitative research. International Journal of Epidemiology 1992;21(5):837‐41. [DOI] [PubMed] [Google Scholar]
Ng 2004
NIH 1992
- NIH. NIH consensus statement on gallstones and laparoscopic cholecystectomy. consensus.nih.gov/1992/1992GallstonesLaparoscopy090html.htm 1992 (accessed 3 September 2013). [PubMed]
RevMan 2012 [Computer program]
- The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.
Royle 2003
- Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591‐603. [DOI] [PubMed] [Google Scholar]
Savovic 2012
- Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Health Technology Assessment 2012;16(35):1‐82. [DOI] [PubMed] [Google Scholar]
Savovic 2012a
- Savovic J, Jones HE, Altman DG, Harris RJ, Jüni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Annals of Internal Medicine 2012;157(6):429‐38. [DOI] [PubMed] [Google Scholar]
Schulz 1995
- Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12. [DOI] [PubMed] [Google Scholar]
Strasberg 1993
- Strasberg SM, Clavien PA. Overview of therapeutic modalities for the treatment of gallstone diseases. American Journal of Surgery 1993;165(4):420‐6. [DOI] [PubMed] [Google Scholar]
Thorlund 2009
- Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta‐analyses. International Journal of Epidemiology 2009;38(1):276‐86. [DOI] [PubMed] [Google Scholar]
Thorlund 2010
- Thorlund K, Anema A, Mills E. Interpreting meta‐analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV‐infected individuals. Clinical Epidemiology 2010;2:57‐66. [DOI] [PMC free article] [PubMed] [Google Scholar]
Thorlund 2011
- Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). ctu.dk/tsa/files/tsa_manual.pdf 2011 (accessed 22 February 2014).
Todd 1996
- Todd KH, Funk JP. The minimum clinically important difference in physician‐assigned visual analog pain scores. Academic Emergency Medicine 1996;3(2):142‐6. [PUBMED: 8808375] [DOI] [PubMed] [Google Scholar]
Wetterslev 2008
- Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta‐analysis. Journal of Clinical Epidemiology 2008;61(1):64‐75. [DOI] [PubMed] [Google Scholar]
Wetterslev 2009
- Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random‐effects model meta‐analyses. BMC Medical Research Methodology 2009;9:86. [DOI] [PMC free article] [PubMed] [Google Scholar]
Wood 2008
- Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta‐epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601‐5. [DOI] [PMC free article] [PubMed] [Google Scholar]