Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy

  • Review
  • Intervention

Authors


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.

Résumé scientifique

Infiltration de la plaie par des agents anesthésiques locaux pour la cholécystectomie laparoscopique

Contexte

Bien que la cholécystectomie laparoscopique soit généralement considérée comme moins douloureuse que la chirurgie ouverte, la douleur est l'un des principaux motifs d’une sortie retardée après la chirurgie ambulatoire entraînant une hospitalisation d'une nuit suite à une cholécystectomie laparoscopique. L'innocuité et l'efficacité d'une infiltration de la plaie par anesthésique local chez les personnes subissant une cholécystectomie laparoscopique ne sont pas connues.

Objectifs

Évaluer les effets bénéfiques et délétères d'une infiltration de la plaie par anesthésique local chez les patients subissant une cholécystectomie laparoscopique et identifier la meilleure méthode d'une infiltration de la plaie par anesthésique local concernant le type d'anesthésique local, de dosage et de durée d'administration de l'anesthésique local.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE, EMBASE et Science Citation Index Expanded jusqu'en février 2013 afin d’identifier des études pertinentes pour cette revue. Nous avons inclus des essais cliniques randomisés pour observer le bénéfice et des études quasi-randomisés et comparatives non randomisées pour observer les préjudices liés au traitement.

Critères de sélection

Seuls les essais cliniques randomisés (indépendamment de la langue, de la mise en aveugle, ou du statut de publication) comparant une infiltration de la plaie par anesthésique local par rapport à un placebo, à l'absence d'intervention ou à un contrôle inactif pendant la cholécystectomie laparoscopique, les essais comparant différents agents anesthésiques locaux pour une infiltration de la plaie par anesthésique local et les essais comparant les différentes périodes d'infiltration de la plaie par anesthésique local, ont été pris en compte pour la revue.

Recueil et analyse des données

Deux auteurs de la revue ont recueilli les données de façon indépendante. Nous avons analysé les données à l'aide des modèles de méta-analyses à effets fixes et à effets aléatoires en utilisant RevMan. Pour chaque critère de jugement, nous avons calculé le risque relatif (RR) ou la différence moyenne (DM) avec des intervalles de confiance (IC) à 95 %.

Résultats principaux

Vingt-six essais remplissaient les critères d'inclusion de la revue. Tous les 26 essais, à l'exception d'un essai de 30 participants, étaient à risque de biais élevé. Dix-neuf des essais avec 1 263 participants randomisés ont fourni des données pour cette revue. Dix des 19 essais ont comparé une infiltration de la plaie par anesthésique local par rapport à un groupe témoin inactif. Un des 19 essais comparait une infiltration de la plaie par anesthésique local à deux groupes témoins inactifs, à une solution saline normale et à l'absence d'intervention. Deux des 19 essais possédaient quatre groupes comparant une infiltration de la plaie par anesthésique local à un groupe témoin inactif en la présence et l'absence de co-interventions pour réduire la douleur après une cholécystectomie laparoscopique. Quatre des 19 essais possédaient trois groupes ou plus susceptibles d'être inclus pour la comparaison d'une infiltration de la plaie par anesthésique local par rapport à un groupe témoin inactif et différentes méthodes d’infiltration de la plaie par anesthésique local. Les deux essais restants comparaient différentes méthodes d’infiltration de la plaie par anesthésique local.

La plupart des essais incluaient uniquement les personnes à faible risque anesthésique subissant une cholécystectomie laparoscopique élective. Dix-sept essais ont randomisé un total de 1 095 participants subissant une infiltration de la plaie par anesthésique local (587 participants) par rapport à l'absence d’infiltration de la plaie par anesthésique local (508 participants). Différents agents anesthésiques étaient utilisés, mais la bupivacaïne était l’anesthésique local le plus couramment utilisé. Aucune mortalité n’a été déclarée dans aucun des groupes des sept essais qui avaient rendu compte de la mortalité (0 / 280 (0 %) dans le groupe d’infiltration avec un anesthésique local par rapport à 0 / 259 (0 %) dans le groupe témoin). L'effet d'un anesthésique local, sur la proportion de personnes ayant développé des effets indésirables graves, était imprécis et compatible avec une différence accrue ou non d’effets indésirables graves (sept essais ; 539 participants ; 2 / 280 (0,8 %) dans le groupe d’anesthésique local par rapport à 1 / 259 (0,4 %) dans le groupe témoin; RR 2,00 ; IC à 95 % 0,19 à 21,59 ; preuves de très faible qualité). Aucun des effets indésirables graves n’était lié à une infiltration de la plaie par anesthésique local. Aucun des essais n'a rapporté la qualité de vie des patients. La proportion de participants qui sont sortis de l’hôpital après une chirurgie ambulatoire était plus élevée dans le groupe d'infiltration avec un anesthésique local que dans le groupe sans infiltration avec un anesthésique local (un essai ; 97 participants ; 33 / 50 (66,0 %) dans le groupe de l'anesthésique local par rapport à 20 / 47 (42,6 %) dans le groupe témoin; RR 1,55 ; IC à 95 % 1,05 à 2,28 ; preuves de très faible qualité). L'effet d'un anesthésique local sur la durée du séjour à l'hôpital était compatible avec une diminution, une augmentation, ou aucune différence dans la durée d'hospitalisation entre les deux groupes (quatre essais ; 327 participants ; DM -0,26 jours ; IC à 95 % -0,67 à 0,16 ; preuves de très faible qualité). Les scores de douleur comme mesurés par l'échelle visuelle analogique (0 à 10 cm) étaient plus faibles dans le groupe d'infiltration avec un anesthésique local que dans le groupe témoin de 4 à 8 heures (13 essais ; 806 participants ; DM -1,33 cm sur l'EVA ; IC à 95 % -1,54 à -1,12 ; preuves de très faible qualité) et de 9 à 24 heures (12 essais ; 756 participants ; DM -0,36 cm sur l'EVA ; IC à 95 % -0,53 à -0,20 ; preuves de très faible qualité). L'effet d'un anesthésique local sur le temps nécessaire à la reprise des activités normales entre les deux groupes était imprécis et compatible avec une diminution, une augmentation, ou aucune différence dans le temps nécessaire à la reprise des activités normales (deux essais ; 195 participants ; DM 0,14 jours ; IC à 95 % -0,59 à 0,87 ; preuves de très faible qualité). Aucun des essais ne rapportait sur le retour au travail.

Quatre essais randomisaient un total de 149 participants pour une infiltration de la plaie par anesthésique local avant l’incision cutanée (74 participants) par rapport à une infiltration de la plaie par anesthésique local à la fin de la chirurgie (75 participants). Deux essais randomisaient un total de 176 participants pour quatre différents anesthésiques locaux (bupivacaïne, lévobupivacaïne, ropivacaïne neosaxitoxin). Bien qu'il y ait des différences entre les groupes dans certains critères de jugement, les changements n'étaient pas cohérents. Il n'y avait aucune preuve permettant de recommander un anesthésique local par rapport à un autre ou l'administration d'un anesthésique local à un moment précis par rapport à un autre.

Conclusions des auteurs

Les effets indésirables graves étaient rares dans les études évaluant une infiltration de la plaie par anesthésique local (preuves de très faible qualité). Des preuves de très faible qualité montrent que l'infiltration réduit la douleur chez les personnes à faible risque anesthésique subissant une cholécystectomie laparoscopique élective. Cependant, l'importance clinique de cette réduction de la douleur est probablement faible. D'autres essais cliniques randomisés à faible risque d'erreurs systématiques et aléatoires sont nécessaires. De tels essais devraient inclure dans leur évaluation des résultats cliniques importants, tels que la qualité de vie et le délai de retour au travail.

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.

Résumé simplifié

Infiltration de la plaie par des agents anesthésiques locaux pour la cholécystectomie laparoscopique (administration d’un anesthésique local dans la plaie chirurgicale chez les personnes subissant une cholécystectomie laparoscopique)

Contexte
Environ 10 % à 15 % de la population adulte occidentale souffre de calculs biliaires. Entre 1 et 4 % deviennent symptomatiques chaque année. L'ablation de la vésicule biliaire (cholécystectomie) est le pilier du traitement pour les calculs biliaires symptomatiques. Plus d'un demi-million de cholécystectomies sont effectuées chaque année uniquement aux États-Unis. La cholécystectomie laparoscopique (ablation de la vésicule biliaire à l’aide de grosses aiguilles, également connue sous le nom de trocarts) est aujourd'hui la méthode de cholécystectomie préférée. Tandis que la cholécystectomie laparoscopique est généralement considérée comme étant moins douloureuse que la chirurgie ouverte, la douleur est l'une des principales raisons expliquant une sortie d'hôpital retardée après une cholécystectomie laparoscopique. L'administration d'anesthésiques locaux (médicaments qui insensibilisent une partie du corps, similaires à ceux utilisés par le dentiste pour que les personnes ne ressentent pas la douleur) dans la plaie chirurgicale (infiltration de la plaie par anesthésique local) pourrait être un moyen efficace pour réduire la douleur après une cholécystectomie laparoscopique. Cependant, les bénéfices et les inconvénients d’une infiltration de la plaie par anesthésique local ne sont pas connus. Nous avons cherché à répondre à ces questions en passant en revue la littérature médicale et en obtenant des informations issues d'essais cliniques randomisés sur les bénéfices liés au traitement. Lorsqu'elles sont menées correctement, de telles études fournissent des informations très précises sur le meilleur traitement. Nous avons également pris en compte les études comparatives non randomisées pour le traitement lié à la nocivité. Deux auteurs ont effectué des recherches dans la littérature jusqu'en février 2013 et obtenu des informations issues d’études afin de minimiser les erreurs.

Les caractéristiques de l'étude
Dans cette revue, nous avons identifié 19 essais cliniques randomisés. La plupart des participants dans les essais subissant une cholécystectomie laparoscopique programmée étaient à faible risque anesthésique.

Résultats principaux
Dans 17 essais, 1 095 participants ont été randomisés pour une infiltration de la plaie par anesthésique local (587 participants) ou sans infiltration de la plaie par anesthésique local (508 participants). Une méthode similaire à un tirage au sort déterminait si le participant recevait un agent anesthésique local (ou non), de sorte que les traitements étaient comparés parmi les groupes de patients qui étaient aussi similaires que possible. Aucun décès n'était rapporté dans aucun des groupes des sept essais (539 participants) qui rapportaient la mortalité. La différence entre les groupes relative auxcomplications graves était imprécise. Il n'y avait pas de complication relative à l’anesthésique local chez presque 450 participants ayant reçu une infiltration de la plaie par anesthésique local dans les différents essais qui avaient rendu compte de complications. Aucun des essais n'a rapporté la qualité de vie ou le temps nécessaire pour le retour au travail. La proportion de participants qui quittaient l’hôpital après une chirurgie ambulatoire était plus élevée dans le groupe d'anesthésique local que dans le groupe témoin dans le seul essai ayant rendu compte de cette information. La différence dans la durée de séjour à l'hôpital ou le temps nécessaire pour le retour à une activité normale était imprécise. La douleur était plus faible chez les participants ayant reçu une administration intra-abdominale d’anesthésique local par rapport à ceux des groupes témoins de 4 à 8 heures et de 9 à 24 heures, telle que mesurée par l'échelle visuelle analogue (une représentation graphique qui évalue la quantité de la douleur sur une échelle de 1 à 10). Lors des comparaisons des différentes méthodes d'infiltration d'anesthésique local, il y avait des différences entre les groupes dans certains critères de jugement, mais les changements n'étaient pas cohérents. Par conséquent, il n’existe aucune preuve permettant de préférer un médicament particulier ou une méthode particulière pour administrer les anesthésiques locaux. Les effets indésirables graves étaient rares dans les études évaluant les infiltrations de la plaie avec un anesthésique local. Des preuves de très faible qualité montrent que l'infiltration réduit la douleur chez les patients à faible risque anesthésique subissant une cholécystectomie laparoscopique élective. Cependant, l'importance clinique de cette réduction de la douleur est probablement faible.

Qualité des preuves
La plupart des essais étaient à risque de biais élevé, ce qui peut conduire à des conclusions erronées en surestimant les bénéfices ou en sous-estimant les inconvénients d'une méthode par rapport à une autre en raison de la manière dont une étude a été réalisée. La qualité globale des preuves était très faible.

Les recherches futures
D'autres essais sont nécessaires. De tels essais devraient inclure des critères de jugement tels que la qualité de vie, le séjour à l'hôpital, le temps nécessaire à la reprise des activités normales et le temps nécessaire pour le retour au travail, qui sont importants pour la personne subissant une cholécystectomie laparoscopique et les personnes qui fournissent des fonds pour le traitement.

Notes de traduction

Traduit par: French Cochrane Centre 22nd June, 2014

Summary of findings(Explanation)

Summary of findings for the main comparison. Local anaesthetic wound infiltration compared to no local anaesthetic wound infiltration for people undergoing laparoscopic cholecystectomy
  1. 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).

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.
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
No local anaesthetic wound infiltration Local anaesthetic wound infiltration
MortalityThere was no mortality in either group.Not estimable539
(7 trials)
⊕⊝⊝⊝
very low 1,2
Serious adverse events 4 per 1000 8 per 1000
(1 to 83)
RR 2
(0.19 to 21.59)
539
(7 trials)
⊕⊝⊝⊝
very low 1,2
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 low 1,3
Length of hospital stayThe 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 low 1,4,5
Pain 4 to 8 hoursThe 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 low 1,4
Pain 9 to 24 hoursThe 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)
⊕⊕⊝⊝
low 1
Return to normal activityThe 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 low 1,5
*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.

Summary of findings 2 Wound infiltration with different local anaesthetic agents for people undergoing laparoscopic cholecystectomy

Summary of findings 2. Wound infiltration with different local anaesthetic agents for people undergoing laparoscopic cholecystectomy
  1. 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).

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.
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
Control Different local anaesthetic agents
Neosaxitoxin versus bupivacaine
MortalityThere was no mortality in either groupNot estimable137
(1 trial)
⊕⊝⊝⊝
very low 1,2
Serious adverse eventsThere were no serious adverse events in either groupNot estimable137
(1 trial)
⊕⊝⊝⊝
very low 1,2
Length of hospital stayThe 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 low 1,3
Return to normal activityThe 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 low 1,3
Ropivacaine versus levobupivacaine
Pain 4 to 8 hoursThe 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 low 1,3
Pain 9 to 24 hoursThe 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 low 1,3
*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.

Summary of findings 3 Local anaesthetic wound infiltration before incision compared to end of surgery for people undergoing laparoscopic cholecystectomy

Summary of findings 3. Local anaesthetic wound infiltration before incision compared to end of surgery for people undergoing laparoscopic cholecystectomy
  1. 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).

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
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
End of surgery Before incision
MortalityThere was no mortality in either groupNot estimable43
(1 trial)
⊕⊝⊝⊝
very low 1,2
 
Serious adverse eventsThere were no serious adverse events in either groupNot estimable43
(1 trial)
⊕⊝⊝⊝
very low 1,2
 
Pain 4 to 8 hoursThe 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 low 1,3
 
Pain 9 to 24 hoursThe 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 low 1,3
 
Return to normal activityThe 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 low 1,3
 
*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.

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
  1. Mortality.

  2. Serious adverse events defined as any event that would increase mortality, is life-threatening, requires inpatient hospitalisation, results in a persistent or significant disability, or any important medical event that might have jeopardised the patient or required intervention to prevent it (ICH-GCP 1997). Complications such as bile duct injury; re-operations; 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.

  3. Patient quality of life (however defined by authors using a validated scale such as Euro-QoL or Short Form (SF)-36).

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

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

  3. Return to activity.

  4. Return to work.

We have reported all the outcomes with at least one trial in the Summary of findings for the main comparison.

Search methods for identification of studies

Electronic searches

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

Searching other resources

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

Data collection and analysis

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

Selection of studies

Two authors (SF and KG) identified the trials for inclusion independently of each other. We have also listed the excluded studies with the reasons for the exclusions.

Data extraction and management

Three authors (SF, KG, and MN) extracted the following data independently of each other.

  1. Year and language of publication.

  2. Country in which the trial was conducted.

  3. Year of trial.

  4. Inclusion and exclusion criteria.

  5. Sample size.

  6. Elective surgery or acute cholecystitis.

  7. Local anaesthetic agent used.

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

  9. Timing of administration.

  10. Depth of infiltration (skin versus skin along with tissues until fascial layer).

  11. Intraperitoneal instillation with local anaesthetic.

  12. Other co-interventions.

  13. Outcomes (mentioned above).

  14. Risk of bias (described below).

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

We resolved any differences in opinion through discussion or arbitration by another author (KG).

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.

Figure 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 1.

Table 1. Details of intervention and co-interventions
  1. 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.

StudyComparisonAdditional informationLocal anaestheticConcentrationDoseTimeDepthIntraperitoneal LARoutine supplemental analgesia*
Bilge 1997LA versus none-bupivacaine0.20%10 mlend of surgeryfascianot statedno
Dath 1999LA versus none-bupivacaine0.50%20 mlend of surgerynot statednot statedno
Feroci 2009LA versus none-bupivacaine2 mg/kgnot statedend of surgeryfascianono
Lee 2001LA versus noneno intraperitoneal instillationbupivacaine0.25%20 mlpre-incisionaluntil parietal peritoneumyesroutine NSAID
Lee 2001LA versus noneintraperitoneal instillationbupivacaine0.25%20 mlend of surgeryuntil parietal peritoneumyesroutine NSAID
Lee 2001LA versus LA (timing)-bupivacaine0.25%20 mlpre-incisional versus end of surgeryuntil parietal peritoneumyesroutine NSAID
Lepner 2003LA versus noneno intervention as controlbupivacaine0.13%80 mlend of surgerypre-peritoneal spacenoroutine NSAID
Lepner 2003LA versus nonenormal saline as controlbupivacaine0.13%80 mlend of surgerypre-peritoneal spacenoroutine NSAID
Liu 2009LA versus none-ropivacaine1.00%20 mlend of surgeryuntil parietal peritoneumnot statednot stated
Louizos 2005LA versus none-levobupivacaine0.25%20 mlpre-incisionalpre-peritoneal spaceyes and nono
Newcomb 2007LA versus noneno rofecoxibbupivacaine0.25%not statedpre-incisionalnot statednot statedno
Newcomb 2007LA versus nonerofecoxibbupivacaine0.25%not statedpre-incisionalnot statednot statedno
Nicolau 2008LA versus noneno intraperitoneal instillationropivacaine0.25%20 mlend of surgerypre-peritoneal spacenoroutine NSAID
Nicolau 2008LA versus noneintraperitoneal instillationropivacaine0.25%20 mlend of surgerypre-peritoneal spaceyesroutine NSAID
Noma 2001LA versus none-bupivacaine0.50%20 mlpre-incisionalpre-peritoneal spacenot statedno
Papagiannopoulou 2003LA versus noneropivacaineropivacaine1.00%20 mlpre-incisionalnot statednot statedno
Papagiannopoulou 2003LA versus nonelevobupivacainelevobupivacaine0.50%20 mlpre-incisionalnot statednot statedno
Papagiannopoulou 2003LA versus LA (drug)-ropivacaine versus levopbupivacaine1% and 0.5% respectively20 mlpre-incisionalnot statednot statedno
Papaziogas 2001LA versus none-ropivacaine1.00%20 mlpre-incisionalnot statednot statedno
Pavlidis 2003LA versus none-ropivacaine1.00%20 mlpre-incisionaluntil parietal peritoneumnot statedno
Rodriguez-Navarro 2011LA versus LA (drug)-neosaxitoxin versus bupivacaine100 mcg versus 50 mgnot statedpre-incisionaluntil parietal peritoneumnot statedno
Sarac 1996LA versus none-bupivacaine0.50%14 mlpre-incisionalnot statednot statedno
Sarac 1996LA versus none-bupivacaine0.50%14 mlend of surgerynot statednot statedno
Sarac 1996LA versus LA (timing)-bupivacaine0.50%14 mlpre-incisional versus end of surgerynot statednot statedno
Sozbilen 2007LA versus LA (timing)-ropivacaine3.75%5 mlpre-incisional versus end of surgeryfasciayesno
Ure 1993LA versus none-bupivacaine0.50%32 mlpre-incisional versus end of surgerypre-peritoneal spacenot statedno
Uzunkoy 2001LA versus none-bupivacaine0.25%30 mlpre-incisionaluntil parietal peritoneumnot statedno
Uzunkoy 2001LA versus none-bupivacaine0.25%30 mlend of surgeryuntil parietal peritoneumnot statedno
Uzunkoy 2001LA versus LA (timing)-bupivacaine0.25%30 mlpre-incisional versus end of surgeryuntil parietal peritoneumnot statedno
Zajaczkowska 2004LA versus none-bupivacaine0.50%20 mlpre-incisionalnot statednot statedno
Co-intervention

The details of the use of intraperitoneal local anaesthetic infiltration and routine supplemental analgesia are shown in Table 1.

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

Risk of bias in included studies

One trial was at low risk of bias (Feroci 2009). All the remaining trials were at high risk of bias. The risk of bias in the included trials is summarised in the risk of bias graph (Figure 2) and risk of bias summary (Figure 3).

Figure 2.

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

Figure 3.

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

Allocation

Only four trials (4/26 (15.4%)) described random sequence generation and allocation concealment adequately (Bilge 1997; Feroci 2009; Liu 2009; Beqiri 2012). These trials were considered to be at low risk of selection bias.

Blinding

Five trials (5/26 (19.2%)) reported that the participants, healthcare personnel involved in patient care, and outcome assessors were blinded and were considered to be at low risk of performance and detection bias (Ure 1993; Lepner 2003; Pavlidis 2003; Zajaczkowska 2004; Feroci 2009).

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

Local anaesthetic wound infiltration versus no local anaesthetic wound infiltration

The main results are summarised in the Summary of findings for the main comparison.

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.

Figure 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.

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.

Figure 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.

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).

Figure 6.

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

Pain
Pain at four to eight hours

Thirteen trials (806 participants) reported this outcome (Sarac 1996; Bilge 1997; Dath 1999; Noma 2001; Papaziogas 2001; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007; Nicolau 2008; Feroci 2009; Liu 2009). The pain scores as measured by the visual analogue scale were lower in the local anaesthetic infiltration group than the control group (MD -1.33 cm on the VAS; 95% CI -1.54 to -1.12) (Analysis 1.4). There were no changes in the interpretation of results using a random-effects model meta-analysis. Either the mean or the standard deviation was imputed in six trials (Ure 1993; Sarac 1996; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007). Exclusion of these trials did not alter the results (MD -1.34 cm on the VAS; 95% CI -1.55 to -1.12) (Analysis 1.8). One trial contributed to nearly 45% of the weight of the analysis (Noma 2001). It was not clear whether the trial reported the standard deviation or standard error. Exclusion of this trial from the analysis in addition to the other trials where the standard deviation was imputed did not alter the results (MD -0.73 cm on the VAS; 95% CI -1.03 to -0.44). All the trial sequential monitoring boundaries were crossed by the cumulative Z-curve favouring local anaesthetic infiltration. The findings were consistent with local anaesthetic infiltration decreasing pain at between four and eight hours compared with no local anaesthetic infiltration with no risk of random errors (Figure 7).

Figure 7.

Trial sequential analysis of pain (4 to 8 hours) (local anaesthetic versus no local anaesthetic)
The diversity-adjusted required information size (DARIS) was 789 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 4.68, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 81.38%. The conventional statistical boundary for benefit (dotted red line) is crossed by the cumulative Z-curve (blue line) after the fifth trial. The trial sequential monitoring boundaries (red line) are crossed by cumulative Z-curve after the sixth trial. The findings are consistent with local anaesthetic infiltration decreasing pain between 4 and 8 hours compared to no local anaesthetic infiltration with no risk of random errors.

Pain at nine to 24 hours

Twelve trials (756 participants) reported this outcome (Sarac 1996; Bilge 1997; Dath 1999; Noma 2001; Papaziogas 2001; Papagiannopoulou 2003; Pavlidis 2003; Zajaczkowska 2004; Newcomb 2007; Nicolau 2008; Feroci 2009; Liu 2009). The pain scores as measured by the visual analogue scale were lower in the local anaesthetic infiltration group than the control group (MD -0.36 cm on the VAS; 95% CI -0.53 to -0.20) (Analysis 1.5). There were no changes in the interpretation of results by using a 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).

Figure 8.

Trial sequential analysis of pain (9 to 24 hours) (local anaesthetic versus no local anaesthetic)
The diversity-adjusted required information size (DARIS) was 168 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 2.66, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 50.3%. The conventional statistical boundary for benefit (dotted red line) is crossed by the cumulative Z-curve (blue line) after the fifth trial. The findings are consistent with local anaesthetic infiltration decreasing pain between 9 and 24 hours compared with no local anaesthetic infiltration without the risk of random errors.

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).

Figure 9.

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

Return to work

None of the trials reported return to work.

Subgroup analysis

Only pain at four to eight hours and pain at nine to 24 hours were suitable for various subgroup analyses because of the paucity of data for the other outcomes. We did not perform the following subgroup analyses.

  • Trials with low bias risk compared to trials with high bias risk: only one trial was at low risk of bias (Feroci 2009).

  • Elective compared to emergency laparoscopic cholecystectomy: none of the trials reported data for emergency laparoscopic cholecystectomy separately.

  • Different depths of wound infiltration: all the trials that reported the depth of wound infiltration reported that they infiltrated at least the fascia.

  • Maximum safe dose used (that is, whether the trials used the dose based on body weight): only one trial calculated the dose of the local anaesthetic based on weight (Feroci 2009).

  • Intraperitoneal local anaesthetic instillation: the information about whether intraperitoneal instillation was used 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).

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 Summary of findings 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).

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.

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.

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.

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 Summary of findings 3.

Mortality

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

Figure 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.

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.

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'.

Data and analyses

Download statistical data

Comparison 1. Local anaesthetic versus no local anaesthetic
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Serious adverse events7539Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.19, 21.59]
2 Proportion discharged as day surgery197Risk Ratio (M-H, Fixed, 95% CI)1.55 [1.05, 2.28]
3 Length of hospital stay4327Mean Difference (IV, Fixed, 95% CI)-0.26 [-0.67, 0.16]
4 Pain 4 to 8 hours13806Mean Difference (IV, Fixed, 95% CI)-1.33 [-1.54, -1.12]
5 Pain 9 to 24 hours12756Mean Difference (IV, Fixed, 95% CI)-0.36 [-0.53, -0.20]
6 Return to normal activity2195Mean 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)7364Mean Difference (IV, Fixed, 95% CI)-1.34 [-1.55, -1.12]
9 Pain 9 to 24 hours (sensitivity analysis)7364Mean Difference (IV, Fixed, 95% CI)-0.34 [-0.51, -0.17]
10 Return to normal activity (sensitivity analysis)145Mean Difference (IV, Fixed, 95% CI)1.02 [-0.37, 2.41]
11 Pain 4 to 8 hours (stratified by local anaesthetic agent)12756Mean Difference (IV, Fixed, 95% CI)-1.33 [-1.55, -1.12]
11.1 Bupivacaine10543Mean Difference (IV, Fixed, 95% CI)-1.42 [-1.66, -1.18]
11.2 Levobupivacaine128Mean Difference (IV, Fixed, 95% CI)-3.90 [-6.52, -1.28]
11.3 Ropivacaine2185Mean Difference (IV, Fixed, 95% CI)-0.93 [-1.39, -0.47]
12 Pain 9 to 24 hours (stratified by local anaesthetic agent)12756Mean Difference (IV, Fixed, 95% CI)-0.36 [-0.53, -0.20]
12.1 Bupivacaine10543Mean Difference (IV, Fixed, 95% CI)-0.29 [-0.46, -0.11]
12.2 Levobupivacaine128Mean Difference (IV, Fixed, 95% CI)-1.70 [-2.84, -0.56]
12.3 Ropivacaine2185Mean Difference (IV, Fixed, 95% CI)-1.07 [-1.74, -0.39]
13 Pain 4 to 8 hours (stratified by time of administration)12756Mean Difference (IV, Fixed, 95% CI)-1.33 [-1.55, -1.12]
13.1 Before incision7419Mean Difference (IV, Fixed, 95% CI)-1.69 [-1.95, -1.43]
13.2 End of surgery6337Mean Difference (IV, Fixed, 95% CI)-0.63 [1.00, -0.27]
14 Pain 9 to 24 hours (stratified by time of administration)12756Mean Difference (IV, Fixed, 95% CI)-0.36 [-0.53, -0.20]
14.1 Before incision7419Mean Difference (IV, Fixed, 95% CI)-0.29 [-0.49, -0.10]
14.2 End of surgery6337Mean Difference (IV, Fixed, 95% CI)-0.51 [-0.80, -0.22]
Analysis 1.1.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 1 Serious adverse events.

Analysis 1.2.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 2 Proportion discharged as day surgery.

Analysis 1.3.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 3 Length of hospital stay.

Analysis 1.4.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 4 Pain 4 to 8 hours.

Analysis 1.5.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 5 Pain 9 to 24 hours.

Analysis 1.6.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 6 Return to normal activity.

Analysis 1.7.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 7 Length of hospital stay (sensitivity analysis).

Analysis 1.8.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 8 Pain 4 to 8 hours (sensitivity analysis).

Analysis 1.9.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 9 Pain 9 to 24 hours (sensitivity analysis).

Analysis 1.10.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 10 Return to normal activity (sensitivity analysis).

Analysis 1.11.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 11 Pain 4 to 8 hours (stratified by local anaesthetic agent).

Analysis 1.12.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 12 Pain 9 to 24 hours (stratified by local anaesthetic agent).

Analysis 1.13.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 13 Pain 4 to 8 hours (stratified by time of administration).

Analysis 1.14.

Comparison 1 Local anaesthetic versus no local anaesthetic, Outcome 14 Pain 9 to 24 hours (stratified by time of administration).

Comparison 2. Comparison of different local anaesthetics
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Length of hospital stay1137Mean Difference (IV, Fixed, 95% CI)0.0 [-0.65, 0.65]
2 Pain 4 to 8 hours139Mean Difference (IV, Fixed, 95% CI)2.3 [0.23, 4.37]
3 Pain 9 to 24 hours139Mean Difference (IV, Fixed, 95% CI)1.90 [1.00, 2.80]
4 Return to normal activity1137Mean Difference (IV, Fixed, 95% CI)-1.90 [-2.71, -1.09]
Analysis 2.1.

Comparison 2 Comparison of different local anaesthetics, Outcome 1 Length of hospital stay.

Analysis 2.2.

Comparison 2 Comparison of different local anaesthetics, Outcome 2 Pain 4 to 8 hours.

Analysis 2.3.

Comparison 2 Comparison of different local anaesthetics, Outcome 3 Pain 9 to 24 hours.

Analysis 2.4.

Comparison 2 Comparison of different local anaesthetics, Outcome 4 Return to normal activity.

Comparison 3. Before incision versus end of surgery
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain 4 to 8 hours276Mean Difference (IV, Fixed, 95% CI)0.18 [-1.90, 2.26]
2 Pain 9 to 24 hours140Mean Difference (IV, Fixed, 95% CI)0.10 [-2.53, 2.73]
3 Return to normal activity130Mean Difference (IV, Fixed, 95% CI)0.5 [-1.05, 2.05]
Analysis 3.1.

Comparison 3 Before incision versus end of surgery, Outcome 1 Pain 4 to 8 hours.

Analysis 3.2.

Comparison 3 Before incision versus end of surgery, Outcome 2 Pain 9 to 24 hours.

Analysis 3.3.

Comparison 3 Before incision versus end of surgery, Outcome 3 Return to normal activity.

Appendices

Appendix 1. Search strategies

DatabasePeriodSearch 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 20131 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

Contributions of authors

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

Declarations of interest

None known.

Sources of support

Internal sources

  • None, Other.

External sources

  • National Institute of Health Research, UK.

Differences between protocol and review

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

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

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ahmad 1998

MethodsRandomised 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.

InterventionsParticipants 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.
OutcomesThe 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Beqiri 2012

MethodsRandomised clinical trial
ParticipantsCountry: 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.

OutcomesNone of the outcomes of interest were reported.
NotesReasons for post-randomisation dropouts: Conversion to an open procedure due to complications.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "4 coloured balls in a non-transparent vase were used to randomise patients between groups".
Allocation concealment (selection bias)Low riskQuote: "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 riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High riskComment: There were post-randomisation dropouts.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Bilge 1997

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesThe outcomes reported were intraoperative complications and pain.
NotesAttempts were made to contact the authors in February 2008 and August 2010. Authors provided information in February 2008.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "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 riskQuote: "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 riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "The person evaluating post-operative pain did not know which group the patients belonged to".
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "There were no post-randomisation drop-outs in any group" (author replies).
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Cantore 2008

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesNone of the outcomes of interest were reported.
NotesAttempts were made to contact the authors in March 2013.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "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 riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Dath 1999

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesThe outcomes reported were mortality, morbidity, proportion discharged as day surgery, and pain.
NotesReasons 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "envelopes containing randomly generated instructions".
Comment: Further details were not available.
Allocation concealment (selection bias)Unclear riskQuote: "an envelope'".
Comment: Further details were not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "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 riskQuote: "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 riskComment: There were post-randomisation dropouts.
Selective reporting (reporting bias)Low riskComment: Mortality and morbidity were reported.
For-profit biasUnclear riskComment: This information was not available.

Feroci 2009

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesThe outcomes reported were mortality, morbidity, and pain.
NotesAttempts were made to contact the authors in August 2010. Authors provided further information in August 2010.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The randomization was obtained through a computer-generated program" (author replies).
Allocation concealment (selection bias)Low riskQuote: "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 riskQuote: "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 riskQuote: "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 riskComment: There were no post-randomisation dropouts.
Selective reporting (reporting bias)Low riskComment: Mortality and morbidity were reported.
For-profit biasLow riskQuote: "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

MethodsRandomised 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.

InterventionsParticipants 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.
OutcomesThe 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Hasaniya 2001

MethodsRandomised clinical trial.
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesNo outcomes of interest for this review were reported.
NotesReasons 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: 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 riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High riskComment: There were post-randomisation dropouts.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Lee 2001

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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).
OutcomesThe outcomes reported were mortality and morbidity.
NotesAttempts were made to contact the authors in February 2008.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskQuote: "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 riskComment: This information was not available.
Selective reporting (reporting bias)Low riskComment: Mortality and morbidity were reported.
For-profit biasUnclear riskComment: This information was not available.

Lepner 2003

MethodsRandomised 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.

OutcomesThe outcomes reported were mortality and morbidity.
NotesAuthors provided information on post-randomisation dropouts in April 2008.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: 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 riskQuote: "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 riskQuote: "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 riskComment: There were no post-randomisation dropouts.
Selective reporting (reporting bias)Low riskComment: Mortality and morbidity were reported.
For-profit biasUnclear riskComment: This information was not available.

Liang 2011

MethodsRandomised 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.

OutcomesNone of the outcomes of interest were reported.
NotesReasons for post-randomisation dropouts: not stated.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThis information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "The person evaluating postoperative pain was not aware of group allocations".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Liu 2009

MethodsRandomised clinical trial
ParticipantsCountry: 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).
InterventionsParticipants 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.
OutcomesThe outcomes reported were mortality, morbidity, hospital stay, and pain.
NotesAttempts were made to contact the author in August 2010.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The randomization was centralized and used a random permuted block design".
Allocation concealment (selection bias)Low riskQuote: "The randomization was centralized and used a random permuted block design".
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: There were no post-randomisation dropouts.
Selective reporting (reporting bias)Low riskComment: All important outcomes were reported.
For-profit biasUnclear riskComment: This information was not available.

Louizos 2005

MethodsRandomised clinical trial
ParticipantsCountry: 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).

OutcomesThe 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The answer to your first question is that the random sequence was computer generated" (author replies).
Allocation concealment (selection bias)Unclear riskQuote: "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 riskQuote: "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 riskQuote: "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 riskComment: There were post-randomisation dropouts.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Newcomb 2007

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesThe outcomes reported were length of hospital stay and pain.
NotesAttempts were made to contact the authors in March 2013.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "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 riskQuote: "Neither the patients not the staff measuring the outcomes knew which group a participant was included".
Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: There were no post-randomisation dropouts.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Nicolau 2008

MethodsRandomised clinical trial
ParticipantsCountry: 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.

OutcomesThe outcomes reported were local anaesthetic-related complications and pain.
NotesAttempts were made to contact the author in October 2009.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Noma 2001

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesThe outcome reported were pain.
NotesAttempts were made to contact the authors in February 2008.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Papagiannopoulou 2003

MethodsRandomised clinical trial
ParticipantsCountry: 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.

OutcomesThe 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "randomized".
Comment: Further details were not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskQuote: "double-blinded".
Comment: Further details were not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High riskComment: There were post-randomisation dropouts.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Papaziogas 2001

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesThe 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: Further details were not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
High riskComment: There were post-randomisation dropouts.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Pavlidis 2003

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesThe outcomes reported were mortality, morbidity, hospital stay, return to activity, and pain.
NotesAttempts were made to contact the authors in February 2008.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly allocated into 2 groups".
Comment: Further details were not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "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 riskQuote: "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 riskComment: There were no post-randomisation dropouts.
Selective reporting (reporting bias)Low riskComment: Mortality and morbidity were reported.
For-profit biasUnclear riskComment: This information was not available.

Rodriguez-Navarro 2011

MethodsRandomised 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.

InterventionsParticipants 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.
OutcomesThe 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "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 riskQuote: "Investigators who conducted the postoperative assessments all remained blinded to the treatment assignments."
Incomplete outcome data (attrition bias)
All outcomes
High riskComment: There were post-randomisation dropouts.
Selective reporting (reporting bias)Low riskComment: Mortality and morbidity were reported.
For-profit biasUnclear riskComment: This information was not available.

Sarac 1996

MethodsRandomised clinical trial.
ParticipantsCountry: 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.

OutcomesThe outcomes reported were drug-related serious adverse events and pain.
NotesAttempts were made to contact the authors in February 2010.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Shikano 1994

MethodsRandomised clinical trial.
ParticipantsCountry: 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
InterventionsParticipants 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).
OutcomesNone of the outcomes of interest were reported.
NotesAttempts were made to contact the authors in March 2013.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Sozbilen 2007

MethodsRandomised clinical trial
ParticipantsCountry: 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.
InterventionsParticipants 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.
OutcomesThe outcome reported was pain.
NotesReasons for post-randomisation dropouts: not stated.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskComment: This information was not available.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Ure 1993

MethodsRandomised clinical trial
ParticipantsCountry: 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.

OutcomesThe outcomes reported were mortality, morbidity, hospital stay, and pain.
NotesAttempts were made to contact the authors in February 2008.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: Further details were not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "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 riskQuote: "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 riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Uzunkoy 2001

MethodsRandomised 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.

OutcomesThe outcome reported was return to activity.
NotesAttempts were made to contact the authors in February 2008.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskComment: This information was not available.
Allocation concealment (selection bias)Unclear riskComment: This information was not available.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskComment: This information was not available.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "Pain that the patients experienced was evaluated by surgery nurses who were unaware of the groups".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: This information was not available.
Selective reporting (reporting bias)High riskComment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Zajaczkowska 2004

MethodsRandomised 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.

InterventionsThe 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.
OutcomesThe outcome reported was pain.
NotesAttempts were made to contact the authors in August 2010.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "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 riskQuote: "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 riskComment: "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 riskComment: "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 riskComment: There were post-randomisation dropouts.
Selective reporting (reporting bias)Low risk Comment: Mortality and morbidity were not reported.
For-profit biasUnclear riskComment: This information was not available.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Alexander 1996Not clear whether intraperitoneal bupivacaine was administered in the intervention group.
Bisgaard 1999This trial was a comparison of periportal and intraperitoneal ropivacaine versus normal saline.
Cha 2012Five 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 2009This trial was performed on patients undergoing various laparoscopic procedures. Results for laparoscopic cholecystectomy not given individually.
Futier 2011Not a randomised clinical trial.
Hilvering 2011Not a randomised clinical trial.
Karadeniz 1998This trial involved intraperitoneal bupivacaine injection and no wound infiltration.
Lopez-Maya 2011This trial compared periportal and intraperitoneal ropivacaine at different timings.
Lotz 1997Not a randomised clinical trial.
Maharjan 2009This trial compared periportal and intraperitoneal bupivacaine versus control.
Memedov 2010This trial compared multi-regional and periportal ropivacaine versus lornoxicam versus placebo.
Michaloliakou 1996This trial compared multimodal analgesia (intramuscular meperidine and ketorolac and periportal bupivacaine) versus control.
Verma 2006In this trial no control group available to match periportal bupivacaine group.
Wallace 1996In this trial wound infiltration with local anaesthetic was combined with intraperitoneal instillation of local anaesthetic.
Wong 1997Not a randomised clinical trial.

Ancillary