Métodos de instilación anestésica local intraperitoneal para la colecistectomía laparoscópica
Resumen
Antecedentes
La instilación anestésica local intraperitoneal puede reducir el dolor en los pacientes a los que se les realiza colecistectomía laparoscópica. Sin embargo, se desconoce el método óptimo para administrar el anestésico local.
Objetivos
Determinar el agente anestésico local óptimo, el momento óptimo y el método de administración óptimo del agente anestésico local utilizado para la instilación intraperitoneal en los pacientes a los que se les realiza colecistectomía laparoscópica.
Métodos de búsqueda
Se realizaron búsquedas en el Registro Cochrane Central de Ensayos Controlados (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, y el portal World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) hasta marzo de 2013 para identificar los ensayos clínicos aleatorios que evalúan los efectos beneficiosos y los estudios no aleatorios comparativos para la evaluación de los efectos perjudiciales relacionados con el tratamiento.
Criterios de selección
Solamente se consideraron para la revisión los ensayos clínicos aleatorios (independientemente del idioma, el cegamiento o el estado de publicación) que compararon diferentes métodos de instilación anestésica local intraperitoneal durante la colecistectomía laparoscópica.
Obtención y análisis de los datos
Dos revisores obtuvieron los datos de forma independiente. Los datos se analizaron con el modelo de efectos fijos y de efectos aleatorios mediante el análisis con Review Manager 5. Para cada resultado, se calculó el cociente de riesgos (CR) o la diferencia de medias (DM) con intervalos de confianza (IC) del 95%.
Resultados principales
Se incluyeron 12 ensayos con 798 participantes a los que se les realizó colecistectomía laparoscópica programada asignados al azar a diferentes métodos de instilación anestésica local intraperitoneal. Todos los ensayos presentaron un alto riesgo de sesgo. En su mayoría los ensayos solamente incluyeron pacientes con bajo riesgo anestésico. Las comparaciones incluidas en los ensayos que cumplieron con los criterios de elegibilidad fueron las siguientes; comparación de un agente anestésico local con otro agente anestésico local (tres ensayos); comparación del momento de la administración (seis ensayos); comparación de diferentes métodos de administración del agente anestésico (dos ensayos); comparación del lugar de instilación del agente anestésico (un ensayo); tres ensayos informaron la mortalidad y la morbilidad.
No hubo mortalidad ni eventos adversos graves en los grupos en las siguientes comparaciones: bupivacaína (0/100 [0%]) versus lidocaína (0/106 [0%]) (un ensayo; 206 participantes); justo después de la creación de neumoperitoneo (0/55 [0%]) versus al final de la cirugía (0/55 [0%]) (dos ensayos; 110 participantes); justo después de la creación de neumoperitoneo (0/15 [0%]) versus después del final de la cirugía (0/15 [0%]) (un ensayo; 30 participantes); al final de la cirugía (0/15 [0%]) versus después del final de la cirugía (0/15 [0%]) (un ensayo; 30 participantes).
Ninguno de los ensayos informó la calidad de vida, el tiempo necesario para volver a la actividad normal, o el tiempo hasta el retorno al trabajo. Las diferencias en la proporción de pacientes que fue dada de alta el día de la cirugía y la duración de la estancia hospitalaria fueron poco precisas en todas las comparaciones incluidas que informaron estos resultados (pruebas de muy baja calidad). Hubo algunas diferencias en las puntuaciones de dolor en la escala analógica visual (1 a 10 cm) pero no fueron consistentes ni sólidas en el metanálisis de efectos fijos versus el de efectos aleatorios ni en el análisis de sensibilidad.
Conclusiones de los autores
Las pruebas actualmente disponibles no son adecuadas para determinar los efectos de un método de instilación anestésica local intraperitoneal comparado con otro método de instilación anestésica local intraperitoneal en pacientes con bajo riesgo anestésico a los que se les realiza colecistectomía laparoscópica programada. Se necesitan más ensayos clínicos aleatorios con bajo riesgo de errores sistemáticos y aleatorios. Dichos ensayos deben incluir en su evaluación resultados clínicos importantes como la calidad de vida y el tiempo hasta el retorno al trabajo.
Resumen en términos sencillos
Métodos de administración de anestésicos locales intraabdominales en pacientes a los que se les realiza colecistectomía laparoscópica
Antecedentes
Entre el 10% y el 15% de la población occidental adulta presenta cálculos biliares. Entre el 1% y el 4% se tornan sintomáticos al año. La extracción de la vesícula biliar (colecistectomía) es el tratamiento principal para los cálculos biliares sintomáticos. Solamente en los Estados Unidos se realizan más de medio millón de colecistectomías por año. Actualmente la colecistectomía laparoscópica (extracción de la vesícula biliar a través de un pequeño orificio, también conocido como puerto) es el método preferido para realizar la colecistectomía. El dolor es uno de los motivos principales de retraso del alta hospitalaria después de la colecistectomía laparoscópica. La administración de anestésicos locales (fármacos que adormecen parte del cuerpo, similares a los utilizados por el dentista para evitar que los pacientes sientan dolor) en el vientre (abdomen) se considera una manera efectiva de reducir el dolor después de la colecistectomía laparoscópica. Sin embargo, no se conoce el mejor método de administración de los anestésicos locales. Las controversias incluyen qué fármaco utilizar, cuándo administrarlo, si se debe administrar en forma de líquido o en forma de aerosol pulverizable y en qué parte del abdomen se debe administrar. Se intentó responder estas preguntas al examinar la bibliografía médica y obtener información de los ensayos clínicos aleatorios para la evaluación de los efectos beneficiosos. Cuando se realizan bien, estos estudios proporcionan la información más exacta sobre el mejor tratamiento. Se incluyeron estudios no aleatorios comparativos para la evaluación de los efectos perjudiciales relacionados con el tratamiento. Dos revisores buscaron en la bibliografía y obtuvieron información de los estudios, lo que minimizó los errores.
Características de los estudios
Se identificaron 12 ensayos clínicos aleatorios que incluyeron 798 pacientes a los que se les realizó colecistectomía laparoscópica planificada. Los ensayos compararon diferentes métodos que abordaron las diversas controversias mencionadas anteriormente. La elección del método de administración del anestésico local se determinó mediante un método similar a lanzar una moneda para que los tratamientos se compararan en participantes que fueran lo más similares posibles.
Resultados clave
No hubo muertes ni complicaciones graves en los grupos en las comparaciones que informaron estos resultados. Ninguno de los ensayos informó la calidad de vida, el tiempo necesario para volver a la actividad normal, o el tiempo hasta el retorno al trabajo. Las diferencias en la estancia hospitalaria entre los métodos que se compararon fueron poco precisas en todas las comparaciones que informaron este resultado. Aunque hubo algunas diferencias en las puntuaciones de dolor en la escala analógica visual (un gráfico que califica la cantidad de dolor en una escala de 1 a 10 cm), estas diferencias no fueron consistentes ni sólidas con los diferentes métodos de análisis estadístico. Las pruebas actualmente disponibles no son suficientes para determinar los efectos de un método de instilación anestésica local intraperitoneal comparado con otro método de instilación anestésica local intraperitoneal en pacientes con bajo riesgo anestésico a los que se les realiza colecistectomía laparoscópica programada.
Calidad de la evidencia
La mayoría de los ensayos tuvo alto riesgo de sesgo, es decir, existe la posibilidad de establecer conclusiones equivocadas que sobrestimen los efectos beneficiosos o subestimen los efectos perjudiciales de un método u otro debido a la forma en que se realizaron los estudios. La calidad general de las pruebas fue muy baja.
Investigación futura
Se necesitan más ensayos. Estos ensayos deben incluir resultados como la calidad de vida, el tiempo hasta el retorno a la actividad normal y el tiempo hasta el retorno al trabajo, que son importantes para los pacientes a los que se les realiza una colecistectomía laparoscópica y para las personas que financian el tratamiento.
Authors' conclusions
Summary of findings
| Methods of intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy | |||||
| Patient or population: people undergoing laparoscopic cholecystectomy | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Intervention | ||||
| Mortality | Not estimable (as there was no mortality in either group in this comparison) | Not estimable |
| ⊕⊝⊝⊝ | |
| Morbidity | Not estimable (as there was no morbidity in either group in this comparison) | Not estimable |
| ⊕⊝⊝⊝ | |
| Proportion discharged as day‐surgery | |||||
| Just after creation of pneumoperitoneum versus end of surgery | 733 per 1000 | 719 per 1000 | RR 0.98 | 33 | ⊕⊝⊝⊝ |
| Subdiaphragmatic instillation versus gallbladder bed instillation | 220 per 1000 | 342 per 1000 | RR 1.56 | 82 | ⊕⊝⊝⊝ |
| Hospital stay | |||||
| Bupivacaine versus lignocaine | The mean hospital stay ‐ bupivacaine versus lignocaine in the control groups was | The mean hospital stay ‐ bupivacaine versus lignocaine in the intervention groups was | ‐ | 206 | ⊕⊝⊝⊝ |
| Aerosol versus liquid | The mean hospital stay ‐ aerosol versus liquid in the control groups was | The mean hospital stay ‐ aerosol versus liquid in the intervention groups was | ‐ | 60 | ⊕⊝⊝⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The trial(s) was (were) of high risk of bias (2 points). | |||||
Background
Description of the condition
About 5% to 25% of the adult western population have gallstones (GREPCO 1984; GREPCO 1988; Bates 1992; Halldestam 2004). The annual incidence of gallstones is about 1 in 200 people (NIH 1992). Only 2% to 4% of people with gallstones become symptomatic with biliary colic (pain), acute cholecystitis (inflammation), obstructive jaundice, or gallstone pancreatitis in a year (Attili 1995; Halldestam 2004). Cholecystectomy (removal of gallstones) is the preferred option in the treatment of symptomatic gallstones (Strasberg 1993) and 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 incision) (Ballal 2009).
Pain is one of the important reasons for delayed discharge after laparoscopic cholecystectomy (Gurusamy 2008a; Gurusamy 2008b). The pain after laparoscopic cholecystectomy could be incisional pain, shoulder pain, or abdominal pain (Ng 2004). The aetiology of abdominal pain and shoulder pain after laparoscopic cholecystectomy is not clear. Peritoneal irritation, caused by carbonic acid and creation of space between diaphragm and liver, leading to loss of suction support of the heavy liver have been suggested as possible mechanisms of pain (Alexander 1987). However, use of overnight drain to let out the gas has not been effective in the reduction of pain (Gurusamy 2013).
Description of the intervention
Intraperitoneal instillation of local anaesthetic agents such as bupivacaine (Alkhamesi 2007), levobupivacaine (Ng 2004; Louizos 2005), lidocaine (Elhakim 2000), and ropivacaine (Gupta 2002) has been suggested as a way of reduction of abdominal and shoulder pain. The instillation can be performed either before or after the development of the pneumoperitoneum (Barczynski 2006), or towards the end of the surgery (Louizos 2005; Alkhamesi 2007). The intraperitoneal instillation of the local anaesthetic could be by washing the gallbladder bed of the liver with the local anaesthetic (Alkhamesi 2007), instillation under diaphragm (Abdel‐Raouf 2004), or as an aerolised spray in the general peritoneum (Alkhamesi 2007). The instillation can be either performed as a bolus or as a continuous infusion (Bayar 1998).
Other routes by which local anaesthetic can be administered to decrease pain after laparoscopic cholecystectomy include wound infiltration (Gurusamy 2014a), paravertebral block (Naja 2011), transversus abdominis plane (TAP) block (Petersen 2012), and epidural block (Nandate 2003).
How the intervention might work
Local anaesthetics inhibit the voltage‐gated sodium channels. This results in decreased excitability of nerves (Butterworth 1990).
Why it is important to do this review
We have assessed whether local anaesthetic wound infiltration is effective in decreasing pain in a Cochrane review (Gurusamy 2014a). We have assessed whether intraperitoneal local anaesthetic instillation is effective in decreasing pain in another Cochrane review (Gurusamy 2014b). These reviews have shown that the wound infiltration and intraperitoneal instillation with local anaesthetics decreased pain scores without significant clinical benefit, although there were no treatment‐related serious adverse events (Gurusamy 2014a; Gurusamy 2014b). There have been no meta‐analyses or systematic reviews comparing the different methods of intraperitoneal local anaesthetic instillation.
Objectives
To determine the optimal local anaesthetic agent, the optimal timing, and the optimal delivery method of the local anaesthetic agent used for intraperitoneal instillation in people undergoing laparoscopic cholecystectomy.
Methods
Criteria for considering studies for this review
Types of studies
We considered all randomised clinical trials (irrespective of language, blinding, publication status, or sample size) for inclusion. We excluded quasi‐randomised trials (where the method of allocating participants to a treatment were not strictly random, eg, 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 planned to include the following interventions:
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comparison of one local anaesthetic agent with another local anaesthetic agent;
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comparison of timing of delivery (eg, before surgery versus towards the end of surgery);
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comparison of different methods of delivery of the anaesthetic agent (eg, bolus versus continuous infusion; aerosol spray versus washout);
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comparison of location of the instillation of the anaesthetic agent (eg, under the diaphragm versus in the gallbladder bed of the liver).
We allowed co‐interventions if carried out equally in the trial groups. We did not include trials comparing intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation in this patient group as this has been covered in a different review (Gurusamy 2014b).
Types of outcome measures
Primary outcomes
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Mortality.
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Serious adverse events defined as any event that would increase mortality, was life‐threatening, required inpatient hospitalisation, resulted in a persistent or significant disability, or any important medical event that might have jeopardised the participant or required intervention to prevent it (ICH‐GCP 1997). We classified complications such as bile duct injury; re‐operations; intra‐abdominal collections requiring drainage (radiological or surgical); infected intra‐abdominal collections; bile leaks requiring drainage, stent, or surgery; convulsions; cardiac arrhythmias that required additional monitoring and hence increased the hospital stay as serious adverse events. Complications such as wound infections, bile leaks, or abdominal collections that did not require any treatment and settle spontaneously were not considered serious adverse events.
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Patient quality of life (however defined by authors using a validated scale such as Euro‐QoL or 36‐item Short Form (SF‐36)) (EuroQol 1990; Ware 1992; McHorney 1993).
Secondary outcomes
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Hospital stay (length of hospital stay, proportion discharged as day‐surgery laparoscopic cholecystectomy).
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Pain (overall pain scores) at different time points (4 to 8 hours and 9 to 24 hours) using a visual analogue scale.
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Return to activity.
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Return to work.
We have reported all the outcomes with at least one trial in the summary of findings Table for the main comparison.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003), and the World Health Organization International Clinical Trials Registry Platform portal (WHO ICTRP) (apps.who.int/trialsearch/) to March 2013. The WHO ICTRP portal allows search of various trial registers including clinicaltrials.gov and ISRCTN among other registers. We have given the search strategies in Appendix 1 with the time span for the searches.
Searching other resources
We also searched the references of the identified trials to identify further relevant trials.
Data collection and analysis
We performed the systematic review according to the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2014).
Selection of studies
Two review authors (KSG and CT, GPG, or MZ) identified the trials for inclusion independently of each other. We have also listed the excluded studies with the reasons for the exclusion.
Data extraction and management
Two review authors (KSG, MN, CT, GPG, or MZ) extracted the following data independently of each other.
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Year and language of publication.
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Country in which the trial was conducted.
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Year of trial.
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Inclusion and exclusion criteria.
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Sample size.
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Elective surgery or acute cholecystitis.
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Local anaesthetic agent used.
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Dose of local anaesthetic agent (per kilogram body weight or total dose however reported by authors).
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Timing of administration.
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Location where instilled.
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Physical form of local anaesthetic agent (aerosol, liquid).
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Duration of administration (bolus/infusion period).
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Drain or no drain.
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Peri‐laparoscopic‐portal infiltration with local anaesthetic.
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Other co‐interventions.
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Outcomes (Primary outcomes; Secondary outcomes).
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Risk of bias (Assessment of risk of bias in included studies).
We sought any unclear or missing information by contacting the authors of the individual trials. If there was any doubt whether the trials shared the same participants ‐ completely or partially (by identifying common authors and centres) ‐ we planned to contact the authors of the trials to clarify whether the trial report had been duplicated.
We resolved any differences in opinion through discussion with or arbitration of the third author (BRD).
Assessment of risk of bias in included studies
We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2014). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012a; Savovic 2012b), we assessed the risk of bias of the trials based on the following bias risk domains.
Allocation sequence generation
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Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial.
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Uncertain risk of bias: the method of sequence generation was not specified.
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High risk of bias: the sequence generation method was not random.
Allocation concealment
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Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (eg, if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
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Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
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High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.
Blinding of participants and personnel
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Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
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Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to introduce bias on the results.
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High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.
Blinding of outcome assessors
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Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.
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Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.
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High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.
Incomplete outcome data
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Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data.
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Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
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High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting
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Low risk of bias: all outcomes were pre‐defined and reported, or all clinically relevant and reasonably expected outcomes were reported. 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 when the trial was run and published in the years when trial registration was not required, we carefully scrutinized all publications reporting on the trial to identify the trial objectives and outcomes, and determine whether usable data were provided in the publications results section on all outcomes specified in the trial objectives.
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Uncertain risk of bias: it is unclear whether all pre‐defined and clinically relevant (mortality and morbidity) and reasonably expected outcomes were reported.
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High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.
For‐profit bias
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Low risk of bias: the trial appeared to be free of industry sponsorship or other type of for‐profit support that may have manipulated the trial design, conductance, or results of the trial.
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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 was provided.
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High risk of bias: the trial was sponsored by the industry or had received other kind of for‐profit support.
We considered trials that were classified as low risk of bias in all the above domains as trials with low risk of bias, and the remaining as trials with high risk of bias.
Measures of treatment effect
For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval (CI). We also calculated the risk difference with 95% CI. We planned to report the risk difference only if the conclusions were different from those of the RR. 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 while calculating the summary treatment effect in the case of RR. It should be noted that we used RR as the primary measure of the treatment effect and so we did not report comparisons in which there were no events in either groups in all the trials included under the comparison. For continuous variables, we calculated the mean difference (MD) with 95% CI for outcomes such as total hospital stay or standardised mean difference (SMD) with 95% CI for outcomes such as quality of life, where different authors use different scales of quality of life.
Unit of analysis issues
The units of analysis was the person about to undergo laparoscopic cholecystectomy and randomised to the different methods of intraperitoneal local anaesthetic instillation.
Dealing with missing data
We performed an intention‐to‐treat analysis (Newell 1992), whenever possible. We planned to impute data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best‐case scenario, and worst‐case 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 CI, we planned to impute the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation would decrease the weight of the study for calculation of MDs and bias the effect estimate to no effect in the case of SMD (Higgins 2011).
Assessment of heterogeneity
We explored heterogeneity using the Chi2 test with significance set at a P value < 0.10, and measured the quantity of heterogeneity using the I2 statistic (Higgins 2002). We also used overlapping of CIs on the forest plot to determine heterogeneity.
Assessment of reporting biases
We planned to use visual asymmetry on a funnel plot to explore reporting bias if 10 or more trials were identified (Egger 1997; Macaskill 2001). We planned to perform the linear regression approach described by Egger 1997 to determine the funnel plot asymmetry. Selective reporting was also considered as evidence for reporting bias.
Data synthesis
We performed the meta‐analyses using the software package Review Manager 5 (RevMan 2012), and following the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2014). We used both a random‐effects model (DerSimonian 1986), and a fixed‐effect model (DeMets 1987) meta‐analysis. In the case of discrepancy between the two models, we have reported both results; otherwise, we have reported the results of the fixed‐effect model. We planned to use the generic inverse method to combine the hazard ratios for time‐to‐event outcomes.
Trial sequential analysis
The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We added the trials according to the year of publication, and, if more than one trial was published in a year, the trials were added alphabetically according to the last name of the first author. On the basis of the required information size, we constructed trial sequential monitoring boundaries. These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. In contrast, if the boundaries are not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010).
We applied trial sequential analysis (CTU 2011; Thorlund 2011) using a required sample size calculated from an alpha error of 0.05, a beta error of 0.20, a control event proportion obtained from the results, and a relative risk reduction of 20% for binary outcomes if there were two or more trials reporting the outcome to determine whether more trials are necessary on this topic (if the trial sequential 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). Since 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 mean difference 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 parameters kept the same as that for pain.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses.
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Trials with low risk of bias compared to trials with high risk of bias.
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Peri‐laparoscopic‐portal infiltration with local anaesthetic.
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Elective versus emergency laparoscopic cholecystectomy.
We planned to use the 'test for subgroup differences' available through Review Manager 5 (RevMan 2012) to identify the differences between subgroups. We also planned to use meta‐regression (in the presence of adequate number of trials) to determine the influence of other factors apart from the main comparison performed such as local anaesthetic agent used, timing of instillation, and location of instillation on the effect estimate. We planned to do this for pain at 4 to 8 hours and pain at 9 to 24 hours (as these are the times at which day‐procedure laparoscopic cholecystectomy and overnight stay laparoscopic cholecystectomy patients are discharged).
Sensitivity analysis
We planned to perform a sensitivity analysis by imputing data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best‐case scenario, and worst‐case scenario (Gurusamy 2009; Gluud 2014). Since there were no post‐randomisation drop‐outs in the only trial that reported binary outcomes, we did not perform the sensitivity analysis. We performed a sensitivity analysis by excluding the trials in which the mean and the standard deviation were imputed.
Summary of findings table
We have summarised the results of all the reported outcomes in summary of findings Table for the main comparison prepared using GRADEPro 3.6 (ims.cochrane.org/revman/gradepro).
Results
Description of studies
Results of the search
We identified 474 references through electronic searches of CENTRAL (N = 85), MEDLINE (N = 127), EMBASE (N = 105), and Science Citation Index Expanded (N = 157). We did not identify any new trials from the trial registers. We excluded 84 duplicates and 371 clearly irrelevant references through reading abstracts. We did not identify any quasi‐randomised studies or comparative non‐randomised studies that reported treatment‐related harms. We identified one reference, which was published after the search date, during the peer review process. This trial is awaiting classification (Ingelmo 2013). We retrieved 19 references for further assessment. No references were identified through scanning reference lists of the identified randomised trials. We excluded five references for the reasons listed in the Characteristics of excluded studies table. Fourteen references of 12 randomised trials fulfilled the inclusion criteria. The reference flow is shown in Figure 1.
Study flow diagram.
Included studies
A total of 798 participants were randomised to different groups in the 12 trials (Rademaker 1994; Pasqualucci 1996; Lee 2001; Karadeniz 2003; Paulson 2003; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Kucuk 2007; Bucciero 2011; Roberts 2011; Khan 2012). All the participants in the trials underwent elective laparoscopic cholecystectomy. The participants in 11 trials were American Society of Anesthesiologists classifications (ASA) 1 or 2 (Rademaker 1994; Pasqualucci 1996; Lee 2001; Paulson 2003; Karadeniz 2003; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Kucuk 2007; Roberts 2011; Khan 2012) or ASA (1 to 3) (Bucciero 2011), that is, low anaesthetic risk patients. Additional wound infiltration with local anaesthetic was used in four trials (Barczynski 2006; Alkhamesi 2007; Roberts 2011; Khan 2012). In one trial, it was possible to use two comparisons, one with local anaesthetic wound infiltration and one without local anaesthetic wound infiltration (Lee 2001). In the remaining trials, local anaesthetic wound infiltration was not clearly stated but probably was not used (Rademaker 1994; Pasqualucci 1996; Karadeniz 2003; Paulson 2003; Karaaslan 2006; Kucuk 2007; Bucciero 2011). We could infer that a drain was not used in two trials since trial participants were excluded when a drain was used (Karadeniz 2003; Paulson 2003). A perfusion pump was used in one of the groups to infuse local anaesthetically continuously after the end of surgery (Karadeniz 2003). It was not clear whether this perfusion was done through a drain. In another trial, drains were used selectively but the reasons for drain use in these selected participants was not stated (Roberts 2011). Drain usage was not reported in the remaining trials but probably were not used. The local anaesthetics used included bupivacaine (all trials) (Rademaker 1994; Pasqualucci 1996; Lee 2001; Karadeniz 2003; Paulson 2003; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Kucuk 2007; Bucciero 2011; Roberts 2011; Khan 2012), ropivacaine (Kucuk 2007), and lignocaine (Rademaker 1994; Khan 2012). The mean age in the participants was 29 to 52 years in the trials that provided this information. The proportion of female participants was 46.3% to 88.3% in the trials that provided this information. The comparisons included in the different trials were as follows:
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comparison of one local anaesthetic agent with another local anaesthetic agent (Rademaker 1994; Kucuk 2007; Khan 2012);
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comparison of timing of delivery (Pasqualucci 1996; Lee 2001; Karadeniz 2003; Paulson 2003; Barczynski 2006; Karaaslan 2006);
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comparison of different methods of delivery of the anaesthetic agent (Alkhamesi 2007; Bucciero 2011);
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comparison of location of the instillation of the anaesthetic agent (Roberts 2011).
In one trial, continuous infusion was used for the participants who received the local anaesthetic after the end of the surgery. Since this was related to the timing, we included these two trials under the comparison of timing of delivery (Karadeniz 2003).
Further details about sample size, participant characteristics, the inclusion and exclusion criteria used in the trials, post‐randomisation drop‐outs, intervention and control, comparisons, outcomes reported in the trials, and the risk of bias in the trials are shown in the Characteristics of included studies table and Table 1.
| Study name | Number randomised | Post‐randomisation drop‐outs (%) | Revised sample size | Intervention | Control | Comparison | Wound local anaesthetic infiltration | Drain use | Outcomes reported | ||
| Number randomised | Local anaesthetic | Number randomised | Local anaesthetic | ||||||||
| 40 | Not stated | 40 | 20 | Bupivacaine | 20 | Bupivacaine | Form | Yes | Not stated | Pain | |
| 60 | 0 (0%) | 60 | 30 | Bupivacaine | 30 | Bupivacaine | Timing | Yes | Not stated | Intra‐operative complications and pain | |
| 60 | 3 (5%) | 57 | 30 | Ropivacaine | 30 | Ropivacaine | Form | Not stated | Not stated | Local anaesthetic‐related complications, hospital stay, and pain | |
| 62 | 12 (19.4%) | 50 | 16 | Bupivacaine | 18 | Bupivacaine | Timing | Not stated | Not stated | Local anaesthetic‐related complications | |
| Not applicable | 16 | Bupivacaine | 18 | Bupivacaine | Timing | Not stated | Not stated | Local anaesthetic‐related complications | |||
| 52 | 7 (13.5%) | 45 | 15 | Bupivacaine | 15 | Bupivacaine | Timing | Not stated | No | Mortality, morbidity, and pain | |
| Not applicable | 15 | Bupivacaine | 15 | Bupivacaine | Timing | Not stated | Possibly for the continuous infusion group | Mortality, morbidity, and pain | |||
| Not applicable | 15 | Bupivacaine | 15 | Bupivacaine | Timing | Not stated | Possibly for the continuous infusion group | Mortality, morbidity, and pain | |||
| 224 | 18 (8%) | 206 | 100 | Bupivacaine | 106 | Lignocaine | Different local anaesthetic | Yes | Not stated | Mortality, morbidity, and hospital stay | |
| 60 | Not stated | 60 | 20 | Ropivacaine | 10* | Bupivacaine | Different local anaesthetic | No | Not stated | Local anaesthetic‐related complications and pain | |
| Not applicable | 20 | Ropivacaine | 10* | Bupivacaine | Different local anaesthetic | No | Not stated | Local anaesthetic related complications and pain | |||
| 88 | 8 (9.1%) | 80 | 20 | Bupivacaine | 19 | Bupivacaine | Timing | Yes | Not stated | Mortality and morbidity | |
| not applicable | 20 | Bupivacaine | 21 | Bupivacaine | Timing | No | Not stated | Mortality and morbidity | |||
| 60 | 6 (10%) | 54 | 26 | Bupivacaine | 28 | Bupivacaine | Timing | Not stated | Not stated | Local anaesthetic‐related complications and pain | |
| 33 | Not stated | 33 | 18 | Bupivacaine | 15 | Bupivacaine | Timing | Not stated | No | Local anaesthetic‐related complications and discharge as day‐surgery | |
| 30 | Not stated | 30 | 15 | Bupivacaine | 15 | Lignocaine | Different local anaesthetic | Not stated | Not stated | Local anaesthetic‐related complications and pain | |
| 84 | 1 (1.2%) | 83 | 41 | Bupivacaine | 41 | Bupivacaine | Location | Yes | Selectively (reasons not stated) | Hospital stay and pain | |
§ Multiple groups from the same trial.
* Sample size divided by 2 as otherwise the same participants would be included twice in the meta‐analysis.
Risk of bias in included studies
All the trials were at high risk of bias. The risk of bias in the included trials is summarised in the 'Risk of bias' graph (Figure 2) and 'Risk of bias' summary (Figure 3).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Only four trials described random sequence generation and allocation concealment adequately (Karadeniz 2003; Barczynski 2006; Bucciero 2011; Khan 2012). These four trials were considered to be at low risk of selection bias.
Blinding
Seven trials 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 (Lee 2001; Paulson 2003; Karaaslan 2006; Alkhamesi 2007; Bucciero 2011; Roberts 2011; Khan 2012).
Incomplete outcome data
Only one trial had no post‐randomisation drop‐outs and was considered to be at low risk of attrition bias (Barczynski 2006).
Selective reporting
Three trials reported mortality and morbidity and were considered to be at low risk of selective reporting bias (Lee 2001; Karadeniz 2003; Khan 2012).
Other potential sources of bias
Two trials were considered to be at low risk of 'for‐profit' bias (Bucciero 2011; Khan 2012).
Effects of interventions
The main results are summarised in the summary of findings Table for the main comparison.
Mortality and morbidity
Three trials clearly mentioned that there was no mortality or morbidity in either group (Lee 2001; Karadeniz 2003; Khan 2012). The total number of participants in these trials was 331. There were multiple comparisons in two of the three trials (Karadeniz 2003; Khan 2012). We have presented these comparisons below. It should be noted some participants were included in more than one comparison. The comparisons and the number of participants in each comparison are shown below.
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Bupivacaine (0/100 (0%)) versus lignocaine (0/106 (0%)) (Khan 2012).
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Just after creation of pneumoperitoneum (0/55 (0%)) versus end of surgery (0/55 (0%)) (Lee 2001; Karadeniz 2003).
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Just after creation of pneumoperitoneum (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (Karadeniz 2003).
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End of surgery (0/15 (0%)) versus after the end of surgery (0/15 (0%)) (Karadeniz 2003).
Trial sequential analysis was performed for the comparison 'just after creation of pneumoperitoneum versus end of surgery' since this was the only comparison with more than one trial. Since there was no mortality in either group, we were unable to use the control group proportion for the calculation of the required information size of the trial sequential analysis. Instead, we used a proportion of 0.2% in the control group based on data from approximately 30,000 people included in a database in Switzerland as before (Giger 2011). The proportion of information accrued was only 0.03% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 4). The cumulative Z curve did not cross the conventional statistical boundaries.
Trial sequential analysis of mortality (just after creation of pneumoperitoneum versus end of surgery)
The diversity‐adjusted required information size (DARIS) was calculated to 352,564 participants, based on the proportion of participants in the control group with the outcome of 0.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 110 participants in two trials, only 0.03% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Since there was no serious adverse event in either group, we were unable to use the control group proportion for the calculation of the required information size of the trial sequential analysis as before. Laparoscopic cholecystectomy is generally considered to have low morbidity in people with low anaesthetic risk. We used a control group proportion of 2%. The proportion of information accrued was only 0.32% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 5). The cumulative Z curve did not cross the conventional statistical boundaries.
Trial sequential analysis of morbidity (just after creation of pneumoperitoneum versus end of surgery)
The diversity‐adjusted required information size (DARIS) was calculated to 34,685 participants, based on the proportion of participants in the control group with the outcome of 2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 110 participants in two trials, only 0.32% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Although the remaining trials did not report the overall morbidity, one trial (60 participants) reported that there were no intra‐operative complications (Barczynski 2006). Six trials (284 participants) stated that there were no complications related to local anaesthetic (Rademaker 1994; Pasqualucci 1996; Paulson 2003; Karaaslan 2006; Kucuk 2007; Bucciero 2011). Two participants in one trial developed mild bradycardia that settled spontaneously (Khan 2012). One trial did not report the complications adequately but stated that one person developed lactic acidosis but this was not considered to be due to the local anaesthetic since the person had developed a similar problem with previous anaesthesia (Roberts 2011). Bupivacaine was used in this trial.
Patient quality of life
None of the trials reported patient quality of life.
Hospital stay
Proportion discharged as day surgery
Two trials reported the proportion of participants discharged as day‐surgery but did not report the reasons for the delayed discharge in participants who were not discharged as day‐surgery (Paulson 2003; Roberts 2011). There were no significant differences in the proportion of participants discharged as day‐surgery whether the local anaesthetic was administered just after creation of pneumoperitoneum or at the end of surgery (RR 0.98; 95% CI 0.65 to 1.50) (Paulson 2003) or whether the local anaesthetic was administered subdiaphragmatically or in the gallbladder bed (RR 1.56; 95% CI 0.76 to 3.19) (Roberts 2011) (Analysis 1.1). The number of post‐randomisation drop‐outs was not reported in one trial (Paulson 2003). The results did not change by imputation of different scenarios mentioned in the Sensitivity analysis section. Trial sequential analysis was not performed because of the presence of only one trial under each comparison.
Length of hospital stay
Two trials reported the length of hospital stay (Bucciero 2011; Khan 2012). There were no significant differences in the length of hospital stay irrespective of whether bupivacaine or lignocaine was used as the local anaesthetic agent (MD 0.10 days; 95% CI ‐0.16 to 0.36) (Khan 2012) or whether the local anaesthetic was administered in the aerosol or liquid form (Bucciero 2011) (MD 0.00 days; 95% CI ‐0.13 to 0.13) (Analysis 1.2). Neither the mean nor the standard deviation was imputed in either of these trials. Therefore, a sensitivity analysis was not performed. Trial sequential analysis was not performed because of the presence of only one trial under each comparison.
Pain
Pain at 4 to 8 hours
Eight trials reported pain at 4 to 8 hours (Rademaker 1994; Pasqualucci 1996; Karadeniz 2003; Barczynski 2006; Alkhamesi 2007; Kucuk 2007; Bucciero 2011; Roberts 2011). The comparisons, the number of participants in each comparison, the trials contributing to the analysis, and the effect estimates are shown below (Analysis 1.3). The statistically significant results are shown in italics.
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Bupivacaine versus lignocaine (one trial; 30 participants (Rademaker 1994)) (MD ‐2.00 cm VAS; 95% CI ‐6.53 to 2.53).
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Ropivacaine versus bupivacaine (one trial; 60 participants (Kucuk 2007)) (MD ‐0.22 cm VAS; 95% CI ‐0.79 to 0.35).
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Before pneumoperitoneum versus just after pneumoperitoneum (one trial; 60 participants (Barczynski 2006)) (MD ‐0.30 cm VAS; 95% CI ‐0.53 to ‐0.07).
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Just after creation of pneumoperitoneum versus end of surgery (two trials; 84 participants (Pasqualucci 1996; Karadeniz 2003)) (MD ‐0.60 cm VAS; 95% CI ‐1.41 to 0.20).
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Just after creation of pneumoperitoneum versus after end of surgery (one trial; 30 participants (Karadeniz 2003)) (MD 1.28 cm VAS; 95% CI 0.08 to 2.48).
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End of surgery versus after end of surgery (one trial; 30 participants (Karadeniz 2003)) (MD 0.95 cm VAS; 95% CI ‐0.41 to 2.31).
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Aerosol versus liquid (two trials; 97 participants (Alkhamesi 2007; Bucciero 2011)) (fixed‐effect model: MD ‐2.20 cm VAS; 95% CI ‐2.89 to ‐1.50; random‐effects model: MD ‐3.19 cm VAS; 95% CI ‐9.66 to 3.28).
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Subdiaphragmatic instillation versus gallbladder bed instillation (one trial; 83 participants (Roberts 2011)) (MD ‐0.30 cm VAS; 95% CI ‐1.01 to 0.41).
Trial sequential analysis was performed for two comparisons with more than one trial.
Just after creation of pneumoperitoneum versus after end of surgery
Trial sequential analysis revealed that the information fraction was too small (14.92%) to draw the futility area and the trial sequential boundaries for benefits or harms of the intervention were not crossed (Figure 6). The conventional statistical boundaries were also not crossed.
Trial sequential analysis of pain (4 to 8 hours) (just after creation of pneumoperitoneum versus end of surgery)
The diversity‐adjusted required information size (DARIS) was 563 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 7.09, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 60.45%. After accruing 84 participants in two trials, only 14.92% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. Neither the conventional statistical boundaries (dotted red line) or the trial sequential monitoring boundaries (continuous red line) for benefits or harms of just after creation of pneumoperitoneum versus end of surgery were crossed by the cumulative Z curve (blue line).
Aerosol versus liquid
The proportion of information accrued was only 0.58% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 7). Although the cumulative Z‐curve crossed the conventional statistical boundaries when the fixed‐effect model was used, the Z‐curve did not cross the conventional statistical boundaries when the random‐effects model was used.
Trial sequential analysis of pain (4 to 8 hours) (aerosol versus liquid)
The diversity‐adjusted required information size (DARIS) was 17,109 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 6.3, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 98.34%. After accruing 97 participants in two trials, only 0.58% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the trial sequential monitoring boundaries or the information size. Although the conventional statistical boundaries (dotted red line) is crossed by the cumulative Z‐curve (blue line) favouring aerosol, the conventional statistical boundaries were not crossed when the random‐effects model was used.
Sensitivity analysis
Either the mean or the standard deviation or both were imputed in four trials (Rademaker 1994; Pasqualucci 1996; Alkhamesi 2007; Roberts 2011). Only two of the trials were involved in meta‐analysis (two different comparisons). Exclusion of these trials resulted in alteration of the results, that is, the significant differences in these comparisons were lost when these trials were excluded.
Pain at 9 to 24 hours
Six trials reported this outcome (Pasqualucci 1996; Karadeniz 2003; Barczynski 2006; Alkhamesi 2007; Kucuk 2007; Bucciero 2011). The comparisons, the number of participants in each comparison, the trials contributing to the analysis, and the effect estimates are shown below (Analysis 1.4). The statistically significant results are shown in italics.
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Ropivacaine versus bupivacaine (one trial; 60 participants (Kucuk 2007)) (MD ‐0.05 cm VAS; 95% CI ‐0.25 to 0.16).
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Before pneumoperitoneum versus just after pneumoperitoneum (one trial; 60 participants (Barczynski 2006)) (MD 0.00 cm VAS; 95% CI ‐0.18 to 0.18).
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Just after creation of pneumoperitoneum versus end of surgery (two trials; 84 participants (Pasqualucci 1996; Karadeniz 2003)) (MD ‐0.31 cm VAS; 95% CI ‐1.64 to 1.02).
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Just after creation of pneumoperitoneum versus after end of surgery (one trial; 30 participants (Karadeniz 2003)) (MD 0.06 cm VAS; 95% CI ‐0.70 to 0.82).
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End of surgery versus after end of surgery (one trial; 30 participants (Karadeniz 2003)) (MD ‐0.30 cm VAS; 95% CI ‐1.32 to 0.72).
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Aerosol versus liquid (two trials; 100 participants (Alkhamesi 2007; Bucciero 2011)) (fixed‐effect model: MD ‐1.27 cm VAS; 95% CI ‐1.80 to ‐0.74; random‐effects model: MD ‐2.48 cm VAS; 95% CI ‐7.38 to 2.42).
We performed trial sequential analysis for two comparisons with more than one trial.
Just after creation of pneumoperitoneum versus after end of surgery
Trial sequential analysis revealed that the information fraction was too small (13.72%) to draw the futility area and the trial sequential boundaries for benefits or harms of the intervention were not crossed (Figure 8). The conventional statistical boundaries were also not crossed.
Trial sequential analysis of pain (9 to 24 hours) (just after creation of pneumoperitoneum versus end of surgery)
The diversity‐adjusted required information size (DARIS) was 612 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 4.79, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 75.35%. After accruing 84 participants in two trials, only 13.72% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. Neither the conventional statistical boundaries (dotted red line) or the trial sequential monitoring boundaries (continuous red line) for benefits or harms of just after creation of pneumoperitoneum versus end of surgery were crossed by the cumulative Z curve (blue line).
Aerosol versus liquid
The proportion of information accrued was only 1.02% of the diversity‐adjusted required information size and so the trial sequential monitoring boundaries were not drawn (Figure 9). Although cumulative Z‐curve crossed the conventional statistical boundaries when the fixed‐effect model was used, the Z‐curve did not cross the conventional statistical boundaries when the random‐effects model was used.
Trial sequential analysis of pain (9 to 24 hours) (aerosol versus liquid)
The diversity‐adjusted required information size (DARIS) was 9847 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 3.68, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 98.82%. After accruing 97 participants in two trials, only 1.02% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the trial sequential monitoring boundaries or the information size. Although the conventional statistical boundaries (dotted red line) is crossed by the cumulative Z‐curve (blue line) favouring aerosol, the conventional statistical boundaries were not crossed when the random‐effects model was used.
Sensitivity analysis
Either the mean or the standard deviation or both were imputed in two trials contributing to two different comparisons (Pasqualucci 1996; Alkhamesi 2007). Exclusion of these trials resulted in alteration of the results, that is, the significant differences in these comparisons were lost when these trials were excluded.
Return to normal activity
None of the trials reported return to normal activity.
Return to work
None of the trials reported return to work.
Subgroup analysis
We did not perform a subgroup analysis because all the trials were at high risk of bias and because of the few trials included under each comparison.
Reporting bias
We did not explore reporting bias by funnel plots because of the few trials included under each comparison.
Discussion
Summary of main results
In this review, we have compared the different methods of intraperitoneal instillation of local anaesthetic to reduce pain during laparoscopic cholecystectomy. We included 12 randomised clinical trials involving 798 participants for this systematic review. There were no significant differences in mortality or morbidity between the different methods of intraperitoneal instillation. The overall mortality after laparoscopic cholecystectomy is low (0.2%) (Giger 2011). In this review, the trials excluded high‐risk participants and we would anticipate that mortality would be even lower in these studies. To detect a 20% relative risk difference in mortality, more than 350,000 people are necessary. It is unlikely that trials will be powered to measure differences in mortality during laparoscopic cholecystectomy. Major complications are also rare. Three trials (331 participants) reported no serious complications due to surgery (Lee 2001; Karadeniz 2003; Khan 2012), or local anaesthetic and six trials (284 participants) stated that there were no complications related to local anaesthetic (Rademaker 1994; Pasqualucci 1996; Paulson 2003; Karaaslan 2006; Kucuk 2007; Bucciero 2011). One trial did not report the intra‐operative complications adequately but stated that one person developed lactic acidosis (Roberts 2011). Bupivacaine was used in this trial. Lactic acidosis has not been reported as a complication of local anaesthetic use (Martindale 2011). Overall, there were no serious adverse events related to local anaesthetics in the participants included in this review. The morbidity associated with local anaesthetics is very low with a reporting rate of approximately five adverse drug reactions per one million ampoules sold (Fuzier 2009). About 45% of these adverse drug reactions were serious (Fuzier 2009). Given the low morbidity associated with local anaesthetics and considering that laparoscopic cholecystectomy is performed under general anaesthesia with people likely to be monitored because of the use of other anaesthetic agents, the lack of adverse events reported in the trials is not surprising.
None of the trials reported quality of life, return to normal activity, and return to work. The main purpose of the local anaesthetic is to decrease pain enabling the participants to be discharged from hospital and to return to normal activity and work as early as possible. These outcomes are not only important for the patients but also important for the state‐funded health system.
While quality of life is the outcome that is used for assessing the cost‐effectiveness of an intervention, return to normal activity and return to work may also have relevance to the state in terms of lack of productivity of the individual. There were no significant differences in the hospital stay either in terms of proportion discharged as day‐surgery or in terms of the length of the hospital stay in the comparisons that reported these outcomes (Analysis 1.1; Analysis 1.2). These outcomes are important for the patients in a private health setting and for the state in a state‐funded health system because of the costs associated with hospital stay. However, only four trials reported this important outcome (Paulson 2003; Bucciero 2011; Roberts 2011; Khan 2012). Future trials on this topic should include these outcomes.
Although there were significant differences in the pain in some comparisons (Analysis 1.3; Analysis 1.4), these differences were not consistent or have been based on observation in a single trial and as such importance should not be attached to these differences. The clinical importance of these differences can be questioned with no significant differences in the reported clinical outcomes.
Overall completeness and applicability of evidence
All the trials included in this review included only people undergoing elective laparoscopic cholecystectomy (Included studies; Characteristics of included studies). Most trials included only low anaesthetic risk participants undergoing laparoscopic cholecystectomy (Included studies; Characteristics of included studies). The findings of this review are applicable only to such people.
Quality of the evidence
The overall quality of evidence is very low (summary of findings Table for the main comparison). 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 literature. However, we included 'pain' as one of the domains in this search strategy. Considering that reduction in pain is the main reason for the use of intraperitoneal local anaesthetic instillation, we expected that all the trials related to the topic would be identified, and given the number of trials included in this review, it is likely that most of the trials on this topic have been identified, However, it is possible that trials did not mention pain or words related to pain, and such trials might have been missed by this search strategy. The impact of this is likely to be small since it is likely that most trials would have mentioned the purpose of the use of the intervention. At least two review authors independently identified trials for inclusion and extracted data, thus minimising errors. However, we imputed the mean and standard deviation when these were not available. We performed a sensitivity analysis excluding the trials, which changed the results. This adds further confirmation that any significant differences noted in the trials were unreliable. The alternative was to present the data without imputing these values, which would have been even more confusing.
Agreements and disagreements with other studies or reviews
This is the first systematic review to compare the different methods of intraperitoneal local anaesthetic instillation in people undergoing laparoscopic cholecystectomy. We disagree with the authors of many trials in this review who recommended that it was preferable to administer the local anaesthetics by a certain method (Pasqualucci 1996; Barczynski 2006; Karaaslan 2006; Alkhamesi 2007; Bucciero 2011; Roberts 2011). The reasons for different conclusions are likely to be the importance given to clinical outcomes in this review and the requirement for consistency in the effect to make firm recommendations.
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Trial sequential analysis of mortality (just after creation of pneumoperitoneum versus end of surgery)
The diversity‐adjusted required information size (DARIS) was calculated to 352,564 participants, based on the proportion of participants in the control group with the outcome of 0.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 110 participants in two trials, only 0.03% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of morbidity (just after creation of pneumoperitoneum versus end of surgery)
The diversity‐adjusted required information size (DARIS) was calculated to 34,685 participants, based on the proportion of participants in the control group with the outcome of 2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 110 participants in two trials, only 0.32% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the required information size and the trial sequential monitoring boundaries. As shown, the conventional boundaries have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of pain (4 to 8 hours) (just after creation of pneumoperitoneum versus end of surgery)
The diversity‐adjusted required information size (DARIS) was 563 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 7.09, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 60.45%. After accruing 84 participants in two trials, only 14.92% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. Neither the conventional statistical boundaries (dotted red line) or the trial sequential monitoring boundaries (continuous red line) for benefits or harms of just after creation of pneumoperitoneum versus end of surgery were crossed by the cumulative Z curve (blue line).
Trial sequential analysis of pain (4 to 8 hours) (aerosol versus liquid)
The diversity‐adjusted required information size (DARIS) was 17,109 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 6.3, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 98.34%. After accruing 97 participants in two trials, only 0.58% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the trial sequential monitoring boundaries or the information size. Although the conventional statistical boundaries (dotted red line) is crossed by the cumulative Z‐curve (blue line) favouring aerosol, the conventional statistical boundaries were not crossed when the random‐effects model was used.
Trial sequential analysis of pain (9 to 24 hours) (just after creation of pneumoperitoneum versus end of surgery)
The diversity‐adjusted required information size (DARIS) was 612 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 4.79, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 75.35%. After accruing 84 participants in two trials, only 13.72% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. Neither the conventional statistical boundaries (dotted red line) or the trial sequential monitoring boundaries (continuous red line) for benefits or harms of just after creation of pneumoperitoneum versus end of surgery were crossed by the cumulative Z curve (blue line).
Trial sequential analysis of pain (9 to 24 hours) (aerosol versus liquid)
The diversity‐adjusted required information size (DARIS) was 9847 participants based on a minimal relevant difference (MIRD) of 1 cm on the visual analogue scale, a variance (VAR) of 3.68, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 98.82%. After accruing 97 participants in two trials, only 1.02% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the trial sequential monitoring boundaries or the information size. Although the conventional statistical boundaries (dotted red line) is crossed by the cumulative Z‐curve (blue line) favouring aerosol, the conventional statistical boundaries were not crossed when the random‐effects model was used.
Comparison 1 Intervention versus control, Outcome 1 Proportion discharged as day‐surgery.
Comparison 1 Intervention versus control, Outcome 2 Hospital stay.
Comparison 1 Intervention versus control, Outcome 3 Pain 4 to 8 hours.
Comparison 1 Intervention versus control, Outcome 4 Pain 9 to 24 hours.
| Methods of intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy | |||||
| Patient or population: people undergoing laparoscopic cholecystectomy | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Intervention | ||||
| Mortality | Not estimable (as there was no mortality in either group in this comparison) | Not estimable |
| ⊕⊝⊝⊝ | |
| Morbidity | Not estimable (as there was no morbidity in either group in this comparison) | Not estimable |
| ⊕⊝⊝⊝ | |
| Proportion discharged as day‐surgery | |||||
| Just after creation of pneumoperitoneum versus end of surgery | 733 per 1000 | 719 per 1000 | RR 0.98 | 33 | ⊕⊝⊝⊝ |
| Subdiaphragmatic instillation versus gallbladder bed instillation | 220 per 1000 | 342 per 1000 | RR 1.56 | 82 | ⊕⊝⊝⊝ |
| Hospital stay | |||||
| Bupivacaine versus lignocaine | The mean hospital stay ‐ bupivacaine versus lignocaine in the control groups was | The mean hospital stay ‐ bupivacaine versus lignocaine in the intervention groups was | ‐ | 206 | ⊕⊝⊝⊝ |
| Aerosol versus liquid | The mean hospital stay ‐ aerosol versus liquid in the control groups was | The mean hospital stay ‐ aerosol versus liquid in the intervention groups was | ‐ | 60 | ⊕⊝⊝⊝ |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The trial(s) was (were) of high risk of bias (2 points). | |||||
| Study name | Number randomised | Post‐randomisation drop‐outs (%) | Revised sample size | Intervention | Control | Comparison | Wound local anaesthetic infiltration | Drain use | Outcomes reported | ||
| Number randomised | Local anaesthetic | Number randomised | Local anaesthetic | ||||||||
| 40 | Not stated | 40 | 20 | Bupivacaine | 20 | Bupivacaine | Form | Yes | Not stated | Pain | |
| 60 | 0 (0%) | 60 | 30 | Bupivacaine | 30 | Bupivacaine | Timing | Yes | Not stated | Intra‐operative complications and pain | |
| 60 | 3 (5%) | 57 | 30 | Ropivacaine | 30 | Ropivacaine | Form | Not stated | Not stated | Local anaesthetic‐related complications, hospital stay, and pain | |
| 62 | 12 (19.4%) | 50 | 16 | Bupivacaine | 18 | Bupivacaine | Timing | Not stated | Not stated | Local anaesthetic‐related complications | |
| Not applicable | 16 | Bupivacaine | 18 | Bupivacaine | Timing | Not stated | Not stated | Local anaesthetic‐related complications | |||
| 52 | 7 (13.5%) | 45 | 15 | Bupivacaine | 15 | Bupivacaine | Timing | Not stated | No | Mortality, morbidity, and pain | |
| Not applicable | 15 | Bupivacaine | 15 | Bupivacaine | Timing | Not stated | Possibly for the continuous infusion group | Mortality, morbidity, and pain | |||
| Not applicable | 15 | Bupivacaine | 15 | Bupivacaine | Timing | Not stated | Possibly for the continuous infusion group | Mortality, morbidity, and pain | |||
| 224 | 18 (8%) | 206 | 100 | Bupivacaine | 106 | Lignocaine | Different local anaesthetic | Yes | Not stated | Mortality, morbidity, and hospital stay | |
| 60 | Not stated | 60 | 20 | Ropivacaine | 10* | Bupivacaine | Different local anaesthetic | No | Not stated | Local anaesthetic‐related complications and pain | |
| Not applicable | 20 | Ropivacaine | 10* | Bupivacaine | Different local anaesthetic | No | Not stated | Local anaesthetic related complications and pain | |||
| 88 | 8 (9.1%) | 80 | 20 | Bupivacaine | 19 | Bupivacaine | Timing | Yes | Not stated | Mortality and morbidity | |
| not applicable | 20 | Bupivacaine | 21 | Bupivacaine | Timing | No | Not stated | Mortality and morbidity | |||
| 60 | 6 (10%) | 54 | 26 | Bupivacaine | 28 | Bupivacaine | Timing | Not stated | Not stated | Local anaesthetic‐related complications and pain | |
| 33 | Not stated | 33 | 18 | Bupivacaine | 15 | Bupivacaine | Timing | Not stated | No | Local anaesthetic‐related complications and discharge as day‐surgery | |
| 30 | Not stated | 30 | 15 | Bupivacaine | 15 | Lignocaine | Different local anaesthetic | Not stated | Not stated | Local anaesthetic‐related complications and pain | |
| 84 | 1 (1.2%) | 83 | 41 | Bupivacaine | 41 | Bupivacaine | Location | Yes | Selectively (reasons not stated) | Hospital stay and pain | |
| § Multiple groups from the same trial. * Sample size divided by 2 as otherwise the same participants would be included twice in the meta‐analysis. | |||||||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Proportion discharged as day‐surgery Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Just after creation of pneumoperitoneum versus end of surgery | 1 | 33 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.65, 1.50] |
| 1.2 Subdiaphragmatic instillation versus gallbladder bed instillation | 1 | 82 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [0.76, 3.19] |
| 2 Hospital stay Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1 Aerosol versus liquid | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [‐0.13, 0.13] |
| 2.2 Bupivacaine versus lignocaine | 1 | 206 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐0.16, 0.36] |
| 3 Pain 4 to 8 hours Show forest plot | 8 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1 Bupivacaine versus lignocaine | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐2.0 [‐6.53, 2.53] |
| 3.2 Ropivacaine versus bupivacaine | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.22 [‐0.79, 0.35] |
| 3.3 Before pneumoperitoneum versus just after creation of pneumoperitoneum | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.30 [‐0.53, ‐0.07] |
| 3.4 Just after creation of pneumoperitoneum versus end of surgery | 2 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐0.60 [‐1.41, 0.20] |
| 3.5 Just after creation of pneumoperitoneum versus after end of surgery | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 1.28 [0.08, 2.48] |
| 3.6 End of surgery versus after end of surgery | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.95 [‐0.41, 2.31] |
| 3.7 Aerosol versus liquid | 2 | 100 | Mean Difference (IV, Fixed, 95% CI) | ‐2.20 [‐2.89, ‐1.50] |
| 3.8 Subdiaphragmatic versus gallbladder bed instillation | 1 | 82 | Mean Difference (IV, Fixed, 95% CI) | ‐0.30 [‐1.01, 0.41] |
| 4 Pain 9 to 24 hours Show forest plot | 6 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.1 Ropivacaine versus bupivacaine | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.05 [‐0.25, 0.16] |
| 4.2 Before pneumoperitoneum versus just after creation of pneumoperitoneum | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [‐0.18, 0.18] |
| 4.3 Just after creation of pneumoperitoneum versus end of surgery | 2 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐0.28 [‐0.95, 0.38] |
| 4.4 Just after creation of pneumoperitoneum versus after end of surgery | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | 0.06 [‐0.70, 0.82] |
| 4.5 End of surgery versus after end of surgery | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.30 [‐1.32, 0.72] |
| 4.6 Aerosol versus liquid | 2 | 100 | Mean Difference (IV, Fixed, 95% CI) | ‐1.27 [‐1.80, ‐0.74] |
