Menos de cuatro puertos versus cuatro puertos para la colecistectomía laparoscópica
Resumen
Antecedentes
La colecistectomía laparoscópica tradicionalmente se realiza mediante dos puertos de 10 mm y dos puertos de 5 mm. Recientemente se ha indicado una reducción del número de puertos como una modificación de la técnica estándar con el objetivo de reducir el dolor y mejorar la estética. Todavía no se ha establecido la seguridad ni la efectividad de utilizar menos de cuatro puertos.
Objetivos
Evaluar los efectos beneficiosos (como la mejoría en la estética y el retorno temprano a la actividad) y perjudiciales (como un aumento en las complicaciones) de utilizar menos de cuatro puertos (colecistectomía laparoscópica con menos de cuatro puertos) versus cuatro puertos en pacientes a los que se les realiza colecistectomía laparoscópica por cualquier motivo (cálculos biliares sintomáticos, colecistitis sin cálculos, pólipo de la vesícula biliar u otra afección).
Métodos de búsqueda
Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL; número 8, 2013), MEDLINE, EMBASE, Science Citation Index Expanded, y en la World Health Organization International Clinical Trials Registry Platform portal hasta septiembre de 2013.
Criterios de selección
Se incluyeron todos los ensayos clínicos aleatorios que compararon menos de cuatro puertos versus cuatro puertos, es decir, con la colecistectomía laparoscópica estándar que se realiza con dos puertos de al menos 10 mm de incisión y dos puertos de al menos 5 mm de incisión.
Obtención y análisis de los datos
Dos revisores de forma independiente identificaron los ensayos y extrajeron los datos. Los datos se analizaron con los modelos de efectos fijos y de efectos aleatorios. Siempre que fue posible, para cada variable se calculó el cociente de riesgos (CR) o la diferencia de medias (DM) con los intervalos de confianza (IC) del 95%, según el análisis por intención de tratar.
Resultados principales
Se encontraron nueve ensayos con 855 pacientes que se asignaron al azar a colecistectomía laparoscópica con menos de cuatro puertos (n = 427) versus colecistectomía laparoscópica de cuatro puertos (n = 428). La mayoría de los ensayos incluyó pacientes con bajo riesgo anestésico a los que se les realizó colecistectomía laparoscópica electiva. Siete de los nueve ensayos utilizaron colecistectomía laparoscópica de un único puerto y los dos ensayos restantes utilizaron colecistectomía laparoscópica de tres puertos como intervención experimental. Sólo un ensayo que incluyó a 70 participantes tuvo bajo riesgo de sesgo. En la mayoría de los ensayos la colecistectomía laparoscópica con menos de cuatro puertos se pudo completar de forma exitosa en más del 90% de los pacientes. En los pacientes restantes se convirtió principalmente al tratamiento con colecistectomía laparoscópica con cuatro puertos, aunque en algunos hubo que realizar colecistectomía abierta.
No hubo muertes en los grupos de los siete ensayos que informaron la mortalidad (318 participantes en el grupo de colecistectomía laparoscópica con menos de cuatro puertos y 316 participantes en el grupo de colecistectomía laparoscópica de cuatro puertos). La proporción de pacientes con eventos adversos graves fue baja en ambos grupos de tratamiento y el CR calculado fue compatible con una reducción y un aumento significativo del riesgo en el grupo de menos de cuatro puertos (6/318 [1,9%]) y en el grupo de colecistectomía laparoscópica de cuatro puertos (0/316 [0%]) (CR 3,93; IC del 95%: 0,86 a 18,04; siete ensayos; 634 participantes; pruebas de muy baja calidad). La diferencia calculada en la calidad de vida (medida entre los diez y 30 días) fue imprecisa (diferencia de medias estandarizada [DME] 0,18; IC del 95%: ‐0,05 a 0,42; cuatro ensayos; 510 participantes; pruebas de muy baja calidad), al igual que en la proporción de pacientes en los que la cirugía laparoscópica se tuvo que convertir a colecistectomía abierta entre los grupos (menos de cuatro puertos 3/289 [proporción ajustada 1,2%] versus cuatro puertos: 5/292 (1,7%); CR 0,68; IC del 95%: 0,19 a 2,35; cinco ensayos; 581 participantes; pruebas de muy baja calidad). La colecistectomía laparoscópica con menos de cuatro puertos demoró 14 minutos más en completarse (DM 14,44 minutos; IC del 95%: 5,95 a 22,93; nueve ensayos; 855 participantes; pruebas de muy baja calidad). No hubo diferencias significativas en la estancia hospitalaria entre los grupos (DM ‐0,01 días; IC del 95%: ‐0,28 a 0,26; seis ensayos; 731 pacientes) ni en la proporción de pacientes a los que se les dio de alta como cirugía ambulatoria (CR 0,92; IC del 95%: 0,70 a 1,22; un ensayo; 50 participantes; pruebas de muy baja calidad) entre los dos grupos. El tiempo necesario para retornar a la actividad normal y al trabajo fue más corto, con una diferencia de dos días, en el grupo de menos de cuatro puertos en comparación con colecistectomía laparoscópica de cuatro puertos (retorno a la actividad normal: DM ‐1,20 días; IC del 95%: ‐1,58 a ‐0,81; dos ensayos; 325 participantes; pruebas de muy baja calidad; retorno al trabajo: DM ‐2,00 días; IC del 95%: ‐3,31 a ‐0,69; un ensayo; 150 participantes; pruebas de muy baja calidad). No hubo diferencias significativas en las puntuaciones estéticas entre los seis y 12 meses entre los dos grupos (DME 0,37; IC del 95%: ‐0,10 a 0,84; dos ensayos; 317 participantes; pruebas de muy baja calidad).
Conclusiones de los autores
Existen pruebas de muy baja calidad que son insuficientes para determinar si existen efectos clínicos beneficiosos significativos con el uso de la colecistectomía laparoscópica con menos de cuatro puertos en comparación con la colecistectomía laparoscópica de cuatro puertos. Todavía no se ha establecido el perfil de seguridad de utilizar menos de cuatro puertos y la colecistectomía laparoscópica de menos de cuatro puertos se debe reservar para ensayos clínicos aleatorios bien diseñados.
Resumen en términos sencillos
Menos de cuatro puertos versus cuatro puertos para la 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 cada año. La extracción de la vesícula biliar (colecistectomía) es el pilar del tratamiento de los cálculos biliares sintomáticos. Solo en los Estados Unidos se realizan más de medio millón de colecistectomías por año. La colecistectomía laparoscópica (extracción de la vesícula biliar a través de un pequeño orificio, también conocido como puerto) es actualmente el método preferido para realizar la colecistectomía. En la colecistectomía laparoscópica convencional o estándar (extracción de la vesícula biliar a través de un pequeño orificio), habitualmente se utilizan cuatro puertos (dos de 10 mm de diámetro y dos de 5 mm de diámetro). Se ha informado el uso de menos puertos (colecistectomía laparoscópica con menos de cuatro puertos). Sin embargo, se desconoce la seguridad de la colecistectomía laparoscópica con menos de cuatro puertos, y si ofrece alguna ventaja sobre la colecistectomía laparoscópica con cuatro puertos. Se trató de responder esta pregunta mediante la revisión de la literatura médica y la obtención de información a partir de ensayos clínicos aleatorios, llamados frecuentemente ensayos controlados aleatorios. Cuando estos ensayos están bien realizados proporcionan la información más precisa. Dos revisores buscaron en la literatura hasta septiembre de 2013 y obtuvieron información de los ensayos, lo que minimiza los errores.
Características de los estudios
Se identificaron nueve ensayos que compararon colecistectomía laparoscópica con menos de cuatro puertos con colecistectomía laparoscópica de cuatro puertos. En estos nueve estudios se incluyeron 855 participantes. A 427 pacientes se les realizó colecistectomía laparoscópica con menos de cuatro puertos y a los 428 pacientes restantes se les realizó colecistectomía laparoscópica de cuatro puertos. La elección del tratamiento que recibieron los pacientes se determinó por un método similar al de lanzar una moneda para que los dos tratamientos se administraran a pacientes con características similares. La mayoría de estos estudios incluyó pacientes con bajo riesgo anestésico a los que se les realizó colecistectomía laparoscópica planificada.
Resultados clave
En la mayoría de los ensayos la colecistectomía laparoscópica con menos de cuatro puertos se pudo completar de forma exitosa en más del 90% de los pacientes. En los pacientes restantes se convirtió principalmente a colecistectomía laparoscópica con cuatro puertos, aunque en algunos hubo que realizar colecistectomía abierta (mediante una incisión grande en el abdomen). No hubo muertes en los grupos de los siete ensayos que informaron la mortalidad (634 participantes en los dos grupos). No hubo diferencias significativas en la proporción de pacientes que presentó complicaciones graves, en la calidad de vida entre los 10 y 30 días después de la cirugía, en la proporción de pacientes en la que la cirugía laparoscópica se tuvo que convertir a colecistectomía abierta ni en la duración de la estancia hospitalaria entre los grupos. La colecistectomía laparoscópica con menos de cuatro puertos demoró cerca de 15 minutos más para completarse que la colecistectomía laparoscópica de cuatro puertos. El tiempo necesario para retornar a la actividad normal fue un día menos y para retornar al trabajo dos días menos en el grupo de menos de cuatro puertos en comparación con la colecistectomía laparoscópica de cuatro puertos. No hubo diferencias significativas en la apariencia cosmética entre los dos grupos entre los 6 y 12 meses después de la cirugía. Parece no haber ventajas de la colecistectomía laparoscópica con menos de cuatro puertos en cuanto a la disminución de las complicaciones quirúrgicas, la estancia hospitalaria o en la mejoría de la calidad de vida y la apariencia cosmética. Por el contrario, todavía no se ha establecido la seguridad de la colecistectomía laparoscópica de menos de cuatro puertos. La colecistectomía laparoscópica con menos de cuatro puertos no se puede recomendar de forma habitual fuera de ensayos clínicos bien diseñados.
Calidad de la evidencia
La mayoría de los ensayos tuvo alto riesgo de sesgo, es decir, hay posibilidades de establecer conclusiones erróneas debido a la manera en la que se realizaron los ensayos. La calidad general de las pruebas fue muy baja.
Investigación futura
Se necesitan ensayos clínicos aleatorios bien diseñados adicionales (con bajas probabilidades de establecer conclusiones erróneas por azar y debido a la parcialidad de los participantes o los investigadores) para determinar si la colecistectomía laparoscópica con menos de cuatro puertos es segura y si hay alguna ventaja de la colecistectomía laparoscópica con menos de cuatro puertos sobre la colecistectomía laparoscópica de cuatro puertos.
Authors' conclusions
Summary of findings
| Fewer‐than‐four ports compared with four ports 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 | ||||
| Four ports | Fewer‐than‐four ports | ||||
| Mortality | There was no mortality in either group | Not estimable | 634 (7 studies) | ⊕⊝⊝⊝ | |
| Serious adverse events | Low | RR 3.93 | 634 | ⊕⊝⊝⊝ | |
| 10 per 1000 | 39 per 1000 | ||||
| Moderate | |||||
| 30 per 1000 | 118 per 1000 | ||||
| Quality of life | ‐ | The mean quality of life in the intervention groups was | ‐ | 510 | ⊕⊝⊝⊝ |
| Conversion to open cholecystectomy | 17 per 1000 | 12 per 1000 | RR 0.68 | 581 | ⊕⊝⊝⊝ |
| Operating time | The mean operating time in the control groups was | The mean operating time in the intervention groups was | ‐ | 855 | ⊕⊝⊝⊝ |
| Hospital stay | The mean hospital stay in the control groups was | The mean hospital stay in the intervention groups was | ‐ | 731 | ⊕⊝⊝⊝ |
| Proportion discharged as day surgery | 833 per 1000 | 767 per 1000 | RR 0.92 | 50 | ⊕⊝⊝⊝ |
| Return to normal activity | The mean return to normal activity in the control groups was | The mean return to normal activity in the intervention groups was | ‐ | 325 | ⊕⊝⊝⊝ |
| Return to work | The mean return to work in the control groups was | The mean return to work in the intervention groups was | ‐ | 150 | ⊕⊝⊝⊝ |
| Cosmetic score | ‐ | The mean cosmetic score in the intervention groups was | ‐ | 317 | ⊕⊝⊝⊝ |
| *The basis for the assumed risk was the control group risk across studies in all outcomes other serious adverse events. There were no serious adverse events in the control group and so the information is presented for different control group risks. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 The trial(s) was (were) of high risk of bias. | |||||
Background
Description of the condition
About 10% to 15% of the adult western population have gallstones (Jørgensen 1987; NIH 1992; Muhrbeck 1995; Halldestam 2004). Between 1% and 4% become symptomatic in one year (NIH 1992; Halldestam 2004). More than half a million cholecystectomies (removal of gallbladder) are performed per year in the United States alone (NIH 1992). Regional differences exist in the cholecystectomy rates (Mjäland 1998). Laparoscopic ('key‐hole') cholecystectomy, which was introduced in 1987, is now the preferred method of cholecystectomy (NIH 1992; Fullarton 1994; Bakken 2004; Livingston 2004; Keus 2006; David 2008).
Description of the intervention
Traditionally four ports are used to perform laparoscopic cholecystectomy. These include one port for the camera; one port for instruments used to carry out the dissection, diathermy, and clip application; and two ports for manipulation of the gallbladder for adequate exposure of the field of surgery. Two ports are usually 10 mm in size and two ports are usually 5 mm in size (Alponat 2002; Bisgaard 2002). Laparoscopic cholecystectomy has been performed using one, two, or three ports (Poon 2003; Gupta 2005). The technique in performing laparoscopic cholecystectomy with fewer ports, in particular, single‐port laparoscopic cholecystectomy varies from conventional four‐port method laparoscopic cholecystectomy with regards to the dissection of the gallbladder and the use of roticulating instruments that have articulations with the ability to rotate the tip at the articulation (Roberts 2010).
How the intervention might work
The use of fewer ports may decrease the pain (and analgesic requirements) (Gupta 2005). Because of the fewer scars, it may result in better cosmesis (Gupta 2005).
Why it is important to do this review
Any new technique has to be evaluated with regards to safety and effectiveness before it can be adopted in routine practice. There are concerns about the safety of using fewer‐than‐four ports (Hall 2012). The concern about using fewer‐than‐four ports is about damage to the bile duct or other important structures such as blood vessels supplying the liver because of the fewer ports not allowing adequate vision and sufficient traction on the structures because of the angle at the which the instruments work and because of the fewer instruments that can be used within the body at any given time. The potential advantages include decreased pain and improved cosmesis because of fewer ports being used. There has been no Cochrane systematic review on this topic.
Objectives
To assess the benefits (such as improvement in cosmesis and earlier return to activity) and harms (such as increased complications) of using fewer‐than‐four ports (fewer‐than‐four‐ports laparoscopic cholecystectomy) versus four ports in people undergoing laparoscopic cholecystectomy for any reason (symptomatic gallstones, acalculous cholecystitis, gallbladder polyp, or any other condition).
Methods
Criteria for considering studies for this review
Types of studies
We included only randomised clinical trials irrespective of language, blinding, sample size, or publication status.
We excluded quasi‐randomised studies (where the method of allocating participants to a treatment were not strictly random (eg, date of birth, hospital record number, alternation), cohort studies, and case‐control studies because of the selection bias in such studies. People who were generally considered easy to operate would have undergone laparoscopic cholecystectomy by fewer ports while those who were considered to be difficult to operate would have undergone four‐port laparoscopic cholecystectomy. Besides, people in whom the surgery was started as fewer‐than‐four‐ports laparoscopic cholecystectomy and converted to four‐port laparoscopic cholecystectomy might have been excluded (as we found was the case even in randomised clinical trials using a similar intervention, ie, smaller size ports or miniport laparoscopic cholecystectomy (Gurusamy 2013)), or would have been included in four‐port laparoscopic cholecystectomy making any such comparisons in non‐randomised studies meaningless or misleading. However, we recorded any rare harms attributed to fewer‐than‐four‐ports laparoscopic cholecystectomy in such non‐randomised studies.
Types of participants
People undergoing laparoscopic cholecystectomy (elective or emergency) for any reason (symptomatic gallstones, acalculous cholecystitis, gallbladder polyp, or any other condition).
Types of interventions
Fewer‐than‐four ports (one, two, or three) versus four ports (two ports of at least 10 mm and two ports of at least 5 mm) in people undergoing laparoscopic cholecystectomy. We considered laparoscopic cholecystectomy using four‐port laparoscopic cholecystectomy with two 10‐mm ports and two 5‐mm ports as standard laparoscopic cholecystectomy. We excluded trials that did not use the above definition of four‐port laparoscopic cholecystectomy. The reason for excluding trials in which smaller ports were used in the control group was because of the lack of information on safety in miniport laparoscopic cholecystectomy (Gurusamy 2013).
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 hospitalisation, resulted in a persistent or significant disability, or any important medical event that might have jeopardised the person or required intervention to prevent it (ICH‐GCP 1997). We classified complications such as bile duct injury, re‐operations, intra‐abdominal collections requiring drainage (radiological or surgical), infected intra‐abdominal collections, bile leaks requiring drainage, stent, or surgery as serious adverse events. We did not consider complications such as wound infections, bile leaks, or abdominal collections that did not require any treatment and settled spontaneously to be serious adverse events.
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Patient quality of life (however defined by authors).
Secondary outcomes
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Conversion to open cholecystectomy.
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Operating time.
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Hospital stay (length of hospital stay, proportion discharged as day‐case laparoscopic cholecystectomy).
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Return to activity.
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Return to work.
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Cosmesis (however defined by authors but at least six months after surgery).
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE, EMBASE, Science Citation Index Expanded (Royle 2003), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) portal (apps.who.int/trialsearch). The WHO ICTRP portal allows search of various trial registers including clinicaltrials.gov and International Standard Randomised Controlled Trial Number (ISRCTN) among other registers to September 2013. We have given the search strategies in Appendix 1 with the time spans for the searches.
Searching other resources
We handsearched the references of the identified trials to identify further relevant trials.
Data collection and analysis
We performed the systematic review according to the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2013).
Selection of studies
KG and JV or MR independently identified the trials for inclusion. KG and JV or MR listed the excluded trials with the reasons for the exclusion. We resolved any differences in opinion through discussion.
Data extraction and management
KG and JV or MR independently extracted the following data.
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Year and language of publication.
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Country.
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Year of conduct of the trial.
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Inclusion and exclusion criteria.
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Sample size.
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Population characteristics such as age and sex ratio.
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Proportion of people who underwent successful fewer‐than‐four‐ports laparoscopic cholecystectomy.
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Intra‐operative cholangiogram.
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Outcomes (see Primary outcomes; Secondary outcomes).
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Risk of bias (see Assessment of risk of bias in included studies).
We sought any unclear or missing information by contacting the authors of the individual trials. If there was any doubt whether the trials shared the same participants ‐ completely or partially (by identifying common authors and centres) ‐ we planned to contact the authors of the trials to clarify whether the trial report had been duplicated. We resolved any differences in opinion through discussion.
Assessment of risk of bias in included studies
We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2013). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012; Savovic 2012a), the risk of bias of the trials were assessed based on the following domains.
Sequence generation
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Low risk of bias (the methods used was either adequate (eg, computer‐generated random numbers, table of random numbers) or unlikely to introduce confounding).
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Uncertain risk of bias (there was insufficient information to assess whether the method used was likely to introduce confounding).
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High risk of bias (the method used (eg, quasi‐randomised studies) was improper and likely to introduce confounding).
Allocation concealment
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Low risk of bias (the method used (eg, central allocation) was unlikely to induce bias on the final observed effect).
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Uncertain risk of bias (there was insufficient information to assess whether the method used was likely to induce bias on the estimate of effect).
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High risk of bias (the method used (eg, open random allocation schedule) was likely to induce bias on the final observed effect).
Blinding of participants, personnel, and outcome assessors
It is impossible to blind the surgeons who performed the surgery. However, by the use of a second surgical team, it is possible to determine whether a patient needs conversion to open cholecystectomy or whether the patient can be discharged from hospital (ie, the performance bias can be reduced by using a second surgical team to determine patient care).
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Low risk of bias (blinding was performed adequately, or the outcome measurement 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 the type of blinding used was likely to induce bias on the estimate of effect).
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High risk of bias (no blinding or incomplete blinding, and the outcome or the outcome measurement was likely to be influenced by lack of blinding).
Incomplete outcome data
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Low risk of bias (the underlying reasons for missingness are unlikely to make treatment effects departure from plausible values, or proper methods have been employed to handle missing data).
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Uncertain risk of bias (there was insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data was likely to induce bias on the estimate of effect).
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High risk of bias (the crude estimate of effects (eg, complete case estimate) was clearly biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory).
Selective outcome reporting
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Low risk of bias (the trial protocol was available and all of the trial's pre‐specified outcomes that are of interest in the review had been reported or similar; if the trial protocol was not available, mortality and morbidity were reported).
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Uncertain risk of bias (there was insufficient information to assess whether the magnitude and direction of the observed effect was related to selective outcome reporting).
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High risk of bias (not all of the trial's pre‐specified primary outcomes had been reported or similar).
For this purpose, the trial should have been registered either on the www.clinicaltrials.gov website or a similar register, or there should be a protocol (eg, published in a paper journal). In the case when the trial was run and published in the years when trial registration was not required, we scrutinised all publications reporting on the trial carefully to identify the trial objectives and outcomes and determine whether usable data were provided in the publication's results section on all outcomes specified in the trial objectives.
Vested interest bias
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Low risk of bias (the trial was not performed or supported by any parties that might have conflicting interest, eg, instrument manufacturer).
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Uncertain risk of bias (any conflicts of interest of the trialist or trial funder was not clear).
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High risk of bias (the trial was performed or supported by any parties that might have conflicting interest, eg, instrument manufacturer).
We classified trials with high risk of bias or uncertain risk of bias in any of the domains as trials with high risk of bias. The trials judged with low risk of bias in all domains were classified as trials with low risk of bias.
Measures of treatment effect
For binary outcomes, we calculated the risk ratio (RR) with 95% confidence interval (CI). RR calculations do not include trials in which no events occurred in either group, whereas risk difference calculations do. We planned to report the risk difference if the conclusions using this association measure were different from RR. For continuous outcomes, we calculated the mean difference (MD) with 95% CI for outcomes such as operating time and hospital stay and the standardised mean difference (SMD) with 95% CI for quality of life (where different scales might be used).
Unit of analysis issues
The unit of analysis were individual participants undergoing fewer‐than‐four‐ports laparoscopic cholecystectomy or four‐port laparoscopic cholecystectomy.
Dealing with missing data
We sought any unclear or missing information by contacting the authors of the individual trials. We performed an intention‐to‐treat analysis (Newell 1992), whenever possible. We planned to impute data for binary outcomes using various scenarios such as best‐best scenario, worst‐worst scenario, best‐worst scenario, and worst‐best scenario (Gurusamy 2009; Gluud 2013).
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 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 CIs, we imputed the standard deviation as the highest standard deviation in the other trials included under that outcome, fully recognising that this form of imputation will decrease the weight of the study for calculation of mean differences and bias the effect estimate to no effect in case of SMD (Higgins 2011).
Assessment of heterogeneity
We explored heterogeneity using the Chi2 test with significance set at 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 also planned to perform linear regression approach described by Egger 1997 to determine the funnel plot asymmetry.
Data synthesis
Meta‐analysis
We performed the meta‐analyses using the software package Review Manager 5 (RevMan 2012), and following the recommendations of The Cochrane Collaboration (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2013). We used both random‐effects model (DerSimonian 1986) and fixed‐effect model (DeMets 1987) meta‐analyses. In case of discrepancy between the two models resulting in change of conclusions, we have reported both results in the full text and the more conservative model in the abstract, summary of findings Table for the main comparison, and the plain language summary; otherwise, we have reported the results of the fixed‐effect model.
Trial sequential analysis
We used trial sequential analysis to control for random errors due to sparse data and repetitive testing of the accumulating data for the primary outcomes (CTU 2011; Thorlund 2011). We added the trials according to the year of publication. If more than one trial was published in a year, we added the trials in alphabetical order according to the last name of the first author. We constructed the trial sequential monitoring boundaries on the basis of the diversity‐adjusted required information size (Wetterslev 2008; Wetterslev 2009).
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 group proportion obtained from the results, and a relative risk reduction of 20% for primary binary outcomes with two or more trials to determine whether more trials are necessary on this topic (if the trial sequential monitoring boundary and the required information size is reached or the futility zone is crossed, then more trials may be unnecessary) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010). For quality of life, the required sample size was calculated 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 minimal clinically relevant difference of 0.25. In trial sequential analyses in which the accrued information size surpassed the diversity‐adjusted required information size (DARIS) (ie, days of hospital stay and days of return to normal activity), we post‐hoc challenged the accrued information size with trial sequential analyses based on a minimal relevant difference equal to the smallest of the 95% CIs of the meta‐analysis.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses.
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Trials with high risk of bias compared to trials with low risk of bias.
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Elective cholecystectomy compared to trials with emergency cholecystectomy.
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Number of ports (one or two or three).
Of these, we performed only the last subgroup analysis because of the reasons stated in the results section. We used the Chi2 test for subgroup differences to identify subgroup differences.
Sensitivity analysis
We planned to perform a sensitivity analysis by imputing data for binary outcomes using various scenarios such as best‐best scenario, worst‐worst scenario, best‐worst scenario, and worst‐best scenario in the presence of missing outcome data (Gurusamy 2009; Gluud 2013). We performed a sensitivity analysis by excluding the trials in which the mean and the standard deviation were imputed.
Summary of findings table
We have reported all the outcomes with at least one trial in summary of findings Table for the main comparison. This table provides a summary of the number of participants, number of trials, intervention effect estimates, and the quality of evidence for each outcome.
Results
Description of studies
Results of the search
We identified 4780 references through electronic searches of CENTRAL (N = 761), MEDLINE (N = 1240), EMBASE (N = 1086), Science Citation Index Expanded (N = 1663), and WHO ICTRP (N = 30). We identified one further reference on handsearching of reference lists of identified trials. We excluded 1563 duplicates and 3147 clearly irrelevant references through reading abstracts. We retrieved 71 references in full text for further assessment. Three trials were ongoing trials with no interim reports available (Characteristics of ongoing studies). We excluded 58 references of 54 studies or reports. The reasons for exclusion are stated in the Characteristics of excluded studies. In total, we included 10 references of nine completed trials in this review. The reference flow is shown in Figure 1.
Study flow diagram.
Included studies
Nine trials randomised 855 participants to fewer‐than‐four‐ports laparoscopic cholecystectomy (n = 427) and four‐port laparoscopic cholecystectomy (n = 428). Four trials included low anaesthetic risk participants undergoing elective laparoscopic cholecystectomy (Kumar 2007; Lirici 2011; Abd Ellatif 2013; Saad 2013). The anaesthetic risk status was not available in the remaining five trials (Cerci 2007; Bucher 2011; Herrero 2012; Sinan 2012; Luna 2013). Seven trials stated that they included people undergoing elective laparoscopic cholecystectomy (Kumar 2007; Bucher 2011; Lirici 2011; Herrero 2012; Sinan 2012; Abd Ellatif 2013; Saad 2013). The information on the inclusion of emergency laparoscopic cholecystectomies was not available in two trials (Cerci 2007; Luna 2013). The mean age ranged between 39 and 50 years in the eight trials that provided this information (Kumar 2007; Cerci 2007; Bucher 2011; Lirici 2011; Herrero 2012; Sinan 2012; Abd Ellatif 2013; Saad 2013). The proportion of females ranged between 23% and 83% in the seven trials that reported this information (Cerci 2007; Kumar 2007; Lirici 2011; Herrero 2012; Sinan 2012; Abd Ellatif 2013; Saad 2013). In seven trials, a single umbilical port was used (Bucher 2011; Lirici 2011; Herrero 2012; Sinan 2012; Abd Ellatif 2013; Luna 2013; Saad 2013). There were two channels (Abd Ellatif 2013), three channels (Bucher 2011; Lirici 2011; Herrero 2012; Saad 2013), or four channels (Luna 2013) in the single port through which the instruments could be introduced. The number of channels in the single port was not available in one trial (Sinan 2012). The length of the umbilical incision ranged between 15 and 25 mm in the five trials that provided this information (Bucher 2011; Lirici 2011; Herrero 2012; Sinan 2012; Saad 2013). The length of the incision was not reported in the two other trials in which a single port was used (Abd Ellatif 2013; Luna 2013). Two trials included three ports, where one of the subcostal incisions was left out in the intervention group (Cerci 2007; Kumar 2007).
Excluded studies
We excluded some studies because they were not randomised trials. We excluded othertrials because the control group was not standard laparoscopic cholecystectomy although the authors stated that the control group was standard laparoscopic cholecystectomy. We considered standard laparoscopic cholecystectomy as that performed with two ports of at least 10 mm in size and two ports of at least 5 mm in size. A few trials were ongoing trials and it is difficult to judge whether these trials will meet the inclusion criteria in future because of the limited information available from interim reports or trial registers. The reasons for exclusion in the individual trials are stated in the 'Characteristics of excluded studies' table.
Risk of bias in included studies
The risk of bias is summarised in Figure 2. The risk of bias in individual trials is stated in Figure 3. Only one trial had low risk of bias (Saad 2013). The remaining trials had high risk of bias (Cerci 2007; Kumar 2007; Bucher 2011; Lirici 2011; Herrero 2012; Sinan 2012; Abd Ellatif 2013; Luna 2013).
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.
Effects of interventions
Fewer‐than‐four‐ports laparoscopic cholecystectomy was successful in between 90% and 100% of the participants in the seven trials in which it was possible to calculate this (Kumar 2007; Bucher 2011; Lirici 2011; Herrero 2012; Abd Ellatif 2013; Luna 2013; Saad 2013). The remaining participants were mostly converted to four‐port laparoscopic cholecystectomy, but some were also converted to open cholecystectomy. The findings are summarised in summary of findings Table for the main comparison.
Primary outcomes
Mortality
Mortality data were available from seven trials (Bucher 2011; Lirici 2011; Herrero 2012; Sinan 2012; Abd Ellatif 2013; Luna 2013; Saad 2013). There was no mortality in either group in these seven trials (318 participants in fewer‐than‐four‐ports laparoscopic cholecystectomy group and 316 participants in four‐port laparoscopic cholecystectomy group). 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 as before. Instead, we used a proportion of 0.2% in the control group based on data from approximately 30,000 people included in a database in Switzerland (Giger 2011). The proportion of information accrued was only 0.18% of the DARIS and so the trial sequential monitoring boundaries were not drawn (Figure 4). The cumulative Z‐curve did not cross the conventional statistical boundaries.
Trial sequential analysis of mortality
The diversity‐adjusted required information size (DARIS) was calculated to 352,564 participants, based on the proportion of participants in the control group with the outcome of 0.2%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. To account for zero event groups, a continuity correction of 0.01 was used in the calculation of the cumulative Z‐curve (blue line). After accruing 634 participants in seven trials, only 0.18% 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 (dotted red line) have also not been crossed by the cumulative Z‐curve.
Surgical morbidity (serious adverse events)
Seven trials reported the proportion of participants with serious adverse events (Bucher 2011; Lirici 2011; Herrero 2012; Sinan 2012; Abd Ellatif 2013; Luna 2013; Saad 2013). There were no serious adverse events in the four‐port group. There was no significant difference in the proportion of participants with serious adverse events between the fewer‐than‐four‐ports group and four‐port laparoscopic cholecystectomy group using the fixed‐effect model (RR 3.93; 95% CI 0.86 to 18.04) (Analysis 1.1). There were no changes in the results with the random‐effects model for the meta‐analysis or by using risk difference as the effect measure. Since there were no serious adverse events in the control 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. Instead, we used a proportion of 0.3% 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 0.27% of the DARIS and so the trial sequential monitoring boundaries were not drawn (Figure 5). The cumulative Z‐curve does not cross the conventional statistical boundaries.
Trial sequential analysis of serious adverse events
The diversity‐adjusted required information size (DARIS) was calculated to 234,831 participants, based on the proportion of participants in the control group with the outcome of 0.3%, 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 634 participants in seven trials, only 0.27% 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 (dotted red line) have also not been crossed by the cumulative Z‐curve.
Quality of life
Four trials reported this outcome (Bucher 2011; Lirici 2011; Abd Ellatif 2013; Saad 2013). The quality of life was measured between 10 days and one month after surgery in these trials (Bucher 2011; Lirici 2011; Abd Ellatif 2013; Saad 2013). The scales used included EQ‐5D (Abd Ellatif 2013), Gastrointestinal Quality of Life Index (GIQLI) (Saad 2013), Short Form ‐ 12 (SF‐12) (Bucher 2011), and Short Form ‐ 36 (Lirici 2011). Quality of life was significantly better with fewer‐than‐four‐ports than four‐port laparoscopic cholecystectomy with the fixed‐effect model (SMD 0.21; 95% CI 0.03 to 0.38). There was no significant difference between the two treatments with the random‐effects model (SMD 0.18; 95% CI ‐0.05 to 0.42) (Analysis 1.2). Trial sequential analysis was not performed since the software does not allow calculation of SMD.
Secondary outcomes
Conversion to open cholecystectomy
Five trials reported the proportion of participants in whom the laparoscopic cholecystectomy had to be converted to open cholecystectomy (Cerci 2007; Kumar 2007; Bucher 2011; Lirici 2011; Abd Ellatif 2013). There was no significant difference in the proportion of participants in whom the laparoscopic cholecystectomy had to be converted to open cholecystectomy between the two groups using the fixed‐effect model (RR 0.68; 95% CI 0.19 to 2.35) (Analysis 1.3). Using the random‐effects model or risk difference did not alter the conclusions. Trial sequential analysis revealed that the proportion of information accrued was only 1.42% of the DARIS and so the trial sequential monitoring boundaries were not drawn (Figure 6). The cumulative Z‐curve did not cross the conventional statistical boundaries.
Trial sequential analysis of conversion to open cholecystectomy
The diversity‐adjusted required information size (DARIS) was calculated to 40,918 participants, based on the proportion of patients in the control group with the outcome of 1.7%, 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 581 participants in five trials, only 1.42% 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 (dotted red line) have also not been crossed by the cumulative Z‐curve.
Operating time
All the trials reported operating time. The fewer‐than‐four‐ports laparoscopic cholecystectomy took seven minutes longer to complete than the four‐ports laparoscopic cholecystectomy using the fixed‐effect model (MD 14.44 minutes; 95% CI 5.95 to 22.93) (Analysis 1.4). There was no change in the results by using the random‐effects model. Trial sequential analysis revealed that the trial sequential boundaries were crossed suggesting that the operating time was likely to be longer in the fewer‐than‐four‐ports group than four‐ports group with low risk of random errors (Figure 7).
Trial sequential analysis of operating time
The diversity‐adjusted required information size (DARIS) was 1124 participants based on a minimal relevant difference (MIRD) of 15 minutes, a variance (VAR) of 385.03, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 95.2%.The cumulative Z‐curve (blue line) crosses the conventional boundary (dotted red line) and the trial sequential monitoring boundaries (continuous red line) after the seventh trial. Although the DARIS has not been reached after accrual of 855 participants in nine trials, the results suggest that operating time is longer with fewer‐than‐four‐ports laparoscopic cholecystectomy as compared with four‐ports laparoscopic cholecystectomy with low risk of random errors.
Hospital stay
Six trials reported the length of hospital stay (Cerci 2007; Kumar 2007; Bucher 2011; Lirici 2011; Abd Ellatif 2013; Saad 2013). Hospital stay was significantly longer in the fewer‐than‐four‐ports group than four‐ports group using the fixed‐effect model (MD 0.14 days; 95% CI 0.02 to 0.26). There was no significant difference in the hospital stay between the groups by using the random‐effects model (MD ‐0.01 days; 95% CI ‐0.28 to 0.26) (Analysis 1.5). One trial reported the proportion of participants discharged as day‐surgery laparoscopic cholecystectomy (Herrero 2012). There was no significant difference in the proportion of participants who underwent day‐surgery laparoscopic cholecystectomy between the groups (RR 0.92; 95% CI 0.70 to 1.22) (Analysis 1.6). Trial sequential analysis revealed that the DARIS has been reached and the conventional boundaries were not crossed (Figure 8). This suggests that there is unlikely to be a difference in the length of hospital stay between the groups with low risk of random errors. Trial sequential analysis after changing the minimal relevant difference (MIRD) to the smallest limit of the 95% CI of the meta‐analysis showed that the proportion of information accrued was only 26.09% of the DARIS and that neither the trial sequential monitoring boundaries nor the conventional boundaries were crossed (Figure 9).
Trial sequential analysis of hospital stay
The diversity‐adjusted required information size (DARIS) was 222 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 1.29, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 81.55%. Seven hundred and thirty‐one participants were accrued in six trials. The cumulative Z‐curve (blue line) crosses the DARIS after the third trial (vertical red line). However, it does not cross the conventional boundaries (dotted red line). This suggests that there is no significant difference in the length of hospital stay between fewer‐than‐four‐ports laparoscopic cholecystectomy versus four‐ports laparoscopic cholecystectomy with low risk of random errors.
Trial sequential analysis of hospital stay with smallest confidence interval used as minimal relevant difference
The diversity‐adjusted required information size (DARIS) was 2802 participants based on a minimal relevant difference (MIRD) of 0.28 days, a variance (VAR) of 1.29, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 81.55%. After accruing 731 participants in six trials, only 26.09% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. As shown, the cumulative Z‐curve (blue line) does not cross the trial sequential boundaries (red line). Conventional boundaries (dotted red line) have also not been crossed by the cumulative Z‐curve.
Return to activity and work
Two trials reported the time taken to return to activity (Kumar 2007; Abd Ellatif 2013). The time taken to return to normal activity was significantly shorter in the fewer‐than‐four‐ports group than the four‐ports group using the fixed‐effect model (MD ‐1.20 days; 95% CI ‐1.58 to ‐0.81) (Analysis 1.7). There was no change in the results between the two groups using the random‐effects model. Trial sequential analysis revealed that the trial sequential boundaries were crossed suggesting that the time taken to return to activity was likely to be shorter in the fewer‐than‐four‐ports group than four‐ports group with low risk of random errors (Figure 10). The trial sequential analysis results did not change by changing the MIRD to the smallest of the 95% CI of the meta‐analysis (Figure 11).
Trial sequential analysis of return to normal activity
The diversity‐adjusted required information size (DARIS) was 200 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 6.35, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. Three hundred and twenty‐five participants were accrued in two trials. The cumulative Z‐curve crosses the trial sequential monitoring boundaries (continuous red lines) and the conventional boundaries (dotted red line) after the second trial. The results are compatible with significantly fewer days to return to normal activity in the fewer‐than‐four‐ports group with four‐ports group with low risk of random errors.
Trial sequential analysis of return to normal activity with smallest confidence interval used as minimal relevant difference
The diversity‐adjusted required information size (DARIS) was 304 participants based on a minimal relevant difference (MIRD) of 0.81 day, a variance (VAR) of 6.35, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. Three hundred and twenty‐five participants were accrued in two trials. The cumulative Z‐curve crosses the trial sequential monitoring boundaries (continuous red lines) and the conventional boundaries (dotted red line) after the second trial. The results are compatible with significantly fewer days to return to normal activity in the fewer‐than‐four‐ports group with four‐ports group with low risk of random errors.
One trial reported the time taken to return to work (Bucher 2011). The time taken to return to work was shorter by two days in the fewer‐than‐four‐ports group compared with four‐port laparoscopic cholecystectomy (MD ‐2.00 days; 95% CI ‐3.31 to ‐0.69) (Analysis 1.8). Since this was the only trial, the issue of fixed‐effect versus random‐effects meta‐analysis does not arise and trial sequential analysis was not performed.
Cosmesis
Two trials reported cosmesis at multiple time points (Abd Ellatif 2013; Saad 2013). We obtained the values at six months and one year since wound remodelling can take place even one year after surgery (Gurtner 2008). The cosmesis scores were significantly better in the fewer‐than‐four‐ports group than four‐ports group using the fixed‐effect model (SMD 0.46; 95% CI 0.24 to 0.69). There was no significant difference in the cosmesis scores between the groups using the random‐effects model (SMD 0.37; 95% CI ‐0.10 to 0.84) (Analysis 1.9). Trial sequential analysis cannot be performed when SMD is calculated.
Subgroup analysis
Two planned subgroup analyses (trials with high risk of bias versus low risk of bias and elective cholecystectomy versus emergency cholecystectomy) were not performed because one of the subgroups had only one trial (only one trial was of low risk of bias (Saad 2013) and only one trial had a possible inclusion of emergency laparoscopic cholecystectomy (Cerci 2007)). Such a subgroup analysis is prone to error.
We performed a subgroup analysis based on the number of ports. We compared whether the results were different between the trials that used a single port versus those that used three ports. The Chi2 test for subgroup differences was not statistically significant for any of the outcomes in which the two subgroups were represented (conversion to open cholecystectomy (Analysis 1.3; P value = 0.62), hospital stay (Analysis 1.5; P value = 0.67), return to normal activity (Analysis 1.7; P value = 0.89) except operating time (Analysis 1.4; P value = 0.001). For operating time, the operating time was longer for one‐port than four‐ports group (MD 21.04 minutes; 95% CI 10.45 to 31.62) while there was no significant difference in the operating time between three‐port and four‐port groups (MD ‐5.32 minutes; 95% CI ‐17.38 to 6.73) (Analysis 1.4).
Sensitivity analysis
We did not perform the planned sensitivity analysis by imputing data for binary outcomes using various scenarios such as best‐best scenario, worst‐worst scenario, best‐worst scenario, and worst‐best scenario in the presence of missing outcome data (Gurusamy 2009; Gluud 2013). This was because there were no post‐randomisation drop‐outs in six of the nine included trials (Cerci 2007; Kumar 2007; Bucher 2011; Lirici 2011; Abd Ellatif 2013; Saad 2013). In the remaining three trials, it was not clear whether there were any post‐randomisation drop‐outs (Herrero 2012; Sinan 2012; Luna 2013).
We performed a sensitivity analysis by excluding the trials in which either the mean or the standard deviation or both were imputed. This was only possible for quality of life (Analysis 2.1), operating time (Analysis 2.2), hospital stay (Analysis 2.3), and return to normal activity (Analysis 2.4). There was no change in the conclusions by performing this sensitivity analysis for operating time, hospital stay, and return to normal activity. However, there was no significant difference in the quality of life between the groups when the trials in which either the mean or the standard deviation or both were imputed (SMD 0.14; 95% CI ‐0.08 to 0.36).
Of the remaining continuous outcomes, there was no imputation of mean or standard deviation of cosmetic score in the two trials that reported this outcome (Abd Ellatif 2013; Saad 2013). Although the mean and the standard deviation were imputed for return to work, we did not perform a sensitivity analysis since only one trial reported this outcome (Analysis 1.8).
Funnel plot
We did not explore reporting bias using funnel plot because this review included nine trials only.
Discussion
Summary of main results
In this review, we did not find any difference in mortality or morbidity between fewer‐than‐four‐ports laparoscopic cholecystectomy versus four‐port laparoscopic cholecystectomy. There were no deaths in the seven trials that reported this outcome (Bucher 2011; Lirici 2011; Herrero 2012; Sinan 2012; Abd Ellatif 2013; Luna 2013; Saad 2013). Mortality after laparoscopic cholecystectomy is approximately 0.2% (Giger 2011). Most of the trials included in this review randomised people with low anaesthetic risk and undergoing elective laparoscopic cholecystectomy. Therefore, it is not surprising that there was no mortality in either group. There was no significant difference in the proportion of people who developed serious adverse events. However, it is unsure if this was because there was no difference in the proportion of people who develop serious adverse events between fewer‐than‐four‐ports laparoscopic cholecystectomy and four‐port laparoscopic cholecystectomy or whether this is because of lack of evidence of a difference between the groups. This is because of wide CI values that overlapped no effect (RR of 1) and a 25% relative risk reduction or increase (0.75 or 1.25). It should be noted that the proportion of people with serious adverse events was higher in the fewer‐than‐four‐ports group (6/318 (1.9%)) versus four‐port laparoscopic cholecystectomy (0/318 (0%)). This could have happened by chance, but there is also a possibility that this was a true difference. Until further trials demonstrate the safety of fewer‐than‐four‐ports laparoscopic cholecystectomy, it cannot be recommended routinely particularly because it does not seem to offer any significant benefits in terms of improved quality of life or decreased length of hospital stay. Although the fewer‐than‐four‐ports group returned to normal activity and work significantly earlier compared to the four‐port laparoscopic cholecystectomy group, it must be noted that the trials appeared to lack blinding, which may have a significant influence on these outcomes.
Given the low incidence of complications in four‐port laparoscopic cholecystectomy, it is unlikely that the trials assessing the fewer ports can be powered to measure a reduction in the complications after laparoscopic cholecystectomy. Use of pain as one of the primary outcomes can also be misleading, as the clinical significance of reduction in pain scores measured by visual analogue scale is unknown for laparoscopic cholecystectomy. Future trials assessing fewer‐than‐four ports could use the length of hospital stay or the proportion of people discharged as day‐surgery laparoscopic cholecystectomy as the outcome based on which sample size calculations are performed to decrease type I and type II errors. This has significant cost benefits to the healthcare funder. Any cost savings can be used to fund other treatments or other socially beneficial projects in a state‐sponsored health scheme.
It is important that the participants and outcome assessors are blinded to the groups if discharge following day‐procedure laparoscopic cholecystectomy is used as primary outcome in such trials, as the decision to discharge a participant following day procedure is subjective. Quality of life is another outcome that should be measured in such trials as they have implications in cost‐effectiveness analysis. Cosmesis is only one aspect of quality of life and cannot be used in any economic health evaluation. However, it is an important patient outcome. Wound remodelling occurs even at one year after surgery (Gurtner 2008). Trials should follow participants for at least one year if cosmesis is assessed. It is important to perform intention‐to‐treat analyses so that the mean clinical efficacy and cost‐effectiveness of the intervention (fewer‐than‐four ports) can be easily determined and used in economic evaluation.
Overall completeness and applicability of evidence
This review is applicable only to elective laparoscopic cholecystectomy performed in low anaesthetic risk participants as most trials included such participants. Most of the trials excluded moderately obese (Herrero 2012; Abd Ellatif 2013; Luna 2013), severely obese (Lirici 2011; Saad 2013), or very severely obese participants undergoing laparoscopic cholecystectomy (Sinan 2012). Therefore, the findings of the review are applicable only in non‐obese people undergoing laparoscopic cholecystectomy.
Quality of the evidence
Only one trial was of low risk of bias (Saad 2013). There was moderate to severe inconsistency in some of the outcomes, such as hospital stay and operating time. Overall, the evidence is of very low quality as shown in summary of findings Table for the main comparison. However, it must be noted that this is the best level of evidence available.
Potential biases in the review process
We imputed the mean from median and standard deviation based on guidance from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This might have introduced bias in the review process.
Agreements and disagreements with other studies or reviews
Several reviews exist on fewer‐than‐four ports (mostly single‐port laparoscopic cholecystectomy) versus conventional laparoscopic cholecystectomy in people undergoing laparoscopic cholecystectomy for various indications such as symptomatic gallstones and gallbladder polyps. Some reviews suggested that single‐port laparoscopic cholecystectomy was safe (Markar 2012; Song 2012) and effective (Garg 2012a; Pisanu 2012), and can be offered as alternatives to conventional laparoscopic cholecystectomy while other reviews suggested that there was no benefit with single‐port laparoscopic cholecystectomy or that there was a balance between benefits and harms and suggested a more cautious approach (Sun 2009; Hall 2012; Wang 2012). We have recommended that using fewer‐than‐four ports should be reserved to well‐designed randomised clinical trials. Some of the reasons for our disagreements with other researchers are that the other researchers included trials in which the control group was not necessarily four ports with at least two 10‐mm ports and two 5‐mm ports, misinterpretation between lack of evidence of harm and lack of harm, and use of very early cosmesis scores that are ultimately of no clinical significance.
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
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 634 participants in seven trials, only 0.18% 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 (dotted red line) have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of serious adverse events
The diversity‐adjusted required information size (DARIS) was calculated to 234,831 participants, based on the proportion of participants in the control group with the outcome of 0.3%, 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 634 participants in seven trials, only 0.27% 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 (dotted red line) have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of conversion to open cholecystectomy
The diversity‐adjusted required information size (DARIS) was calculated to 40,918 participants, based on the proportion of patients in the control group with the outcome of 1.7%, 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 581 participants in five trials, only 1.42% 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 (dotted red line) have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of operating time
The diversity‐adjusted required information size (DARIS) was 1124 participants based on a minimal relevant difference (MIRD) of 15 minutes, a variance (VAR) of 385.03, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 95.2%.The cumulative Z‐curve (blue line) crosses the conventional boundary (dotted red line) and the trial sequential monitoring boundaries (continuous red line) after the seventh trial. Although the DARIS has not been reached after accrual of 855 participants in nine trials, the results suggest that operating time is longer with fewer‐than‐four‐ports laparoscopic cholecystectomy as compared with four‐ports laparoscopic cholecystectomy with low risk of random errors.
Trial sequential analysis of hospital stay
The diversity‐adjusted required information size (DARIS) was 222 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 1.29, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 81.55%. Seven hundred and thirty‐one participants were accrued in six trials. The cumulative Z‐curve (blue line) crosses the DARIS after the third trial (vertical red line). However, it does not cross the conventional boundaries (dotted red line). This suggests that there is no significant difference in the length of hospital stay between fewer‐than‐four‐ports laparoscopic cholecystectomy versus four‐ports laparoscopic cholecystectomy with low risk of random errors.
Trial sequential analysis of hospital stay with smallest confidence interval used as minimal relevant difference
The diversity‐adjusted required information size (DARIS) was 2802 participants based on a minimal relevant difference (MIRD) of 0.28 days, a variance (VAR) of 1.29, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 81.55%. After accruing 731 participants in six trials, only 26.09% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the futility area. As shown, the cumulative Z‐curve (blue line) does not cross the trial sequential boundaries (red line). Conventional boundaries (dotted red line) have also not been crossed by the cumulative Z‐curve.
Trial sequential analysis of return to normal activity
The diversity‐adjusted required information size (DARIS) was 200 participants based on a minimal relevant difference (MIRD) of 1 day, a variance (VAR) of 6.35, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. Three hundred and twenty‐five participants were accrued in two trials. The cumulative Z‐curve crosses the trial sequential monitoring boundaries (continuous red lines) and the conventional boundaries (dotted red line) after the second trial. The results are compatible with significantly fewer days to return to normal activity in the fewer‐than‐four‐ports group with four‐ports group with low risk of random errors.
Trial sequential analysis of return to normal activity with smallest confidence interval used as minimal relevant difference
The diversity‐adjusted required information size (DARIS) was 304 participants based on a minimal relevant difference (MIRD) of 0.81 day, a variance (VAR) of 6.35, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. Three hundred and twenty‐five participants were accrued in two trials. The cumulative Z‐curve crosses the trial sequential monitoring boundaries (continuous red lines) and the conventional boundaries (dotted red line) after the second trial. The results are compatible with significantly fewer days to return to normal activity in the fewer‐than‐four‐ports group with four‐ports group with low risk of random errors.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 1 Serious adverse events.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 2 Quality of life.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 3 Conversion to open cholecystectomy.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 4 Operating time.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 5 Hospital stay.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 6 Proportion discharged as day‐surgery.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 7 Return to normal activity.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 8 Return to work.
Comparison 1 Fewer‐than‐four ports versus four ports, Outcome 9 Cosmetic score.
Comparison 2 Fewer‐than‐four ports versus four ports (sensitivity analysis), Outcome 1 Quality of life.
Comparison 2 Fewer‐than‐four ports versus four ports (sensitivity analysis), Outcome 2 Operating time.
Comparison 2 Fewer‐than‐four ports versus four ports (sensitivity analysis), Outcome 3 Hospital stay.
Comparison 2 Fewer‐than‐four ports versus four ports (sensitivity analysis), Outcome 4 Return to normal activity.
| Fewer‐than‐four ports compared with four ports 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 | ||||
| Four ports | Fewer‐than‐four ports | ||||
| Mortality | There was no mortality in either group | Not estimable | 634 (7 studies) | ⊕⊝⊝⊝ | |
| Serious adverse events | Low | RR 3.93 | 634 | ⊕⊝⊝⊝ | |
| 10 per 1000 | 39 per 1000 | ||||
| Moderate | |||||
| 30 per 1000 | 118 per 1000 | ||||
| Quality of life | ‐ | The mean quality of life in the intervention groups was | ‐ | 510 | ⊕⊝⊝⊝ |
| Conversion to open cholecystectomy | 17 per 1000 | 12 per 1000 | RR 0.68 | 581 | ⊕⊝⊝⊝ |
| Operating time | The mean operating time in the control groups was | The mean operating time in the intervention groups was | ‐ | 855 | ⊕⊝⊝⊝ |
| Hospital stay | The mean hospital stay in the control groups was | The mean hospital stay in the intervention groups was | ‐ | 731 | ⊕⊝⊝⊝ |
| Proportion discharged as day surgery | 833 per 1000 | 767 per 1000 | RR 0.92 | 50 | ⊕⊝⊝⊝ |
| Return to normal activity | The mean return to normal activity in the control groups was | The mean return to normal activity in the intervention groups was | ‐ | 325 | ⊕⊝⊝⊝ |
| Return to work | The mean return to work in the control groups was | The mean return to work in the intervention groups was | ‐ | 150 | ⊕⊝⊝⊝ |
| Cosmetic score | ‐ | The mean cosmetic score in the intervention groups was | ‐ | 317 | ⊕⊝⊝⊝ |
| *The basis for the assumed risk was the control group risk across studies in all outcomes other serious adverse events. There were no serious adverse events in the control group and so the information is presented for different control group risks. 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. | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Serious adverse events Show forest plot | 7 | 634 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.93 [0.86, 18.04] |
| 1.1 One port | 7 | 634 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.93 [0.86, 18.04] |
| 2 Quality of life Show forest plot | 4 | 510 | Std. Mean Difference (IV, Random, 95% CI) | 0.18 [‐0.05, 0.42] |
| 2.1 One port | 4 | 510 | Std. Mean Difference (IV, Random, 95% CI) | 0.18 [‐0.05, 0.42] |
| 3 Conversion to open cholecystectomy Show forest plot | 5 | 581 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.68 [0.19, 2.35] |
| 3.1 One port | 3 | 360 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.72] |
| 3.2 Three ports | 2 | 221 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.20, 3.14] |
| 4 Operating time Show forest plot | 9 | 855 | Mean Difference (IV, Random, 95% CI) | 14.44 [5.95, 22.93] |
| 4.1 One port | 7 | 634 | Mean Difference (IV, Random, 95% CI) | 21.04 [10.45, 31.62] |
| 4.2 Three ports | 2 | 221 | Mean Difference (IV, Random, 95% CI) | ‐5.32 [‐17.38, 6.73] |
| 5 Hospital stay Show forest plot | 6 | 731 | Mean Difference (IV, Random, 95% CI) | ‐0.01 [‐0.28, 0.26] |
| 5.1 One port | 4 | 510 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.32, 0.37] |
| 5.2 Three ports | 2 | 221 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐0.47, 0.30] |
| 6 Proportion discharged as day‐surgery Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.70, 1.22] |
| 6.1 One port | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.70, 1.22] |
| 7 Return to normal activity Show forest plot | 2 | 325 | Mean Difference (IV, Fixed, 95% CI) | ‐1.20 [‐1.58, ‐0.81] |
| 7.1 One port | 1 | 250 | Mean Difference (IV, Fixed, 95% CI) | ‐1.20 [‐1.59, ‐0.81] |
| 7.2 Three ports | 1 | 75 | Mean Difference (IV, Fixed, 95% CI) | ‐0.90 [‐5.08, 3.28] |
| 8 Return to work Show forest plot | 1 | 150 | Mean Difference (IV, Random, 95% CI) | ‐2.0 [‐3.31, ‐0.69] |
| 8.1 One port | 1 | 150 | Mean Difference (IV, Random, 95% CI) | ‐2.0 [‐3.31, ‐0.69] |
| 9 Cosmetic score Show forest plot | 2 | 317 | Std. Mean Difference (IV, Random, 95% CI) | 0.37 [‐0.10, 0.84] |
| 9.1 One port | 2 | 317 | Std. Mean Difference (IV, Random, 95% CI) | 0.37 [‐0.10, 0.84] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Quality of life Show forest plot | 2 | 320 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.14 [‐0.08, 0.36] |
| 1.1 One port | 2 | 320 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.14 [‐0.08, 0.36] |
| 2 Operating time Show forest plot | 7 | 665 | Mean Difference (IV, Fixed, 95% CI) | 7.40 [5.48, 9.31] |
| 2.1 One port | 5 | 444 | Mean Difference (IV, Fixed, 95% CI) | 9.45 [7.34, 11.57] |
| 2.2 Three ports | 2 | 221 | Mean Difference (IV, Fixed, 95% CI) | ‐2.03 [‐6.56, 2.50] |
| 3 Hospital stay Show forest plot | 3 | 466 | Mean Difference (IV, Random, 95% CI) | 0.21 [0.08, 0.35] |
| 3.1 One port | 2 | 320 | Mean Difference (IV, Random, 95% CI) | 0.21 [0.02, 0.41] |
| 3.2 Three ports | 1 | 146 | Mean Difference (IV, Random, 95% CI) | 0.15 [‐0.34, 0.64] |
| 4 Return to normal activity Show forest plot | 1 | 250 | Mean Difference (IV, Fixed, 95% CI) | ‐1.20 [‐1.59, ‐0.81] |
| 4.1 One port | 1 | 250 | Mean Difference (IV, Fixed, 95% CI) | ‐1.20 [‐1.59, ‐0.81] |
