Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis
Abstract
Background
Gallstones are present in about 10% to 15% of the adult western population. Between 1% and 4% of these adults become symptomatic in a year (the majority due to biliary colic but a significant proportion due to acute cholecystitis). Laparoscopic cholecystectomy for acute cholecystitis is mainly performed after the acute cholecystitis episode settles because of the fear of higher morbidity and of need for conversion from laparoscopic to open cholecystectomy. However, delaying surgery exposes the people to gallstone‐related complications.
Objectives
The aim of this systematic review was to compare early laparoscopic cholecystectomy (less than seven days of clinical presentation with acute cholecystitis) versus delayed laparoscopic cholecystectomy (more than six weeks after index admission with acute cholecystitis) with regards to benefits and harms.
Search methods
We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and World Health Organization International Clinical Trials Registry Platform until July 2012.
Selection criteria
We included all randomised clinical trials comparing early versus delayed laparoscopic cholecystectomy in participants with acute cholecystitis.
Data collection and analysis
We used standard methodological procedures expected by The Cochrane Collaboration.
Main results
We identified seven trials that met the inclusion criteria. Out of these, six trials provided data for the meta‐analyses. A total of 488 participants with acute cholecystitis and fit to undergo laparoscopic cholecystectomy were randomised to early laparoscopic cholecystectomy (ELC) (244 people) and delayed laparoscopic cholecystectomy (DLC) (244 people) in the six trials. Blinding was not performed in any of the trials and so all the trials were at high risk of bias. Other than blinding, three of the six trials were at low risk of bias in the other domains such as sequence generation, allocation concealment, incomplete outcome data, and selective outcome reporting. The proportion of females ranged between 43.3% and 80% in the trials that provided this information. The average age of participants ranged between 40 years and 60 years. There was no mortality in any of the participants in five trials that reported mortality. There was no significant difference in the proportion of people who developed bile duct injury in the two groups (ELC 1/219 (adjusted proportion 0.4%) versus DLC 2/219 (0.9%); Peto OR 0.49; 95% CI 0.05 to 4.72 (5 trials)). There was no significant difference between the two groups (ELC 14/219 (adjusted proportion 6.5%) versus DLC 11/219 (5.0%); RR 1.29; 95% CI 0.61 to 2.72 (5 trials)) in terms of other serious complications. None of the trials reported quality of life from the time of randomisation. There was no significant difference between the two groups in the proportion of people who required conversion to open cholecystectomy (ELC 49/244 (adjusted proportion 19.7%) versus DLC 54/244 (22.1%); RR 0.89; 95% CI 0.63 to 1.25 (6 trials)). The total hospital stay was shorter in the early group than the delayed group by four days (MD ‐4.12 days; 95% CI ‐5.22 to ‐3.03 (4 trials; 373 people)). There was no significant difference in the operating time between the two groups (MD ‐1.22 minutes; 95% CI ‐3.07 to 0.64 (6 trials; 488 people)). Only one trial reported return to work. The people belonging to the ELC group returned to work earlier than the DLC group (MD ‐11.00 days; 95% CI ‐19.61 to ‐2.39 (1 trial; 36 people)). Four trials did not report any gallstone‐related morbidity during the waiting period. One trial reported five gallstone‐related morbidities (cholangitis: two; biliary colic not requiring urgent operation: one; acute cholecystitis not requiring urgent operation: two). There were no reports of pancreatitis during the waiting time. Gallstone‐related morbidity was not reported in the remaining trials. Forty (18.3%) of the people belonging to the delayed group had either non‐resolution of symptoms or recurrence of symptoms before their planned operation and had to undergo emergency laparoscopic cholecystectomy in five trials. The proportion with conversion to open cholecystectomy was 45% (18/40) in this group of people.
Authors' conclusions
We found no significant difference between early and late laparoscopic cholecystectomy on our primary outcomes. However, trials with high risk of bias indicate that early laparoscopic cholecystectomy during acute cholecystitis seems safe and may shorten the total hospital stay. The majority of the important outcomes occurred rarely, and hence the confidence intervals are wide. It is unlikely that future randomised clinical trials will be powered to measure differences in bile duct injury and other serious complications since this might involve performing a trial of more than 50,000 people, but several smaller randomised trials may answer the questions through meta‐analyses.
Plain language summary
Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis
The liver produces bile which has many functions including elimination of waste processed by the liver and digestion of fat. The bile is temporarily stored in the gallbladder (an organ situated underneath the liver) before it reaches the small bowel. Concretions in the gallbladder are called gallstones. Gallstones are present in about 10% to 15% of the adult western population. Between 1% and 4% become symptomatic in a year. The symptoms include pain related to the gallbladder (biliary colic), inflammation of the gallbladder (cholecystitis), obstruction to the flow of bile from the liver and gallbladder into the small bowel resulting in jaundice (yellowish discolourisation of the body usually most prominently noticed in the white of the eye, which turns yellow), bile infection (cholangitis), and inflammation of the pancreas, an organ which secretes digestive juices and harbours the insulin secreting cells which maintain blood sugar level (pancreatitis). Removal of the gallbladder (cholecystectomy) is currently considered the best treatment option for people with symptomatic gallstones. This is generally performed by key‐hole surgery (laparoscopic cholecystectomy). Cholecystitis (inflammation) of the gallbladder is one of the indications for laparoscopic cholecystectomy. Cholecystitis can occur suddenly, with symptoms such as fever along with intense pain in the right upper tummy. This is called acute cholecystitis. In comparison, chronic cholecystitis is a smouldering inflammation of the gallbladder which presents with less intense pain in the right upper tummy. For many years, surgeons have preferred to perform laparoscopic cholecystectomy once the inflammation settles down completely (which usually takes about six weeks) because of the fear of higher complication rates including injury to the bile duct (a tube through which the bile flows from the gallbladder to the small bowel). Injury to the bile duct is a life‐threatening condition which requires urgent corrective operation in most instances. In spite of the corrective surgery, people have poor quality of life several years after the operation due to repeated instances of bile infection caused by obstruction to the flow of bile into the small bowel. Another reason for the surgeons' preference for delaying the operation is to avoid an open operation, as there has been a perception that early operation increases the risk of an open operation. However, delaying the surgery exposes the people to the risk of complications related to gallstones. The review authors set out to determine whether it is preferable to perform early laparoscopic cholecystectomy (within seven days of people presenting to doctors with symptoms) or delayed laparoscopic cholecystectomy (more than six weeks after the initial admission). A systematic search of medical literature was performed in order to identify studies which provided information on the above question. The authors obtained information from randomised trials only since such types of trials provide the best information if conducted well. Two authors independently identified the trials and collected the information.
Six trials providing information on the review question were identified. A total of 488 people with acute cholecystitis were included. Laparoscopic cholecystectomy was performed early (within seven days of people presenting to the doctor with symptoms) in 244 people while it was performed after at least six weeks in the remaining 244 people. The proportion of females ranged between 43.3% and 80% in the trials that provided this information. The average age of participants ranged between 40 years and 60 years. All the trials were at high risk of bias (and might have overestimated the benefits or underestimated the harms of either early laparoscopic cholecystectomy or delayed laparoscopic cholecystectomy). All the people included in the trials were discharged home alive after operation in the five trials from which this information was available. There was no significant difference in the proportion of people who developed bile duct injury, surgical complications, or who required conversion from key‐hole to open operation between the two groups. None of the trials reported quality of life from the time of randomisation. The total hospital stay was shorter in the early group than the delayed group by four days. There was no significant difference in the operating time between the two groups. Only one trial reported the time taken for employed people to return to work. The people belonging to the early laparoscopic cholecystectomy group returned to work 11 days, on average, earlier than the delayed laparoscopic cholecystectomy group. Four trials did not report any gallstone‐related complications during the waiting period. One trial reported five gallstone‐related complications, including two people with cholangitis. There were no reports of pancreatitis during the waiting time. Gallstone‐related morbidity was not reported in the remaining trial. Approximately one‐sixth of people belonging to the delayed group had either non‐resolution of symptoms or recurrence of symptoms before their planned operation and had to undergo emergency laparoscopic cholecystectomy in five trials. Based on information from a varied number of participants as well as trials at high risk of bias, early laparoscopic cholecystectomy during acute cholecystitis appears safe and shortens the total hospital stay. The majority of the important outcomes occurred rarely and hence one cannot rule out that future trials may show that one treatment or another may be better in terms of complications. However, the trial size required to show such differences involves a clinical trial on more than 50,000 people and so it is unlikely that such large trials will be performed. Several smaller randomised trials may answer the questions through meta‐analyses.
Authors' conclusions
Summary of findings
| Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis | |||||
| Patient or population: people with acute cholecystitis. | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Early versus delayed laparoscopic cholecystectomy | ||||
| Mortality | 0 per 1000 | 0 per 1000 | not estimable (there were no deaths in either group) | 438 (5 studies) | ⊕⊝⊝⊝ |
| Bile duct injury | 9 per 1000 | 4 per 1000 | Peto OR 0.49 | 438 | ⊕⊝⊝⊝ |
| Other serious complications | 50 per 1000 | 65 per 1000 | RR 1.29 | 438 | ⊕⊝⊝⊝ |
| Conversion to open cholecystectomy | 221 per 1000 | 197 per 1000 | RR 0.89 | 488 | ⊕⊝⊝⊝ |
| Hospital stay | The mean hospital stay in the control groups was | The mean hospital stay in the intervention groups was | 373 | ⊕⊕⊕⊝ | |
| Operating time | The mean operating time in the control groups was | The mean operating time in the intervention groups was | 488 | ⊕⊕⊕⊝ | |
| Return to work | The mean return to work in the control groups was | The mean return to work (to be removed before submission) in the intervention groups was | 36 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Some trial(s) was/were of high risk of bias. | |||||
Background
Description of the condition
About 5% to 25% of the adult western population have gallstones (GREPCO 1984; GREPCO 1988; Bates 1992; Halldestam 2004). The annual incidence of gallstones is about 1 in 200 people (NIH 1992). Only 2% to 4% of people with gallstones become symptomatic with biliary colic (pain), acute cholecystitis (inflammation), obstructive jaundice, or gallstone pancreatitis in a year (Attili 1995; Halldestam 2004). Acute cholecystitis involves inflammation of the gallbladder while biliary colic does not involve inflammation of the gallbladder. Cholecystectomy (removal of gallstones) is the preferred option in the treatment of symptomatic gallstones (Strasberg 1993). Every year, 1.5 million cholecystectomies are performed in the US and 60,000 in the UK (Dolan 2009; HES 2011). Approximately 80% of the cholecystectomies are performed laparoscopically (by key‐hole surgery) (Ballal 2009). A third of the people undergoing laparoscopic cholecystectomy undergo the procedure after an episode of acute cholecystitis (Glasgow 2000). Thus, approximately 13,000 laparoscopic cholecystectomies are performed annually in the UK for acute cholecystitis.
Description of the intervention
There is controversy over the timing of laparoscopic cholecystectomy in acute cholecystitis. In the era of open cholecystectomy, early surgery (within seven days of onset of symptoms) had no increased morbidity or mortality over delayed surgery (at least six weeks after symptoms settle) (Papi 2004). Delay in surgery increases the risks of further gallstone‐related complications (Lawrentschuk 2003; Papi 2004). With laparoscopic cholecystectomy, there are concerns about higher morbidity rates in an emergency procedure (Cuschieri 1991; Wilson 1991; Kum 1996) and about the higher conversion rate to an open procedure during the acute phase (Cheema 2003; Livingston 2004). The main reason for conversion in early laparoscopic cholecystectomy is inflammation obscuring the view of Calot's triangle (Peng 2005), whilst in the delayed group it is fibrotic adhesions (Lo 1998; Peng 2005). Severe inflammation and fibrotic adhesions are associated with bile duct injury (Richardson 1996).
In the USA, about 30% of people with acute cholecystitis undergo cholecystectomy during the acute attack (Livingston 2004). In the UK, only 20% of surgeons perform laparoscopic cholecystectomy during acute cholecystitis (Senapati 2003). The remaining surgeons let the symptoms settle down for a period of at least six weeks before performing laparoscopic cholecystectomy (delayed laparoscopic cholecystectomy) (Senapati 2003).
How the intervention might work
Early laparoscopic cholecystectomy may help avoid gallstone‐related complications including acute gallstone pancreatitis, obstructive jaundice, biliary colic, non‐resolution of acute cholecystitis, and recurrence of acute cholecystitis during the waiting period.
Why it is important to do this review
This is an update of our Cochrane Hepato‐Biliary Group (CHBG) systematic review published in 2006 and updated in 2009 (Gurusamy 2006; Gurusamy 2010).
Objectives
To assess the benefits and harms of early laparoscopic cholecystectomy compared with delayed laparoscopic cholecystectomy in people with acute cholecystitis.
Methods
Criteria for considering studies for this review
Types of studies
We included all randomised clinical trials which compared early versus delayed laparoscopic cholecystectomy in acute cholecystitis (irrespective of language, blinding, or publication status).
We excluded quasi‐randomised studies (where the method of allocating participants to a treatment was not strictly random, for example, date of birth, hospital record number, alternation) and non‐randomised studies for the assessment of benefits because of the risk of bias in these studies. We also excluded such studies for the assessment of adverse events because of the potential problem of misclassification of delayed laparoscopic cholecystectomy as early laparoscopic cholecystectomy in non‐randomised studies (Gurusamy 2006).
Types of participants
People with acute cholecystitis who were about to undergo laparoscopic cholecystectomy.
Types of interventions
We included only trials comparing early versus delayed laparoscopic cholecystectomy (irrespective of the size and the number of ports, abdominal lift, or open or closed method of induction of pneumoperitoneum). Early laparoscopic cholecystectomy was defined as laparoscopic cholecystectomy performed within seven days of clinical presentation. Delayed laparoscopic cholecystectomy was defined as routine laparoscopic cholecystectomy, which was intended to be performed six weeks after the index admission.
Types of outcome measures
Primary outcomes
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Mortality (90‐day mortality and mortality at maximal follow‐up).
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Bile duct injury.
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Other serious adverse events.
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Adverse events are defined as any untoward medical occurrence not necessarily having a causal relationship with the treatment, but resulting in a dose reduction or discontinuation of treatment (ICH‐GCP 1997). Serious adverse events are defined as any event that would increase mortality; is life‐threatening; requires inpatient hospitalisation; results in a persistent or significant disability; or any important medical event which might have jeopardised the patient or requires intervention to prevent it. While bile duct injury falls under this category, the disability can be long term and hence this is considered separately.
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Quality of life (three months).
Secondary outcomes
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Conversion to open cholecystectomy.
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Total hospital stay.
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Operating time.
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Return to work.
In addition to the above outcomes, we collected the information on the complications during the waiting time in trial participants undergoing delayed laparoscopic cholecystectomy.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003) until July 2012. We have given the search strategies in Appendix 1 with the time spans for the searches.
Searching other resources
We also searched the references of the identified trials and the World Health Organization International Clinical Trials Registry Platform, which includes the International Clinical Trials Registry Platform (ISRCTN), clinicaltrials.gov, and many other trial registers, to identify further relevant trials.
Data collection and analysis
Selection of studies
KG and CD independently identified the trials for inclusion. We have listed the excluded studies with the reasons for the exclusion.
Data extraction and management
KG and CD 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 study.
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Inclusion and exclusion criteria.
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Details of intervention and control.
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Co‐interventions.
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Outcomes (listed above).
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Risk of bias (described below).
Assessment of risk of bias in included studies
We independently assessed the risk of bias in the trials without masking the trial names. We followed the instructions given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2013). Due to the risk of biased overestimation of beneficial intervention effects in randomised trials with high risk of bias (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a), we assessed the trials for the following risk of bias domains.
Sequence generation
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Low risk of bias: the method used is either adequate (for example, computer generated random numbers, table of random numbers) or unlikely to introduce confounding.
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Uncertain risk of bias: there is insufficient information to assess whether the method used is likely to introduce confounding.
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High risk of bias: the method used (for example, quasi‐randomised studies) is inappropriate and likely to introduce confounding.
Allocation concealment
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Low risk of bias: the method used (for example, central allocation) is unlikely to introduce bias in determining the final observed effect.
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Uncertain risk of bias: there is insufficient information to assess whether the method used is likely to introduce bias for the estimate of effect.
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High risk of bias: the method used (for example, open random allocation schedule) is likely to introduce bias in the final observed effect estimate.
Blinding of participants and healthcare providers
It is impossible to blind the participants and healthcare providers surgeons who perform the surgery. We will consider all the outcomes to be at high risk of bias for this domain.
Blinding of outcome assessors
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Low risk of bias: the outcome assessors were blinded and the method of blinding was described.
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Uncertain risk of bias: the outcome assessors were blinded and the method of blinding was not described or if it was not clear whether the outcome assessors were blinded.
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High risk of bias: the outcome assessors were not blinded.
Incomplete outcome data
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Low risk of bias: the underlying reasons for missing data are unlikely to make treatment effects depart from plausible values, or proper methods have been employed to handle missing data.
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Uncertain risk of bias: there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data are likely to introduce bias for the estimate of effect.
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High risk of bias: the crude estimate of effects (for example, complete case estimate) will clearly be biased due to the underlying reasons for missing data and the methods used to handle missing data are unsatisfactory.
Selective outcome reporting
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Low risk of bias: pre‐defined or clinically relevant and reasonably expected outcomes (such as short‐term mortality and serious adverse events either reported as number of people with serious adverse events or total number of serious adverse events) are reported on.
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Uncertain risk of bias: not all pre‐defined or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not.
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High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded.
We considered trials to have a low risk of bias if we assessed all the above domains as being at low risk of bias. In all other cases, the trials were considered to have a high risk of bias.
Measures of treatment effect
For binary outcomes, we calculated the risk ratio (RR) with 95% confidence interval (CI). We used Peto's odds ratios (Peto OR) for binary outcomes when the proportion of people who developed the outcome was less than 1% (for example, bile duct injury). We also planned to report the risk difference if it was different from the RR since risk difference allows meta‐analysis including trials with zero events in both groups. For continuous variables, we calculated the mean difference (MD) with 95% CI for hospital stay; and we planned to calculate standardised mean difference (SMD) with 95% CI for variables such as quality of life.
Unit of analysis issues
The unit of analysis was the aggregate data on people with acute cholecystitis who were about to undergo surgery according to the group to which they were randomised.
Dealing with missing data
We performed an intention‐to‐treat analysis (Newell 1992) whenever possible. We imputed data for binary outcomes using various scenarios, namely best‐best analysis, worst‐worst analysis, best‐worst analysis, and worst‐best analysis (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 trial for calculation of mean differences and bias the effect estimate to no effect in the case of standardised mean difference (Higgins 2011).
Assessment of heterogeneity
We examined the forest plot to visually assess heterogeneity. Overlapping of CIs was used to assess the heterogeneity visually. We explored heterogeneity by the Chi2 test, with significance set at a P value of 0.10, and measured the quantity of heterogeneity by the I2 statistic (Higgins 2002).
Assessment of reporting biases
We planned to use a funnel plot to explore bias in the presence of at least 10 trials (Egger 1997; Macaskill 2001). We planned to use asymmetry in the funnel plot of trial size against treatment effect to assess this bias. We also planned to use the linear regression approach described by Egger et al to determine the funnel plot asymmetry (Egger 1997).
Data synthesis
We performed the meta‐analyses according to the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato‐Biliary Group Module (Gluud 2013) using the software package Review Manager 5.2 (RevMan 2012). We use a random‐effects model (DerSimonian 1986) and a fixed‐effect model (DeMets 1987). In the case of a discrepancy between the two models we have reported both results; otherwise we have reported only the results from the fixed‐effect model.
Subgroup analysis and investigation of heterogeneity
We performed the following subgroup analyses.
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Trials with low risk of bias compared with trials at high risk of bias.
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Early laparoscopic cholecystectomy at less than four days of admission compared with early laparoscopic cholecystectomy at less than seven days of admission.
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Laparoscopic cholecystectomy performed by surgeons who have performed at least 50 laparoscopic cholecystectomies compared with those performed by surgeons with less than 50 laparoscopic cholecystectomies.
We performed the Chi2 test for subgroup differences, setting a P value of 0.05 to identify any differences.
Sensitivity analysis
We performed a sensitivity analysis by imputing the outcomes for binary outcomes under different scenarios, namely best‐best analysis, worst‐worst analysis, best‐worst analysis, and worst‐best analysis (Gurusamy 2009; Gluud 2013), for any significant binary outcome. We also performed a sensitivity analysis by excluding the trials in which medians or standard deviations were imputed for the continuous outcomes.
Trial sequential analysis
Trial sequential analysis was applied because cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (CTU 2011; Thorlund 2011). The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis resulting in an increased risk of random errors. 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, trial sequential monitoring boundaries were constructed. These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous. On the other hand, if the boundary is 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 of the meta‐analysis, and a relative risk reduction of 20% for binary outcomes with two or more trials 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). For continuous outcomes, 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 and a minimal clinically relevant difference of one day for hospital stay and 15 minutes for operating time.
Summary of findings table
We have summarised the results of all the outcomes in a summary of findings table prepared using GRADEPro 3.6 (http://ims.cochrane.org/revman/gradepro).
Results
Description of studies
Results of the search
We identified a total of 1002 references through the electronic searches of the Cochrane Hepato‐Biliary Group Controlled Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (n = 186), MEDLINE (n = 368), EMBASE (n = 174), Science Citation Index Expanded (n = 273), and trial registers (1). We excluded 203 duplicates and 784 clearly irrelevant references through reading abstracts. Fifteen references were retrieved for further assessment. No references were identified through scanning reference lists of the identified randomised trials or by searching the trial register. Of the 15 references, we were unable to assess whether two references met the inclusion criteria as these references were not available and the abstract did not contain sufficient information to assess the eligibility (Khan 2002; Ghani 2005). We excluded four other references (three studies) because of the reasons listed under the table 'Characteristics of excluded studies'. In total, nine publications describing seven randomised trials fulfilled the inclusion criteria. The reference flow is shown in Figure 1. All the seven trials were completed trials (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004; Macafee 2009; Yadav 2009) and six trials could provide data for the analyses (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004; Yadav 2009). Details of the trials are shown in the table 'Characteristics of included studies'.
Study flow diagram.
Included studies
Participants
The number of participants with clinical diagnosis of acute cholecystitis was not stated in one trial which included participants with clinical diagnosis of biliary colic or acute cholecystitis (Macafee 2009). A total of 488 participants with acute cholecystitis were randomised in the remaining six trials (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004; Yadav 2009). The number of participants in each trial ranged from 40 to 145. The proportion of females ranged between 43.3% and 80% in the trials that provided this information. The average age of participants ranged between 40 years and 60 years. Three trials excluded people with common bile duct stones (Lai 1998; Kolla 2004; Yadav 2009). The methods of management of people with common bile duct stones in the remaining trials are shown in Table 1. The experience of surgeons performing the operations in both the groups is shown in Table 1.
| Study | Timing of early laparoscopic cholecystectomy | Timing of delayed laparoscopic cholecystectomy | Surgeon’s experience | Number of participants | Post‐randomisation drop‐outs | Treatment of common bile duct stones |
| Less than 4 days | 8 weeks | Not stated. | 27 versus 36 | Not stated. | 'Resolved at the same operation' ‐ No further details given. | |
| Less than 7 days | 6 to 8 weeks | Minimum 25 laparoscopic cholecystectomies. | 74 versus 71 | 0 versus 0 2 people in the delayed group refused surgery. | Laparoscopic common bile duct exploration or post‐operative ERCP. | |
| Less than 4 days | 6 to 12 weeks | Surgical consultant | 20 versus 20 | 0 versus 0 | People with common bile duct stones were excluded. | |
| Less than 7 days | 6 to 8 weeks | Minimum 50 laparoscopic cholecystectomies. | 53 versus 51 | 0 versus 0 5 patients in the delayed group refused surgery. | People with common bile duct stones were excluded. | |
| Less than 7 days | 8 to 12 weeks | More than 300 laparoscopic cholecystectomies. | 49 versus 50 | 4 versus 9 These people were excluded from the analysis. | Preoperative selective ERCP. | |
| Less than 4 days | 13 weeks | Competent surgical trainees under the supervision of consultants. | Not stated | 0 versus 0 | Not stated. | |
| Less than 4 days | 6 to 8 weeks | Not stated. | 25 versus 25 | Not stated. | People with common bile duct stones were excluded. |
ERCP = endoscopic retrograde cholangiopancreatography.
Early laparoscopic cholecystectomy
Early laparoscopic cholecystectomy was conducted within seven days of clinical presentation in all trials. The timing is described in the 'Characteristics of included studies' table.
Delayed laparoscopic cholecystectomy
Delayed laparoscopic cholecystectomy was conducted at least six weeks after the onset of symptoms in all trials. The timing is described in the 'Characteristics of included studies' table.
Excluded studies
The full text was not available for two studies (Khan 2002; Ghani 2005). It was not possible to determine whether this trial met the inclusion criteria from the information available in the abstract (Khan 2002; Ghani 2005). Two excluded studies were not completed trials and no data were available from these trials (Weigand 2007; Mare 2012). One trial compared compared delayed laparoscopic cholecystectomy and cholecystectomy deferral (wait‐and‐watch policy) (Vetrhus 2003).
Risk of bias in included studies
All the trials were at high risk of bias. The proportion of trials with low risk of bias for each of the domains is shown in Figure 2. The risk of bias in each domain is shown for each trial in Figure 3. It should be noted that most trials have been classified as trials at high risk of bias because of the lack of blinding. However, blinding of participants involves sham operations in both groups, which may be unethical. Considering this information, the trials that have low risk of bias in domains other than blinding are likely to be trials with the lowest possible risk of bias. So, such trials that were low risk of bias in all domains other than blinding were considered to be at low risk of bias for subgroup analysis and trial sequential analysis.
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
The results are summarised in the summary of findings Table for the main comparison.
Primary outcomes
Mortality
Five trials reported immediate post‐operative mortality (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004). There was no mortality among any of the participants in the five trials that reported mortality (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004). Mortality was not reported in one trial (Yadav 2009). In one trial, participants with uncomplicated biliary colic and acute cholecystitis were included (Macafee 2009). The number of participants with clinical diagnosis of acute cholecystitis on admission and the outcomes of such people were not available from this trial (Macafee 2009).
Bile duct injury
Five trials reported bile duct injury requiring re‐operations (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004). There was no significant difference between the two groups for this most feared complication (Peto OR 0.49; 95% CI 0.05 to 4.72) (Analysis 1.1). There was no significant heterogeneity (I2 = 28%; P = 0.25). There was no change in the interpretation of results using the random‐effects model or the risk difference. Imputing the outcomes for the one trial where there were post‐randomisation drop‐outs did not alter the interpretation of the findings in three of the four scenarios. In the best‐worst scenario, the proportion of people who developed bile duct injury was significantly lower in the early group than the delayed group (Peto OR 0.17; 95% CI 0.05 to 0.54) (Analysis 1.2). There was no significant difference between the groups in the other scenarios.
Trial sequential analysis
Less than 1% of the required sample size was reached in the trials included in the meta‐analysis. This was too little to draw the trial sequential monitoring boundaries for trial sequential analysis (Figure 4).
Trial sequential analysis of bile duct injury
The diversity‐adjusted required information size (DARIS) was calculated to 77,854 participants, based on the proportion of participants in the control group with the outcome of 0.9%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. After accruing 438 participants in the five trials, we have only reached 0.56% of the DARIS. 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. Less than 1% of the required sample size was reached in the trials included in the meta‐analysis. This was too little to draw the trial sequential monitoring boundaries.
Other serious complications
Five trials reported serious adverse events (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004). There was no significant difference between the two groups (RR 1.29; 95% CI 0.61 to 2.72) (Analysis 1.3). There was no significant heterogeneity (I2 = 0%; P = 0.46). There was no change in the interpretation of results using the random‐effects model or the risk difference. Imputing the outcomes for the one trial where there were post‐randomisation drop‐outs did not alter the interpretation of the findings in any of the four scenarios (Analysis 1.4).
Trial sequential analysis
Only 3.25% of the required sample size was reached in the trials included in the meta‐analysis. This was too little to draw the boundaries for trial sequential analysis (Figure 5).
Trial sequential analysis of other serious complications
The diversity‐adjusted required information size (DARIS) was calculated to 13,493 participants, based on the proportion of participants in the control group with the outcome of 5.0%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. After accruing 438 participants in the five trials, we have only reached 3.25% of the DARIS. 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.
Quality of life
None of the trials reported quality of life from the time of randomisation.
Secondary outcomes
Conversion to open cholecystectomy
Six trials reported this outcome (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004; Yadav 2009). There was no significant difference between the two groups regarding conversion to open cholecystectomy (RR 0.89; 95% CI 0.63 to 1.25) (Analysis 1.5). There was no significant heterogeneity (I2 = 0%; P = 0.54). There was no change in the interpretation of results using the random‐effects model or the risk difference. Imputing the outcomes for the one trial where there were post‐randomisation drop‐outs did not alter the interpretation of the findings in any of the four scenarios (Analysis 1.6).
Trial sequential analysis
The proportion of the required sample size recruited in the trials included in the meta‐analysis was too small to draw the area of futility. The trial sequential monitoring boundaries were not crossed (Figure 6).
Trial sequential analysis of conversion to open cholecystectomy
The diversity‐adjusted required information size (DARIS) was calculated to 2225 participants, based on the proportion of participants in the control group with the outcome of 24.7%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. After accruing 488 participants in the six trials, only 21.9% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the inner wedge futility area. As shown, none of the boundaries have been crossed, ie, neither the trial sequential monitoring boundaries nor the conventional boundaries.
Hospital stay
Four trials reported this outcome (Lai 1998; Lo 1998; Johansson 2003; Kolla 2004). The total hospital stay was shorter in the early group than the delayed group by four days (MD ‐4.12 days; 95% CI ‐5.22 to ‐3.03) (Analysis 1.7). There was no significant heterogeneity (I2 = 0%; P = 0.67). There was no change in the interpretation of results using the random‐effects model. Two trials reported the mean hospital stay and standard deviation (Lai 1998; Kolla 2004) and two trials reported the median hospital stay (Lo 1998; Johansson 2003). The median was used in the meta‐analysis after imputing the standard deviation from the P value. The median hospital stays reported in the two trials were three days and five days lower in the early group than in the delayed group (Lo 1998; Johansson 2003). Excluding these trials did not noticeably alter the mean difference for the interpretation of the results for the total hospital stay (MD ‐4.16 days; 95% CI ‐5.45 to ‐2.86).
Trial sequential analysis
The trial sequential monitoring boundaries were crossed favouring early laparoscopic cholecystectomy (Figure 7) suggesting that new trials are unlikely to dispute the finding that the total hospital stay is significantly shorter in the early laparoscopic cholecystectomy group compared with the delayed laparoscopic cholecystectomy group.
Trial sequential analysis of hospital stay
Trial sequential analysis of operating time showing that the accumulative Z‐curve crosses the trial sequential monitoring boundary after the third trial. The diversity‐adjusted required information size (DARIS) was 1649 participants based on a minimal relevant difference (MIRD) of one day, a variance (VAR) of 52.5, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. The results are compatible with significant reduction of hospital stay favouring the early laparoscopic cholecystectomy group without risk of random errors.
Operating time
There was no significant difference in the operating time between the two groups (MD ‐1.22 minutes; 95% CI ‐3.07 to 0.64) (Analysis 1.8). There was significant heterogeneity (I2 = 76%; P = 0.001). Adopting the random‐effects model showed that the operating time was significantly longer in the early group than the delayed group (MD 15.31 minutes; 95% CI 1.09 to 29.53). Two trials reported the mean (Lai 1998; Kolla 2004), one trial reported the mean and standard deviation of the operating times in the people who underwent successful laparoscopic cholecystectomy and in those who underwent conversion to open surgery separately (Yadav 2009), and three trials reported the median operating time (Lo 1998; Davila 1999; Johansson 2003). The median was used in the meta‐analysis. The median operating times reported in the two of the three trials was 21 minutes and 30 minutes longer in the early group than the delayed group (Lo 1998; Davila 1999). The median operating time in one trial in which laparoscopic common bile duct exploration was used for suspected common bile duct stones on routine peri‐operative cholangiogram (with surgical residents carrying out these procedures) was two minutes shorter in the early group (Johansson 2003). Excluding this trial, there was no significant heterogeneity noted (I2 = 0%; P = 0.76). Excluding this trial, the total operating time was significantly longer in the early group than in the delayed group (MD 20.06 minutes; 95% CI 10.21 to 29.90). Excluding the three trials which reported the median and the one trial where the mean was calculated by combining the information from two groups, the mean operating time was longer in the early group than in the delayed group (MD 15.19 minutes; 95% CI 2.63 to 27.74).
Trial sequential analysis
The trial sequential analysis shows that neither the trial sequential monitoring boundaries nor the conventional boundaries have been crossed (Figure 8).
Trial sequential analysis of operating time
The diversity‐adjusted required information size (DARIS) was 1107 participants based on a minimal relevant difference (MIRD) of 15 minutes, a variance (VAR) of 130.52, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 98.28%. After accruing 488 participants in the six trials, only 44.08% of the DARIS has been reached. Accordingly, the inner wedge futility area was not drawn. The trial sequential analysis shows that the trial sequential monitoring boundaries for benefits and harms were not crossed, but the conventional boundary for harm was initially crossed.
Return to work
Only one trial reported this outcome (Lo 1998). Thirty‐six people were in active employment during the trial period. The people belonging to the early laparoscopic cholecystectomy group returned to work earlier than the delayed laparoscopic cholecystectomy group (MD ‐11.00 days; 95% CI ‐19.61 to ‐2.39). Since there was only one trial, the issue of fixed‐effect model versus random‐effects model did not exist.
Gallstone‐related morbidity during waiting period
Four trials did not report any gallstone‐related morbidity during the waiting period (Lai 1998; Davila 1999; Johansson 2003; Kolla 2004). One trial reported five gallstone‐related morbidities (Lo 1998). Two people in the delayed group developed cholangitis during the waiting time. One patient developed biliary colic and two people developed recurrence of acute cholecystitis, which was treated conservatively. There were no reports of pancreatitis during the waiting time (Analysis 1.10). The remaining trials did not report the gallstone‐related morbidity during the waiting period. Forty people (18.3%) of the people belonging to the delayed group had either non‐resolution of symptoms or recurrence of symptoms before their planned operation and had to undergo emergency laparoscopic cholecystectomy in five trials (Lai 1998; Lo 1998; Davila 1999; Johansson 2003; Kolla 2004) (Analysis 1.10). The proportion with conversion to open cholecystectomy was 45% (18/40) in this group (Analysis 1.10).
Subgroup and sensitivity analyses
All the trials were at high risk of bias. This was mainly due to the lack of blinding. Considering that blinding is difficult or impossible to achieve, we performed subgroup analyses of trials that had low risk of bias in other important domains (Lai 1998; Johansson 2003; Kolla 2004) compared with trials at high risk of bias. The tests for subgroup differences were not significant for any of the comparisons (Analysis 2.1; Analysis 2.2; Analysis 2.3; Analysis 2.4) other than operating time (Analysis 2.5). The test for a subgroup difference was significant for operating time (P = 0.0003) but this was mainly due to the trial by Johansson 2003 in which the trainees performed the surgeries and routine cholangiogram was used.
We performed a subgroup analysis of trials that included only people within less than four days of onset of presentation and those that also included people with more than four days from onset of presentation in the early group. There was no significant difference between the early group and delayed group in any of the outcomes (Analysis 2.6; Analysis 2.7; Analysis 2.8; Analysis 2.9) other than operating time (Analysis 2.10) in spite of the difference in the time of presentation. The test for subgroup differences was significant for operating time (P = 0.007), but this again was mainly due to the trial by Johansson 2003 in which the trainees performed the surgeries and routine cholangiogram was used.
We performed a subgroup analysis of trials in which the experience of the surgeons was either more than 50 laparoscopic cholecystectomies or the surgeons were consultants compared with trainees with less than 50 laparoscopic cholecystectomies. There was no significant difference between the early group and delayed group in any of the comparisons (Analysis 2.11; Analysis 2.12; Analysis 2.13; Analysis 2.14) other than operating time (Analysis 2.15). As mentioned previously, this was due to the trial by Johansson 2003 in which the trainees performed the surgeries and routine cholangiogram was used. However, it should be noted that even in Johansson 2003, where the operations were performed by the trainees, the trainees had a minimum experience of 25 laparoscopic cholecystectomies and the techniques had to be modified and gallbladder decompression had to be performed more often in the early laparoscopic cholecystectomy group than in the delayed laparoscopic cholecystectomy group, suggesting more complex surgery (Lai 1998; Lo 1998; Kolla 2004).
Funnel plots
We did not explore bias through a funnel plot because there were fewer than 10 trials. Neither did we perform the Egger's test for exploration of bias.
Discussion
Summary of main results
This systematic review with meta‐analysis of randomised clinical trials has found no significant difference in the proportion of patients with complications or conversion to open cholecystectomy whether laparoscopic cholecystectomy is performed at presentation with acute cholecystitis or six to 12 weeks after the symptoms settle. Early surgery has the advantage of decreased hospital stay and avoids the risk of emergency surgery for non‐resolved or recurrent symptoms which lead to a high rate of conversion to open cholecystectomy. Open cholecystectomy is associated with an increase in morbidity, pain, and time to return to work (Keus 2006).
Bile duct injury is the most feared complication during cholecystectomy and can be fatal (Sicklick 2005). Corrective surgery for bile duct injury has a high morbidity and mortality (Schmidt 2005; Sicklick 2005) and the quality of life can be poor, even three years after corrective surgery (Moore 2004). Cholecystitis has been considered as a risk factor for bile duct injury (Richardson 1996; Nuzzo 2005). Observational studies have suggested a higher number of bile duct injuries with early surgery, but this was not evident from the randomised clinical trials included in this review (Russell 1996; Soderlund 2005). This difference could be due to the lack of 'intention‐to‐treat' analysis in observational studies, with people from the delayed surgery group planned to undergo emergency surgery being included in the early surgery group, that is, the performance of an inappropriate ‘treatment‐received analysis’. Larger studies are required to demonstrate the small differences in bile duct injury rates between an early or delayed approach to acute cholecystitis. However, it is unlikely that large trials will be performed as the required sample size that would allow to assess differences in the bile duct is high;the five trials providing data for this meta‐analysis contributed to much less than 1% of the participants' required sample size.
There was no significant differences in the other serious complications related to surgery between the two groups. There was also no significant difference in the proportion of people who required conversion to open surgery between the two groups. Observational studies have suggested a higher proportion of people undergoing conversion to open cholecystectomy in the early group whereas randomised trials have shown no difference between the groups. Again, this may be due to lack of 'intention‐to‐treat' analysis in observational studies with people from the delayed surgery group planned to undergo emergency surgery being included in the early surgery group, that is, the performance of an inappropriate ‘treatment‐received analysis’. While there are reports of an increased proportion of conversion to open cholecystectomy when the cholecystectomy is delayed for more than 48 to 96 hours after the onset of symptoms (Eldar 1997; Madan 2002; Liguori 2003; Peng 2005), there are also studies that do not confirm this (Chandler 2000; Knight 2004). Two trials included only people with symptoms lasting for less than four days from onset (Davila 1999; Kolla 2004). Three trials included people with symptoms lasting less than seven days from onset (Lai 1998; Lo 1998; Johansson 2003). A subgroup analysis showed no significant difference in the proportion of people with conversion to open cholecystectomy or complications between people operated within four days and within seven days after the onset of symptoms, suggesting that laparoscopic cholecystectomy is possible and appropriate up to seven days from onset of symptoms.
The total hospital stay of the trial participants was shorter by four days with early laparoscopic cholecystectomy than with delayed surgery. This is due to the participants in the delayed group requiring two treatment episodes, one for the conservative treatment of acute cholecystitis and another for the definitive surgical treatment. In addition, a significant proportion of the participants in the delayed group (18.3%) had non‐resolution or recurrent cholecystitis requiring urgent surgery or readmission due to recurrent symptoms. The trial sequential analysis revealed that the trial sequential alpha‐spending boundaries were crossed suggesting that the difference in hospital stay is unlikely to be due to chance and is not a spurious finding because of repeated analysis. However, it has to be pointed out that lack of blinding can be an important source of bias in the length of hospital stay. The number of workdays lost was also less with early laparoscopic cholecystectomy in the only trial that reported this outcome (Lo 1998), possibly because of two episodes of admission.
Another important issue is gallstone‐related morbidity during the waiting period for cholecystectomy. Cholecystectomy in the delayed group was performed within 12 weeks in all the trials which may explain the few gallstone‐related events. However, the reality of elective cholecystectomy outside trials is likely to be different (Glasgow 2000; Lawrentschuk 2003). People waiting longer than 12 weeks will have a significant risk of developing complications of gallstones while waiting for surgery (Rutledge 2000; Lawrentschuk 2003).
Another main issue is the experience of the surgeons (Johansson 2003). Although the performed subgroup analyses did not reveal significant differences in the outcomes between early and delayed cholecystectomy depending upon the experience of the surgeons, the techniques had to be modified and gallbladder decompression had to be performed more often in the early group than in the delayed group, suggesting more complex surgery (Lai 1998; Lo 1998; Kolla 2004). Laparoscopic cholecystectomy performed by upper gastrointestinal (upper GI) surgeons has lower conversion to open cholecystectomy rates and shorter hospital stay than laparoscopic cholecystectomy performed by non‐upper GI surgeons (Boddy 2007). Early laparoscopic cholecystectomy should therefore be performed in units with appropriate surgical expertise.
A formal economic analysis revealed that a policy of early laparoscopic cholecystectomy for acute cholecystitis results in an overall better quality of life for people at one year post‐presentation compared with delayed laparoscopic cholecystectomy for acute cholecystitis (Wilson 2010). The quality of life in the economic analysis was determined from simulation studies based on 1000 people and took into account the quality of life during the waiting period for surgery and post‐operative complications. Furthermore, considering costs incurred up to one year post‐presentation, early laparoscopic cholecystectomy could save approximately eight million pounds sterling annually (Wilson 2010). The recommendation from that study, therefore, was that a policy of early laparoscopic cholecystectomy should be adopted in favour of delayed laparoscopic cholecystectomy.
Overall completeness and applicability of evidence
This review is applicable to people suffering from acute cholecystitis due to gallstones who are eligible for laparoscopic cholecystectomy and it is less than seven days from onset of symptoms, with or without common bile duct stones. Two trials clearly stated that they included people fit to undergo surgery (Lai 1998; Lo 1998). It is likely that the other trials included only such people. So, this review is only applicable for people fit to undergo laparoscopic surgery.
There is a high risk of type I (erroneously concluding that an intervention is beneficial when it is actually not beneficial) and type II errors (erroneously concluding that an intervention is not beneficial when it is actually beneficial) because of the few trials included, the small sample size in each trial, and the small number of outcomes such as bile duct injury, other serious complications, and conversion to open surgery (Wetterslev 2008). New trials with adequate sample sizes will decrease the risk of type I and type II errors, but it is unlikely that individual trials will be powered to measure the differences in bile duct injury or serious complications in the foreseeable future.
Quality of the evidence
The overall quality of evidence was moderate for hospital stay and operating time, and was very low for the other outcomes, as shown in summary of findings Table for the main comparison. All the trials that contributed to the meta‐analyses in this review were at high risk of bias. However, blinding is impossible to achieve for participants and care providers in this comparison (early versus delayed laparoscopic cholecystectomy for acute cholecystitis), so it is unlikely that trials with low risk of bias can be designed. Future trials ought to blind outcome assessors.
Potential biases in the review process
We have performed a thorough search of the literature and two people independently selected the trials and performed the data extraction. We have performed the review according to the recommendations of The Cochrane Collaboration (Higgins 2011). We imputed the standard deviation and mean from P values and medians when they were not available for continuous outcomes. Excluding such trials in which these measures were imputed did not alter the conclusions of this review. Thus the potential bias due to the imputation of these values appears minimal. Overall, we are limited by the quality of the evidence available rather than the methods used in this review.
Agreements and disagreements with other studies or reviews
Our review agrees with the many reviews published on this topic (Shikata 2005; Gurusamy 2006; Lau 2006; Siddiqui 2008; Gurusamy 2010; Chong 2012).
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 bile duct injury
The diversity‐adjusted required information size (DARIS) was calculated to 77,854 participants, based on the proportion of participants in the control group with the outcome of 0.9%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. After accruing 438 participants in the five trials, we have only reached 0.56% of the DARIS. 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. Less than 1% of the required sample size was reached in the trials included in the meta‐analysis. This was too little to draw the trial sequential monitoring boundaries.
Trial sequential analysis of other serious complications
The diversity‐adjusted required information size (DARIS) was calculated to 13,493 participants, based on the proportion of participants in the control group with the outcome of 5.0%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. After accruing 438 participants in the five trials, we have only reached 3.25% of the DARIS. 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.
Trial sequential analysis of conversion to open cholecystectomy
The diversity‐adjusted required information size (DARIS) was calculated to 2225 participants, based on the proportion of participants in the control group with the outcome of 24.7%, a relative risk reduction of 20%, an alpha of 5%, a beta of 20%, and a diversity of 0%. After accruing 488 participants in the six trials, only 21.9% of the DARIS has been reached. Accordingly, the trial sequential analysis does not show the inner wedge futility area. As shown, none of the boundaries have been crossed, ie, neither the trial sequential monitoring boundaries nor the conventional boundaries.
Trial sequential analysis of hospital stay
Trial sequential analysis of operating time showing that the accumulative Z‐curve crosses the trial sequential monitoring boundary after the third trial. The diversity‐adjusted required information size (DARIS) was 1649 participants based on a minimal relevant difference (MIRD) of one day, a variance (VAR) of 52.5, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 0%. The results are compatible with significant reduction of hospital stay favouring the early laparoscopic cholecystectomy group without risk of random errors.
Trial sequential analysis of operating time
The diversity‐adjusted required information size (DARIS) was 1107 participants based on a minimal relevant difference (MIRD) of 15 minutes, a variance (VAR) of 130.52, an alpha (a) of 5%, a beta (b) of 20%, and a diversity (D2) of 98.28%. After accruing 488 participants in the six trials, only 44.08% of the DARIS has been reached. Accordingly, the inner wedge futility area was not drawn. The trial sequential analysis shows that the trial sequential monitoring boundaries for benefits and harms were not crossed, but the conventional boundary for harm was initially crossed.
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 1 Bile duct injury.
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 2 Bile duct injury (sensitivity analysis).
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 3 Other serious complications.
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 4 Other serious complications (sensitivity analysis).
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 5 Conversion to open cholecystectomy.
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 6 Conversion to open cholecystectomy (sensitivity analysis).
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 7 Hospital stay.
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 8 Operating time.
| Study | Early laparoscopic cholecystectomy (21 patients) Mean (standard deviation) | Delayed laparoscopic cholecystectomy (15 patients) Mean (standard deviation) | Mean difference (95% confidence intervals) |
| Lo 1998 | 15.0 (13.0) | 26.0 (13.0) | (MD ‐11.00 days; 95% CI ‐19.61 days to ‐2.39 days) |
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 9 Return to work [days].
| Study | Proportion of patients who required urgent laparoscopic cholecystectomy in delayed laparoscopic cholecystectomy group | Proportion of patients who required conversion to open cholecystectomy in those who required urgent surgery in the delayed laparoscopic cholecystectomy group | Symptoms during waiting period in delayed laparoscopic cholecystectomy |
| Davila 1999 | 5/36 (13.9%) | 4/5 (80%) | 0/36 (0%) |
| Johansson 2003 | 18/71 (25.4%) | 10/18 (55.6%) | 0/71 (0%) |
| Kolla 2004 | 0/20 (0%) | Not applicable | 0/20 (0%) |
| Lai 1998 | 8/51 (15.7%) | 2/8 (25%) | 0/51 (0%) |
| Lo 1998 | 9/41 (22%) | 2/9 (22.2%) | 6/41 (14.6%) (biliary colic (1); acute cholecystitis who did not require urgent operation (3); acute cholangitis (2)) |
Comparison 1 Early versus delayed laparoscopic cholecystectomy, Outcome 10 Morbidity in patients waiting for surgery in delayed laparoscopic cholecystectomy.
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 1 Bile duct injury (stratified by risk of bias).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 2 Other serious complications (stratified by risk of bias).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 3 Conversion to open cholecystectomy (stratified by risk of bias).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 4 Hospital stay (stratified by risk of bias).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 5 Operating time (stratified by risk of bias).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 6 Bile duct injury (stratified by timing of early LC)).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 7 Other serious complications (stratified by timing of early LC).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 8 Conversion to open cholecystectomy (stratified by timing of early LC).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 9 Hospital stay (stratified by timing of early LC).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 10 Operating time (stratified by timing of early LC).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 11 Bile duct injury (stratified by surgeon's experience).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 12 Other serious complications (stratified by surgeon's experience).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 13 Conversion to open cholecystectomy (stratified by surgeon's experience).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 14 Hospital stay (stratified by surgeon's experience).
Comparison 2 Early versus delayed laparoscopic cholecystectomy (subgroup analysis), Outcome 15 Operating time (stratified by surgeon's experience).
| Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis | |||||
| Patient or population: people with acute cholecystitis. | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | |
| Assumed risk | Corresponding risk | ||||
| Control | Early versus delayed laparoscopic cholecystectomy | ||||
| Mortality | 0 per 1000 | 0 per 1000 | not estimable (there were no deaths in either group) | 438 (5 studies) | ⊕⊝⊝⊝ |
| Bile duct injury | 9 per 1000 | 4 per 1000 | Peto OR 0.49 | 438 | ⊕⊝⊝⊝ |
| Other serious complications | 50 per 1000 | 65 per 1000 | RR 1.29 | 438 | ⊕⊝⊝⊝ |
| Conversion to open cholecystectomy | 221 per 1000 | 197 per 1000 | RR 0.89 | 488 | ⊕⊝⊝⊝ |
| Hospital stay | The mean hospital stay in the control groups was | The mean hospital stay in the intervention groups was | 373 | ⊕⊕⊕⊝ | |
| Operating time | The mean operating time in the control groups was | The mean operating time in the intervention groups was | 488 | ⊕⊕⊕⊝ | |
| Return to work | The mean return to work in the control groups was | The mean return to work (to be removed before submission) in the intervention groups was | 36 | ⊕⊝⊝⊝ | |
| *The basis for the assumed risk is the mean control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Some trial(s) was/were of high risk of bias. | |||||
| Study | Timing of early laparoscopic cholecystectomy | Timing of delayed laparoscopic cholecystectomy | Surgeon’s experience | Number of participants | Post‐randomisation drop‐outs | Treatment of common bile duct stones |
| Less than 4 days | 8 weeks | Not stated. | 27 versus 36 | Not stated. | 'Resolved at the same operation' ‐ No further details given. | |
| Less than 7 days | 6 to 8 weeks | Minimum 25 laparoscopic cholecystectomies. | 74 versus 71 | 0 versus 0 2 people in the delayed group refused surgery. | Laparoscopic common bile duct exploration or post‐operative ERCP. | |
| Less than 4 days | 6 to 12 weeks | Surgical consultant | 20 versus 20 | 0 versus 0 | People with common bile duct stones were excluded. | |
| Less than 7 days | 6 to 8 weeks | Minimum 50 laparoscopic cholecystectomies. | 53 versus 51 | 0 versus 0 5 patients in the delayed group refused surgery. | People with common bile duct stones were excluded. | |
| Less than 7 days | 8 to 12 weeks | More than 300 laparoscopic cholecystectomies. | 49 versus 50 | 4 versus 9 These people were excluded from the analysis. | Preoperative selective ERCP. | |
| Less than 4 days | 13 weeks | Competent surgical trainees under the supervision of consultants. | Not stated | 0 versus 0 | Not stated. | |
| Less than 4 days | 6 to 8 weeks | Not stated. | 25 versus 25 | Not stated. | People with common bile duct stones were excluded. | |
| ERCP = endoscopic retrograde cholangiopancreatography. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Bile duct injury Show forest plot | 5 | 438 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.49 [0.05, 4.72] |
| 2 Bile duct injury (sensitivity analysis) Show forest plot | 5 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 2.1 Best‐best scenario | 5 | 451 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.51 [0.05, 4.90] |
| 2.2 Best‐worst scenario | 5 | 451 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.17 [0.05, 0.54] |
| 2.3 Worst‐best scenario | 5 | 451 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 2.44 [0.54, 10.97] |
| 2.4 Worst‐worst scenario | 5 | 451 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.44 [0.15, 1.23] |
| 3 Other serious complications Show forest plot | 5 | 438 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.61, 2.72] |
| 4 Other serious complications (sensitivity analysis) Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Best‐best scenario | 5 | 451 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.62, 2.77] |
| 4.2 Best‐worst scenario | 5 | 451 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.38, 1.42] |
| 4.3 Worst‐best scenario | 5 | 451 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.69 [0.82, 3.49] |
| 4.4 Worst‐worst scenario | 5 | 451 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.51, 1.71] |
| 5 Conversion to open cholecystectomy Show forest plot | 6 | 488 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.63, 1.25] |
| 6 Conversion to open cholecystectomy (sensitivity analysis) Show forest plot | 6 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Best‐best scenario | 6 | 501 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.64, 1.27] |
| 6.2 Best‐worst scenario | 6 | 501 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.56, 1.08] |
| 6.3 Worst‐best scenario | 6 | 501 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.70, 1.37] |
| 6.4 Worst‐worst scenario | 6 | 501 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.61, 1.16] |
| 7 Hospital stay Show forest plot | 4 | 373 | Mean Difference (IV, Fixed, 95% CI) | ‐4.12 [‐5.22, ‐3.03] |
| 8 Operating time Show forest plot | 6 | 488 | Mean Difference (IV, Fixed, 95% CI) | ‐1.22 [‐3.07, 0.64] |
| 9 Return to work [days] Show forest plot | Other data | No numeric data | ||
| 10 Morbidity in patients waiting for surgery in delayed laparoscopic cholecystectomy Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Bile duct injury (stratified by risk of bias) Show forest plot | 5 | 438 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.49 [0.05, 4.72] |
| 1.1 Low risk of bias other than blinding | 3 | 289 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.98 [0.06, 15.66] |
| 1.2 High risk of bias | 2 | 149 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.12 [0.00, 6.21] |
| 2 Other serious complications (stratified by risk of bias) Show forest plot | 5 | 438 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.61, 2.72] |
| 2.1 Low risk of bias other than blinding | 3 | 289 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.19 [0.83, 5.81] |
| 2.2 High risk of bias | 2 | 149 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.11, 1.82] |
| 3 Conversion to open cholecystectomy (stratified by risk of bias) Show forest plot | 6 | 488 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.63, 1.25] |
| 3.1 Low risk of bias other than blinding | 3 | 289 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.71, 1.54] |
| 3.2 High risk of bias | 3 | 199 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.56 [0.27, 1.18] |
| 4 Hospital stay (stratified by risk of bias) Show forest plot | 4 | 373 | Mean Difference (IV, Fixed, 95% CI) | ‐4.12 [‐5.22, ‐3.03] |
| 4.1 Low risk of bias other than blinding | 3 | 287 | Mean Difference (IV, Fixed, 95% CI) | ‐3.97 [‐5.16, ‐2.79] |
| 4.2 High risk of bias | 1 | 86 | Mean Difference (IV, Fixed, 95% CI) | ‐3.00 [‐7.88, ‐2.12] |
| 5 Operating time (stratified by risk of bias) Show forest plot | 6 | 488 | Mean Difference (IV, Fixed, 95% CI) | ‐1.22 [‐3.07, 0.64] |
| 5.1 Low risk of bias other than blinding | 3 | 289 | Mean Difference (IV, Fixed, 95% CI) | ‐1.62 [‐3.49, 0.25] |
| 5.2 High risk of bias | 3 | 199 | Mean Difference (IV, Fixed, 95% CI) | 27.84 [11.98, 43.71] |
| 6 Bile duct injury (stratified by timing of early LC)) Show forest plot | 5 | 438 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.49 [0.05, 4.72] |
| 6.1 Less than 4 days | 2 | 103 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 7.39 [0.15, 372.38] |
| 6.2 Less than 7 days | 3 | 335 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.13 [0.01, 2.02] |
| 7 Other serious complications (stratified by timing of early LC) Show forest plot | 5 | 438 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.61, 2.72] |
| 7.1 Less than 4 days | 2 | 103 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.96 [0.24, 3.80] |
| 7.2 Less than 7 days | 3 | 335 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.46 [0.60, 3.56] |
| 8 Conversion to open cholecystectomy (stratified by timing of early LC) Show forest plot | 6 | 488 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.63, 1.25] |
| 8.1 Less than 4 days | 3 | 153 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.36, 1.65] |
| 8.2 Less than 7 days | 3 | 335 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.63, 1.36] |
| 9 Hospital stay (stratified by timing of early LC) Show forest plot | 4 | 373 | Mean Difference (IV, Fixed, 95% CI) | ‐4.12 [‐5.22, ‐3.03] |
| 9.1 Less than 4 days | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | ‐4.00 [‐10.62, ‐1.38] |
| 9.2 Less than 7 days | 3 | 333 | Mean Difference (IV, Fixed, 95% CI) | ‐4.01 [‐5.14, ‐2.88] |
| 10 Operating time (stratified by timing of early LC) Show forest plot | 6 | 488 | Mean Difference (IV, Fixed, 95% CI) | ‐1.22 [‐3.07, 0.64] |
| 10.1 Less than 4 days | 3 | 153 | Mean Difference (IV, Fixed, 95% CI) | 21.13 [4.76, 37.49] |
| 10.2 Less than 7 days | 3 | 335 | Mean Difference (IV, Fixed, 95% CI) | ‐1.51 [‐3.37, 0.36] |
| 11 Bile duct injury (stratified by surgeon's experience) Show forest plot | 4 | 375 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.49 [0.05, 4.72] |
| 11.1 At least 50 laparoscopic cholecystectomies or consultant | 3 | 230 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.95 [0.06, 15.28] |
| 11.2 Trainees without an experience of at least 50 laparoscopic cholecystectomies | 1 | 145 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.13 [0.00, 6.54] |
| 12 Other serious complications (stratified by surgeon's experience) Show forest plot | 4 | 375 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.55 [0.66, 3.65] |
| 12.1 At least 50 laparoscopic cholecystectomies or consultant | 3 | 230 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.29, 3.20] |
| 12.2 Trainees without an experience of at least 50 laparoscopic cholecystectomies | 1 | 145 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.56 [0.71, 9.26] |
| 13 Conversion to open cholecystectomy (stratified by surgeon's experience) Show forest plot | 4 | 375 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.65, 1.34] |
| 13.1 At least 50 laparoscopic cholecystectomies or consultant | 3 | 230 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.48, 1.35] |
| 13.2 Trainees without an experience of at least 50 laparoscopic cholecystectomies | 1 | 145 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.67, 1.82] |
| 14 Hospital stay (stratified by surgeon's experience) Show forest plot | 4 | 373 | Mean Difference (IV, Fixed, 95% CI) | ‐4.12 [‐5.22, ‐3.03] |
| 14.1 At least 50 laparoscopic cholecystectomies or consultant | 3 | 230 | Mean Difference (IV, Fixed, 95% CI) | ‐4.30 [‐5.48, ‐3.12] |
| 14.2 Trainees without an experience of at least 50 laparoscopic cholecystectomies | 1 | 143 | Mean Difference (IV, Fixed, 95% CI) | ‐3.0 [‐5.98, ‐0.02] |
| 15 Operating time (stratified by surgeon's experience) Show forest plot | 4 | 375 | Mean Difference (IV, Fixed, 95% CI) | ‐1.45 [‐3.31, 0.41] |
| 15.1 At least 50 laparoscopic cholecystectomies or consultant | 3 | 230 | Mean Difference (IV, Fixed, 95% CI) | 18.10 [6.84, 29.35] |
| 15.2 Trainees without an experience of at least 50 laparoscopic cholecystectomies | 1 | 145 | Mean Difference (IV, Fixed, 95% CI) | ‐2.0 [‐3.89, ‐0.11] |
