Early versus delayed laparoscopic cholecystectomy for acute gallstone pancreatitis

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To compare the benefits and harms of early versus delayed laparoscopic cholecystectomy in patients with acute biliary pancreatitis.

Background

Description of the condition

The pancreas is an abdominal organ that secretes several digestive enzymes into the pancreatic ductal system that empties into the small bowel. It also lodges the Islets of Langerhans, which secrete several hormones including insulin (NCBI 2011a). Acute pancreatitis is a sudden inflammatory process in the pancreas, with variable involvement of adjacent organs or other organ systems (Bradley 1993). Depending upon the presence of organ failure (such as kidneys, lungs or blood circulation) and the presence of local complications such as necrosis (destruction with liquefaction of tissues), an abscess (collection of pus) or pseudocyst (circumscribed collection of fluid without a cellular lining of the collection), pancreatitis can be classified as acute severe pancreatitis or acute mild pancreatitis (Bradley 1993). Patients with severe pancreatitis have organ failure or local complications, or both, while those with mild pancreatitis do not have such features (Bradley 1993).

There are regional variations in the incidence of first attacks of pancreatitis ranging from 10 per 100,000 in England to 44 per 100,000 in the USA (Spanier 2008). In European countries other than England, such as Germany, Sweden, Norway, Denmark, Netherlands and Finland, the incidence of first attacks of pancreatitis ranges between 15 and 37 per 100,000 (Omdal 2011; Sandzen 2009; Spanier 2008). The main reason for the differences in the incidence of first attacks of pancreatitis is considered to be the differences in alcohol consumption (Spanier 2008). There has been an increase in the incidence of pancreatitis worldwide (Spanier 2008). The two main causes of acute pancreatitis are gallstones and alcohol, accounting for more than 80% of acute pancreatitis (Spanier 2008). Gallstones can cause temporary obstruction at the ampulla of Vater, which is a common channel shared by the bile duct and pancreatic duct, resulting in increased pressure within the pancreas leading on to enzyme activation within the pancreas and acute pancreatitis (Wang 2009).

Removal of the gallbladder (cholecystectomy) is the definitive treatment for prevention of further attacks of acute gallstone pancreatitis if the patient is suitable for surgery. Current British Society of Gastroenterology guidelines state that all patients with biliary pancreatitis (gallstone related pancreatitis) should undergo cholecystectomy during the same hospital admission, unless a clear plan has been made for definitive treatment within the next two weeks, based on a low level of evidence (BSG 2005).

Laparoscopic removal (key-hole surgery) of the gallbladder is the currently preferred way of cholecystectomy (Ballal 2009; Dolan 2009; Harboe 2011). The standard laparoscopic procedure involves inflating the stomach (tummy) with carbon dioxide (pneumoperitoenum), introducing cameras and instruments through four small incisions (two of about 1 cm and two of about 0.5 cm) and removing the gallbladder. Various variations include lifting the anterior abdominal wall (front of the tummy) rather than inflating the tummy and using fewer ports and smaller incisions (Gurusamy 2010; Gurusamy 2012; Ma 2011).

Description of the intervention

There is no universally accepted definition of early laparoscopic cholecystectomy. In patients with mild acute gallstone pancreatitis, we consider any laparoscopic cholecystectomy performed within three days after onset of pancreatitis as early laparoscopic cholecystectomy. The reason for choosing the arbitrary three days is that this allows time for the clinicians to make the diagnosis of mild pancreatitis and organise the laparoscopic cholecystectomy. We considered more than three days as delayed laparoscopic cholecystectomy.

In patients with severe acute gallstone pancreatitis, we consider any laparoscopic cholecystectomy performed during the same admission as early laparoscopic cholecystectomy. This is because the patients may be at high risk of anaesthetic and surgical complications until recovery from systemic organ failure. In these patients, we considered laparoscopic cholecystectomy performed in a later admission as delayed laparoscopic cholecystectomy.

How the intervention might work

Delaying laparoscopic cholecystectomy exposes the patient to a risk of potentially fatal recurrent acute pancreatitis (BSG 2005). On the other hand, considering that pancreatitis is a systemic disorder, the delay by 72 hours allows the patient to recover fully prior to laparoscopic cholecystectomy in the case of mild pancreatitis patients. In the case of severe pancreatitis, the delay may allow the inflammation to settle down completely before the laparoscopic cholecystectomy.

Why it is important to do this review

As mentioned previously, current British Society of Gastroenterology guidelines state that all patients with biliary pancreatitis should undergo cholecystectomy (open or laparoscopic) during the same hospital admission, unless a clear plan has been made for definitive treatment within the next two weeks, based on a low level of evidence (BSG 2005). It is not clear whether delaying surgery after diagnosis of mild acute gallstone pancreatitis is beneficial or harmful to these patients. It is not clear whether delaying surgery for another two weeks, or more, is beneficial or harmful to the patients with either mild or severe acute pancreatitis. Ito et al showed in a retrospective cohort study that even a delay of two weeks after discharge exposes the patients to complications of gallstones including recurrent pancreatitis (Ito 2008). Wilson et al performed a literature review of early versus delayed cholecystectomy after acute pancreatitis and concluded that patients with mild gallstone pancreatitis should have cholecystectomy during the index admission within 48 hours of arrival and that patients with more severe disease should undergo the procedure at a later time, which could even be weeks or months after the pancreatitis episode depending on the clinical circumstances (Wilson 2010). There has been no Cochrane review assessing whether laparoscopic cholecystectomy should be performed early or be delayed in patients with acute gallstone pancreatitis.

Objectives

To compare the benefits and harms of early versus delayed laparoscopic cholecystectomy in patients with acute biliary pancreatitis.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised clinical trials irrespective of blinding, language, publication status, or sample size. We will exclude quasi-randomised studies or other study designs.

Types of participants

Patients eligible to undergo laparoscopic cholecystectomy for acute pancreatitis.

Types of interventions

Early versus delayed laparoscopic cholecystectomy for acute pancreatitis. The definitions and justification for the use of the terms has been stated. We will not include other definitions by individual authors.

Types of outcome measures

We will consider all the outcomes measured up to six months after the onset of acute pancreatitis. We anticipate that any differences in the treatments will be evident within this time period.

Primary outcomes
  1. All cause mortality.

  2. Other 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 required intervention to prevent it (ICH-GCP 1996).

  3. Overall quality of life (using any validated measurement scale such as EQ5D or SF-36). If quality of life is reported at multiple time points in the same trial, we will use the latest time point within six months after onset of acute pancreatitis.

Secondary outcomes
  1. Conversion to open cholecystectomy (because of inability to complete the operation laparoscopically or because of injury to important structures requiring open operation).

  2. Total hospital stay.

Search methods for identification of studies

Electronic searches

We will search the following databases from 1987 onwards:

Searching other resources

We will search the references of the identified trials to identify further relevant trials. We will search the metaRegister of Controlled Trials (mRCT) (http://www.controlled-trials.com/mrct/). The meta-register includes the ISRCTN register and National Institutes of Health (NIH) ClinicalTrials.gov register among other registers.

Data collection and analysis

We will perform the systematic review following the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011).

Selection of studies

Two authors (KG and another author) will identify the trials for inclusion independently of each other. We will list the excluded studies with the reasons for exclusion. Any differences will be resolved through discussion.

Data extraction and management

Both authors will independently extract the following data.

  1. Year and language of publication.

  2. Country.

  3. Year of conduct of the trial.

  4. Inclusion and exclusion criteria.

  5. Sample size.

  6. Outcomes (described above).

  7. Risk of bias (described below).

Any unclear or missing information will be sought by contacting the authors of the individual trials. If there is any doubt whether the trials share the same patients, either completely or partially (by identifying common authors and centres), we will contact the authors of the trials to clarify whether the trial report has been duplicated. We will resolve any differences in opinion through discussion.

Assessment of risk of bias in included studies

We will follow the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). According to empirical evidence (Kjaergard 2001; Moher 1998; Schulz 1995; Wood 2008), the risk of bias of the trials will be assessed based on the following bias risk domains.

Sequence generation
  • Low risk of bias (the method used is either adequate (e.g., computer generated random numbers, table of random numbers) or unlikely to introduce confounding).

  • Uncertain risk of bias (there is insufficient information to assess whether the method used is likely to introduce confounding).

  • High risk of bias (the method used (e.g., quasi-randomised studies) is improper and likely to introduce confounding). Such studies will be excluded.

Allocation concealment
  • Low risk of bias (the method used (e.g., central allocation) is unlikely to induce bias in the final observed effect).

  • Uncertain risk of bias (there is insufficient information to assess whether the method used is likely to induce bias in the estimate of effect).

  • High risk of bias (the method used (e.g., open random allocation schedule) is likely to induce bias in the final observed effect).

Blinding of participants, personnel, and outcome assessors
  • Low risk of bias (blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding).

  • Uncertain risk of bias (there is insufficient information to assess whether the type of blinding used is likely to induce bias in the estimate of effect).

  • High risk of bias (no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding).

We anticipate that blinding of participants will be unethical as this involves exposure of both groups to a sham operation. We will assess the trials to be at high risk of bias for outcomes such as severe adverse events other than mortality, quality of life, and hospital stay. Blinding of personnel and outcome assessors is possible and we will consider all the outcomes other than mortality if there is lack of blinding of personnel or outcome assessors.

Incomplete outcome data
  • 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).

  • 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 is likely to induce bias in the estimate of effect).

  • High risk of bias (the crude estimate of effects (e.g., 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
  • Low risk of bias (the trial protocol is available and all of the trial's pre-specified outcomes that are of interest in the review have been reported, or similar; if the trial protocol is not available, all the primary outcomes in this review are reported).

  • Uncertain risk of bias (there is insufficient information to assess whether the magnitude and direction of the observed effect is related to selective outcome reporting).

  • High risk of bias (not all of the trial's pre-specified primary outcomes have been reported, or similar).

We will consider trials which are classified as low risk of bias in all the above domains as low bias-risk trials.

Measures of treatment effect

For dichotomous variables, we will calculate the risk ratio (RR) with 95% confidence interval (CI). Risk ratio calculations do not include trials in which no events occurred in either group, whereas risk difference calculations do. We will report the risk difference if the results using this association measure were different from risk ratio. For continuous variables, we will calculate the mean difference (MD) with 95% CI for outcomes such as hospital stay and 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 will be individual patients who have acute gallstone pancreatitis and who are eligible for laparoscopic cholecystectomy.

Dealing with missing data

We will perform an intention-to-treat analysis (Newell 1992) whenever possible. We will impute data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best-case scenario, and worst-case scenario (Gurusamy 2009).

For continuous outcomes, we will use available-case analysis. We will impute the standard deviation from P values according to the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011), and we will use the median for the meta-analysis when the mean is not available. If it is not possible to calculate the standard deviation from the P value or the CIs, we will impute 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 MDs and bias the effect estimate to no effect in the case of SMDs (Higgins 2011).

Assessment of heterogeneity

We will explore heterogeneity by the Chi2 test with significance set at a P value of 0.10, and measure the quantity of heterogeneity by the I2 statistic (Higgins 2002). We will also use overlapping of CIs on the forest plot to determine heterogeneity.

Assessment of reporting biases

We will use visual asymmetry on a funnel plot to explore reporting bias (Egger 1997; Macaskill 2001). We will perform the linear regression approach described by Egger 1997 to determine funnel plot asymmetry. Selective reporting will also be considered as evidence for reporting bias.

Data synthesis

We will perform the meta-analyses using the software package RevMan 5 (RevMan 2011) and following the recommendations of The Cochrane Collaboration (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2010). We will use both a random-effects model (DerSimonian 1986) and a fixed-effect model (DeMets 1987) fpr meta-analyses. In the case of discrepancy between the two models we will report both results; otherwise we will report the results of the fixed-effect model. We will use the generic inverse method to combine the hazard ratios for time-to-event outcomes.

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses.

  • Trials with low risk of bias compared to trials with high risk of bias.

  • Patients with mild acute gallstone pancreatitis compared with trials with severe acute gallstone pancreatitis.

We will use the 'test for interaction' in a fixed-effect model meta-analysis to identify the differences between subgroups (Altman 1995).

Sensitivity analysis

We will perform a sensitivity analysis by imputing data for binary outcomes using various scenarios such as good outcome analysis, bad outcome analysis, best-case scenario, and worst-case scenario (Gurusamy 2009). We will perform a sensitivity analysis by excluding the trials in which the mean and the standard deviation were imputed.

Summary of findings table

We will present the results of all the available outcomes in a summary of findings of table.

Acknowledgements

To the Cochrane Upper Gastro-intestinal and Pancreatic Diseases Group.

Peer reviewers.

Appendices

Appendix 1. CENTRAL search strategy

#1 laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*
#2 cholecystectom*
#3 MeSH descriptor Cholecystectomy, Laparoscopic explode all trees
#4 (( #1 AND #2 ) OR #3)
#5 MeSH descriptor Pancreatitis explode all trees
#6 pancreatiti*
#7 (#5 OR #6)
#8 (#4 AND #7)

Appendix 2. MEDLINE search strategy

(((laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*) AND (cholecystectom*)) OR “cholecystectomy, laparoscopic”[MeSH]) AND (pancreatiti* OR "Pancreatitis"[Mesh]) AND ((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))

Appendix 3. EMBASE search strategy

1. (laparoscop$ or coelioscop$ or celioscop$ or peritoneoscop$).af.
2. exp Laparoscopic surgery/
3. 1 or 2
4. cholecystectom$.af.
5. exp Cholecystectomy/
6. 4 or 5
7. pancreatiti$.af.
8. exp Pancreatitis/
9. 7 and 8
10. 3 and 6 and 9
11. Clinical trial/
12. Randomized controlled trial/
13. Randomization/
14. Single-Blind Method/
15. Double-Blind Method/
16. Cross-Over Studies/
17. Random Allocation/
18. Placebo/
19. Randomi?ed controlled trial$.tw.
20. Rct.tw.
21. Random allocation.tw.
22. Randomly allocated.tw.
23. Allocated randomly.tw.
24. (allocated adj2 random).tw.
25. Single blind$.tw.
26. Double blind$.tw.
27. ((treble or triple) adj blind$).tw.
28. Placebo$.tw.
29. Prospective study/
30. or/11-29
31. Case study/
32. Case report.tw.
33. Abstract report/ or letter/
34. or/31-33
35. 30 not 34
36. 10 and 35

Appendix 4. Science Citation Index Expanded search strategy

#1 TS=(laparoscop* OR coelioscop* OR celioscop* OR peritoneoscop*)
#2 TS=(cholecystectom*)
#3 TS=(pancreatiti*)
#4 TS=(random* OR rct* OR crossover OR masked OR blind* OR placebo* OR meta-analysis OR systematic review* OR meta-analys*)
#5 #4 AND #3 AND #2 AND #1

Contributions of authors

KS Gurusamy wrote the protocol and will assess the trials for inclusion and extract data from included trials at the review stage. A second author will independently assess the trials for inclusion and extract data from included trials at the review stage. BR Davidson approved the protocol, and will critically comment on the review and will provide advice for improving the review.

Declarations of interest

None

Sources of support

Internal sources

  • None, Not specified.

External sources

  • National Insitute for Health Research (NIHR), UK.

    NIHR is the health research wing of the UK Government. It part funds Dr K Gurusamy's salary and funds all the materials needed for the preparation of this review.

Ancillary