Cholecystectomy for suspected gallbladder dyskinesia (Review) Gurusamy KS, Junnarkar S, Farouk M, Davidson BR This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 1 http://www.thecochranelibrary.com Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Cholecystectomy versus no cholecystectomy (observation), Outcome 1 Failure of improvement in symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Cholecystectomy versus no cholecystectomy (observation), Outcome 2 Failure of cure of symptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 1 2 2 3 3 5 6 7 7 8 8 8 10 13 13 14 14 16 16 16 16 17 17 i [Intervention Review] Cholecystectomy for suspected gallbladder dyskinesia Kurinchi Selvan Gurusamy1 , Sameer Junnarkar2 , Marwan Farouk3 , Brian R Davidson1 1 University Department of Surgery, Royal Free Hospital and University College School of Medicine, London, UK. 2 Hepato-Biliary Surgery, Royal Free Hospital and University College School of Medicine, London, UK. 3 Surgery, Buckinghamshire Hospitals NHS Trust, Aylesbury, UK Contact address: Kurinchi Selvan Gurusamy, University Department of Surgery, Royal Free Hospital and University College School of Medicine, 9th Floor, Royal Free Hospital, Pond Street, London, NW3 2QG, UK. [email protected]. Editorial group: Cochrane Hepato-Biliary Group. Publication status and date: New, published in Issue 1, 2009. Review content assessed as up-to-date: 13 March 2008. Citation: Gurusamy KS, Junnarkar S, Farouk M, Davidson BR. Cholecystectomy for suspected gallbladder dyskinesia. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD007086. DOI: 10.1002/14651858.CD007086.pub2. Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT Background The optimal treatment for patients with suspected biliary dyskinesia is controversial. Some studies found that cholecystectomy produced symptomatic improvement in patients with gallbladder dyskinesia (diagnosed by low gallbladder ejection fraction) while others found no significant benefit. Some studies have shown that gallbladder ejection fraction can discriminate patients who would benefit from cholecystectomy. Other studies have not confirmed this. Objectives The aim of this review was to compare the benefits and harms of cholecystectomy for patients with suspected gallbladder dyskinesia. Search methods We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until March 2008. Selection criteria We considered for inclusion all randomised clinical trials comparing cholecystectomy versus no cholecystectomy on patients with gallbladder dyskinesia. Data collection and analysis We collected the data on the characteristics, methodological quality, mortality, number of patients in whom symptoms were improved or cured from the one identified trial. We planned to analyse the data using the fixed-effect and the random-effects models using RevMan Analysis. For each outcome we planned to calculate the risk ratio (RR) with 95% confidence intervals based on intention-totreat analysis. Main results We included one trial with 21 patients randomised: 11 to cholecystectomy and 10 to control (no cholecystectomy). This trial was considered to be of high risk of bias as patients were not blinded and the procedure-related morbidity was not reported. There was no mortality in either group. All patients in the cholecystectomy group and only one patient in the control group had improvement in symptoms (P = 0.0001) after a mean follow-up period of 33.6 months. Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 Authors’ conclusions The evidence for the benefits and harms of cholecystectomy in gallbladder dyskinesia from randomised clinical trials is based on a single small trial at risk of bias. Further randomised clinical trials with improved bias control are necessary to confirm or reject the promising results. PLAIN LANGUAGE SUMMARY Need for further randomised clinical trials to assess the role of cholecystectomy in patients with suspected gallbladder dyskinesia Gallbladder dyskinesia is a motility disorder of the gallbladder (the gallbladder does not contract properly). The disorder is associated with intermittent right upper abdominal pain typically lasting for at least half an hour. The optimal treatment for patients with suspected biliary dyskinesia is controversial. This review evaluates the two alternatives for the diagnosed patient group, that is, cholecystectomy (removal of the gallbladder) versus no intervention. The removal of the gallbladder can be performed by key hole surgery (laparoscopic cholecystectomy) or open surgery (open cholecystectomy). Cholescintigraphy after radiolabeled cholecystokinin (hormone that promotes gallbladder contraction) infusion can measure gallbladder contraction and has been used for the diagnosis of gallbladder dyskinesia. The duration of the cholecystokinin infusion and the cut-off values of ejection fraction (of radioisotope cleared from the gallbladder on contraction) used for the diagnosis of gallbladder dyskinesia are variable, although the most popular cut-off is 35%. Thus, currently, a gallbladder ejection fraction below 35% is considered to be gallbladder dyskinesia. However, there are some doctors who believe that irrespective of ejection fraction, pain related to the gallbladder in the absence of other causes of such pain can be considered gallbladder dyskinesia. One randomised clinical trial including 21 patients found significant cure in pain symptoms after removal of gallbladder (by open surgery) post cholecystectomy (10/11) in patients with a low ejection fraction prior to cholecystectomy compared to those who did not undergo cholecystectomy and had a low ejection fraction (1/10). Further randomised clinical trials of low bias-risk (low risk of systematic error) are necessary to assess the role of cholecystectomy in suspected gallbladder dyskinesia. BACKGROUND Gallbladder dyskinesia is a motility disorder of the gallbladder associated with intermittent right upper quadrant pain (Rastogi 2005). Typically biliary pain has been defined as pain in the right upper abdomen lasting for more than half an hour (Berger 2000). While this definition has been used in the context of gallstones (Berger 2000), this is also applicable in gallbladder dyskinesia. Thus, gallbladder dyskinesia is a diagnosis of exclusion after ruling out other possible causes of right hypochondrial (right, upper abdomen) or epigastric (midline, upper abdomen) pain such as gallstones (Gall 2002; Delgado-Aros 2003; Ozden 2003) or peptic ulcer disease (DiBaise 2003; Scott Nelson 2006). Cholescintigraphy after radiolabeled cholecystokinin infusion can measure gallbladder contraction and has been used for the diagnosis of gallbladder dyskinesia (DiBaise 2003; Krishnamurthy 2004). The duration of the cholecystokinin infusion and the cut-off values of ejection fraction (of radioisotope cleared from the gallbladder on contraction) used for the diagnosis of gallbladder dyskinesia are variable (Delgado-Aros 2003; Rastogi 2005), although the most popular cut-off is 35% (Delgado-Aros 2003; DiBaise 2003). Thus, currently, a gallbladder ejection fraction below 35% is considered to be gallbladder dyskinesia. The treatment for gallbladder dyskinesia is controversial. Cholecystectomy (removal of gallbladder) is being advocated for relief of pain as more patients were relieved of their symptoms after cholecystectomy than those who did not undergo cholecystectomy (Goncalves 1998). More than two-thirds of the patients with gallbladder dyskinesia have chronic acalculous cholecystitis on histology of the resected gallbladder (Gall 2002; Ozden 2003). Other reports have shown that an improvement of symptoms has been noticed in patients with gallbladder dyskinesia who did not undergo cholecystectomy (Ozden 2003). Gallbladder dyskinesia occurs in the paediatric age group also; and cholecystectomy and observation have been reported to provide similar relief in symptoms (Scott Nelson 2006). Cholecystectomy has also been performed even in patients with normal gallbladder ejection fraction. There was no statistically significant improvement in the symptoms after cholecystectomy between those with low ejection fraction and those with normal ejection fraction (Delgado-Aros 2003). Laparoscopic cholecystectomy (key hole removal of gallbladder) is currently preferred over open cholecystectomy for elective chole- Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 cystectomy (NIH 1992; Fullarton 1994; Livingston 2004). Cholecystectomy is not without complications. The complications include mortality due to the various complications, injury to vessels or bowel during port insertion for laparoscopic cholecystectomy (Fletcher 1999), and bile duct injury. The reported incidence of bile duct injury is between 0.3% (Richardson 1996; Krahenbuhl 2001) and 1% (Buanes 1996; Gurusamy 2006). Major bile duct injuries can even cause death due to uncontrolled sepsis (Sicklick 2005). A previous review by Rastogi 2005 et al, based on evidence from prospective (randomised and non-randomised) and retrospective studies, suggested that cholecystectomy should be carried out in people with low gallbladder ejection fraction. There have been no Cochrane systematic reviews or meta-analyses on this topic. OBJECTIVES The aim of this review was to compare the benefits and harms of cholecystectomy in patients with suspected gallbladder dyskinesia. METHODS Criteria for considering studies for this review Types of studies We included all randomised clinical trials, which compared cholecystectomy (open or laparoscopic) versus no cholecystectomy (irrespective of language, blinding, publication status, or sample size) in patients with suspected gallbladder dyskinesia. Types of participants Patients with suspected gallbladder dyskinesia (irrespective of whether ejection fraction was measured or not and whether it was low or normal). Types of interventions Cholecystectomy (open or laparoscopic) versus no cholecystectomy. Types of outcome measures Primary outcomes 1. Mortality - mortality at maximal follow-up, procedurerelated mortality. 2. Procedure-related morbidity, such as injury to common bile duct, cholangitis, bile leak, biliary peritonitis, wound infection. 3. Improvement or cure of biliary symptoms (as defined by authors). Secondary outcomes 1. Operations (due to disease recurrence or progression and due to procedure-related complications). 2. Number of outpatient visits to doctor for biliary symptoms (including planned reviews). 3. Number of hospital admissions for biliary symptoms. 4. Total hospital stay. 5. Quality of life (however defined by authors). 6. Number of days of loss of work due to biliary symptoms. Search methods for identification of studies We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2008), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (Royle 2003). We have given the preliminary search strategies in Appendix 1 with the time span for the searches. We also searched the reference list of included trials to identify additional trials. Data collection and analysis Trial selection and extraction of data The first two authors, independently of each other, identified the trials for inclusion. We have also listed the excluded studies with the reasons for the exclusion. The first two authors independently extracted the following data: 1. Year and language of publication. 2. Country. 3. Year of conduct of trial. 4. Inclusion and exclusion criteria. 5. Diagnostic tests performed. 6. Sample size. 7. Population characteristics, such as age and sex ratio. 8. Period of infusion of cholecystokinin. 9. Cut-off value for diagnosis of gallbladder dyskinesia. 10. Mean gallbladder ejection fraction. 11. Outcomes (mentioned above). 12. Methodological quality (described below). We sought any unclear or missing information by contacting the authors of the individual trials. If there were any doubt whether the trials share the same patients, completely or partially (by identifying common authors and centres), we intended to contact the Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 authors of the trials to clarify whether the trial report had been duplicated. However, there were no such concerns. We resolved any differences in opinion through discussion. Assessment of methodological quality Methodological quality was defined as the confidence that the design and the report of the randomised clinical trial would restrict bias in the comparison of the intervention (Moher 1998). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008), the methodological quality of the trials was assessed based on sequence generation, allocation concealment, blinding of (participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, and other sources of bias. Quality components were classified as follows: Incomplete outcome data • Low risk of bias (the underlying reasons for missingness are unlikely to make treatment effects departure from plausible values, or proper methods have been employed to handle missing data). • 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 on the estimate of effect). • High risk of bias (the crude estimate of effects (eg, complete case estimate) will clearly be biased due to the underlying reasons for missingness, and the methods used to handle missing data are unsatisfactory). Selective outcome reporting Sequence generation • Low risk of bias (the methods used is either adequate (eg, 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 (eg, quasi-randomised trials) is improper and likely to introduce confounding). • 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). • 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). Other bias Allocation concealment • Low risk of bias (the method used (eg, central allocation) is unlikely to induce bias on the final observed effect). • Uncertain risk of bias (there is insufficient information to assess whether the method used is likely to induce bias on the estimate of effect). • High risk of bias (the method used (eg, open random allocation schedule) is likely to induce bias on the final observed effect). Baseline imbalance • Low risk of bias (there was no baseline imbalance in important characteristics). • Uncertain risk of bias (the baseline characteristics were not reported). • High risk of bias (there was an baseline imbalance due to chance or due to imbalanced exclusion after randomisation). Blinding of participants, personnel, and outcome assessors It is difficult to blind the patients and surgeons to the groups. However, not blinding the patients will introduce bias. It is possible to blind the patients using sham operation. • 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 on 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). Early stopping • Low risk of bias (sample size calculation was reported and the trial was not stopped or the trial was stopped early by a formal stopping rule at a point where the likelihood of observing an extreme intervention effect due to chance was low). • Uncertain risk of bias (sample size calculations were not reported and it is not clear whether the trial was stopped early or not). • High risk of bias (the trial was stopped early due to an informal stopping rule or the trial was stopped early by a formal stopping rule at a point where the likelihood of observing an extreme intervention effect due to chance was high). Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4 Academic bias Subgroup analysis • Low risk of bias (the author of the trial has not conducted previous trials addressing the same interventions). • Uncertain risk of bias (It is not clear if the author has conducted previous trials addressing the same interventions). • High risk of bias (the author of the trial has conducted previous trials addressing the same interventions). We intended to perform the following subgroup analyses: - Trials with low bias risk compared to trials with high bias risk. - Different gallbladder ejection fractions. - Adults and paediatric patients. - Open and laparoscopic cholecystectomy. Source of funding bias • Low risk of bias (the trial’s source(s) of funding did not come from any parties that might conflicting interest (eg, instrument manufacturer). • Uncertain risk of bias (the source of funding was not clear). • High risk of bias (the trial was funded by an instrument manufacturer). We considered trials which were classified as low risk of bias in sequence generation, allocation concealment, blinding, incomplete data, and selective outcome reporting as low bias-risk trials. Bias exploration We intended to use a funnel plot to explore bias (Egger 1997; Macaskill 2001). We intended to use asymmetry in funnel plot of trial size against treatment effect to assess potential for this bias. We intended to perform linear regression approach described by Egger et al to determine the funnel plot asymmetry (Egger 1997). We did not explore bias because of the inclusion of only one trial in the review. RESULTS Statistical methods We examined the differences between the two arms of the only trial we identified with the Fischer exact test. We planned to perform the meta-analyses according to the recommendations of The Cochrane Collaboration (Higgins 2008) and the Cochrane Hepato-Biliary Group Module (Gluud 2008) using the software package RevMan 5 (RevMan 2008). For dichotomous variables, we calculated the risk ratio (RR) with 95% confidence interval. For continuous variables, we intended to calculate the mean difference (MD) or the standardised mean difference (SMD) with 95% confidence interval. We intended to use a random-effects model (DerSimonian 1986) and a fixed-effect model (DeMets 1987). In case of discrepancy between the two models, we intended to report both results; otherwise we intended to report only the results from one of the models based on the heterogeneity. Since there was only one trial included in this review, the use of random-effects or fixed-effect model was not relevant. We intended to explore heterogeneity by chi-squared test with significance set at P value 0.10, and the quantity of heterogeneity measured by I2 (Higgins 2002) set at 30% (Higgins 2008). Since there was only trial, we did not explore heterogeneity. We performed the analysis on an intention-to-treat analysis (Newell 1992) whenever possible. Otherwise, we intended to perform ’available-case analysis’. Since there were no drop-outs in the only trial included in this review, we used intention-to-treat analysis for all the outcomes. In case we found ’zero-event’ trials in statistically significant outcomes, we intended to perform a sensitivity analysis with and without empirical continuity correction factors as suggested by Sweeting et al (Sweeting 2004). We have also reported the risk difference if the results were different from risk ratio. Description of studies See: Characteristics of included studies; Characteristics of excluded studies. We identified a total of 238 references through 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 = 15), MEDLINE (n = 49), EMBASE (n = 134), and Science Citation Index Expanded (n = 40). We excluded 61 duplicates and 175 clearly irrelevant references through reading abstracts. Full texts of two references were retrieved for further assessment. We excluded one reference (Levine 1992) because this was a comment on the included trial. The other reference (Yap 1991) was a completed trial and could provide data for the analyses. This trial compared cholecystectomy and observation in patients with gallbladder dyskinesia. Details of the trial are shown in the table ’Characteristics of included studies’. There was no trial comparing cholecystectomy and observation in patients with biliary symptoms with normal gallbladder ejection fraction. Participants A total of 21 participants with gallbladder dyskinesia (as diagnosed by an ejection fraction less than 40%) were randomised in this trial. The proportion of females was 91%. The mean age was 30.3 years. The age range was 16 to 64 years. Experimental intervention Cholecystectomy (open cholecystectomy by right subcostal incision). Control intervention Observation. Outcome measures Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5 The outcome measures reported were the number of patients cured of the symptoms and the number of patients in whom the symptoms improved. Risk of bias in included studies The allocation sequence was generated by the flip of the coin. The allocation concealment was performed by the sealed envelope technique. Observer blinding in the assessment of symptoms was attempted. However, the patients reporting pain were not blinded. There were no post-randomisation drop-outs and the trial was free from missing outcome bias. The trial did not report the mor- bidity associated with surgery and suffers from selective outcome reporting bias. There was no baseline imbalance bias. It is not clear whether the trial suffered from early stopping bias (sample size calculations were not reported), or sponsor bias. There was no previous published report or conference abstract of a similar trial conducted by the author of this trial. Since procedure-related morbidity was not reported, we considered this trial to be of high risk of bias. While we understand the difficulties in blinding the patient, improvement or cure of symptoms is subject to bias because of lack of patient blinding (see discussion). For graphical presentation and summary of the bias risk of the trial see Figure 1 and Figure 2. Figure 1. Methodological quality graph: review authors’ judgements about each methodological quality item presented as percentages across all included studies. Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study. Effects of interventions Other outcomes One trial with 21 patients randomised was included in this review: 11 patients were randomised to cholecystectomy and 10 patients to the observation group. The mean follow-up was 33.6 months. None of the other outcomes of interest were reported in this trial. Mortality There was no mortality in either group. Procedure-related morbidity This was not reported in the trial. Number of patients with improvement in symptoms All the 11 patients in the cholecystectomy group showed improvement of symptoms compared with one patient in the control group (P = 0.0001). Number of patients cured of symptoms Ten patiens were cured of symptoms in the cholecystectomy compared with none in the control group (P = 0.0001). DISCUSSION Only one trial of high risk of bias including 21 patients could be included for this review. This trial found that patients with gallbladder dyskinesia as defined by a gallbladder ejection fraction less than 40% benefited from cholecystectomy. All the patients who underwent cholecystectomy had acalculous chronic cholecystitis. Apart from the symptoms, there was no other complications reported in the control group. The severity and frequency of these symptoms in the control group were not reported in this trial. However, at least some episodes of biliary pain might result in loss of work days and decrease the quality of life for patients. Currently, there is no evidence from randomised clinical trials that this is the case. Hence, future trials on the optimal management of gallbladder dyskinesia should include severity and frequency of symptoms, loss of work days due to these symptoms, and quality of life measures. Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7 While some non-randomised studies have demonstrated a discriminatory ability of the gallbladder ejection fraction in predicting the symptom relief after cholecystectomy, other studies have not confirmed this (Delgado-Aros 2003; DiBaise 2003). In order to determine the optimal management of patients with biliary symptoms (in the absence of gallstones) with normal ejection fraction, randomised clinical trials are necessary. Another approach is to design a trial comparing cholecystectomy versus no intervention in patients with suspected gallbladder dyskinesia without measuring the gallbladder ejection fraction. The main drawback of this review is the lack of trials of low risk of bias.The primary outcome “improvement in symptoms” is subjective and may be influenced by patient’s perspectives of the operation. In order to achieve adequate bias control, a sham operation may have to be performed. The sham operation is not difficult and does not endanger the patient in any way as this involves a skin deep umbilical scar (1 cm), a skin deep upper abdominal scar (1 cm), and 2 subcostal scars (5 mm each) under local anaesthetic. The patients have to be sedated for this for about 30 to 45 minutes but this carries a very small risk of any mishap. The treatment group would also require to have local anaesthetic wound infiltration so that it is not possible to identify the group of the patients by finding out if there was an local anaesthetic wound infiltration or not. Local anaesthetic wound infiltration is safe in laparoscopic cholecystectomy (Gurusamy 2008).Thus one has to balance between the risk of providing (a large number of patients) a treatment based on biased trials or subject a small number of patients to tiny incisions under sedation to obtain a relatively unbiased effect estimate. While there are little concerns about the safety of the ’sham operation’, the patients may prefer to not have scars which did not result in a definitive treatment of their symptoms. The trial included in this review was performed in the ’open cholecystectomy’ era. Sham operation would have been unethical con- sidering the extent of the scar that would have resulted. Observer blinding was performed in the trial. However, the trial did not report the surgery-related morbidity and was classified as high biasrisk trial. AUTHORS’ CONCLUSIONS Implications for practice The evidence for the benefits and harms of cholecystectomy in gallbladder dyskinesia from randomised clinical trials is based on a single small trial being at risk of bias. Implications for research Further randomised clinical trials are necessary to assess the role of cholecystectomy in gallbladder dyskinesia. They have to be with a sufficient sample size, low risk of bias, and with outcome assessment by blinded assessors. These trials should be reported according to the CONSORT Statement (http://www.consort-statement.org) (Moher 2001). ACKNOWLEDGEMENTS To TC Mahendran, Chennai, who was my first surgical teacher. To Martyn Parker, author of more than 15 Cochrane reviews, who inspired me to write Cochrane reviews. To The Cochrane Hepato-Biliary Group for the support that they have provided. Peer Reviewers: AP Ainsworth, Denmark; AF Abdalla, Egypt. Contact Editor: C Gluud, Denmark. REFERENCES References to studies included in this review Yap 1991 {published data only} Yap L, Wycherley AG, Morphett AD, Toouli J. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101(3):786–93. References to studies excluded from this review Levine 1992 {published data only} Levine R, Fromm H. Acalculous abdominal pain in patients with abnormal cholescintigraphy: Is cholecystectomy the answer?. Gastroenterology 1992;102(2):742–3. Additional references Berger 2000 Berger MY, van der Velden JJ, Lijmer JG, de Kort H, Prins A, Bohnen AM. Abdominal symptoms: do they predict gallstones? A systematic review. Scandinavian Journal of Gastroenterology 2000;35(1):70–6. Buanes 1996 Buanes T, Waage A, Mjaland O, Solheim K. Bile leak after cholecystectomy significance and treatment: results from the National Norwegian Cholecystectomy Registry. International Surgery 1996;81(3):276–9. Delgado-Aros 2003 Delgado-Aros S, Cremonini F, Bredenoord AJ, Camilleri M. Systematic review and meta-analysis: does gall-bladder ejection fraction on cholecystokinin cholescintigraphy Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 8 predict outcome after cholecystectomy in suspected functional biliary pain?. Alimentary Pharmacology & Therapeutics 2003;18(2):167–74. Higgins 2002 Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539–58. DeMets 1987 DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987; 6(3):341–50. Higgins 2008 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Intervention 5.0.0 [updated February 2008]. The Cochrane Colloboration, 2008. Available from www.cochrane–handbook.org. DerSimonian 1986 DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177–88. DiBaise 2003 DiBaise JK, Oleynikov D. Does gallbladder ejection fraction predict outcome after cholecystectomy for suspected chronic acalculous gallbladder dysfunction? A systematic review. American Journal of Gastroenterology 2003;98(12):2605–11. Egger 1997 Egger M, Davey SG, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ (Clinical Research Ed.) 1997;315(7109):629–34. Fletcher 1999 Fletcher DR, Hobbs MS, Tan P, Valinsky LJ, Hockey RL, Pikora TJ, et al.Complications of cholecystectomy: risks of the laparoscopic approach and protective effects of operative cholangiography: a population-based study. Annals of Surgery 1999;229(4):449–57. Fullarton 1994 Fullarton GM, Bell G. Prospective audit of the introduction of laparoscopic cholecystectomy in the west of Scotland. West of Scotland Laparoscopic Cholecystectomy Audit Group. Gut 1994;35(8):1121–6. Gall 2002 Gall CA, Chambers KJ. Cholecystectomy for gall bladder dyskinesia: Symptom resolution and satisfaction in a rural surgical practice. ANZ Journal of Surgery 2002;72(10): 731–4. Gluud 2008 Gluud C, Nikolova D, Klingenberg SL, Whitfield K, Alexakis N, Als-Nielsen B, et al.Cochrane Hepato-Biliary Group. About The Cochrane Collaboration (Cochrane Review Groups (CRGs)) 2008, Issue 1. Art. No.: LIVER. Goncalves 1998 Goncalves RM, Harris JA, Rivera DE. Biliary dyskinesia: natural history and surgical results. The American Surgeon 1998;64(6):493–8. Gurusamy 2006 Gurusamy KS, Samraj K. Early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD005440. DOI: 10.1002/14651858.CD005440.pub2. Gurusamy 2008 Gurusamy KS, Kumar Y, Davidson BR. Wound infiltration with local anaesthetic agents for laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/14651858.CD007049] Kjaergard 2001 Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of Internal Medicine 2001;135(11):982–9. Krahenbuhl 2001 Krahenbuhl L, Sclabas G, Wente MN, Schafer M, Schlumpf R, Buchler MW. Incidence, risk factors, and prevention of biliary tract injuries during laparoscopic cholecystectomy in Switzerland. World Journal of Surgery 2001;25(10): 1325–30. Krishnamurthy 2004 Krishnamurthy GT, Krishnamurthy S, Brown PH. Constancy and variability of gallbladder ejection fraction: impact on diagnosis and therapy. Journal of Nuclear Medicine 2004;45(11):1872–7. Livingston 2004 Livingston EH, Rege RV. A nationwide study of conversion from laparoscopic to open cholecystectomy. American Journal of Surgery 2004;188(3):205–11. Macaskill 2001 Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta-analysis. Statistics in Medicine 2001;20(4):641–54. Moher 1998 Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al.Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? . Lancet 1998;352(9128):609–13. Moher 2001 Moher D, Schulz KF, Altman DG (for the CONSORT Group). The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357(9263): 1191–4. Newell 1992 Newell DJ. Intention-to-treat analysis: implications for quantitative and qualitative research. International Journal of Epidemiology 1992;21(5):837–41. NIH 1992 NIH. NIH consensus statement on gallstones and laparoscopic cholecystectomy. http://consensus.nih.gov/ 1992/1992GallstonesLaparoscopy090html.htm 1992 (accessed 26 September 2008). Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 Ozden 2003 Ozden N, DiBaise JK. Gallbladder ejection fraction and symptom outcome in patients with acalculous biliary-like pain. Digestive Diseases and Sciences 2003;48(5):890–7. Rastogi 2005 Rastogi A, Slivka A, Moser AJ, Wald A. Controversies concerning pathophysiology and management of acalculous biliary-type abdominal pain. Digestive Diseases and Sciences 2005;50(8):1391–401. RevMan 2008 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008. Richardson 1996 Richardson MC, Bell G, Fullarton GM. Incidence and nature of bile duct injuries following laparoscopic cholecystectomy: an audit of 5913 cases. West of Scotland Laparoscopic Cholecystectomy Audit Group. The British Journal of Surgery 1996;83(10):1356–60. Royle 2003 Royle P, Milne R. Literature searching for randomized controlled trials used in Cochrane reviews: rapid versus exhaustive searches. International Journal of Technology Assessment in Health Care 2003;19(4):591–603. Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408–12. Scott Nelson 2006 Scott Nelson R, Kolts R, Park R, Heikenen J. A comparison of cholecystectomy and observation in children with biliary dyskinesia. Journal of Pediatric Surgery 2006;41(11): 1894–8. Sicklick 2005 Sicklick JK, Camp MS, Lillemoe KD, Melton GB, Yeo CJ, Campbell KA, et al.Surgical management of bile duct injuries sustained during laparoscopic cholecystectomy: perioperative results in 200 patients. Annals of Surgery 2005; 241(5):786–92. Sweeting 2004 Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Statistics in Medicine 2004;23 (9):1351–75. Wood 2008 Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al.Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ (Clinical research ed.) 2008;336(7644):601–5. [PUBMED: 18316340] ∗ Indicates the major publication for the study Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Yap 1991 Methods Randomised clinical trial Generation of the allocation sequence: flip of coin (adequate). Allocation concealment: sealed envelope (adequate). Blinding: observer blinding (but no patient blinding (unclear)). Incomplete outcome data: adequate. Selective reporting: inadequate. Baseline imbalance: adequate. Early stopping: unclear. Academic bias: unclear. Sponsor bias: unclear. Participants Country: Australia. Number randomised: 21. Mean age: 30.3 years. Age range: 16 to 64 years. Females: 19 (90.5%). Ejection fraction used as cut-off to diagnose gallbladder dyskinesia: 40%. Mean gallbladder ejection fraction: 17.3%. Proportion of patients with gallbladder dyskinesia: 100%. Mean duration of follow-up: 33.6 months. Inclusion criteria: 1. Clinical symptoms suggestive of biliary tract disease. 2. No evidence of gallstones on ultrasound and cholecystogram. 3. Gallbladder ejection fraction < 40%. 4. Normal serum amylase and liver function tests. Interventions Participants were randomly assigned to two groups. Group 1: cholecystectomy (n = 11). Group 2: no cholecystectomy (observation) (n = 10). Outcomes The main outcome measures were number of patients in whom symptoms improved and the number of patients cured of the symptoms Notes 2 patients in the observation group underwent cholecystectomy The authors answered questions related to allocation concealment on 06/04/2007 Risk of bias Item Authors’ judgement Description Adequate sequence generation? Yes Quote: “flip of a coin”. Allocation concealment? Yes Quote: “sealed envelope”. Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11 Yap 1991 (Continued) Blinding? All outcomes No Quote: “Symptomatic evaluation was determined by an observer who was not involved in the initial treatment of the patients and who used a standard format of questions relating to pain symptoms. This included defining pain type, site, periodicity, and frequency, and whether there were any aggravating or relieving factors for the pain, as well as any other associated symptoms”. In spite of these efforts, the patients reporting the systems were not blinded Incomplete outcome data addressed? All outcomes Yes Comment: “There were no post-randomisation drop-outs”. Free of selective reporting? No Comment: “Procedure related morbidity was not reported”. Follow-up? Yes Yes. Free from baseline imbalance? Yes Comment: “There was no notable difference between the groups on the important characteristics” Free from early stopping? Unclear Comment: “Sample size calculations were not reported in this trial” Free from academic bias? Yes Comment: “There were no published reports or conference abstracts about a similar trial conducted by the author” Free from sponsor bias? Unclear Unclear. Characteristics of excluded studies [ordered by study ID] Study Reason for exclusion Levine 1992 Comment on an included trial. Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 DATA AND ANALYSES Comparison 1. Cholecystectomy versus no cholecystectomy (observation) Outcome or subgroup title No. of studies No. of participants 1 21 Risk Ratio (M-H, Fixed, 95% CI) 0.05 [0.00, 0.74] 1 21 Risk Ratio (M-H, Fixed, 95% CI) 0.13 [0.03, 0.59] 1 Failure of improvement in symptoms 2 Failure of cure of symptoms Statistical method Effect size Analysis 1.1. Comparison 1 Cholecystectomy versus no cholecystectomy (observation), Outcome 1 Failure of improvement in symptoms. Review: Cholecystectomy for suspected gallbladder dyskinesia Comparison: 1 Cholecystectomy versus no cholecystectomy (observation) Outcome: 1 Failure of improvement in symptoms Study or subgroup Yap 1991 Cholecystectomy Observation n/N n/N 0/11 9/10 100.0 % 0.05 [ 0.00, 0.74 ] 11 10 100.0 % 0.05 [ 0.00, 0.74 ] Total (95% CI) Risk Ratio Weight M-H,Fixed,95% CI Risk Ratio M-H,Fixed,95% CI Total events: 0 (Cholecystectomy), 9 (Observation) Heterogeneity: not applicable Test for overall effect: Z = 2.18 (P = 0.029) 0.005 0.1 Favours cholecystectomy 1 10 200 Favours observation Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 13 Analysis 1.2. Comparison 1 Cholecystectomy versus no cholecystectomy (observation), Outcome 2 Failure of cure of symptoms. Review: Cholecystectomy for suspected gallbladder dyskinesia Comparison: 1 Cholecystectomy versus no cholecystectomy (observation) Outcome: 2 Failure of cure of symptoms Study or subgroup Cholecystectomy Observation n/N n/N 1/11 10/10 100.0 % 0.13 [ 0.03, 0.59 ] 11 10 100.0 % 0.13 [ 0.03, 0.59 ] Yap 1991 Total (95% CI) Risk Ratio Weight M-H,Fixed,95% CI Risk Ratio M-H,Fixed,95% CI Total events: 1 (Cholecystectomy), 10 (Observation) Heterogeneity: not applicable Test for overall effect: Z = 2.65 (P = 0.0080) 0.05 0.2 Favours cholecystectomy 1 5 20 Favours observation APPENDICES Appendix 1. Search strategies Database Period of Search Search Strategy The Cochrane Hepato-Biliary Group Con- March 2008 trolled Trials Register (((biliary OR gallbladder OR gall-bladder OR “gall bladder”) AND (dyskinesia OR dyskinesias OR motility OR dysmotility OR “ejection fraction”)) OR (acalculous AND (((gallbladder OR biliary) AND (colic or pain)) OR cholecystitis))) AND (cholecystecto* OR colecystecto*) Cochrane Central Register of Controlled Issue 1, 2008. Trials (CENTRAL) in The Cochrane Library #1 MeSH descriptor Biliary Dyskinesia explode all trees #2 (biliary OR gallbladder OR gall-bladder OR “gall bladder”) AND (dyskinesia OR dyskinesias OR motility OR dysmotility OR “ejection fraction”) #3 MeSH descriptor Acalculous Cholecystitis explode all trees #4 MeSH descriptor Cholecystitis explode all trees #5 cholecystitis #6 (gallbladder OR biliary) AND (colic or pain) #7 #4 or #5 or #6 #8 acalculous #9 (#7 AND #8) #10 (#1 OR #2 OR #3 OR #9) Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 (Continued) #11 MeSH descriptor Cholecystectomy explode all trees #12 cholecystecto* OR colecystecto* #13 (#11 OR #12) #14 (#10 AND #13) MEDLINE (Pubmed) 1951 to March 2008. (“Biliary Dyskinesia”[MeSH] OR ((biliary OR gallbladder OR gall-bladder OR “gall bladder”) AND (dyskinesia OR dyskinesias OR motility OR dysmotility OR “ejection fraction”)) OR “Acalculous Cholecystitis”[MeSH] OR (acalculous AND (( (gallbladder OR biliary) AND (colic or pain)) OR cholecystitis OR “Cholecystitis”[MeSH]))) AND (cholecystecto* OR colecystecto* OR “cholecystectomy”[MeSH]) AND (((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR (“clinical trial” [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh: noexp]) NOT (animals [mh] NOT human [mh])))) EMBASE (Dialog Datastar) 1974 to March 2008. 1 GALLBLADDER-MOTILITY.DE. 2 (BILIARY OR GALLBLADDER OR GALL-BLADDER OR GALL ADJ BLADDER) AND (DYSKINESIA OR DYSKINESIAS OR MOTILITY OR DYSMOTILITY OR EJECTION ADJ FRACTION) 3 acalculous AND ((gallbladder OR biliary) AND (colic OR pain) OR CHOLECYSTITIS#.W..DE.) OR ACALCULOUSCHOLECYSTITIS#.DE. 4 1 OR 2 OR 3 5 CHOLECYSTECTOMY#.W..DE. 6 CHOLECYSTECTO$ OR COLECYSTECTO$ 7 5 OR 6 8 4 AND 7 9 RANDOMIZED-CONTROLLEDTRIAL#.DE. OR RANDOMIZATION#.W..DE. OR CONTROLLED-STUDY#.DE. OR MULTICENTER-STUDY#. DE. OR PHASE-3-CLINICAL-TRIAL#.DE. OR PHASE4-CLINICAL-TRIAL#.DE. OR DOUBLE-BLIND-PROCEDURE#.DE. OR SINGLE-BLIND-PROCEDURE#.DE. 10 RANDOM$ OR CROSSOVER$ OR CROSS-OVER OR CROSS ADJ OVER OR FACTORIAL$ OR PLACEBO$ OR VOLUNTEER$ 11 (SINGLE OR DOUBLE OR TREBLE OR TRIPLE) NEAR (BLIND OR MASK) 12 9 OR 10 OR 11 13 12 AND HUMAN=YES 14 8 AND 13 Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 15 (Continued) Science Citation Index Expanded (http:// 1970 to March 2008. portal.isiknowledge.com/portal.cgi? DestApp=WOS&Func=Frame) #1 TS=((biliary OR gallbladder OR gall-bladder OR gall bladder) AND (dyskinesia OR dyskinesias OR motility OR dysmotility OR ejection fraction)) #2 TS=(acalculous AND (((gallbladder OR biliary) AND (colic or pain)) OR cholecystitis)) #3 #2 OR #1 #4 TS=(cholecystecto* OR colecystecto*) #5 TS=(random* OR blind* OR placebo* OR meta-analysis) #6 #5 AND #4 AND #3 HISTORY Protocol first published: Issue 2, 2008 Review first published: Issue 1, 2009 Date Event Description 16 March 2008 Amended Converted to new review format. CONTRIBUTIONS OF AUTHORS KS Gurusamy wrote the review and assessed the trials for inclusion and extracted data on included trials. S Junnarkar is the co-author of the review and independently assessed the trials for inclusion and extracted data on included trials. M Farouk and BR Davidson critically commented on the review and provided advice for improving the review. DECLARATIONS OF INTEREST None known. SOURCES OF SUPPORT Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 16 Internal sources • none, Not specified. External sources • none, Not specified. DIFFERENCES BETWEEN PROTOCOL AND REVIEW We have classified the outcome measures as primary and secondary outcomes. We have added ’procedure-related morbidity’ as a primary outcome. We have revised the methods of assessment of risk of bias in line with the updated version of the Cochrane Handbook (Higgins 2008) and The CHBG Module (Gluud 2008). In the protocol we stated that double blinding would not be assessed as we expected that there would be no ’double-blind’ trials and that we would record whether any of the outcomes were assessed by a blinded observer. However, as the review progressed, we realised the importance of blinding the patients and outcome assessors in decreasing the bias-risk in the trial. So, we have used blinding as one of the ways of classifying trials based on their bias-risk. INDEX TERMS Medical Subject Headings (MeSH) ∗ Cholecystectomy; Biliary Dyskinesia [∗ surgery] MeSH check words Humans Cholecystectomy for suspected gallbladder dyskinesia (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 17
© Copyright 2024