Cholecystectomy for suspected gallbladder dyskinesia (Review) The Cochrane Library

Transcription

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
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i
[Intervention Review]
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.
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.
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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-
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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
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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).
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).
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).
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).
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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
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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.
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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.
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
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
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∗
Indicates the major publication for the study
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”.
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.
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:
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
13
Analysis 1.2. Comparison 1 Cholecystectomy versus no cholecystectomy (observation), Outcome 2 Failure
of cure of symptoms.
Review:
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)
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
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
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
17

Cholecystectomy for suspected gallbladder dyskinesia (Review) The Cochrane Library

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