https://doi.org/10.1177/14574969221111027
Scandinavian Journal of Surgery
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National clinical practice guidelines for the
treatment of symptomatic gallstone disease:
2021 recommendations from the Danish
Surgical Society
Daniel M?nsted Shabanzadeh , Dorthe Wiinholdt Christensen,
Caroline Ewertsen, Hans Friis-Andersen, Frederik Helgstrand,
Lars Nannestad J?rgensen, Anders Kirkegaard-Klitbo,
Anders Christian Larsen, Jonas Sanberg Ljungdalh,
Palle Nordblad Schmidt, Rikke Therkildsen, Peter Vilmann,
Jes Sefland Vogt and Lars Tue S?rensen
Abstract
Background and objective: Gallstones are highly prevalent, and more than 9000
cholecystectomies are performed annually in Denmark. The aim of this guideline was to
improve the clinical course of patients with gallstone disease including a subgroup of high-
risk patients. Outcomes included reduction of complications, readmissions, and need for
additional interventions in patients with uncomplicated gallstone disease, acute cholecystitis,
and common bile duct stones (CBDS).
Methods: An interdisciplinary group of clinicians developed the guideline according to the GRADE
methodology. Randomized controlled trials (RCTs) were primarily included. Non-RCTs were
included if RCTs could not answer the clinical questions. Recommendations were strong or weak
depending on effect estimates, quality of evidence, and patient preferences.
Results: For patients with acute cholecystitis, acute laparoscopic cholecystectomy is recommended
(16 RCTs, strong recommendation). Gallbladder drainage may be used as an interval procedure
before a delayed laparoscopic cholecystectomy in patients with temporary contraindications to
surgery and severe acute cholecystitis (1 RCT and 1 non-RCT, weak recommendation). High-risk
patients are suggested to undergo acute laparoscopic cholecystectomy instead of drainage (1 RCT
and 1 non-RCT, weak recommendation). For patients with CBDS, a one-step procedure with
simultaneous laparoscopic cholecystectomy and CBDS removal by laparoscopy or endoscopy is
recommended (22 RCTs, strong recommendation). In high-risk patients with CBDS, laparoscopic
cholecystectomy is suggested to be included in the treatment (6 RCTs, weak recommendation).
For diagnosis of CBDS, the use of magnetic resonance imaging or endoscopic ultrasound prior
to surgical treatment is recommended (8 RCTs, strong recommendation). For patients with
uncomplicated symptomatic gallstone disease, observation is suggested as an alternative to
laparoscopic cholecystectomy (2 RCTs, weak recommendation).
Conclusions: Seven recommendations, four weak and three strong, for treating patients with
symptomatic gallstone disease were developed. Studies for treatment of high-risk patients are few
and more are needed.
Endorsement: The Danish Surgical Society.
Corresponding author:
Daniel M?nsted Shabanzadeh
Bispebjerg Hospital
Digestive Disease Center
Bispebjerg Bakke 23
DK-2400 Copenhagen
Denmark
daniel.moensted.shabanzadeh@regionh.dk
Dorthe Wiinholdt Christensen
Digestive Disease Center, Surgical Section,
Bispebjerg Hospital, Copenhagen, Denmark
Caroline Ewertsen
Department of Diagnostic Radiology,
Rigshospitalet, Copenhagen, Denmark
Hans Friis-Andersen
Department of Surgery, Regionshospitalet
Horsens, Horsens, Denmark
Institute for Clinical Medicine, Faculty of Health,
University of Aarhus, Aarhus, Denmark
Frederik Helgstrand
Department of Surgery, Zealand University
Hospital, K?ge, Denmark
Lars Nannestad J?rgensen
Digestive Disease Center, Surgical Section,
Bispebjerg Hospital, Copenhagen, Denmark
Institute for Clinical Medicine, Faculty of Health
and Medical Sciences, University of Copenhagen,
Copenhagen, Denmark
Anders Kirkegaard-Klitbo
Digestive Disease Center, Surgical Section,
Bispebjerg Hospital, Copenhagen, Denmark
Anders Christian Larsen
Department of Gastrointestinal Surgery,
Aalborg University Hospital, Aalborg, Denmark
Department of Clinical Medicine, The Faculty of
Medicine, Aalborg University, Aalborg, Denmark
Jonas Sanberg Ljungdalh
Department of Surgery, Odense University
Hospital, Odense, Denmark
Palle Nordblad Schmidt
Department of Gastroenterology and
Gastrointestinal Surgery, Hvidovre Hospital,
Copenhagen, Denmark
Rikke Therkildsen
Department of Surgery, Aarhus University
Hospital, Aarhus, Denmark
Peter Vilmann
Institute for Clinical Medicine, Faculty of
Health and Medical Sciences, University of
Copenhagen, Denmark
Department of Surgery, Herlev Gentofte
Hospital, Herlev, Denmark
Jes Sefland Vogt
Department of Gastrointestinal Surgery, Aalborg
University Hospital, Aalborg, Denmark
Lars Tue S?rensen
Digestive Disease Center, Surgical Section,
Bispebjerg Hospital, Copenhagen, Denmark
Institute for Clinical Medicine, Faculty of Health
and Medical Sciences, University of Copenhagen,
Copenhagen, Denmark
1111027SJS Shabanzadeh et al.Shabanzadeh et al.
Original Article
2 Scandinavian Journal of Surgery
Keywords
Cholelithiasis, cholecystolithiasis, choledocholithiasis, guideline, systematic review, meta-analysis
Date received: 8 March 2022, accepted: 14 June 2022
Context and Relevance
More than 9000 cholecystectomies are performed annually
in Denmark. The latest Danish clinical practice guideline for
the treatment of symptomatic gallstone disease was pub-
lished in 2006. Other published international guidelines may
not be entirely suitable for a healthcare system such as the
Danish. There is a need for an updated guideline to optimize
the course of patients with gallstone disease and the hospital
resources. An interdisciplinary group working under the
Danish Surgical Society developed new guidelines accord-
ing to the GRADE methodology. Seven recommendations
were reported including three strong and four weak. The rec-
ommendations describe the treatment of patients with
uncomplicated gallstone disease, acute cholecystitis, and
common bile duct stones including treatments for the sub-
group of high-risk patients. We suggest several areas of
interest for future research.
Introduction
Laparoscopic cholecystectomy is one of the most frequently
performed surgical procedures in Scandinavia. More than
9000 procedures are performed annually in Denmark.
1
Standard treatment for gallstone disease is laparoscopic chol-
ecystectomy, but treatments may also include other endo-
scopic and radiological procedures.
2
Gallstone disease causes
high costs and is a burden to health care providers due to
admissions and treatments.
3
Danish clinical practice guide-
lines were published in 2006.
4
An updated guideline includ-
ing novel treatments and evidence is needed to ensure optimal
patient treatment and appropriate use of health care resources.
Current clinical challenges involve treatment of uncompli-
cated gallstone disease, acute cholecystitis, common bile duct
stones (CBDS) and of the subgroup of high-risk patients.
Gallstones cause a continuum from an asymptomatic state
to symptomatic disease including uncomplicated pain attacks
and complications such as acute cholecystitis, CBDS, pan-
creatitis, and cholangitis.
5
The prevalence of gallstones is
about 10%–20% in the general Danish population depending
on age and gender.
6
About 20% of gallstone carriers will
develop symptomatic gallstone disease requiring hospital
admission of which 12% will have uncomplicated disease
and 8% complicated disease.
7
There is no consensus regarding the diagnosis of acute
cholecystitis. The Tokyo guidelines from 2013 and 2018
define this pathology as: (1) local signs of inflammation like
Murphy’s sign or right upper quadrant tenderness, (2) sys-
temic signs of inflammation such as fever or elevated serum
markers of inflammation, and (3) imaging findings of acute
cholecystitis such as gallstones and ultrasonic wall thicken-
ing, edema, or transducer tenderness. Acute cholecystitis is
suspected if local and systemic signs are present and the
diagnosis is definitive with imaging. It is graded as mild,
moderate, or severe with the latter defined by the presence of
organ failure.
8
The World Society of Emergency Surgery
(WSES) does not suggest a set of criteria but merely empha-
sizes that the diagnosis should be based on a combination of
detailed history, complete clinical examination, laboratory
tests, and imaging.
9
Abdominal ultrasound is usually sufficient to diagnose
gallbladder stones in patients with symptomatic gallstone
disease.
10
A diagnosis of CBDS often requires invasive or
non-invasive examinations that are not readily available and
unnecessary for most cases. Simple clinical risk estimation
tools have been developed to estimate the need for further
diagnostic workup in patients with gallbladder stones. The
European Society of Gastrointestinal Endoscopy (ESGE) and
the American Society for Gastrointestinal Endoscopy (ASGE)
define a high, intermediate and low risk of CBDS.
11,12
High
risk may be characterized by clinical signs of acute cholangi-
tis or detection of CBDS on ultrasound. Furthermore, the
ASGE includes severely elevated serum bilirubin in the high-
risk group. Patients with a high risk may be treated directly
with endoscopic retrograde cholangiography (ERC). An
intermediate risk may be defined as elevated hepatic function
tests and/or bile duct dilation on abdominal ultrasound.
ASGE also includes an age above 55 years or clinical pres-
ence of gallstone pancreatitis. Intermediate risk patients
should undergo magnetic resonance cholangiopancreatogra-
phy (MRCP) or endoscopic ultrasound (EUS) examination to
rule out CBDS. No risk factors predict a low risk of CBDS,
and no further diagnostic workup is needed.
The definition of the high-risk surgical patient often relies
on both surgical and anesthesiologic aspects. Several anesthe-
siologic risk estimation tools have been developed to identify
high-risk patients based on pre-, intra-, and post-operative
factors.
13
Previous laparotomy and obesity often result in
exclusion from clinical trials due to a suspected higher risk of
surgical complications.
14,15
The perioperative mortality has
significantly decreased over the last decades, especially
throughout the 1990–2000s probably due to persistent changes
and improvements of anesthesiologic and surgical practice.
16
The definition of the surgical high-risk patient is ultimately
Shabanzadeh et al. 3
ill-defined and may have changed over time. Possibilities for
and willingness to perform surgery in an aging high-risk
patient population have increased over time.
Several pending clinical challenges have promoted the
need for updated guidelines. Following cholecystectomy in
patients with uncomplicated symptomatic gallstone disease,
up to one in three patients report persistent upper abdominal
pain.
17,18
This may suggest challenges in patient selection or
that too many cholecystectomies are currently performed.
For acute cholecystitis, delayed versus acute surgery is per-
sistently debated. Several arguments support delayed sur-
gery, such as the idea of “cooling off a hot gallbladder,”
patient comorbidity, delayed patient presentation, surgeon
preference, and resource constraints with limited access to
the operating room.
19
Gallbladder drainage is used as an
alternative to surgery in high-risk patients or as a bridge to
surgery. In high-risk patients with acute cholecystitis, argu-
ments for the use of gallbladder drainage are the same as for
delayed surgery in non-high-risk patients.
20
Gallbladder
drainage may be used to treat moderate or severe acute chol-
ecystitis according to the Tokyo guidelines.
21
The most com-
monly used treatment of CBDS is ERC-guided removal of
CBDS and laparoscopic cholecystectomy as two separate
procedures.
22
Newer treatments including one-step proce-
dures have gained popularity recently including intraopera-
tive ERC-guided or laparoscopic removal of CBDS during
laparoscopic cholecystectomy.
23,24
There are a few updated published international guidelines
for treatment of symptomatic gallstones. The Tokyo
Guidelines from 2018 propose frequent use of gallbladder
drainage treatment and/or reference to an expert center for
treatment of acute cholecystitis.
21
Such algorithms are not
suitable for smaller countries like Denmark where high-vol-
ume laparoscopic cholecystectomy surgical centers are read-
ily available as compared to larger countries such as Japan.
Treatments for CBDS and acute cholecystitis are described in
ESGE guidelines from 2019
11
and in WSES guidelines from
2020.
9
These comprehensive guidelines emphasize the multi-
ple lines of treatments that may be applied based on local
expertise. A small country like Denmark with a publicly
financed healthcare system may apply nationwide changes in
treatments more readily according to the highest level of evi-
dence enabling more uniform treatments and guidelines.
The overall aim of this clinical guideline was to improve
the clinical course of patients with gallstone disease includ-
ing the subgroup of high-risk patients. The objectives were to
reduce the rates of complications, readmissions with gall-
stone disease, and the need for additional interventions in
patients with uncomplicated gallstone disease, acute chole-
cystitis, and CBDS. This guideline does not include treatment
of patients with acute pancreatitis, severe acute cholangitis,
or acalculous cholecystitis.
This guideline primarily addresses clinicians involved
in the treatment of patients with gallstone disease in
hospital settings, but also general practitioners in primary
care and policy makers. Practice guidelines are essential to
optimize the clinical course and reduce costs in a publicly
financed healthcare system. These guidelines are particu-
larly relevant for Scandinavian countries and other high or
middle-income countries with similar healthcare systems.
Although we aimed at the shortest patient course with
lowest costs, we summarize the highest level of evidence
for treatment of gallstone disease rather than mere cost-
effectiveness analyses.
Methods
The steering group included two of the authors (LTS and DMS)
who explored the need for updated guidelines in gallstone dis-
ease, which was confirmed by the Danish Surgical Society.
The steering group invited a broad group of Danish healthcare
professionals to participate in the guideline working group.
The final working group included 14 clinicians from the five
Danish regions involved in treatment of patients with gallstone
disease and included surgeons, advanced endoscopy special-
ists, a gastroenterologist, a radiologist, and a nurse. The guide-
line was developed from May 2020 to October 2021 with
regular online meetings. The working group was split into six
subgroups that each worked with one or two of the defined
clinical questions (see below). A final 2-day seminar with the
entire working group was held in Copenhagen June 2021, and
the entire guideline was presented and discussed. Consensus
regarding recommendations was reached according to the used
methodology and was defined as all group members agreeing
on the recommendations. To ensure process and quality accord-
ing to Danish Health Authority standards, a methodology con-
sultant was hired to supervise the guideline process and
analyses. The final guideline was reviewed at the Danish
Health Authorities, Danish Regions, Danish Patients, the board
of the Danish Surgical Society, and all other Danish Medical
Societies. An experienced hepato-pancreatic-biliary surgeon
and a clinical professor in general surgery performed external
peer review. The reviewer comments were considered, and the
guidelines were modified accordingly in agreement with the
entire working group. Reviewer comments and answers were
published online together with the final revised guideline.
25
The full report in Danish is available as Supplemental Material
(Supplemental Material 1).
Based on current challenges in the treatment of gallstone
disease, seven clinical questions were developed. The PICOS
(patient, intervention, comparator, outcome, and study
design) format served as the strategy that facilitated a system-
atic review process. Search strategies were based on key-
words and Medical Subject Heading (MeSH) terms (Table 1).
An information specialist designed search strategies and per-
formed the literature searches. Five search strategies were
conducted in September 2020. Systematic searches were
4 Scandinavian Journal of Surgery
performed in the databases CENTRAL, MEDLINE, Embase,
LILACS, Science Citation Index Expanded, and Cochrane
Hepato-Biliary Group Controlled Trials Register. Ovid was
used to search, and results were transferred to the online ref-
erence program Covidence. All group members had access to
Covidence. At least two independent working group mem-
bers performed study selection, data extraction, and study
quality assessment in each PICOS. Final assessment was
according to subgroup discussion and consensus. No lan-
guage restrictions were applied at study selection. PRISMA
study flow-charts were obtained in Covidence. Available pre-
liminary results from relevant ongoing trials were sought
identified through online sources such as a trial webpage. The
RIGHT statement was used to report recommendations.
Odds ratio (OR) or mean difference were calculated with
corresponding 95% confidence intervals (CIs). Risk in com-
parator and intervention groups were reported. Meta-analyses
were performed where relevant with the random effects
model. Review Manager version 5.4 was used for analyses.
Analyses were performed by the first author (DMS) and the
methodology consultant.
Evidence was assessed across studies on an outcome-by-
outcome basis as suggested by the GRADE Working Group.
GRADE methodology separates the assessment of the quality
of evidence and of the strength of recommendations. Quality
of evidence was assessed based on the risk of bias according
to the Cochrane’s tool for randomized controlled trials
(RCTs), imprecision, indirectness of evidence, inconsistency
of results, and reporting bias.
26
Risk of bias in nonrandomized
studies was assessed according to ROBINS-I.
27
Quality of
evidence was defined as high, moderate, low, or very low. We
defined quality of evidence as our confidence in the estimate
of the effect to support a recommendation. The strength of the
final recommendation was assessed as either strong or weak
depending on the quality of evidence, desirable, and undesir-
able effects, and patient preferences.
26
All working group
members either had experience with the GRADE methodol-
ogy or participated in an online course held by the Danish
Health Authorities.
Relevant clinical outcomes were chosen based on clinical
experience and in respect of healthcare resources. Between
two and three outcomes were considered critical for each
PICOS and moderate to good quality of evidence was
required to allow a strong recommendation. Post-operative
complications and readmissions with gallstone disease were
considered critical for most PICOS. Quality of life was
included in most PICOS. Need for additional interventions
and length of hospital stay were included when comparing
specific procedures. When exploring high-risk patients, mor-
tality was included. Assessing uncomplicated disease,
absence or reduction of pain intensity, and the rate of chole-
cystectomies were included. Successful CBDS diagnosis or
removal and conversion to open surgery were included if rel-
evant. Patient-reported outcome measures (PROMs) were
sought in the identified literature and in a separate literature
search to explore patient perspectives. Outcome measures
were defined prior to the results of the search strategies. All
outcomes were defined in detail in Table 2.
Table 1. Specific clinical questions answered in this guideline.
Question Medical subject heading terms or keywords for searches
PICOS 1 Should patients with uncomplicated symptomatic gallstone disease be
offered observation or laparoscopic cholecystectomy?
Cholecystectomy, laparoscopy, gallbladder, resection, removal AND
Cholelithiasis, bile, biliary, calculi, cholecystolithiasis, choledocholithias,
gall, gallstone, lithiasis, lithogen, stone AND
Abdominal pain, ache, colic, cramp, pain, symptom
PICOS 2 Should patients with acute cholecystitis be offered acute or delayed
laparoscopic cholecystectomy?
Cholecystectomy, laparoscopy, gallbladder, resection, removal AND
Cholelithiasis, cholecystitis, empyema, inflammation, infection,
cholangiocholecystitis
PICOS 3 + 4
Should patients with acute cholecystitis be offered interval gallbladder
drainage before laparoscopic cholecystectomy?
Cholecystostomy, drainage, gallbladder emptying, gall, drain, empty,
aspirat, evacuation AND
Should high-risk patients with acute cholecystitis be offered gallbladder
drainage rather than acute laparoscopic cholecystectomy?
Cholelithiasis, cholecystitis, cholangiocholecystitis, empyema, gallbladder,
infection, inflammation
PICOS 5 + 6
Should patients with CBDS be offered laparoscopic or ERC removal
of CBDS with concomitant laparoscopic cholecystectomy as a one-
step procedure rather than ERC removal of CBDS with subsequent
laparoscopic cholecystectomy as a two-step procedure?
Cholecystectomy, laparoscopy, endoscopic retrograde
cholangiopancreatography, endoscopic sphincterotomy, cholangio,
endoscopic, ERC, rendezvous AND
Should high-risk patients with CBDS be offered CBDS removal without
rather than with cholecystectomy?
Cholelithiasis, biliary, bile, calculus, cholecystolithias, choledocholithias,
gall, gallstone, lithiasis, lithogen, stone
PICOS 7 Should patients with acute gallstone disease and suspicion of CBDS
have examination with MRCP or EUS rather than ERC or peroperative
cholangiography?
Cholangiography, tomography, ultrasonography, X-Ray computed,
cholangiopancreatography, CT, CAT, echography, echotomography,
endosonography, ERCP, EUS, imaging, MRC, MRI AND
Choledocholithiasis, gallstones, bile, biliary, gall, stone, or calculus, lithiasis,
lithogen
PICOS: patient, intervention, comparator, outcome, and study design; CBDS: common bile duct stones; ERC: endoscopic retrograde cholangiography; MRCP: magnetic
resonance cholangio-cholangiopancreatography; EUS: endoscopic ultrasound; ERCP: endoscopic retrograde cholangiopancreatography; MRI: magnetic resonance imaging. Most
strings also included: randomized controlled trial, controlled clinical trial, blind, placebo, or meta-analysis. Shorter versions of keywords and truncations were also used.
Shabanzadeh et al. 5
Results
A total of 58 original studies were identified and published
as 61 papers including 56 RCTs and two non-randomized
studies. Non-randomized studies were included to answer
PICOS three and four. PRISMA study flow-charts for all
seven PICOS are presented in the Supplemental Material
(Supplemental Material 2). During the study selection, we
decided not to include published systematic reviews and
meta-analyses as they did not match our defined outcomes,
were not up to date, or included non-randomized studies.
Multiple RCTs with comparable outcomes were identified
for PICOS 2, 5, 6, and 7 allowing meta-analyses to be con-
ducted. The remaining PICOS were answered by referencing
single studies qualitatively. Table 2 shows GRADE sum-
mary of findings for all PICOS, analyses, quality of evi-
dence, and reasons for downgrading at the outcome level. A
summarizing flowchart for the Danish clinical practice
guidelines is presented in Fig. 1.
Two studies were identified that specifically explored
patient preferences with PROMs using questionnaires.
One study included both emergency and elective surgery.
Patient satisfaction was not associated with traditional
clinical outcome measures, but with higher self-perceived
health, less patient-reported wound pain, and return to nor-
mal leisure activities.
28
In another study patients scored
long-term quality of life after emergency surgery as the
most important factor.
29
PROMs for specific treatments
are described in the individual recommendations below.
Lack of evidence with respect to PROMs prompted us to
try to anticipate patient preferences. Highest quality of
life, shortest length of stay and no readmissions were
appreciated.
Recommendation 1: Observation as an alternative to lap-
aroscopic cholecystectomy in patients with uncomplicated
gallstone disease is suggested.
(Weak recommendation, very low quality of evidence)
We included two original studies that were published as four
papers. The first study explored observation versus cholecys-
tectomy
30,31
and included a 14-year long-term follow-up
study.
32
The other study explored a restrictive strategy versus
usual care for cholecystectomy. The restrictive strategy
required presence of a five symptoms complex before chole-
cystectomy was offered: (1) severe pain attacks, (2) pain last-
ing 15–30 min or longer, (3) epigastric or right upper quadrant
pain, (4) pain radiating to the back, and (5) a positive pain
response to simple analgesics.
33
Only 72% of patients
remained in the restrictive strategy group in one study
33
and
only 49% in the observation group in the other study
32
whereas
most patients stayed in the usual care (98%)
33
and surgery
groups (88%).
32
Due to large cross-over in both studies, both
per-protocol and intention-to-treat analyses were performed.
One of the studies
30,32
was downgraded due risk of bias as
neither patients or outcome assessors were blinded and
imprecision due to the presence of only one study. The other
study was further downgraded due to indirectness since it did
not explore observation directly but a restrictive strategy.
33
Absence of pain was examined in one study exploring
restrictive strategy versus usual care.
33
No significant differ-
ences were identified. No differences in per-protocol and
intention-to-treat analyses were identified (very low quality
of evidence). Observation versus operation resulted in a sig-
nificant and clinically relevant reduction in rate of cholecys-
tectomies in the observation group at long-term follow-up
32
(moderate quality of evidence).
Readmissions and post-operative complications were
pooled in the analyses of this PICOS, and they were more
frequent in the observation group.
30,32
The difference was sig-
nificant in intention-to-treat analysis but not in per-protocol
analysis. Readmissions were largely due to uncomplicated
disease comprising 92% of readmissions in the observation
group and 89% in the surgery group.
No significant differences were found in reduction of pain
intensity or quality of life measured through the Psychological
General Well-Being Index at 60 months of follow-up,
31
but
with low quality of evidence due to the presence of one study
only. No specific studies explored patient preferences, but we
assume that patients prefer surgery due to the large cross-over
from observation to surgery in the studies.
Findings suggest no change in quality of life at long-term
follow-up of laparoscopic cholecystectomy compared to
observation. In accordance with an increasing rate of laparo-
scopic cholecystectomies in Denmark and a significant rate
of patients with persistent post-operative pain, we suggest an
observational strategy to reduce the number of procedures in
uncomplicated gallstone disease. Observation causes more
readmissions, but these are largely due to uncomplicated gall-
stone disease.
We recommend observation in presence of non-severe
symptoms, long interval between pain attacks, high age, or
presence of multimorbidity. Low quality of evidence and dis-
crepancy between presumed patient preferences and desira-
ble and undesirable effects, result in a weak recommendation.
Observation versus laparoscopic cholecystectomy in case of
symptoms that can be ascribed to uncomplicated gallstone
disease ultimately must involve shared decision holding.
Recommendation 2: Acute instead of delayed laparo-
scopic cholecystectomy for patients with acute cholecysti-
tis is recommended.
(Strong recommendation, moderate quality of evidence)
We included 16 original studies published as 17 papers. The
studies concerned either suspected or definitive acute chol-
ecystitis when graded according to the current Tokyo
6 Scandinavian Journal of Surgery
T
ab
le 2.
GRADE summar
y of f
indings.
Out
come
Comparat
or
Comparat
or
risk
Int
er
v
ention
Int
er
v
ention risk (risk
diff
er
ence (95% CI))
OR [95% CI]
Number of studies (n
umber
of par
ticipant
s)
Quality of e
vidence
Reasons f
or
do
wn
gradin
g
Re
commendation
summar
y
PICOS 1: Should patients with uncomplicated symptomatic gallstone disease be offered obs
ervation or laparoscopic cholecystectomy?
Absence of pain
Laparoscopic cholecystectomy
599 per 1000
Observation
562 per 1000 (–37 (–95; 23)
0.86 [0.68; 1.10]
1 study (1065)
Very low
Risk of bias, indirectness, imprecision
Uncertainty
Rate of cholecystectomies
882 per 1000
511 per 1000 (–371 (–572; –170))
0.14 [0.06; 0.33]
1 study (137)
Moderate
Imprecision
For intervention
Reduction of pain intensity (continuous)
–
–
No differences in pain scores
1 study (137)
Low
Risk of bias, imprecision
No important difference
Readmission with gallstone disease
a
279 per 1000
448 per 1000 (169 (6; 345)
2.10 [1.03; 4.28]
1 study (137)
Low
Risk of bias, imprecision
For comparator
Quality of life
–
No difference in Psychological general well- being index
–
1 study (137)
Low
Risk of bias, imprecision
No important difference
PICOS 2: Should patients with acute cholecystitis be offered acute or delayed laparoscopic
cholecystectomy?
Post-operative complications
Delayed laparoscopic cholecystectomy
229 per 1000
Acute laparoscopic cholecystectomy
196 per 1000 (–33 (–100; 54)
0.82 [0.50; 1.33]
14 studies (1555)
Moderate
Risk of bias
No important difference
Readmission with gallstone disease
265 per 1000
14 per 1000 (–251 (–261; –204)
0.04 [0.01; 0.18]
3 studies (349)
Moderate
Risk of bias
For intervention
Mortality
1 per 1000
1 per 1000 (0 (–1; 15)
1.03 [0.06–16.6]
9 studies (1347)
Moderate
Imprecision
Uncertainty
Conversion to open cholecystectomy
122 per 1000
124 per 1000 (2 (–26; 37)
1.02 [0.76; 1.36]
15 studies (1773)
High
None
No important difference
Length of stay
–
MD –2.43
days [–3.94;
–0.92]
–
7 studies (584)
Low
Risk of bias, inconsistency
For intervention
Quality of life
–
No difference in Psychological General Well-Being Index
–
1 study (145)
Low
Risk of bias, imprecision
No important difference
(Con
t
inu
ed)
Shabanzadeh et al. 7
Out
come
Comparat
or
Comparat
or
risk
Int
er
v
ention
Int
er
v
ention risk (risk
diff
er
ence (95% CI))
OR [95% CI]
Number of studies (n
umber
of par
ticipant
s)
Quality of e
vidence
Reasons f
or
do
wn
gradin
g
Re
commendation
summar
y
PICOS 3: Should patients with acute cholecystitis be offered interval gallbladder drainage be
fore laparoscopic cholecystectomy?
Non high-risk patients
Post-operative complications
Acute laparoscopic cholecystectomy
267 per 1000
Interval gallbladder drain and laparoscopic cholecystectomy
122 per 1000 (–145 (–212; –22)
0.38 [0.16; 0.89]
1 study (150)
Low
Risk of bias, imprecision
For intervention
Readmission with gallstone disease
0 per 1000
0 per 1000
–
1 study (150)
Low
Risk of bias, imprecision
Uncertainty
Mortality
0 per 1000
0 per 1000
–
1 study (150)
Moderate
Imprecision
Uncertainty
Conversion to open cholecystectomy
240 per 1000
28 per 1000 (–212 (–234; –130)
0.09 [0.02; 0.39]
1 study (150)
Moderate
Imprecision
For intervention
Length of stay
–
MD –1.17
days [–1.17;
–0.41]
–
1 study (150)
Low
Risk of bias, imprecision
No important difference
Quality of life
–
–
–
None
–
–
–
High-risk patients (subgroup)
Post-operative complications
229 per 1000
143 per 1000 (–86 (–184; 135)
0.56 [0.16; 1.93]
1 non-randomized study (70)
Very low
Risk of bias (ROBINS-I), imprecision
Uncertainty
Readmission with gallstone disease
–
–
–
None
–
–
–
Mortality
0 per 1000
0 per 1000
–
1 non-randomized study (70)
Very low
Risk of bias (ROBINS-I), Imprecision
Uncertainty
Conversion to open cholecystectomy
286 per 1000
84 per 1000 (–202 (–263; –12)
0.23 [0.06; 0.94]
1 non-randomized study (70)
Very low
Imprecision
For intervention
Length of stay
–
MD –4
days [–4.71; –3.29]
–
1 non-randomized study (70)
Very low
Risk of bias (ROBINS-I), imprecision
For intervention
Quality of life
–
–
–
None
–
–
–
(Con
t
inu
ed)
T
ab
le 2.
(Contin
ued)
8 Scandinavian Journal of Surgery
Out
come
Comparat
or
Comparat
or
risk
Int
er
v
ention
Int
er
v
ention risk (risk
diff
er
ence (95% CI))
OR [95% CI]
Number of studies (n
umber
of par
ticipant
s)
Quality of e
vidence
Reasons f
or
do
wn
gradin
g
Re
commendation
summar
y
PICOS 4: Should high-risk patients with acute cholecystitis be offered gallbladder drainage ra
ther than acute laparoscopic cholecystectomy?
Post-operative complications
Acute laparoscopic cholecystectomy
121 per 1000
Gallbladder drain
647 per 1000 (526 (308; 696)
13.3 [5.45; 32.4]
1 study (134)
Moderate
Imprecision
For comparator
Readmission with gallstone disease
45 per 1000
527 per 1000 (482 (196; 751)
23.6 [6.75; 82.7]
1 study (134)
Moderate
Imprecision
For comparator
Mortality
30 per 1000
87 per 1000 (57 (–12; 300)
3.10 [0.60; 15.9]
1 study (134)
Moderate
Imprecision
Uncertainty
Need for additional interventions
121 per 1000
661 per 1000 (540 (323; 706)
14.2 [5.80; 34.7]
1 study (134)
Moderate
Imprecision
For comparator
Length of stay
median
5
days
(IQR 4–8)
median 9
days (IQR 6–19)
(p
<
0.001)
–
1 study (134)
Moderate
Imprecision
For comparator
Quality of life
–
–
–
None
–
–
–
EUS-guided gallbladder drainage
Post-operative complications
133 per 1000
133 per 1000 (0 (–99; 272)
1.00 [0.23; 4.43]
1 non-randomized study (60)
Very low
Risk of bias, imprecision
Uncertainty
Readmission with gallstone disease
100 per 1000
100 per 1000 (0 (–79; 275)
1.00 [0.19; 5.40]
1 non-randomized study (60)
Very low
Risk of bias, imprecision
Uncertainty
Mortality
0 per 1000
0 per 1000
5.35 [0.25; 116.3]
1 non-randomized study (60)
Very low
Risk of bias, imprecision
Uncertainty
Need for additional interventions
100 per 1000
133 per 1000 (33 (–70; 330)
1.38 [0.28; 6.80]
1 non-randomized study (60)
Very low
Risk of bias, imprecision
Uncertainty
Length of stay
–
MD 1.30
days [–1.76; 4.36]
–
1 non-randomized study (60)
Very low
Imprecision
Uncertainty
Quality of life
–
–
–
None
–
–
–
(Con
t
inu
ed)
T
ab
le 2.
(Contin
ued)
Shabanzadeh et al. 9
Out
come
Comparat
or
Comparat
or
risk
Int
er
v
ention
Int
er
v
ention risk (risk
diff
er
ence (95% CI))
OR [95% CI]
Number of studies (n
umber
of par
ticipant
s)
Quality of e
vidence
Reasons f
or
do
wn
gradin
g
Re
commendation
summar
y
PICOS 5: Should patients with CBDS be offered laparoscopic or ERC removal of CBDS with
concomitant laparoscopic cholecystectomy as a one-step procedure rather than ERC removal of CBDS with subsequent laparoscopic
cholecystectomy as a two-step procedure? Post-operative complications
Two-step procedure (ERC removal of CBDS and laparoscopic cholecystectomy)
142 per 1000
One-step procedure (ERC or laparoscopic removal of CBDS with laparoscopic cholecystectomy)
97 per 1000 (–45 (–70; –12)
0.65 [0.47; 0.90]
22 studies (2519)
Moderate
Risk of bias
For intervention
Readmission with gallstone disease
60 per 1000
32 per 1000 (–28 (–43; –2)
0.51 [0.27; 0.96]
10 studies (1250)
Moderate
Risk of bias
For intervention
Mortality
12 per 1000
9 per 1000 (–3 (–8; 11)
0.78 [0.31; 1.96]
14 studies (1967)
Moderate
Imprecision
Uncertainty
Need for additional interventions
117 per 1000
47 per 1000 (–70 (–94; –24)
0.37 [0.18; 0.77]
11 studies (1237)
Moderate
Risk of bias
For intervention
Successful CBDS removal
889 per 1000
930 per 1000 (41 (13; 61)
1.65 [1.15; 2.37]
21 studies (2401)
Moderate
Risk of bias
For intervention
Length of stay
–
MD –2.97
days [–4.42;
–1.52]
–
9 studies (824)
Low
Risk of bias, inconsistency
For intervention
Quality of life
–
No difference in SF-36
–
1 study (112)
Low
Risk of bias, imprecision
No important difference
PICOS 6: Should high-risk patients with CBDS be offered CBDS removal without rather th
an with cholecystectomy?
Post-operative complications
CBDS removal with cholecystectomy
180 per 1000
CBDS removal without cholecystectomy
118 per 1000 (–62 (–112; 16)
0.61 [0.33; 1.11]
3 studies (356)
Low
Risk of bias, imprecision
Uncertainty
Readmission with gallstone disease
54 per 1000
255 per 1000 (–201 (102–334)
6.01 [3.25; 11.1]
4 studies (518)
Moderate
Risk of bias
For comparator
Mortality
137 per 1000
205 per 1000 (69 (–11; 179)
1.63 [0.91; 2.91]
5 studies (534)
Moderate
Imprecision
Uncertainty
Need for additional interventions
73 per 1000
335 per 1000 (262 (85–500)
6.39 [2.39; 17.1]
3 studies (356)
Moderate
Risk of bias
For comparator
Length of stay
–
MD –5.02
days (–6.50;
–3.54)
–
2 studies (276)
Moderate
Risk of bias
For intervention
Quality of life
–
No difference in MOS-24
–
1 study (108)
Very low
Risk of bias, indirectness, imprecision
Uncertainty
T
ab
le 2.
(Contin
ued)
(Con
t
inu
ed)
10 Scandinavian Journal of Surgery
Out
come
Comparat
or
Comparat
or
risk
Int
er
v
ention
Int
er
v
ention risk (risk
diff
er
ence (95% CI))
OR [95% CI]
Number of studies (n
umber
of par
ticipant
s)
Quality of e
vidence
Reasons f
or
do
wn
gradin
g
Re
commendation
summar
y
PICOS 7: Should patients with acute gallstone disease and suspicion of CBDS have examina
tion with MRCP or EUS rather than ERC or peroperative cholangiography?
CBDS diagnosis
ERC or peroperative cholangiography
313 per 1000
MRCP or EUS
290 per 1000 (–22 (–121; 102)
0.90 [0.52; 1.56]
8 studies (943)
Moderate
Risk of bias
No important difference
Adverse events to diagnostic examination
149 per 1000
10 per 1000 (–139 (–147; –91)
0.06 [0.01; 0.35]
3 studies (338)
Moderate
Risk of bias
For intervention
Pooled adverse events to diagnostic and therapeutic examination
115 per 1000
62 per 1000 (–53 (–87; 15)
0.51 [0.22; 1.15]
7 studies (880)
Low
Risk of bias, imprecision
Uncertainty
Need for additional therapeutic/diagnostic examinations
324 per 1000
414 per 1000 (91 (–67; 270)
1.48 [0.72; 3.05]
7 studies (843)
Very low
Risk of bias, inconsistency, imprecision
Uncertainty
Readmission with gallstone disease
60 per 1000
76 per 1000 (16 (–16; 68)
1.29 [0.72; 2.31]
7 studies (880)
Low
Risk of bias, imprecision
Uncertainty
CBDS: common bile duct stone; CI: confidence interval; ERC: endoscopic retrograde cholang
iography; EUS: endoscopic ultrasound; IQR: interquartile range; MD: mean difference; MRCP: magnetic resonance
cholangiopancreatography; OR: odds ratio. Critical outcomes are marked with
italics.
a
Post-operative complications and readmissions with gallstone disease were pooled in this o
utcome.
T
ab
le 2.
(Contin
ued)
guidelines. The preoperative maximum patient-reported
symptom duration was 7,
34–40
5,
41,42
3 days,
43–46
or was not
reported.
47–50
All studies intended laparoscopic cholecystec-
tomy. The intervention constituted a conservative approach
with delayed surgery after 6–8 weeks. Most studies excluded
high-risk patients defined as those deemed unfit for surgery
due to high age, comorbidities, an American Society of
Anesthesiologists (ASA) score of more than 3, sepsis, or
severe acute cholecystitis according to the Tokyo guide-
lines. Studies were published in 1998 to 2016 from
Asia (India, Pakistan, and Hong Kong),
34,35,37–39,41–44,50
Europe,
36,40,46,47,49
and the Middle East.
45,48
No studies reported blinding of outcome assessment and
most studies reported insufficiently on follow-up measures or
completeness. There is a risk of bias across studies for most
outcomes, and we downgraded to moderate for critical out-
comes. Meta-analyses were performed for all outcomes
except for quality of life.
No significant differences in post-operative complications
were identified (Fig. 2). Estimates were accurate and indi-
cated no true clinical important difference. Readmissions
were much less frequent in the acute surgery group and the
difference was significant (moderate quality of evidence) and
clinically relevant.
Length of stay was shorter with acute surgery, and no sig-
nificant or clinically relevant differences were found for con-
version to open surgery. Eight studies reported no mortalities
and one study reported one death in each group,
47
resulting in
a mortality proportion of less than 0.1%. No significant dif-
ferences in Psychological General Well-Being Index after
6 months were noted in one study assessing quality of life.
40
Estimates for mortality and quality of life were not signifi-
cantly different between the treatment arms.
Subgroup analysis of preoperative maximum patient-
reported symptom duration showed no differences in signifi-
cance levels compared to the original meta-analysis for
post-operative complications (Fig. 2), readmissions, and con-
version to open surgery. Length of stay was significantly
shorter for acute surgery in all subgroups, except for studies
that did not report symptom duration (data not shown).
Patient perspectives were explored in one of the included
studies through non-validated measures showing higher
patient satisfaction for acute surgery.
45
Meta-analysis con-
firmed that delayed surgery causes readmissions, and we thus
assume that patients prefer acute rather than delayed laparo-
scopic cholecystectomy.
The strong recommendation in favor of acute laparoscopic
cholecystectomy is largely based on fewer readmissions and
non-inferiority regarding post-operative complications.
Preoperative maximum patient-reported symptom duration
does not seem to have an impact on post-operative complica-
tions and should not influence the choice of treatment. In case
of acute laparoscopic cholecystectomy, we recommend sur-
gery as soon as possible, but only when a competent surgeon
is present and preferably during daytime.
Shabanzadeh et al. 11
Recommendation 3: Consider percutaneous transhepatic
gallbladder drainage as an interval procedure until delayed
laparoscopic cholecystectomy in patients with acute chol-
ecystitis and temporary contraindications to surgery.
(Weak recommendation, very low quality of evidence)
We included one RCT and one non-randomized retrospective
study. The RCT included high-risk and non-high-risk patients
with moderate acute cholecystitis according to the Tokyo
guidelines and a preoperative patient-reported symptom
duration of more than 72 hours.
51
The non-randomized retro-
spective study included high-risk patients defined as age
65 years or more, morbidities, severe acute cholecystitis
according to the Tokyo guidelines, assessed as unfit for sur-
gery, and without a sufficient response to an initial conserva-
tive approach. The interval drainage group was matched with
a similar acute laparoscopic cholecystectomy group.
52
The
study was included to represent high-risk patients, as the
option for drainage often is considered in this subgroup. Both
studies included ultrasound-guided percutaneous transhe-
patic gallbladder drainage and delayed laparoscopic chole-
cystectomy after 6–10 weeks compared to acute laparoscopic
cholecystectomy. No meta-analyses were performed due to
differences in study designs.
Quality of evidence of the RCT was low, due to risk of
bias because of no reporting of allocation sequence, no
blinding of outcome assessment, and due to the presence of
only one study, causing imprecision. Quality of the non-ran-
domized study was downgraded due to risk of bias according
to ROBINS-I for measurements of outcome. Further down-
grading was for imprecision due to the presence of only one
study with wide CIs for critical outcomes.
A significant and clinically relevant reduction in post-
operative complications occurred in the interval drainage
group. The estimate for readmissions was uncertain (low
quality of evidence).
Conversion to open surgery was significantly decreased in
the interval drainage group and assessed as clinically rele-
vant. Estimate for mortality was uncertain and no important
difference was found for length of stay.
In the subgroup of high-risk patients, estimates for post-
operative complications were uncertain (very low quality of
evidence). Conversion to open surgery and length of stay
were significantly decreased in the drainage group and
assessed as clinically relevant. The estimate for mortality was
uncertain.
No studies reported quality of life or patient preferences.
We assume that interval drainage may cause patient discom-
fort as the catheter is left in situ for several weeks while the
patient is at home. Our clinical experience is that drainage
treatment may cause several readmissions due to catheter-
related dysfunction.
Fig. 1. The Danish clinical practice guidelines for treatment of symptomatic gallstone disease flowchart.
AC: acute cholecystitis; CBDS: common bile duct stones; EUS: endoscopic ultrasound; LC: laparoscopic cholecystectomy; MRCP: magnetic resonance
cholangiopancreatography.
12 Scandinavian Journal of Surgery
We generally recommend acute laparoscopic cholecystec-
tomy for patients with acute cholecystitis (see recommenda-
tion 2) including high-risk patients (see recommendation 4).
Currently available literature on gallbladder drainage as a
bridge to surgery does not sufficiently address critical out-
comes as post-operative complications and readmissions and
especially not for high-risk patients. But studies do, however,
suggest that interval drainage may result in fewer post-opera-
tive complications, fewer conversions to open surgery, and
may reduce length of stay. The mechanism may be infection
control by drainage, resulting in preoperative optimization of
the frail high-risk patient. We suggest that clinicians may
consider interval drainage as an option in the presence of
severe acute cholecystitis in high-risk patients with advanced
age, low performance score, or multi-morbidity. The clinical
case may be represented by the frail patient with severe acute
cholecystitis admitted at the intensive care unit or with the
need for intensive care treatment but deemed unfit.
Recommendation 4: Acute laparoscopic cholecystec-
tomy in favor of gallbladder drainage in high-risk patients
with acute cholecystitis is suggested.
(Weak recommendation, low quality of evidence)
We included one RCT and one non-randomized retrospective
cohort study. The RCT included high-risk patients defined as
an APACHE II score of 7–14. APACHE II is a scoring system
prediction of mortality based on 12 acute physiological
parameters, age, and morbidities. Intervention was ultra-
sound-guided percutaneous gallbladder catheter for at least 3
weeks.
53
The non-randomized study included high-risk
patients defined as age of 80 years or more, ASA score of 3 or
above, a Charlson comorbidity index of 5 or above or a
Karnofsky score of 50 or below. Propensity score matching
was performed on these baseline variables. Intervention was
an EUS-guided drain placed between the gallbladder and the
duodenum (lumen-apposing metal stent). Most patients had
Fig. 2. Subgroup analysis of preoperative maximum patient-reported symptom duration and post-operative complications
following acute versus delayed laparoscopic cholecystectomy for patients with acute cholecystitis (PICOS 2)
Shabanzadeh et al. 13
moderate acute cholecystitis.
54
The comparator was acute
laparoscopic cholecystectomy in both studies.
53,54
The non-
randomized study was included to explore the impact of a
novel EUS-guided technique compared to conventional per-
cutaneous drainage.
Quality of evidence of the RCT was high with no risk of
bias but we downgraded to moderate due to the presence of
only one study causing imprecision. Quality of the non-rand-
omized study was downgraded due to risk of bias according
to ROBINS-I for missing data and for difference in follow-up
lengths in measurements of outcome. The study was further
downgraded for imprecision due to the presence of only one
study with wide CIs.
Percutaneous gallbladder drainage caused a significant
and highly clinically relevant increase in post-operative com-
plications and readmissions. Estimate for mortality was
uncertain (moderate quality of evidence).
Both the need for additional interventions and length of
stay were significantly higher in the drainage group.
Intervention with EUS-guided gallbladder drainage
caused uncertain estimates for both critical and non-critical
outcomes (very low quality of evidence).
No identified studies explored PROMs. Due to increased
post-operative complications, readmissions, and need for
additional interventions as well as increased length of stay,
we believe that most high-risk patients with acute cholecysti-
tis would decline percutaneous gallbladder drainage if they
were well-informed.
The decision not to recommend percutaneous gallbladder
drainage is based on the highly clinically relevant and signifi-
cantly higher risk of post-operative complications and read-
missions in frail high-risk patients.
Recommendation 5: Laparoscopic cholecystectomy
combined with laparoscopic or ERC-assisted CBDS
removal as a one-step procedure rather than a two-step
procedure in patients with imaging confirmed CBDS is
recommended.
(Strong recommendation, moderate quality of evidence)
We included 22 original studies. Fourteen studies included
patients with CBDS confirmed by MRCP, EUS, or ERC
15,55–67
and eight with merely clinical suspicion of CBDS.
14,68–74
Most
studies excluded high-risk patients defined as an ASA score of
3 or above, age of 70 years or more, cardiac or pulmonary mor-
bidity or otherwise defined as unfit for surgery. Only one study
exclusively included high-risk patients.
14
Control groups
underwent laparoscopic cholecystectomy performed during
the same admission or up to 8 weeks after ERC with CBDS
removal. One-step interventions varied between studies
? Laparoscopic common bile duct exploration with
cholecystectomy (LCBDE) in 14
studies.
14,15,55,56,58,60,62,66,68–71,73,74
? Rendezvous technique where a guidewire is inserted
through the cystic and common bile duct at laparo-
scopic cholecystectomy to facilitate simultaneous
ERC and CBDS removal in five studies.
59,63,65,67,72
? Laparoscopic cholecystectomy and concomitant ERC
and CBDS removal without a guidewire (non-rendez-
vous) in three studies.
57,61,64
? No report on how the one-step procedure with ERC
was performed in one study.
69
Studies were published between 1999 and 2020 from
Europe,
14,59,63,67,70–72,74
Asia,
15,55,56,60–62,65
the Middle East,
57,58,64,66
South or Middle America,
68,69
and North America.
73
No studies reported blinding of outcome assessment, and
most studies did not report sufficiently on follow-up meas-
ures or completeness causing a risk of bias across studies for
most outcomes. Quality of evidence was downgraded to
moderate for critical outcomes. Meta-analyses were per-
formed for all outcomes except for quality of life.
One-step procedures reduced post-operative complica-
tions and readmissions significantly and clinically relevant
(moderate quality of evidence).
The need for additional interventions was significantly
lower and the rate of successful CBDS removal higher for the
one-step procedure. Mortality was reported in 14 studies and
20 deaths occurred in six studies resulting in a mortality pro-
portion of approximately 1%. No significant differences were
found for mortality. Length of stay was significantly less with
the one-step procedure and assessed as clinically relevant.
Only one study reported quality of life measured through the
Short Form 36 for LCBDE versus the two-step procedure and
no significant differences were found.
73
Subgroup analysis revealed that patients with CBDS imag-
ing confirmation experienced significantly fewer post-opera-
tive complications (OR 0.57, CI 95% 0.40–0.83; Fig. 3), less
need for additional interventions (OR 0.31, CI 95% 0.12–
0.79), and higher rate of successful CBDS removal (OR 1.87,
CI 95% 1.22–2.86) following the one-step procedure just like
in the original meta-analysis. In the group without imaging
confirmation, a substantial number of patients did not have
CBDS at surgery and meta-analyses showed more non-signif-
icant estimates and substantial heterogeneity (data not shown).
Estimates from the group without imaging confirmed CBDS
were inconsistent and uncertain.
One-step interventions resulted in higher patient satisfaction
in two studies using unvalidated measures.
15,66
We assume that
patient preferences are in favor of the one-step interventions.
We strongly recommend a one-step procedure based
mainly on a lower risk of post-operative complications,
readmissions, but also on the higher rate of CBDS clearance
and lesser need for additional interventions. The one-step
procedure is currently not standard treatment at all hospitals
and thorough staff training should be pursued prior to
implementation.
14 Scandinavian Journal of Surgery
Recommendation 6: Laparoscopic cholecystectomy in
addition to the treatment of high-risk patients with
CBDS is suggested.
(Weak recommendation, low quality of evidence)
We included six original studies. High-risk patients were
defined as age above 60 or 75 years,
75,76
age above 70 years
and morbidity,
77
age above 75 years and ASA score of 3 or
above,
78
or presence of either body mass index above 30 kg/m
2
,
age above 70 years, or a severe degree of morbidity.
79
ERC
confirmation of CBDS prior to inclusion of patients was per-
formed in three studies,
75,76,79
one study included patients
based only on clinical suspicion of CBDS,
78
and one study did
not specify preoperative CBDS diagnosis.
77
All five studies
reported interventions with ERC and sphincterotomy for
CBDS removal. Control group treatments varied and included:
? Open surgical common bile duct exploration with
cholecystectomy in three studies.
76,78,79
? ERC and laparoscopic cholecystectomy after 11 weeks
in one study.
75
? No report of control group cholecystectomy method in
one study.
77
One supplemental study reported PROMs, but included
patients were not high-risk and therefore only results for
quality of life were included.
80
No studies reported blinding of outcome assessment and
most studies did not report sufficiently on follow-up meas-
ures or completeness causing a risk of bias across studies for
most outcomes. Quality of evidence was downgraded to
moderate for critical outcomes. Meta-analyses were per-
formed for all outcomes except for quality of life.
Fig. 3. Subgroup analysis of imaging confirmed CBDS and post-operative complications following one-step versus two-step
procedures for patients with CBDS (PICOS 5).
Shabanzadeh et al. 15
No significant differences were found for post-operative
complications (low quality of evidence) and mortality, but
estimates were imprecise and uncertain and therefore down-
graded. Mortality proportions were 20% in the group with no
cholecystectomy and 14% in the group with cholecystec-
tomy. Significantly higher rate of readmissions was found in
the non-cholecystectomy group which was assessed as clini-
cally relevant (moderate quality of evidence).
The need for additional interventions was significantly
higher and length of stay was shorter in the no cholecystec-
tomy group. Quality of life measured with MOS-24, which is
a shorter version of the Short Form 36, showed no significant
differences between groups, but estimates were uncertain due
to imprecision, indirectness of evidence, and risk of bias
causing a very low quality.
Subgroup analysis showed that the group with imaging
confirmed CBDS had a significantly higher mortality of 24%
with no cholecystectomy compared to 13% in the cholecys-
tectomy group (Fig. 4). The other estimates were not scien-
tifically different when compared to the original meta-analyses
(data not shown).
Quality of life could not be explored for high-risk patients.
We assume that most high-risk patients prefer cholecystec-
tomy in addition to CBDS removal, given a higher risk of
readmission, additional interventions, and probably a higher
risk of mortality without cholecystectomy. On the contrary,
some patients may not want to run the immediate risk of sur-
gery to avoid uncertain future complications and therefore
abstain from cholecystectomy at first CBDS presentation. We
expect variation in patient preferences.
The decision to suggest cholecystectomy to high-risk
patients with CBDS is based on lower risk of readmissions
and the possible lower risk of mortality. The recommendation
is weak since two critical outcomes have uncertain estimates.
Recommendation 7: The use of MRCP or EUS for diag-
nosis of CBDS prior to surgical treatment of patients with
gallstone disease is recommended.
(Strong recommendation, low quality of evidence)
We included eight original studies concerning patients with
gallbladder stones and intermediate risk of CBDS, defined
as either elevated bilirubin and/or dilated bile duct on
ultrasound,
81–84
mild gallstone pancreatitis,
85,86
elevated liver
enzymes,
87
or presence of one of the mentioned risk factors.
88
All studies excluded patients with high risk of CBDS such as
presence of cholangitis, sepsis, or imaging confirmed CBDS.
EUS versus ERC was explored in five studies,
81,83–85,88
EUS
versus peroperative cholangiography in one study,
87
MRCP
versus ERC in one study,
82
and MRCP versus peroperative
cholangiography in one study.
86
In all studies, CBDS were
removed by ERC. Pooled adverse events were reported for
diagnostic examination, CBDS removal, and CBDS disease in
most studies. Only three studies reported on adverse events for
the diagnostic examination separately and all used EUS.
84,85,88
PICO 7 was intended as a diagnostic question and analyses
were therefore reported for both the pooled rates of adverse
events and adverse events related to examination only.
Most studies did not report blinding of outcome assess-
ment or report sufficiently on follow-up measures causing a
Fig. 4. Subgroup analysis of imaging confirmed CBDS and mortality following CBDS clearance without versus with
cholecystectomy for high-risk patients with CBDS (PICOS 6).
16 Scandinavian Journal of Surgery
risk of bias across studies for most outcomes. Quality of evi-
dence was downgraded to moderate for critical outcomes.
Meta-analyses were performed for all outcomes.
There were no important differences in CBDS diagnosis
between MRCP/EUS and cholangiographic examinations
(moderate quality of evidence). Rates of pooled adverse
events for examination, treatment, and disease were uncertain
for EUS and cholangiographic examinations (low quality of
evidence). There were significantly lower rates of adverse
events for EUS compared to cholangiographic examinations,
and it was assessed as clinically relevant (moderate quality of
evidence).
Estimates for additional examinations and readmissions
were not significantly different between groups. Estimates
for additional examinations had high heterogeneity and were
therefore further downgraded for inconsistency. Estimates for
both outcomes were uncertain.
Subgroup analyses of the intervention group examinations
showed less frequent adverse events for EUS (OR 0.41, CI 95%
0.17–0.99) and no significant difference for MRCP (OR 1.37,
CI 95% 0.42–4.42). Need for additional examinations was
higher with MRCP when compared to cholangiography (OR
2.53, CI 95% 1.13–5.69), and no significant differences were
found for EUS (OR 1.28, CI 95% 0.52–3.12). Subgroup analy-
ses of the control groups with peroperative cholangiography
and ERC showed lower rates of adverse events with MRCP/
EUS when ERC was the control group (OR 0.40, CI 95% 0.18–
0.89) and no significant differences when peroperative cholan-
giography was the control group (OR 1.87, CI 95% 0.51–6.85).
No differences were seen for need for additional treatments.
No studies reported patient preferences for diagnosis of
CBDS. We assume that patients prefer MRCP or EUS as the
least-invasive examinations, with a minimum of discomfort
and risk of complications.
The decision to recommend MRCP or EUS in favor of
ERC to diagnose CBDS was based on a higher risk of adverse
events for ERC and on a comparable diagnostic yield in case
of intermediate CBDS risk. Hospitals may choose between
MRCP or EUS depending on local availability. ERC should
not be used for diagnostic purpose only. Peroperative cholan-
giography may be used for diagnosis at the discretion of the
surgeon. However, we generally recommend MRCP or EUS
for CBDS diagnosis prior to surgery for gallstone disease.
Discussion
We have reported seven recommendations for treatment of
gallstone disease. Three recommendations are strong and
four are weak due to a lack of published studies. We suggest
several areas of interest for future research.
Treatment with gallbladder drainage for acute cholecys-
titis in high-risk patients was found to increase readmis-
sions and complications. A large British non-randomized
study of high-risk patients with acute cholecystitis con-
firmed that about half of patients initially treated with
gallbladder drainage subsequently experienced readmission
due to gallstone disease and that drainage or conservative
treatment may result in higher mortality when compared to
cholecystectomy.
89
A recent RCT suggested that EUS-
guided gallbladder drainage may be superior to percutane-
ous drainage in high-risk patients.
90
EUS-guided drainages
may serve as a treatment of high-risk patients with acute
cholecystitis. Future RCTs should compare laparoscopic
cholecystectomy and EUS-guided drainage and explore the
feasibility of EUS-guided drainages in an emergency set-
ting. There was a general paucity in published studies on
gallbladder drainage for acute cholecystitis and more stud-
ies are needed to make stronger recommendations. Further
research is also needed to determine if interval drainage as
a bridge to surgery is a useful tool in high-risk patients.
Subgroup analyses of patients with acute cholecystitis
showed that the preoperative maximum patient-reported
symptom duration, does not predict the development of com-
plications following acute laparoscopic cholecystectomy and
should therefore not influence treatment choices. Large data-
base studies have shown that increased length of preoperative
admission is associated with post-operative complications,
bile duct injuries, mortality, conversion to open surgery, reop-
erations, and length of stay.
91,92
If laparoscopic cholecystec-
tomy is indicated, we recommend surgery as soon as possible
and, preferably, during daytime and when appropriate surgi-
cal competency is available.
The one-step compared to the two-step procedures for
treatment of high-risk patients with CBDS have only been
explored in one RCT included in this guideline,
14
and more
studies are needed. We suggest that laparoscopic cholecystec-
tomy should be added to the treatment of high-risk patients
with CBDS to reduce readmission and possibly mortality.
However, all except one of the included RCTs have outdated
interventions such as open cholecystectomy with surgical
exploration of the common bile duct. Non-randomized stud-
ies of high-risk patients treated with CBDS removal also sug-
gest that laparoscopic cholecystectomy is performed to
decrease complications, readmissions, and the need of addi-
tional interventions.
93,94
Future RCTs should explore mini-
mally invasive one-step procedures (recommendation 5)
versus CBDS removal without laparoscopic cholecystectomy
in high-risk patients.
Symptomatic uncomplicated gallstone disease comprises
a large group of the patients undergoing laparoscopic chole-
cystectomy, but only two RCTs were identified exploring
observation or a restrictive patient selection for surgery. More
studies should explore observation or patient selection strate-
gies for cholecystectomy. A large ongoing RCT from the
United Kingdom exploring observation versus surgery is
expected to be published soon.
95
The use of MRCP for diagnosis of CBDS was only
explored in two studies. Since MRCP is the least-invasive
examination for CBDS, we suggest that more studies are per-
formed in the future. A large ongoing RCT from the United
Shabanzadeh et al. 17
Kingdom exploring MRCP versus observation is expected to
be published in some years.
96
Most studies were not published in Denmark or
Scandinavia and one may therefore question if they are repre-
sentative for treatments performed at Danish hospitals. For
patients with acute cholecystitis and treated with laparoscopic
cholecystectomy, conversion to open surgery was 12% and
post-operative complications 20% in our meta-analyses.
Estimates for mortality are generally low but were also uncer-
tain in our included data (0.1%) due to overall low number of
patients (Recommendation 2, Table 2). A Danish database
study from the period 2006–2011 shows a conversion rate of
15%
97
and a mortality of 1.2%.
98
A Swedish database study
from 2006 to 2014 shows post-operative complications in
12%.
91
The operative and post-operative courses of patients
undergoing laparoscopic cholecystectomy for acute chole-
cystitis in our meta-analysis were thereby comparable to
observational data from Denmark and Sweden. No
Scandinavian observational data on one versus two-step pro-
cedures for treatment for CBDS were identified.
Generally, most studies reported no blinding of outcome
assessment and many did not report sufficiently on follow-up
measures or completeness causing a risk of bias. Future stud-
ies should be performed according to current recommenda-
tions for high-quality evidence. Quality of life or PROMs
were rarely explored in any of the included studies. Patient
preferences for high-risk populations are unexplored. We
highly recommend the inclusion of PROMs in future RCTs of
treatment for gallstone disease.
Strengths in this guideline development include the multi-
disciplinary working group which represent all specialties
and all five Danish regions involved in the treatment of
patients with gallstone disease. Limitations include sparsely
reported patient preferences in identified studies, and we did
not include relevant patient groups to explore patient prefer-
ences any further.
Acknowledgements
The authors thank Henning Keinke Andersen from the Danish
Health Authorities for cooperation during the entire process, meth-
odology consultant Jeanett Friis Rohde from The Parker Institute for
method supervision and analyses, information specialist Sarah
Louise Klingenberg at the Cochrane Hepato-Biliary Group for per-
forming search strategies and literature searches, and Karin M?nsted
Shabanzadeh for language editing.
Author contributions
DMS contributed to the design, acquisition of data, analyses, inter-
pretation of results, and drafting of the manuscript. The remaining
authors contributed to the design, acquisition of data, interpretation
of results, and critical review of manuscript.
Consent
No new patients were involved in this study and therefore no con-
sent required.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Ethical approval
No ethical statement required since no new data were collected from
individuals.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
work was supported financially by the Danish Health Authorities.
The Danish Health Authorities accepted the PICOS that the work
group had defined, but otherwise had no roles in guideline develop-
ment, dissemination, or implementation of the recommendations.
ORCID iD
Daniel M?nsted Shabanzadeh https://orcid.org/0000-0001-9415-
3443
Supplemental material
Supplemental material for this article is available online.
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