Tokyo guidelines for cholangitis and cholecystitis

J Hepatobiliary Pancreat Surg (2007) 14:1–10
DOI 10.1007/s00534-006-1150-0
Background: Tokyo Guidelines for the management of acute
cholangitis and cholecystitis
Tadahiro Takada1
, Yoshifumi Kawarada2
, Yuji Nimura3
, Masahiro Yoshida1
, Toshihiko Mayumi4
,
Miho Sekimoto5
, Fumihiko Miura1
, Keita Wada1
, Masahiko Hirota6
, Yuichi Yamashita7
, Masato Nagino3
,
Toshio Tsuyuguchi8
, Atsushi Tanaka9
, Yasutoshi Kimura10
, Hideki Yasuda11
, Koichi Hirata10
,
Henry A. Pitt12
, Steven M. Strasberg13
, Thomas R. Gadacz14
, Philippus C. Bornman15
, Dirk J. Gouma16
,
Giulio Belli17
, and Kui-Hin Liau18
1
Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
2
Mie University School of Medicine, Mie, Japan
3
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
4
Department of Emergency Medicine and Intensive Care, Nagoya University School of Medicine, Nagoya, Japan
5
Department of Healthcare Economics and Quality Management, Kyoto University Graduate School of Medicine, School of Public Health,
Kyoto, Japan
6
Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Science, Kumamoto, Japan
7
Department of Surgery, Fukuoka University Hospital, Fukuoka, Japan
8
Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
9
Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
10
First Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
11
Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan
12
Department of Surgery, Indiana University School of Medicine, Indianapolis, USA
13
Department of Surgery, Washington University in St Louis and Barnes-Jewish Hospital, St Louis, USA
14
Department of Gastrointestinal Surgery, Medical College of Georgia, Georgia, USA
15
Division of General Surgery, University of Cape Town, Cape Town, South Africa
16
Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
17
General and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy
18
Department of Surgery, Tan Tock Seng Hospital / Hepatobiliary Surgery, Medical Centre, Singapore
work required more than 20 meetings to obtain a consensus
on each item from the working group. Then four forums were
held to permit examination of the Guideline details in Japan,
both by an external assessment committee and by the working
group participants (version 2). As we knew that the diagnosis
and management of acute biliary infection may differ from
country to country, we appointed a publication committee and
held 12 meetings to prepare draft Guidelines in English (ver-
sion 3). We then had several discussions on these draft guide-
lines with leading experts in the ﬁeld throughout the world,
via e-mail, leading to version 4. Finally, an International Con-
sensus Meeting took place in Tokyo, on 1–2 April, 2006, to
obtain international agreement on diagnostic criteria, severity
assessment, and management.
Key words Cholangitis · Cholecystitis · Charcot’s triad ·
Reynold’s pentad · Biliary drainage
Introduction
No guidelines focusing on the management of biliary
infection (cholangitis and cholecystitis) have previously
been published, and no worldwide criteria exist for
diagnostic and severity assessment. “Charcot’s triad”1
is
still used for the diagnosis of acute cholangitis. How-
Abstract
There are no evidence-based-criteria for the diagnosis, sever-
ity assessment, of treatment of acute cholecysitis or acute
cholangitis. For example, the full complement of symptoms
and signs described as Charcot’s triad and as Reynolds’ pen-
tad are infrequent and as such do not really assist the clinician
with planning management strategies. In view of these factors,
we launched a project to prepare evidence-based guidelines
for the management of acute cholangitis and cholecystitis that
will be useful in the clinical setting. This research has been
funded by the Japanese Ministry of Health, Labour, and Wel-
fare, in cooperation with the Japanese Society for Abdominal
Emergency Medicine, the Japan Biliary Association, and the
Japanese Society of Hepato-Biliary-Pancreatic Surgery. A
working group, consisting of 46 experts in gastroenterology,
surgery, internal medicine, emergency medicine, intensive
care, and clinical epidemiology, analyzed and examined the
literature on patients with cholangitis and cholecystitis in or-
der to produce evidence-based guidelines. During the investi-
gations we found that there was a lack of high-level evidence,
for treatments, and the working group formulated the guide-
lines by obtaining consensus, based on evidence categorized
by level, according to the Oxford Centre for Evidence-Based
Medicine Levels of Evidence of May 2001 (version 1). This
Offprint requests to: T. Takada
Received: May 31, 2006 / Accepted: August 6, 2006

2 T. Takada et al.: Background of Tokyo Guidelines
ever, these criteria were first proposed in 1877 (level 4),
more than 100 years ago. Here, and throughout the se-
ries, levels of evidence are stated for referenced articles
in accordance with the Oxford Centre for Evidence-
Based Medicine Levels of Evidence of May 2001 (see
Table 1). However only 50%–70% of cholangitis pa-
tients present clinically with Charcot’s triad.2–8
In addi-
tion, Murphy’s sign9
(level 5) is useful (sensitivity of
50%–70% and specificity of 79%–96%) in diagnosing
cholecystitis, and this sign is widely used in every coun-
try. Moreover, as many of the symptoms and concepts
of these diseases referred to in textbooks and reference
books vary from those originally stated, the issue of
worldwide criteria is problematic. In view of these un-
favorable situations, we considered it necessary to clar-
ify the definitions, concepts of disease, and treatment
methods for acute cholangitis and acute cholecystitis
and establish universal criteria that can be widely rec-
ognized and used.
A working group to establish practical Guidelines for
the Management of Cholangitis and Cholecystitis was
organized in 2003 (chief researcher, Tadahiro Takada).
This project was funded by a grant from the Japanese
Ministry of Health, Labour, and Welfare, and was sup-
ported by the Japanese Society for Abdominal Emer-
gency Medicine, the Japan Biliary Association, and the
Japanese Society of Hepato-Biliary-Pancreatic Surgery.
The working group consisted of physicians engaged in
gastroenterology, internal medicine, surgery, emergency
medicine, intensive care, and clinical epidemiology as
the main members, and they started the work to prepare
the Guidelines.
As the research progressed, the group was faced with
the serious problem that high-level evidence regarding
the treatment of acute biliary infection is poor. There-
fore, an exective committee meeting was convened, and
the committee came to the following decision: the
Guidelines would be evidence-based in general, but
areas without evidence or with poor evidence (such as
diagnosis and severity assessment) should be completed
by obtaining high-level consensus among experts
worldwide.
We established a publication committee and held 12
meetings to prepare draft Guidelines in English (ver-
sion 3). Then we had several discussions on these draft
Guidelines with leading experts in the field throughout
the world, via e-mail, leading to version 4. Finally,
an International Consensus Meeting took place in
Tokyo, on 1–2 April, 2006, to obtain international
agreement on diagnostic criteria, severity assessment,
and management.
We now publish the “Tokyo Guidelines for the
Management of Cholangitis and cholecystitis”. These
Guidelines consist of 13 articles, including “Discussion”
sections containing comments of attendees at the con-
sensus conference and analyses of audience voting at
the meeting.
We hope that these Guidelines will help their users
to give optimal treatment according to their own spe-
cialty and capability, and thus provide their patients
with the best medical treatment.
Background of Tokyo Guidelines
Biliary infections (acute cholangitis and cholecystitis)
require appropriate management in the acute phase.
Serious acute cholangitis may be lethal unless it is ap-
propriately managed in the acute phase. On the other
hand, although various diagnostic and treatment meth-
odologies have been developed in recent years, they
have not been assessed objectively and none of them
has been established as a standard method for the man-
agement of these diseases. We carried out an extensive
review of the English-language literature and found
that there was little high-level evidence in this field, and
no systematically described practical manual for the
field. Most importantly, there are no standardized diag-
nostic criteria and severity assessments for acute cholan-
gitis and cholecystitis, therefore, we would like to
establish standards for these items. The Tokyo Guide-
lines include evidence-based medicine and reflect the
international consensus obtained through earnest dis-
cussions among professionals in the field on 1–2 April,
2006, at the Keio Plaza Hotel, Tokyo, Japan. Concern-
ing the definitions in the practice guidelines, we have
applied to the Japanese Institute of Medicine: Commit-
tee to Advise the Public Health Service on Clinical
Practice Guidelines, to approve the systematically de-
veloped Guidelines to assist practioner and patient de-
cisions about appropriate healthcare for specific clinical
circumstances.
Notes on the use of the Guidelines
The Guidelines are evidence-based, with the grade of
recommendation also based on the evidence. The
Guidelines also present the diagnostic criteria for and
severity assessment of acute biliary infection. As the
Guidelines address so many different subjects, indices
are included at the end for the convenience of
readers.
The practice Guidelines promulgated in this work do
not represent a standard of practice. They are suggested
plans of care, based on best available evidence and the
consensus of experts, but they do not exclude other ap-
proaches as being within the standard of practice. For
example, they should not be used to compel adherence
to a given method of medical management, which meth-

T. Takada et al.: Background of Tokyo Guidelines 3
od should be finally determined after taking account
of the conditions at the relevant medical institution
(staff levels, experience, equipment, etc.) and the char-
acteristics of the individual patient. However, responsi-
bility for the results of treatment rests with those who
are directly engaged therein, and not with the consensus
group. The doses of medicines described in the text of
the Guidelines are for adult patients.
Methods of formulating the guidelines
With evidence-based medicine (EBM) as a core con-
cept, the Guidelines were prepared by the Research
Group on the Preparation and Diffusion of Guidelines
for the Management of Acute Cholangitis and Acute
Cholecystitis (chief researcher, Tadahiro Takada), un-
der the auspices of the Japanese Ministry of Health, La-
bour,andWelfare,andtheWorkingGroupforGuideline
Preparation, whose members were selected from ex-
perts in abdominal emergency medicine and epidemiol-
ogy by the Japanese Society for Abdominal Emergency
Medicine, the Japan Biliary Association, and the Japa-
nese Society of Hepato-Biliary-Pancreatic Surgery.
In principle, the preparation of the Guidelines pro-
gressed with the systematic search, collection, and as-
sessment of references for the objective extraction of
evidence. Next, the External Assessment Committee
examined the Guidelines. Then we posted the draft
guidelines on our website and had four open symposia,
bginning in September 2004, to gain feedback for fur-
ther review. Subsequently, a Publication Committee
was set up, and this committee had 12 meetings to pre-
pare draft Guidelines.
Re-examination of the draft Guidelines was then per-
formed, via e-mail, with experts on cholangitis and
cholecystitis throughout the world. After final agree-
ment was reached at the International Consensus Meet-
ing, held in Tokyo in April 2006, “the Tokyo Guidelines
for the Management of Acute Cholangitis and Chole-
cystitis” were completed.
The process of extending the literature search
The literature was selected as follows: Using “cholangi-
tis” and “cholecystitis” as the medical subject heading
(MeSH; explode) or the key search words, approxim-
ately 17200 items were selected from Medline (Ovid;
1966 to June 2003). These articles were subjected to a
further screening with “human” as the “limiting word”.
This screening provided 9618 items in English and in
Japanese. A further 7093 literature publications were
obtained from the Japana Centra Revuo Medicina
(internet version), using “cholangitis”, “cholecystitis”,
and “biliary infection” as the key words, with further
screening with “human” as the “limiting word”. This
process provided 6141 items. After the titles and ab-
stracts of a total of 15759 works were examined by two
committee members, 2494 were selected for a careful
examination of their full texts.
Other literature quoted in these selected works, to-
gether with works suggested by the specialist committee
members, were included in the examination.
To evaluate each article, a STARD (standards for
reporting of diagnostic accuracy) checklist (Table 1)12
was considered important. The purpose of this checklist
is to evaluate the format and study process, in order to
improve the accuracy and completeness of the reporting
of studies of diagnostic accuracy.
However, the STARD checklist is not suitable for
classifying various categories (e.g., therapy, prevention,
etiology, harm, prognosis, diagnosis, differential diag-
nosis, economic and decision analysis) and levels of evi-
dence. Therefore, in the Guidelines, the science-based
classification used by the Cochrane Library (Table 2)
was adopted.
The evidence obtained from each item of reference
was evaluated in accordance with the science-based
classification used by the Cochrane Library (Table 2),
and the quality of evidence for each parameter associ-
ated with the diagnosis and treatment of acute biliary
infection was determined. As stated above, the level of
evidence presented by each article was determined in
accordance with the Oxford Centre for Evidence-Based
Medicine Levels of Evidence (May 2001), prepared by
Phillips et al.13
(Table 2). The terms used in the catego-
ries are explained in the footnote to Table 2.
Categories of evidence and grading of recommendations
Based on the results obtained from these procedures,
grades of recommendation were determined, according
to the system for ranking recommendations in clinical
guidelines14–16
shown in Table 3, and mentioned, as re-
quired, in the text of the Guidelines. The grades of rec-
ommendation in the Guidelines are based on the Kish14
method of classification and others.15,16
Recommenda-
tions graded “A” (that is, “do it”) and “B” (that is,
“probably do it”), are based on a high level of evidence,
whereas those graded “D” (that is, “probably don’t do
it”) or “E” (that is, “don’t do it”) reflect a low level of
evidence.
Acknowledgments. We would like to express our deep
gratitude to the Japanese Society for Abdominal Emer-
Japanese Society of Hepato-Biliary-Pancreatic Surgery,
who provided us with great support and guidance in the
preparation of the Guidelines. This process was con-
ducted as part of the project for the Preparation and

Table 1. STARD checklist for the reporting of studies of diagnostic accuracy
Section and On page
topic Item no. no.
Title/Abstract/ 1 Identify the article as a study of diagnostic accuracy (recommend MeSH heading
Key words “sensitivity and specificity”)
Introduction 2 State the research questions or study aims, such as estimating diagnostic accuracy
or comparing accuracy between tests or across participant groups
Methods Describe
Participants 3 The study population: the inclusion and exclusion criteria, setting and locations
where the data were collected
4 Participant recruitment: was recruitment based on presenting symptoms, results
from previous tests, or the fact that the participants had received the index tests
or the reference standard?
5 Participant sampling: was the study population a consecutive series of participants
defined by the selection criteria in items 3 and 4? If not, specify how participants
were further selected
6 Data collection: was data collection planned before the index test and reference
standard were performed (prospective study) or after (retrospective study)?
Test methods 7 The reference standard and its rationale
8 Technical specifications of material and methods involved, including how and when
measurements were taken, and/or cite references for index tests and reference
standard
9 Definition of and rationale for the units, cutoffs, and/or categories of the results of
the index tests and the reference standard
10 The number, training, and expertise of the persons executing and reading the index
tests and the reference standard
11 Whether or not the readers of the index tests and reference standard were blind
(masked) to the results of the other test, and describe any other clinical
information available to the readers
Statistical 12 Methods for calculating or comparing measures of diagnostic accuracy, and the
methods statistical methods used to quantify uncertainty (e.g., 95% confidence intervals)
13 Methods for calculating test reproducibility, if done
Results Report
Participants 14 When study was done, including beginning and ending dates of recruitment
15 Clinical and demographic characteristics of the study population (e.g., age, sex
spectrum of presenting symptoms, comorbidity, current treatments, recruitment
centers)
16 The number of participants satisfying the criteria for inclusion that did or did not
undergo the index tests and/or the reference standard; describe why participants
failed to receive either test (a flow diagram is strongly recommended)
Test results 17 Time interval from the index tests to the reference standard, and any treatment
administered between
18 Distribution of severity of disease (define criteria) in those with the target
condition; other diagnoses in participants without the target condition
19 A cross-tabulation of the results of the index tests (including indeterminate and
missing results) by the results of the reference standard; for continuous results,
the distribution of the test results by the results of the reference standard
20 Any adverse events from performing the index tests or the reference standard
Estimates 21 Estimates of diagnostic accuracy and measures of statistical uncertainty (e.g., 95%
confidence intervals)
22 How indeterminate results, missing responses, and outliers of the index tests
were handled
23 Estimates of variability of diagnostic accuracy between subgroups of participants,
readers, or centers, if done
24 Estimates of test reproducibility, if done
Discussion 25 Discuss the clinical applicability of the study findings
Adapted from reference 12
MeSH, medical subject heading; STARD, standards for reporting of diagnostic accuracy

Table2.Categoriesofevidence(refertolevelsofevidenceandgradesofrecommendationsonthehomepageoftheCentreforEvidence-BasedMedicine)
Thescience-basedclassiﬁcationusedbytheCochraneLibrary:OxfordCentreforEvidence-basedMedicineLevelsofEvidence(May2001)(http://www.cebm.net/levels_of_
evidence.asp#levels)13
wasusedasabasistoevaluateevidencepresentedineacharticle;thequalityofevidenceforeachparameterassociatedwiththediagnosisandtreat-
mentofacutecholangitisandacutecholecystitiswasdetermined
Differential
Therapy/prevention,diagnosis/symptomEconomicand
Levelaetiology/harmPrognosisDiagnosisprevalencestudydecisionanalyses
1aSR(withhomogeneitya
)SR(withhomogeneitya
)ofSR(withhomogeneitya
)oflevel1
ofRCTsinceptioncohortstudies;level1diagnosticstudies;ofprospectivecohorteconomicstudies
CDRb
validatedinCDRb
with1bstudiesfromstudies
differentpopulationsdifferentclinicalcenters
1bIndividualRCT(withIndividualinceptionValidatingd
cohortstudywithProspectivecohortstudyAnalysisbasedonclinically
narrowconﬁdencecohortstudywith>80%goode
referencestandards;orwithgoodfollow-upf
sensiblecostsoralternatives;
intervalc
)follow-up;CDRb
validatedCDRb
testedwithinonesystematicreview(s)ofthe
inasinglepopulationclinicalcenterevidence;andincluding
multi-waysensitivityanalyses
1cAllornoneg
Allornonecase-seriesAbsoluteSpPinsandSnNoutsh
Allornonecase-seriesAbsolutebetter-valueor
worse-valueanalysesi
)oflevelSR(withhomogeneitya
)oflevel
ofcohortstudieseitherretrospectivecohort>2diagnosticstudiesof2bandbetterstudies>2economicstudies
studiesoruntreated
controlgroupsinRCTs
2bIndividualcohortstudyRetrospectivecohortstudyExploratoryd
cohortstudywithRetrospectivecohortstudy,Analysisbasedonclinically
(includinglow-qualityRCT;orfollow-upofuntreatedgoode
referencestandards;orpoorfollow-upsensiblecostsoralternatives;
e.g.,<80%follow-up)controlpatientsinanRCT;CDRb
afterderivation,orlimitedreview(s)ofthe
DerivationofCDRb
orvalidatedonlyonsplit-samplej
evidence,orsinglestudies;and
validatedonsplit-samplej
ordatabasesincludingmulti-waysensitivity
onlyanalyses
2c“Outcomes”research;“Outcomes”researchEcologicalstudiesAuditoroutcomesresearch
ecologicalstudies
)of3bSR(withhomogeneitya
)of3b
ofcase-controlstudiesandbetterstudiesof3bandbetterstudiesandbetterstudies
3bIndividualcase-controlNon-consecutivestudy;orNon-consecutivecohortAnalysisbasedonlimited
studywithoutconsistentlyappliedstudy,orverylimitedalternativesorcosts,poor-quality
referencestandardspopulationestimatesofdata,butincluding
sensitivityanalysesincorporating
clinicallysensiblevariations

Table2.Continued
Differential
Therapy/prevention,diagnosis/symptomEconomicand
Levelaetiology/harmPrognosisDiagnosisprevalencestudydecisionanalyses
4Case-series(andpoor-qualityCase-series(andCase-controlstudy,poororCase-seriesorsupersededAnalysiswithnosensitivityanalysis
cohortandcase-controlpoor-qualityprognosticnon-independentreferencereferencestandards
studiesk
)cohortstudiesl
)standard
5ExpertopinionwithoutExpertopinionwithoutExpertopinionwithoutexplicitExpertopinionwithoutExpertopinionwithoutexplicit
explicitcriticalappraisal,orexplicitcriticalappraisal,criticalappraisal,orbasedonexplicitcriticalappraisal,orcriticalappraisal,orbasedon
basedonphysiology,benchorbasedonphysiology,physiology,benchresearch,orbasedonphysiology,bencheconomictheoryor“firstprinciples”
research,or“firstprinciples”benchresearch,“firstprinciples”research,or“firstprinciples”
or“firstprinciples”
Userscanaddaminus-sign“−”todenotethelevelthatfailstoprovideaconclusiveanswerbecauseof:EITHERasingleresultwithawideconfidenceinterval(suchthat,forexample,anARR
inanRCTisnotstatisticallysignificantbutwhoseconfidenceintervalsfailtoexcludeclinicallyimportantbenefitorharm)(Note#1),ORasystematicreviewwithtroublesome(andstatistically
significant)heterogeneity(Note#2).Suchevidenceisinconclusive,andthereforecanonlygenerategradeDrecommendations(Note#3)
SR,Systematicreview;RCT,Randomizedcontrolledtrial;ARR,absoluteriskreduction
a
Byhomogeneity,wemeanasystematicreviewthatisfreeofworrisomevariations(heterogeneity)inthedirectionsanddegreesofresultsbetweenindividualstudies.Notallsystematicreviews
withstatisticallysignificantheterogeneityneedbeworrisome,andnotallworrisomeheterogeneityneedbestatisticallysignificant.Asnotedabove,studiesdisplayingworrisomeheterogeneity
shouldbetaggedwitha“−”attheendoftheirdesignatedlevel
b
Clinicaldecisionrule.Thesearealgorithmsorscoringsystemswhichleadtoaprognosticestimationoradiagnosticcategory
c
Seenote#2foradviceonhowtounderstand,rate,andusetrialsorotherstudieswithwideconfidenceintervals
d
Validatingstudiestestthequalityofaspecificdiagnostictest,basedonpriorevidence.Anexploratorystudycollectsinformationandtrawlsthedata(e.g.,usingaregressionanalysis)tofind
whichfactorsare“significant”
e
Goodreferencestandardsareindependentofthetest,andareappliedblindlyorobjectivelytoallpatients.Poorreferencestandardsarehaphazardlyapplied,butstillindependentofthetest.
Useofanonindependentreferencestandard(wherethe“test”isincludedinthe“reference”,orwherethe“testing”affectsthe“reference”)impliesalevel4study
f
Goodfollow-upinadifferentialdiagnosisstudyis>80%,withadequatetimeforalternativediagnosestoemerge(e.g.,1–6months,acute;1–5,years,chronic)
g
MetwhenallpatientsdiedbeforetheRxbecameavailable,butsomenowsurviveonit;orwhensomepatientsdiedbeforetheRxbecameavailable,butnonenowdieonit
h
An“absoluteSpPin”isadiagnosticfindingwhosespecificityissohighthatapositiveresultrules-inthediagnosis.An“absoluteSnNout”isadiagnosticfindingwhosesensitivityissohighthat
anegativeresultrules-outthediagnosis
i
Better-valuetreatmentsareclearlyasgoodbutcheaper,orbetteratthesameorreducedcost.Worse-valuetreatmentsareasgoodandmoreexpensive,orworseandequallyormore
expensive
j
Split-samplevalidationisachievedbycollectingalltheinformationinasingletranche,thenartificiallydividingthisinto“derivation”and“validation”samples
k
Bypoor-qualitycohortstudy,wemeanonethatfailedtoclearlydefinecomparisongroupsand/orfailedtomeasureexposuresandoutcomesinthesame(preferablyblinded),objectivewayin
bothexposedandnonexposedindividuals,and/orfailedtoidentifyorappropriatelycontrolknownconfounders,and/orfailedtocarryoutasufficientlylongandcompletefollow-upofpatients.
Bypoor-qualitycase-controlstudy,wemeanonethatfailedtoclearlydefinecomparisongroupsand/orfailedtomeasureexposuresandoutcomesinthesame(preferablyblinded),objectiveway
inbothcasesandcontrolsand/orfailedtoidentifyorappropriatelycontrolknownconfounders
l
Bypoor-qualityprognosticcohortstudy,wemeanoneinwhichsamplingwasbiasedinfavorofpatientswhoalreadyhadthetargetoutcome,orthemeasurementofoutcomeswasaccomplished
in<80%ofstudypatients,oroutcomesweredeterminedinanunblinded,nonobjectiveway,ortherewasnocorrectionforconfoundingfactors
Good,better,bad,andworserefertothecomparisonsbetweentreatmentsintermsoftheirclinicalrisksandbenefits

Diffusion of Guidelines for the Management of Acute
Cholangitis (H-15-Medicine-30), with a research subsidy
for fiscal 2003 and 2004 (Integrated Research Project
for Assessing Medical Technology) sponsored by the
Japanese Ministry of Health, Labour, and Welfare.
We also truly appreciate the panelists who cooper-
ated with and contributed significantly to the Interna-
tional Consensus Meeting held in Tokyo on April 1 and
2, 2006.
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Discussion at the Tokyo International
Consensus Meeting
Tadahiro Takada (Japan): “Dr. Strasberg, please ex-
plain the difference between a ‘Guidelines’ and ‘Stand-
ards’ in your mind?”
Steven Strasberg (USA): “To me, ‘guidelines’ repre-
sent a suggested course of action based on available
evidence. They do not imply that other courses of action
are below an acceptable level of care. Practice ‘stand-
ards’ are different, in that they imply that actions other
than those listed as acceptable practice standards are
below the level of acceptable care. It is particularly true
that, in an area in which high levels of evidence are not
available, that guidelines are not construed to be stand-
ards. Reliance on expert opinion to form guidelines may
be useful, but even a consensus of experts may not be
correct. For this reason a statement of the following
type should be inserted in the introduction. ‘The prac-
tice guidelines promulgated in this work do not repre-
sent a standard of practice. They are a suggested plan
of care based on best available evidence and a consen-
sus of experts, but they do not exclude other approaches
as being within the standard of practice’.”
Table 3. Grading system for ranking recommendations in clinical guidelines14–16
Grade of recommendation
A Good evidence to support a recommendation for use
B Moderate evidence to support a recommendation for use
C Poor evidence to support a recommendation, or the effect may not exceed the adverse effects
and/or inconvenience (toxicity, interaction between drugs and cost)
D Moderate evidence to support a recommendation against use
E Good evidence to support a recommendation against use

The Members of Organizing Committee and Contributors for
Tokyo Guidelines
Members of the Organizing Committee of Tokyo Guidelines for the Management of Acute Cholangitis
and Cholecystitis
T. Takada Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
Y. Nimura Division of Surgical Oncology, Department of Surgery, Nagoya University, Graduate School of
Medicine, Nagoya, Japan
Y. Kawarada Mie University, Mie, Japan
K. Hirata First Department of Surgery, Sapporo Medical University School of Medicine, Sapporo,
Japan
H. Yasuda Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan
Y. Yamashita Department of Surgery, Fukuoka University School of Medicine, Fukuoka, Japan
Y. Kimura First Department of Surgery, Sapporo Medical University School of Medicine, Sapporo,
Japan
M. Sekimoto Department of Healthcare Economics and Quality Management, Kyoto University Graduate
School of Medicine, Kyoto, Japan
T. Tsuyuguchi Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba Univer-
sity, Chiba, Japan
M. Nagino Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of
M. Hirota Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical
Sciences, Kumamoto, Japan
T. Mayumi Department of Emergency Medicine and Critical Care, Nagoya University Graduate School of
F. Miura Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
M. Yoshida Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
Advisors and International Members of Tokyo Guidelines for the Management of Acute Cholangitis
and Cholecystitis
N. Abe Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan
S. Arii Department of Hepato-Biliary-Pancreatic / General Surgery, Tokyo Medical and Dental
University, Tokyo, Japan
J. Belghiti Department of Digestive Surgery & Transplantation, Hospital Beaujon, Clichy, France
G. Belli Department of General and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy
P.C. Bornman Division of General Surgery, University of Cape Town, Cape Town, South Africa
M.W. Büchler Department of General Surgery, University of Heidelberg, Germany
A.C.W. Chan Director Endoscopy Centre, Specialist in General Surgery, Minimally Invastive Surgery
Centre
M.F. Chen Chang Gung Memorial Hospital, Chang Gung Medical University, Taiwan
X.P. Chen Department of Surgery, Tongji Hunter College, Tongji Hospital Hepatic Surgery Centre,
China
E.D. Santibanes HPB and Liver Transplant Unit, Hospital Italiano de Buenos Aires, Argentina
C. Dervenis First Department of Surgery, Agia Olga Hospital, Greece
S. Dowaki Department of Digestive Surgery, Tokai University Tokyo Hospita, Kanagawa, Japan
S.T. Fan Department of Surgery, The University of Hong Kong Medicak Centre, Queen Mary Hospital,
Hong Kong
H. Fujii 1st
Department of Surgery, University of Yamanashi Faculty of Medicine, Yamanashi, Japan
T.R. Gadacz Gastrointestinal Surgery, Medical College of Georgia, USA
D.J. Gouma Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands

S.C. Hilvano Department of Surgery, College of Medical & Philippine General Hospital, Philippines
S. Isaji Department of Hepato-Biliary-Pancreatic Surgery, Mie University Graduate School of Medi-
cine, Mie, Japan
M. Ito Department of Surgery, Fujita Health University, Nagoya, Japan
T. Kanematsu Second Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences,
Nagasaki, Japan
N. Kano Special Adviser to the President, Chairman of Department of Surgery and Director of Endo-
scopic Surgical Center, Kameda Medical Center, Chiba, Japan
C.G. Ker Division of HPB Surgery, Yuan’s General Hospital, Taiwan
M.H. Kim Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medi-
cine, Korea
S.W. Kim Department of Surgery, Seoul National University College of Medicine, Korea
W. Kimura First Department of Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan
S. Kitano First Department of Surgery, Oita University Faculty of Medicine, Oita, Japan
E.C.S. Lai Pedder Medical Partners, Hong Kong
J.W.Y. Lau Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
K.H. Liau Department of Surgery, Tan Tock Seng Hospital/Hepatobiliary Surgery, Singapore
S. Miyakawa Department of Surgery, Fujita Health University, Nagoya, Japan
K. Miyazaki Department of Surgery, Saga Medical School, Saga University Faculty of Medicine, Saga,
Japan
H. Nagai Department of Surgery, Jichi Medical School, Tokyo, Japan
T. Nakagohri Department of Surgery, National Cancer Center Hospital East, Chiba, Japan
H. Neuhaus Internal Medicine Evangelisches Krankenhaus Dusseldorf, Germany
T. Ohta Department of Digestive Surgery, Kanazawa University Hospital, Ishikawa, Japan
K. Okamoto First Department of Surgery, School of Medicine, University of Occupational and Environ-
mental Health, Fukuoka, Japan
R.T. Padbury Department of Surgery, The Flinders University of South Australia GPO, Australia)
B.B. Philippi Department of Surgery, University of Indonesia, Cipto Mangunkusumo National Hospital,
Jakarta, Indonesia
H.A. Pitt Department of Surgery, Indiana University School of Medicine, USA
M. Ryu Chiba Cancer Center, Chiba, Japan
V. Sachakul Department of Surgery, Phramongkutklao College of Medecine, Thailand
M. Shimazu Department of Surgery, Keio University School of Medicine, Tokyo, Japan
T. Shimizu Department of Surgery, Nagaoka Chuo General Hospital, Niigata, Japan
K. Shiratori Department of Digestive tract internal medicine, Tokyo Women’s Medical University, Tokyo,
Japan
H. Singh Department of HPB Surgery, Selayang Hospital, Malaysia
J.S. Solomkin Department of Surgery, University of Cincinnati College of Medicine Cincinnati, Ohio, USA
S.M. Strasberg Department of Surgery, Washington University in St Louis and Barnes-Jewish Hospital, USA
K. Suto Department of Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan
A.N. Supe Department of Surgical Gastroenterology, Seth G S Medical College and K E M Hospital,
India
M. Tada Department of Digestive tract internal medicine, Graduate School of Medicine University of
Tokyo, Tokyo, Japan
S. Takao Research Center for life science resources, Kagoshima University Faculty of Medicine,
Kagoshima, Japan
H. Takikawa Teikyo University School of Medicine, Tokyo, Japan
M. Tanaka Department of Surgery and Oncology, Graduate School of Medical Sciences Kyushu University,
Fukuoka, Japan
S. Tashiro Shikoku Central Hospital, Ehime, Japan
S. Tazuma Department of Primary Care Medicine, Hiroshima University School of Medicine, Hiroshima,
Japan
M. Unno Department of Digestive Surgery, Tohoku University Graduate School of Medicine, Miyagi,
Japan
G. Wanatabe Department of Digestive Surgery, Toranomon Hospital Tokyo, Tokyo, Japan

J.A. Windsor Department of General Surgery, Auckland Hospital, New Zealand
H. Yamaue Second Department of Surgery, Wakayama Medical University School of Medicine, Wakayama,
Japan
Working group of the Guidelines for the Management of Acute Cholangitis and Cholecystitis
M. Mayumi Department of Emergency Medicine and Critical Care, Nagoya University School of Medicine,
Nagoya, Japan
M. Yoshida Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
T. Sakai Kyoto Katsura Hospital, General Internal Medicine, Kyoto, Japan
N. Abe Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan
M. Ito Department of surgery, Fujita-Health University, Aichi, Japan
H. Ueno Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba
University, Chiba, Japan
M. Unno Department of Surgery, Tohoku University Graduate School of Medical Science, Sendai,
Japan
Y. Kimura First Department of Surgery, Sapporo Medical University School of Medicine, Sapporo,
Japan
M. Sekimoto Department of Healthcare Economics and Quality Management, Kyoto University Graduate
S. Dowaki Department of Surgery, Tokai University School of Medicine, Kanagawa, Japan
N. Nago Japanese Association for Development of Community Medicine, Yokosuka Uwamachi
Hospital, Yokosuka, Japan
J. Hata Department of Laboratory Medicine, Kawasaki Medical School, Kurashiki, Japan
M. Hirota Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical
Sciences, Kumamoto, Japan
F. Miura Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
Y. Ogura Department of Pediatric Surgery, Nagoya University School of Medicine, Nagoya, Japan
A. Tanaka Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
T. Tsuyuguchi Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba
University, Chiba, Japan
M. Nagino Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of
K. Suto Department of Gastroenterological and General Surgery, Course of Organ Functions and
Controls, Yamagata University School of Medicine, Yamagata, Japan
T. Ohta Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University,
Tokyo, Japan
I. Endo Department of Gastroenterological Surgery, Yokohama City University Graduate School of
Medicine, Yokohama, Japan
Y. Yamashita Department of Surgery, Fukuoka University Hospital, Fukuoka, Japan
S. Yokomuro Nippon Medical School, Graduate School of Medicine Surgery for Organ Function and Biologi-
cal Regulation, Tokyo, Japan
Members of the External Evaluation Committee
T. Fukui St. Luke’s International Hospital, Tokyo, Japan
Y. Imanaka Department of Healthcare Economics and Quality Management, Kyoto University Graduate
Y. Sumiyama Third Department of Surgery, Toho University School of Medicine, Tokyo, Japan
T. Shimizu Department of Surgery, Nagaoka chuo General Hospital, Nagaoka, Japan
H. Saisho Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba Univer-
sity, Chiba, Japan
K. Okamoto First Department of Surgery, School of Medicine, University of Occupational and Environmen-
tal Health, Kitakyushu, Japan

DOI 10.1007/s00534-006-1159-4
Diagnostic criteria and severity assessment of acute
cholecystitis: Tokyo Guidelines
Masahiko Hirota1
, Tadahiro Takada2
, Yuji Nimura4
, Fumihiko Miura2
,
Koichi Hirata5
, Toshihiko Mayumi6
, Masahiro Yoshida2
, Steven Strasberg7
, Henry Pitt8
, Thomas R Gadacz9
,
Eduardo de Santibanes10
, Dirk J. Gouma11
, Joseph S. Solomkin12
, Jacques Belghiti13
, Horst Neuhaus14
,
Markus W. Büchler15
, Sheung-Tat Fan16
, Chen-Guo Ker17
, Robert T. Padbury18
, Kui-Hin Liau19
,
Serafin C. Hilvano20
, Giulio Belli21
, John A. Windsor22
, and Christos Dervenis23
1
Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo,
Kumamoto 860-8556, Japan
2
Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
3
4
5
6
Department of Emergency Medicine and Critical Care, Nagoya University School of Medicine, Nagoya, Japan
7
8
9
10
Department of Surgery, University of Buenos Aires, Buenos Aires, Argentina
11
12
Department of Surgery, Division of Trauma and Critical Care, University of Cincinnati College of Medicine, Cincinnati, USA
13
Department of Digestive Surgery and Transplantation, Hospital Beaujon, Clichy, France
14
Department of Internal Medicine, Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany
15
Department of Surgery, University of Heidelberg, Heidelberg, Germany
16
Department of Surgery, The University of Hong Kong, Hong Kong, China
17
Division of HPB Surgery, Yuan’s General Hospital, Taoyuan, Taiwan
18
Division of Surgical and Specialty Services, Flinders Medical Centre, Adelaide, Australia
19
Department of Surgery, Tan Tock Seng Hospital / Hepatobiliary Surgery, Medical Centre, Singapore, Singapore
20
Department of Surgery, Philippine General Hospital, University of the Philippines, Manila, Philippines
21
Department of General and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy
22
Department of Surgery, The University of Auckland, Auckland, New Zealand
23
First Department of Surgery, Agia Olga Hospital, Athens, Greece
lecystitis is classified into three grades, mild (grade I), moder-
ate (grade II), and severe (grade III). Grade I (mild acute
cholecystitis) is defined as acute cholecystitis in a patient with
no organ dysfunction and limited disease in the gallbladder,
making cholecystectomy a low-risk procedure. Grade II (mod-
erate acute cholecystitis) is associated with no organ dysfunc-
tion but there is extensive disease in the gallbladder, resulting
in difficulty in safely performing a cholecystectomy. Grade II
disease is usually characterized by an elevated white blood cell
count; a palpable, tender mass in the right upper abdominal
quadrant; disease duration of more than 72h; and imaging
studies indicating significant inflammatory changes in the gall-
bladder. Grade III (severe acute cholecystitis) is defined as
acute cholecystitis with organ dysfunction.
Key words Acute cholecystitis · Diagnosis · Severity of illness
index · Guidelines · Infection
Introduction
Early diagnosis of acute cholecystitis allows prompt
treatment and reduces both mortality and morbidity.
Abstract
The aim of this article is to propose new criteria for the diag-
nosis and severity assessment of acute cholecystitis, based on
a systematic review of the literature and a consensus of ex-
perts. A working group reviewed articles with regard to the
diagnosis and treatment of acute cholecystitis and extracted
the best current available evidence. In addition to the evi-
dence and face-to-face discussions, domestic consensus meet-
ings were held by the experts in order to assess the results. A
provisional outcome statement regarding the diagnostic crite-
ria and criteria for severity assessment was discussed and final-
ized during an International Consensus Meeting held in Tokyo
2006. Patients exhibiting one of the local signs of inflamma-
tion, such as Murphy’s sign, or a mass, pain or tenderness in
the right upper quadrant, as well as one of the systemic signs
of inflammation, such as fever, elevated white blood cell
count, and elevated C-reactive protein level, are diagnosed
as having acute cholecystitis. Patients in whom suspected clini-
cal findings are confirmed by diagnostic imaging are also
diagnosed with acute cholecystitis. The severity of acute cho-
Offprint requests to: M. Hirota

DOI 10.1007/s00534-006-1151-z
Need for criteria for the diagnosis and severity assessment of acute
cholangitis and cholecystitis: Tokyo Guidelines
Miho Sekimoto1
, Tadahiro Takada2
, Yuji Nimura4
, Masahiro Yoshida2
,
Toshihiko Mayumi5
, Fumihiko Miura2
, Keita Wada2
, Masahiko Hirota6
, Yuichi Yamashita7
, Steven Strasberg8
,
Henry A. Pitt9
, Eduardo de Santibanes11
, Serafin C. Hilvano13
,
Sun-Whe Kim14
, Kui-Hin Liau15
, Sheung-Tat Fan16
, Giulio Belli17
, and Vibul Sachakul18
1
Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
2
3
4
5
6
7
8
Washington University in St Louis and Barnes-Jewish Hospital, St Louis, USA
9
10
11
12
13
14
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
15
16
17
18
Department of Surgery, Phramongkutklao Hospital, Bangkok, Thailand
describes the highlights of the Tokyo International Consensus
Meeting in 2006. Some important areas focused on at the
meeting include proposals for internationally accepted diag-
nostic criteria and severity assessment for both clinical and
research purposes.
Key words Evidence-based medicine · Practice guidelines ·
Acute cholecystitis · Acute cholangitis
Introduction
More than 100 years have elapsed since Charcot’s triad
was first proposed as the characteristic findings of acute
cholangitis,1
and Murphy’s sign was proposed as a diag-
nostic method for acute cholecystitis.2
During this peri-
od, many new technologies have been developed for the
management of acute biliary infections. Antimicrobial
therapy, endoscopic techniques for both diagnosis and
treatment, minimally invasive operations, including
laparoscopic surgery and mini-laparotomy, and fast-
track surgery3
are good examples of such advances. De-
spite the great advances in medicine, acute cholangitis
and acute cholecystitis are still great health problems in
both developed and developing countries. According to
Abstract
The Tokyo Guidelines formulate clinical guidance for health-
care providers regarding the diagnosis, severity assessment,
and treatment of acute cholangitis and acute cholecystitis. The
Guidelines were developed through a comprehensive litera-
ture search and selection of evidence. Recommendations were
based on the strength and quality of evidence. Expert consen-
sus opinion was used to enhance or formulate important areas
where data were insufficient. A working group, composed of
gastroenterologists and surgeons with expertise in biliary tract
surgery, supplemented with physicians in critical care medi-
cine, epidemiology, and laboratory medicine, was selected to
formulate draft guidelines. Several other groups (including
members of the Japanese Society for Abdominal Emergency
Medicine, the Japan Biliary Association, and the Japanese
Society of Hepato-Biliary-Pancreatic Surgery) have reviewed
and revised the draft guidelines. To build a global consensus
on the management of acute biliary infection, an international
expert panel, representing experts in this area, was estab-
lished. Between April 1 and 2, 2006, an International Consen-
sus Meeting on acute biliary infections was held in Tokyo. A
consensus was determined based on best available scientific
evidence and discussion by the panel of experts. This report
Offprint requests to: M. Sekimoto

12 M. Sekimoto et al.: Standardized diagnostic criteria for acute cholangitis and cholecystitis
epidemiological studies, about 5%–15% of people in
developed countries have gallstones,4–9
and annually,
1% to 3% of these people develop severe gallstone
diseases, including acute cholangitis and acute cholecys-
titis.10
Although mortality related to these diseases is
relatively rare, they lay a heavy burden on the public,
because gallstones are so common and hospitalization
is expensive. According to Kim et al.,11
the total direct
costs for gallbladder diseases per year in the United
States are estimated to be $5.8 billion. Many clinical
studies have been conducted to assess the risk of the
disease, the accuracy of diagnostic techniques, and the
effectiveness of the treatments. However, the accumu-
lation and integration of such scientific knowledge for
application to clinical practice lags behind the progress
achieved in medical and surgical technology.12
For ex-
ample, many studies have suggested that there are wide
variations in the care of acute biliary infections in every
part of the world.13,14
If there were “a best treatment”,
such variation might imply low quality of care.
In order to develop the best possible practice patterns
by integrating clinical experience with the best available
research information, the Committee on the Develop-
ment of Guidelines for the Management of Acute Bili-
ary Infection (principal investigator, Tadahiro Takada)
(hereafter, the Committee) prepared a draft of “Evi-
dence-based clinical practice guidelines for the manage-
ment of acute cholangitis and cholecystitis”. The major
objectives in developing the guidelines were: (1) to
propose standardized diagnostic criteria and severity
assessment for both acute cholangitis and acute chole-
cystitis; and (2) to propose the best strategies for the
management of acute biliary infections. The Committee
selected a multidisciplinary Working Group composed
of experts in hepatobiliary surgery, gastroenterology,
intensive care, laboratory medicine, epidemiology, and
pediatrics.
Through discussions within the Working Group
and between the members of the scientific societies
relevant to clinical practice in acute biliary infections,
the draft was finalized. Subsequently, in April 2006,
an international meeting was held in Tokyo to build
global consensus on the management of acute biliary
infection; the international consensus panel was com-
posed of leaders in hepatobiliary medicine from across
the world. In this article, we describe the methodology
and process of developing of the guidelines, and the
basic principles and strategies we used to reach global
consensus.
Need for standardized diagnostic criteria and
severity assessment
In the Guidelines, we (the Working Group) propose
uniform criteria for the diagnostic criteria and severity
assessment of acute cholangitis and cholecystitis. In the
process of developing the Guidelines, the Committee
members considered that uniform diagnostic criteria for
acute biliary infections were necessary for both research
and clinical purposes. Because more than a dozen dif-
ferent local diagnostic criteria are now in use, compari-
son of treatment effectiveness between studies and
comparisons of clinical outcomes across institutions are
often difficult. For example, although Charcot’s triad
(abdominal pain, fever, and jaundice) has been histori-
cally used as the diagnostic criterion of acute cholangi-
tis, no more than 70% of patients with acute cholangitis
have the triad.15,16
The reported mortality rates of acute
cholangitis have a wide range (3.9%–65%), probably
due to the lack of standardized criteria. Murphy’s sign
has often been used in the diagnosis of acute cholecys-
titis. This sign is only useful when other physical findings
are equivocal, as in mild cholecystitis, and it has a sen-
sitivity and specificity of only 65% and 87%.
Management of acute biliary infections according to
severity grade is also critical, because the urgency of
treatment and patient outcomes differ according to the
severity of the disease. A literature review revealed that
terminologies used to define severe cases often failed to
distinguish such cases from others. For example, Reyn-
olds’ pentad,17
which consists of Charcot’s triad plus
“shock” and “decrease in level of consciousness”, has
been used historically to define severe acute cholangitis.
The incidence of the pentad is extremely low, and is less
than 10% even in severe cases.15
There is no doubt that
better criteria, which enable physicians to provide ap-
propriate care according to the severity of the disease,
are necessary.
Proposals for the diagnostic criteria were developed
by beginning with existing definitions and concepts of
acute biliary infections. The working group first exam-
ined how historical writings and prestigious textbooks
have defined acute cholangitis and cholecystitis, and
tried to propose criteria to comply with these defini-
tions. We gave priority to the easy and early diagnosis
of acute cholangitis by using noninvasive examinations.
We also endeavored to incorporate the results of the
latest clinical research in the diagnostic and severity
assessment criteria.
By a systematic search through the literature and
textbooks, the working group discussed the definitions
of acute cholangitis and cholecystitis. The basic concepts
of the criteria for acute cholangitis include: (1) Char-
cot’s triad as the definite criteria for the diagnosis of
acute cholangitis, and (2) the presence of “biliary infec-

M. Sekimoto et al.: Standardized diagnostic criteria for acute cholangitis and cholecystitis 13
tion” and “bile duct obstruction” proven by laboratory
examinations and imaging. “Severe acute cholangitis”
was defined as cholangitis with organ failure and/or sep-
sis. “Acute cholecystitis” was defined as the presenta-
tion of clinical signs such as epigastric pain, tenderness,
muscle guarding, a palpable mass, Murphy’s sign, and
inflammatory signs. “Severe acute cholecystitis” was
defined as acute cholecystitis with organ dysfunction.
Process of developing the Guidelines
We planned to use an evidence-based approach to
develop our guidelines. We used established criteria
and systematic methods for reviewing evidence of clini-
cal effectiveness. However, using only evidence-based
data, we were unable to establish a useful set of guide-
lines.18
From the literature review, the Working Group
found that, for some topics in the management of acute
biliary infections, few studies could be classified at high
levels of evidence, and that treatment strategies for spe-
cific health conditions sometimes differed widely by re-
gion and country. There was a concern that such lack of
evidence would not produce any recommendations that
would be helpful to clinicians who encountered patients
with acute biliary infections. As in other areas of medi-
cine, we recognized that, if the authors of the Tokyo
Guidelines insisted upon strict adherence to an ap-
proach which accepted only studies rated at a high level
of evidence in order to formulate guidelines, the vast
majority of medical practice would be excluded from
the practice guidelines. Therefore, to develop the Guide-
lines, we shifted our approach to one which combined
the best of the literature studies with the best clinical
opinion, based on a formal consensus approach. This
strategy has the dual advantage of allowing the formula-
tion of the best guidelines possible at the present time,
while pointing out areas in which studies are needed in
order to formulate future guidelines based solely upon
high levels of evidence.
Between April 1 and 2, 2006, an International Con-
sensus Meeting on Acute Biliary Infections was held in
Tokyo, in which an expert panel consisting of 30 over-
seas panelists and 30 Japanese panelists tried to reach
consensus on recommendations at a structured 2-day
conference. The expert panel was provided with the
draft of the guidelines prepared by the Working Group
that reviewed the existing scientific evidence for a pro-
cedure, as well as providing a list of indications for per-
formingtheprocedure.Inprinciple,therecommendations
were based on the best available evidence. However, in
the absence of high-quality evidence, expert consensus
was integral to developing the Guidelines. The Guide-
lines are based on evidence, on discussion by the ex-
perts, and on consensus reached by voting. The panel
recognized that specific patient care decisions may be
at variance with these guidelines and that these deci-
sions are the prerogative of the patient and of the health
professionals providing care.
The Guidelines are intended not only for specialists
engaged in the diagnosis and treatment of acute biliary
diseases but also for the general practitioner who has
first contact with these patients. The Guidelines were
prepared to provide medical workers who play an active
part at the front line with the best medical practice em-
ploying currently available data for the best outcome of
the latest clinical research. The Guidelines consist of
“clinical questions” that clinicians have in their daily
medical practice, and responses to them. For a better
understanding of the Guidelines, the sequences of diag-
nosis and treatment are explained with flowcharts. It is
our goal for the Guidelines to help users to provide best
medical practice according to their specialty and capa-
bility, and thereby to improve the management of acute
biliary infection.
Acknowledgment. We would like to express our deep
gratitude to the members of the Japanese Society for
Abdominal Emergency Medicine, the Japan Biliary As-
sociation, and the Japanese Society of Hepato-Biliary-
Pancreatic Surgery, who provided us with great support
and guidance in the preparation of the Guidelines. This
process was conducted as part of the project for the
Preparation and Diffusion of Guidelines for the Man-
agement of Acute Cholangitis (H-15-Medicine-30), with
a research subsidy for fiscal 2003 and 2004 (Integrated
Research Project for Assessing Medical Technology)
sponsored by the Japanese Ministry of Health, Labor,
and Welfare.
tional Consensus Meeting, held in Tokyo on April 1 and
2, 2006.
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system for the twenty-ﬁrst century. The National Academies
Press; (2001).
13. CameronIC,ChadwickC,PhillipsJ,JohnsonAG.Currentpractice
in the management of acute cholecystitis. Br J Surg 2000;87:
362–73.
14. Sekimoto M, Imanaka Y, Hirose M, Ishizaki T, Murakami G,
Fukata Y. Impact of treatment policies on patient outcomes and
resource utilization in acute cholecystitis in Japanese hospitals.
BMC Health Serv Res. 2006;6:40.
Surg 1982;117:437–41.
16. Boey JH, Way LW. Acute cholangitis. Ann Surg 1980;191:264–
70.
17. Reynolds BM, Dargan EL. Acute obstructive cholangitis. A dis-
tinct syndrome. Ann Surg 1959;150:299–303.
18. American College of Rheumatology. Guidelines for the develop-
ment of practice guidelines. 2005.

M. Hirota et al.: Diagnosis and severity assessment of acute cholecystitis 79
The accurate diagnosis of typical as well as atypical
cases of acute cholecystitis requires specific diagnostic
criteria. Acute cholecystitis has a better prognosis than
acute cholangitis, but may require immediate manage-
ment, especially in patients with torsion of the gallblad-
der and emphysematous, gangrenous, or suppurative
cholecystitis. The lack of standard criteria for diagnosis
and severity assessment is reflected by the wide range
of reported mortality rates in the literature, and this
lack makes it impossible to provide standardized opti-
mal treatment guidelines for patients. In these Guide-
lines we propose specific criteria for the diagnosis and
severity assessment of acute cholecystitis, based on
the best available evidence and the experts’ consensus
achieved at the International Consensus Meeting for
the Management of Acute Cholecystitis and Cholangi-
tis, held on April 1–2, 2006, in Tokyo.
Diagnostic criteria for acute cholecystitis
Diagnosis is the starting point of the management of
acute cholecystitis, and prompt and timely diagnosis
should lead to early treatment and lower mortality and
morbidity. Specific diagnostic criteria are necessary to
accurately diagnose typical, as well as atypical cases.
The Guidelines propose diagnostic criteria for acute
cholecystitis (Table 1). C-reactive protein (CRP) is not
commonly measured in many countries. However, be-
cause acute cholecystitis is usually associatied with an
elevation of CRP level by 3mg/dl or more, CRP was
included. Diagnosis of acute cholecystitis by elevation
of CRP level (3mg/dl or more), with ultrasonographic
findings suggesting acute cholecystitis, has a sensitivity
of 97%, specificity of 76%, and positive predictive value
of 95% (level 1b).1
After the discussion during the
Tokyo International Consensus Meeting, almost unani-
mous agreement was achieved on the criteria (Table 2).
However, 19% of the panelists from abroad expressed
the necessity for minor modifications, because, in the
provisional version, the diagnostic criteria did not in-
clude technetium hepatobiliery iminodiacetic acid (Tc-
HIDA) scan as an item.
Imaging findings of acute cholecystitis
Ultrasonography findings (level 4)2–5
Sonographic Murphy sign (tenderness elicited by press-
ing the gallbladder with the ultrasound probe)
Thickened gallbladder wall (>4mm; if the patient does
not have chronic liver disease and/or ascites or right
heart failure)
Enlarged gallbladder (long axis diameter >8cm, short
axis diameter >4cm)
Incarcerated gallstone, debris echo, pericholecystic fluid
collection
Sonolucent layer in the gallbladder wall, striated intra-
mural lucencies, and Doppler signals.
Magnetic resonance imaging (MRI) findings
(level 1b-4)6–9
Pericholecystic high signal
Enlarged gallbladder
Thickened gallbladder wall.
Computed tomography (CT) findings (level 3b)10
Thickened gallbladder wall
Pericholecystic fluid collection
Enlarged gallbladder
Linear high-density areas in the pericholecystic fat
tissue.
Table 1. Diagnostic criteria for acute cholecystitis
A. Local signs of inflammation etc.:
(1) Murphy’s sign, (2) RUQ mass/pain/tenderness
B. Systemic signs of inflammation etc.:
(1) Fever, (2) elevated CRP, (3) elevated WBC count
C. Imaging findings: imaging findings characteristic of acute
cholecystitis
Definite diagnosis
(1) One item in A and one item in B are positive
(2) C confirms the diagnosis when acute cholecystitis is
suspected clinically
Note: acute hepatitis, other acute abdominal diseases, and chronic
cholecystitis should be excluded
Table 2. Answer pad responses on the diagnostic criteria for acute cholecystitis
Agree, but needs
minor
Agree modifications Disagree
Total (n = 110) 92% 8% 0%
Panelists from abroad (n = 21) 81% 19% 0%
Japanese panelists (n = 20) 100% 0% 0%
Audience (n = 69) 93% 7% 0%

80 M. Hirota et al.: Diagnosis and severity assessment of acute cholecystitis
Tc-HIDA scans (level 4)11,12
Non-visualized gallbladder with normal uptake and
excretion of radioactivity
Rim sign (augmentation of radioactivity around the
gallbladder fossa).
Severity assessment criteria of acute cholecystitis
Concept of severity grading of acute cholecystitis
Patients with acute cholecystitis may present with a
spectrum of disease stages ranging from a mild,
self-limited illness to a fulminant, potentially life-
threatening illness. In these Guidelines we classify the
severity of acute cholecystitis into the following three
categories: “mild (grade I)”, “moderate (grade II)”, and
“severe (grade III)”. A category for the most severe
grade of acute cholecystitis is needed because this grade
requires intensive care and urgent treatment (operation
and/or drainage) to save the patient’s life. However, the
vast majority of patients present with less severe forms
of the disease. In these patients, the major practical
question regarding management is whether it is advis-
able to perform cholecystectomy at the time of presen-
tation in the acute phase or whether other strategies of
management should be chosen during the acute phase,
followed by an interval cholecystectomy. Therefore, to
guide the clinician, the severity grading includes a
“moderate” group based on criteria predicting when
conditions might be unfavorable for cholecystectomy in
the acute phase (level 2b-4).13–18
Patients who fall nei-
ther into the severe nor the moderate group form the
majority of patients with this disease; their disease is
suitable for management by cholecystectomy in the
acute phase, if comorbidities are not a factor. Defini-
tions of the three grades are given below.
Mild (grade I) acute cholecystitis
Mild acute cholecystitis occurs in a patient in whom
there are no findings of organ dysfunction, and there is
mild disease in the gallbladder, allowing for cholecys-
tectomy to be performed as a safe and low-risk proce-
dure. These patients do not have a severity index that
meets the criteria for “moderate (grade II)” or “severe
(grade III)” acute cholecystitis.
Moderate (grade II) acute cholecystitis
In moderate acute cholecystitis, the degree of acute
inflammation is likely to be associated with increased
operative difficulty to perform a cholecystectomy (level
2b-4).13–18
Severe (grade III) acute cholecystitis
Severe acute cholecystitis is associated with organ
dysfunction.
Criteria for the severity assessment of acute cholecystitis
Acute cholecystitis has a better outcome/prognosis than
acute cholangitis but requires prompt treatment if gan-
grenous cholecystitis, emphysematous cholecystitis, or
torsion of the gallbladder are present. The progression
of acute cholecystitis from the mild/moderate to the se-
vere form means the development of the multiple organ
dysfunction syndrome (MODS). Organ dysfunction
scores, such as Marshall’s multiple organ dysfunction
(MOD) score, and the sequential organ failure assess-
ment (SOFA) score, are sometimes used to evaluate
organ dysfunction in critically ill patients. The Guide-
lines classify the severity of acute cholecystitis into three
grades (Tables 3–5): “severe (grade III)”: acute chole-
cystitis associated with organ dysfunction, “moderate
(grade II)”: acute cholecystitis associated with difficulty
to perform cholecystectomy due to local inflammation,
and “mild (grade I)”: acute cholecystitis which does not
meet the criteria of “severe” or “moderate” acute cho-
lecystitis (these patients have acute cholecystitis but no
Table 3. Criteria for mild (grade I) acute cholecystitis
“Mild (grade I)” acute cholecystitis does not meet the
criteria of “severe (grade III)” or “moderate (grade II)”
acute cholecystitis. Grade I can also be defined as acute
cholecystitis in a healthy patient with no organ dysfunction
and only mild inflammatory changes in the gallbladder,
making cholecystectomy a safe and low-risk operative
procedure.
Table 4. Criteria for moderate (grade II) acute cholecystitis
“Moderate” acute cholecystitis is accompanied by any one
of the following conditions:
1. Elevated WBC count (>18000/mm3
)
2. Palpable tender mass in the right upper abdominal
quadrant
3. Duration of complaints >72ha
4. Marked local inflammation (biliary peritonitis,
pericholecystic abscess, hepatic abscess, gangrenous
cholecystitis, emphysematous cholecystitis)
a
Laparoscopic surgery in acute cholecystitis should be performed
within 96h after the onset (level 2b-4)13,14,16
Table 5. Criteria for severe (grade III) acute cholecystitis
“Severe” acute cholecystitis is accompanied by dysfunctions
in any one of the following organs/systems
1. Cardiovascular dysfunction (hypotension requiring
treatment with dopamine м5µg/kg per min, or any dose
of dobutamine)
2. Neurological dysfunction (decreased level of
consciousness)
3. Respiratory dysfunction (PaO2/FiO2 ratio <300)
4. Renal dysfunction (oliguria, creatinine >2.0mg/dl)
5. Hepatic dysfunction (PT-INR >1.5)
6. Hematological dysfunction (platelet count <100000/mm3
)

M. Hirota et al.: Diagnosis and severity assessment of acute cholecystitis 81
organ dysfunction, and there are mild inflammatory
changes in the gallbladder, so that a cholecystectomy
can be performed with a low operative risk). Almost
unanimous agreement on the criteria was achieved
(Tables 6 and 7). When acute cholecystitis is accompa-
nied by acute cholangitis, the criteria for the severity
assessment of acute cholangitis should also be taken
into account. Being “elderly” per se is not a criterion
for severity itself, but indicates a propensity to progress
to the severe form, and thus is not included in the cri-
teria for severity assessment.
who provided us with great support and guidance in
the preparation of the Guidelines. This process was
conducted as part of the Project on the Preparation
and Diffusion of Guidelines for the Management of
Acute Cholangitis (H-15-Medicine-30), with a research
subsidy for fiscal 2003 and 2004 (Integrated Research
Project for Assessing Medical Technology), sponsored
by the Japanese Ministry of Health, Labour, and
Welfare.
tional Consensus Meeting held on April 1 and 2,
2006.
References
1. Juvonen T, Kiviniemi H, Niemela O, Kairaluoma MI. Diagnostic
accuracy of ultrasonography and C-reactive protein concentra-
tion in acute cholecystitis: a prospective clinical study. Eur J Surg
1992;158:365–9 (level 1b).
2. Ralls PW, Colletti PM, Lapin SA, Chandrasoma P, Boswell WD
Jr, Ngo C, et al. Real-time sonography in suspected acute chole-
cystitis. Prospective evaluation of primary and secondary signs.
Radiology 1985;155:767–71 (level 4).
3. Martinez A, Bona X, Velasco M, Martin J. Diagnostic accuracy
of ultrasound in acute cholecystitis. Gastrointest Radiol 1986;11:
334–8 (level 4).
4. Ralls PW, Halls J, Lapin SA, Quinn MF, Morris UL, Boswell W.
Prospective evaluation of the sonographic Murphy sign in sus-
pected acute cholecystitis. J Clin Ultrasound 1982;10:113–5 (level
4).
5. Bree RL. Further observations on the usefulness of the sono-
graphic Murphy sign in the evaluation of suspected acute chole-
cystitis. J Clin Ultrasound 1995;23:169–72 (level 4).
6. Hakansson K, Leander P, Ekberg O, Hakansson HO. MR imag-
ing in clinically suspected acute cholecystitis. A comparison with
ultrasonography. Acta Radiol 2000;41:322–8 (level 2b).
7. Regan F, Schaefer DC, Smith DP, Petronis JD, Bohlman ME,
Magnuson TH. The diagnostic utility of HASTE MRI in the
evaluation of acute cholecystitis: half-Fourier acquisition single-
shot turbo SE. J Comput Assist Tomogr 1998;22:638–42 (level
4).
8. Shea JA, Berlin JA, Escarce JJ, Clarke JR, Kinosian BP, Cabana
MD, et al. Revised estimates of diagnostic test sensitivity and
specificity in suspected biliary tract disease. Arch Intern Med
1994;154:2573–81 (level 1b).
9. Ito K, Fujita N, Noda Y, Kobayashi G, Kimura K, Katakura Y,
et al. The significance of magnetic resonance cholangiopancrea-
tography in acute cholecystitis (in Japanese with English abstract).
Jpn J Gastroenterol 2000;97:1472–9 (level 4).
Table 6. Answer pad responses on the criteria for severe (grade III) acute
cholecystitis
Agree, but needs
minor
Total (n = 110) 90% 10% 0%
Audience (n = 68) 91% 9% 0%
Table 7. Answer pad responses on the criteria for moderate (grade II) acute
cholecystitis
Agree, but needs
minor
Total (n = 109) 78% 22% 0%
Audience (n = 65) 74% 26% 0%

82 M. Hirota et al.: Diagnosis and severity assessment of acute cholecystitis
10. Fidler J, Paulson EK, Layfield L. CT evaluation of acute chole-
cystitis: findings and usefulness in diagnosis. Am J Roentgenol
1996;166:1085–8 (level 3b).
11. Mauro MA, McCartney WH, Melmed JR. Hepatobiliary scan-
ning with 99m Tc-PIPIDA in acute cholecystitis. Radiology
1982;142:193–7 (level 4).
12. Bushnell DL, Perlman SB, Wilson MA, Polcyn RE. The rim sign:
association with acute cholecystitis. J Nucl Med 1986;27:353–6
(level 4).
13. Brodsky A, Matter I, Sabo E, Cohen A, Abrahamson J, Eldar S.
Laparoscopic cholecystectomy for acute cholecystitis: can the
need for conversion and the probability of complications be pre-
dicted? A prospective study. Surg Endosc 2000;14:755–60 (level
2b).
14. Teixeira JP, Sraiva AC, Cabral AC, Barros H, Reis JR, Teixeira
A. Conversion factors in laparoscopic cholecystectomy for
acute cholecystitis. Hepatogastroenterology 2000;47:626–30
(level 2b).
15. Halachmi S, DiCastro N, Matter I, Cohen A, Sabo E, Mogilner
JG, et al. Laparoscopic cholecystectomy for acute cholecystitis:
how do fever and leucocytosis relate to conversion and complica-
tions? Eur J Surg 2000;166:136–40 (level 2b).
16. Araujo-Teixeria JP, Rocha-Reis J, Costa-Cabral A, Barros H,
Saraiva AC, Araujo-Teixeira AM. Laparoscopic versus open cho-
lecystectomy for cholecystitis (200 cases). Comparison of results
and predictive factors for conversion (in French with English
abstract). Chirurgie 1999;124:529–35 (level 4).
17. Rattner DW, Ferguson C, Warshaw AL. Factors associated with
successful laparoscopic cholecystectomy for acute cholecystitis.
Ann Surg 1993;217:233–6 (level 2b).
18. Merriam LT, Kanaan SA, Dawes JG, Angelos P, Prystowsky JB,
Rege RV, et al. Gangrenous cholecystitis: analysis of risk factors
and experience with laparoscopic cholecystectomy. Surgery
1999;126:680–5 (level 4).
Consensus Meeting
Diagnostic criteria for acute cholecystitis
The clinical diagnosis of acute cholecystitis is tradition-
ally based on the patient’s clinical presentation, and it
is confirmed by the imaging findings. Hence, the initial
provisional diagnostic criteria for acute cholecystitis
comprised: (1) clinical signs and symptoms, (2) labora-
tory data, and (3) imaging findings. In the discussion on
criteria for “clinical signs and symptoms”, 92% of the
Japanese panelists agreed, whereas only 65% of the
panelists from abroad agreed and 4% disagreed. In
regard to the criteria for “laboratory data”, 20% of the
Japanese panelists and 39% of the panelists from abroad
voted “agree, but needs minor modifications”. After a
discussion among the panelists, several changes were
made. In regard to the proposed criteria for “imaging
findings”, 66%–71% of the Japanese panelists agreed
and about 30% of the panelists voted “agree, but needs
minor modifications”, and 4% of the panelists from
abroad disagreed, because Tc-HIDA scans were not
included. Discussion at the International Consensus
Meeting led to the reorganization of these categories as:
(1) local signs of inflammation, (2) systemic signs of in-
flammation, and (3) imaging findings. “Suspected diag-
nosis” in the provisional criteria was deleted, and two
conditions for “definite diagnosis” were established in
the final diagnostic criteria. After the discussion, 100%
of the Japanese panelists and 81% of the panelists from
abroad agreed on the final version (refer to Tables 1 and
2; consensus was reached).
Severity assessment criteria for acute cholecystitis
Concerning criteria for severe (grade III) acute cholecys-
titis, 81% of the Japanese panelists and 95% of the panel-
ists from abroad agreed with the criteria (refer
to Tables 5 and 6; consensus was reached). The acute
physiology and chronic health evaluation II (APACHE
II) score was not included in the assessment criteria, be-
cause it is too complicated to apply in community
hospitals.
The criteria for moderate (grade II) acute cholecys-
titis can be defined as acute cholecystitis associated with
local inflammatory conditions that make cholecystecto-
my difficult (Steven Strasberg, USA; Dirk J. Gouma,
the Netherlands; Henry Pitt, USA; Sheung-Tat Fan and
Joseph W.Y. Lau, Hong Kong; Serafin C. Hilvano, Phil-
ippines). On the basis of these aspects, the final criteria
for moderate (grade II) acute cholecystitis were defined
and were agreed on by 91% of the Japanese panelists
and 77% of those from abroad (refer to Tables 4 and 7;
consensus was reached).
The criteria for mild (grade I) acute cholecystitis were
agreed on by approximately 90% of both the Japanese
panelists and the panelists from abroad (consensus was
reached).

DOI 10.1007/s00534-006-1152-y
Definitions, pathophysiology, and epidemiology of acute
Yasutoshi Kimura1
, Tadahiro Takada2
, Yuji Nimura4
, Koichi Hirata5
,
Miho Sekimoto6
, Masahiro Yoshida2
, Toshihiko Mayumi7
, Keita Wada2
, Fumihiko Miura2
, Hideki Yasuda8
,
Yuichi Yamashita9
, Masato Nagino4
, Masahiko Hirota10
, Atsushi Tanaka11
, Toshio Tsuyuguchi12
,
Steven M. Strasberg13
, and Thomas R. Gadacz14
1
First Department of Surgery, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
2
3
4
5
6
Kyoto, Japan
7
8
Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan
9
10
11
12
13
14
Key words Gallstones · Biliary · Bile · Biliary infection ·
Cholangitis · Acute cholecystitis · Guidelines
Introduction
Acute biliary infection is a systemic infectious disease
which requires prompt treatment and has a significant
mortality rate.1
The first report on acute biliary infec-
tion was Charcot’s “The symptoms of hepatic fever” in
1877.2
This section of the Tokyo Guidelines defines acute
cholangitis and acute cholecystitis, and describes the
incidence, etiology, pathophysiology, classification, and
prognosis of these diseases.
Acute cholangitis
Definition
Acute cholangitis is a morbid condition with acute
inflammation and infection in the bile duct.
Historical aspects of terminology
Hepatic fever. “Hepatic fever” was a term used for the
first time by Charcot,2
in his report published in 1877.
Intermittent fever accompanied by chills, right upper
quadrant pain, and jaundice became known as Char-
cot’s triad.
Abstract
This article discusses the definitions, pathophysiology, and
epidemiology of acute cholangitis and cholecystitis. Acute
cholangitis and cholecystitis mostly originate from stones in
the bile ducts and gallbladder. Acute cholecystitis also has
other causes, such as ischemia; chemicals that enter biliary
secretions; motility disorders associated with drugs; infections
with microorganisms, protozoa, and parasites; collagen dis-
ease; and allergic reactions. Acute acalculous cholecystitis is
associated with a recent operation, trauma, burns, multisys-
tem organ failure, and parenteral nutrition. Factors associated
with the onset of cholelithiasis include obesity, age, and drugs
such as oral contraceptives. The reported mortality of less
than 10% for acute cholecystitis gives an impression that it is
not a fatal disease, except for the elderly and/or patients with
acalculous disease. However, there are reports of high mor-
tality for cholangitis, although the mortality differs greatly
depending on the year of the report and the severity of the
disease. Even reports published in and after the 1980s indicate
high mortality, ranging from 10% to 30% in the patients, with
multiorgan failure as a major cause of death. Because many
of the reports on acute cholecystitis and cholangitis use differ-
ent standards, comparisons are difficult. Variations in treat-
ment and risk factors influencing the mortality rates indicate
the necessity for standardized diagnostic, treatment, and
severity assessment criteria.
Offprint requests to: Y. Kimura

16 Y. Kimura et al.: Definition, pathophysiology, and epidemiology of cholangitis and cholecystitis
Acute obstructive cholangitis. Acute obstructive cholan-
gitis was defined by Reynolds and Dargan3
in 1959 as a
syndrome consisting of lethargy or mental confusion
and shock, as well as fever, jaundice, and abdominal
pain, caused by biliary obstruction. They indicated that
emergent surgical biliary decompression was the only
effective procedure for treating the disease. These five
symptoms were then called Reynolds’s pentad.
Longmire’s classification.4
Longmire classified patients
with the three characteristics of intermittent fever ac-
companied by chills and shivering, right upper quadrant
pain, and jaundice as having acute suppurative cholan-
gitis. Patients with lethargy or mental confusion and
shock, along with the triad, were classified as having
acute obstructive suppurative cholangitis (AOSC). He
also reported that the latter corresponded to the mor-
bidity of acute obstructive cholangitis as defined by
Reynolds and Dargan,3
and he classified acute microbial
cholangitis as follows:
1. Acute cholangitis developing from acute
cholecystitis
2. Acute non-suppurative cholangitis
3. Acute suppurative cholangitis
4. Acute obstructive suppurative cholangitis
5. Acute suppurative cholangitis accompanied by
hepatic abscess.
Incidence
Etiology
Acute cholangitis requires the presence of two factors:
(1) biliary obstruction and (2) bacterial growth in bile
(bile infection). Frequent causes of biliary obstruction
are choledocholithiasis, benign biliary stenosis, stricture
of a biliary anastomosis, and stenosis caused by malig-
nant disease (level 4).5,6
Choledocholithiasis used to be
the most frequent cause of the obstruction, but recently,
the incidence of acute cholangitis caused by malignant
disease, sclerosing cholangitis, and non-surgical instru-
mentation of the biliary tract has been increasing. It is
reported that malignant disease accounts for about
10%–30% of cases of acute cholangitis. Tables 1 and 2
show some results of studies on the causes of acute
cholangitis.
Risk factors. The bile of healthy subjects is generally
aseptic. However, bile culture is positive for microor-
ganisms in 16% of patients undergoing a non-biliary
operation, in 72% of acute cholangitis patients, in 44%
of chronic cholangitis patients, and in 50% of those with
biliary obstruction (level 4).12
Bacteria in bile are identi-
fied in 90% of patients with choledocholithiasis accom-
panied by jaundice (level 4).13
Patients with incomplete
Table 1. Etiology of acute cholangitis
Cholelithiasis
Benign biliary stricture
Congenital factors
Postoperative factors (damaged bile duct, strictured
choledojejunostomy, etc.)
Inflammatory factors (oriental cholangitis, etc.)
Malignant occlusion
Bile duct tumor
Gallbladder tumor
Ampullary tumor
Pancreatic tumor
Duodenal tumor
Pancreatitis
Entry of parasites into the bile ducts
External pressure
Fibrosis of the papilla
Duodenal diverticulum
Blood clot
Sump syndrome after biliary enteric anastomosis
Iatrogenic factors
Table 2. Causes of acute cholangitis (%)
Causes
GB Benign Malignant Sclerosing Others/
Author Year Setting N stones stenosis stenosis cholangitis unknown
Gigot6
1963–1983 University of Paris 412 48% 28% 11% 1.5% —
Saharia and Cameron7
1952–1974 Johns Hopkins 76 70% 13% 17% 0% —
Hospital, USA
Pitt and Couse8
1976–1978 Johns Hopkins 40 70% 18% 10% 3% —
Hospital, USA
Pitt and Couse8
1983–1985 Johns Hopkins 48 32% 14% 30% 24% —
Hospital, USA
Thompson9
1986–1989 Johns Hopkins 96 28% 12% 57% 3% —
Hospital, USA
Basoli10
1960–1985 University of Rome 80 69% 16% 13% 0% 4%
Daida11
1979 Questionnaire throughout 472 56% 5% 36% — 3%
Japan

Y. Kimura et al.: Definition, pathophysiology, and epidemiology of cholangitis and cholecystitis 17
obstruction of the bile duct present a higher positive
bile culture rate than those with complete obstruction
of the bile duct. Risk factors for bactobilia include vari-
ous factors, as described above.14
Post-endoscopic retrograde cholangiopancreatography
(ERCP) infectious complications. The incidence of
complications after ERCP ranges from 0.8% to 12.1%,
though it differs depending on the year of the report
and the definition of complications (level 4).15–23
Overall
post-ERCP mortality is reported to be between 0.5%
and 1.5% (level 4).18
The most frequent complication is
acute pancreatitis, but it is usually mild or moderate.
Table 3 shows the reported incidence of various post-
ERCP complications.
The incidences of post-ERCP acute cholangitis and
cholecystitis are, as shown in Table 3, 0.5%–1.7% and
0.2%–0.5%, respectively.15–19
The complications caused
by ERCP performed for diagnostic and for therapeutic
purposes are different. Therapeutic ERCP tends to
cause all complications, including cholangitis, more fre-
quently than diagnostic ERCP.17,20
The increasing use of ERCP and the improved opera-
tors’ skills and techniques in recent years have reduced
the incidence of post-ERCP complications, although
the incidence of acute cholecystitis has not dropped and
seems unpredictable.17
Other etiologies of acute cholangitis. There are two
other etiologies of acute cholangitis; Mirizzi syndrome
and lemmel syndrome. Mirizzi syndrome is a morbid
condition with stenosis of the common bile duct caused
by mechanical pressure and/or inflammatory changes
caused by the presence of stones in the gallbladder
neck and cystic ducts.24
Two types have been described:
type I, which is a morbid condition with the bile duct
compressed from the left by the presence of stones in
the gallbladder neck and cystic ducts and pericholecys-
tic inflammatory changes; and type II, which is a morbid
condition with biliobilary fistulation caused by pressure
necrosis of the bile duct due to cholecystolithiasis.
Lemmel syndrome is a series of morbid conditions in
which the duodenal parapapillary diverticulum com-
presses or displaces the opening of the bile duct or
pancreatic duct and obstructs the passage of bile in the
bile duct or hepatic duct, thereby causing cholestasis,
jaundice, gallstone, cholangitis, and pancreatitis.25
Pathophysiology
The onset of acute cholangitis involves two factors: (i)
increased bacteria in the bile duct, and (ii) elevated in-
traductal pressure in the bile duct that allows transloca-
tion of bacteria or endotoxins into the vascular system
(cholangio-venous reflux). Because of its anatomical
characteristics, the biliary system is likely to be affected
by elevated intraductal pressure. In acute cholangitis,
with the elevated intraductal biliary pressure, the bile
ductules tend to become more permeable to the trans-
location of bacteria and toxins. This process results in
serious infections that can be fatal, such as hepatic
abscess and sepsis.
Prognosis
Patients who show early signs of multiple organ failure
(renal failure, disseminated intravascular coagulation
[DIC], alterations in the level of consciousness, and
shock) as well as evidence of acute cholangitis (fever
accompanied by chills and shivering, jaundice, and ab-
dominal pain), and who do not respond to conservative
treatment, should receive systemic antibiotics and un-
dergo emergent biliary drainage.1
We have to keep in
mind that unless early and appropriate biliary drainage
is performed and systemic antibiotics are administered,
death will occur.
The reported mortality of acute cholangitis varies
from 2.5% to 65%26–37
(Table 4). The mortality rate
before 1980 was 50%,26,27
and after 1980 it was 10%–
30%.28–37
Such differences in mortality are probably
attributable to differences in early diagnosis and im-
proved supportive treatment.
The major cause of death in acute cholangitis is mul-
tiple organ failure with irreversible shock, and mortality
rates have not significantly improved over the years.26–33
Causes of death in patients who survive the acute stage
of cholangitis include multiple organ failure, heart fail-
ure, and pneumonia.34
Acute cholecystitis
Definition
Acute cholecystitis is an acute inflammatory disease of
the gallbladder. It is often attributable to gallstones, but
many factors, such as ischemia; motility disorders; direct
chemical injury; infections with microorganisms, proto-
zoa, and parasites; collagen disease; and allergic reac-
tion are involved.
Incidence
Acute cholecystitis cases account for 3%–10% of all
patients with abdominal pain.38–40
The percentage of
acute cholecystitis cases in patients under 50 years old
with abdominal pain (n = 6317) was low, at 6.3%,
whereas that in patients aged 50 and over (n = 2406)
was high, at 20.9% (average, 10%)40
(Table 5).
Etiology
Cholecystolithiasis accounts for 90%–95% of all causes
of acute cholecystitis, while acalculous cholecystitis
accounts for the remaining 5%–10% (level 4).41–47

Table3.ReportsofcomplicationscausedbyERCP
AcuteAcuteAcuteAcute
AuthorYearofreportTypeofERCPNo.ofcasesTotalpancreatitis(all)pancreatitis(severe)cholecystitischolangitisPainFever
Vandervoort15
2002Diagnostic,122311.2%7.2%0.5%0.25%0.7%0.3%1.6%
therapeutic
ERCP
Freeman16
1996ERCP+EST23479.8%5.4%0.4%0.5%1.0%
Lenriot17
1993Diagnostic4073.6%1.5%1.5%
ERCP(0.96%)(0.2%)(0.5%)
Lenriot17
1993ERCP+EST25712.1%1.6%5.4%
(3.9%)(0.7%)(0.8%)
Benchimol18
1992Diagnostic,32260.9%0.1%0.2%0.5%
therapeutic(0.2%)
ERCP
Cotton19
1991ERCP+EST77291.9%1.7%
Reiertsen20
1987Diagnostic73140.18%
ERCP(0.04%)
Reiertsen20
1987Therapeutic19300.85%
ERCP(0.05%)
Roszler21
1985140—12.8%————
Escourrou22
1984EST4077%
(1.5%)
Bilbao23
1976104353%
(0.2%)
Figuresinparenthesesdenotemortality

Table 4. Mortality of acute cholangitis
Author Period Country No. of subjects Mortality (%)
Andrew26
1957–1967 USA 17c
64.71
Shimada27
1975–1981 Japan 42b
57.1
Csendes28
1980–1988 Chile 512 11.91
Himal and Lindsac29
1980–1989 Canada 61 18.03
Chijiiwa30
1980–1993 Japan 27c
11.11
Liu31
1982–1987 Taiwan 47a
27.66
Lai32
1984–1988 Hong Kong 86b
19.77
Thompson33
1984–1988 USA 127 3.94
Arima34
1984–1992 Japan 163 2.45
Kunisaki35
1984–1994 Japan 82 10.98
Tai36
1986–1987 Taiwan 225 6.67
Thompson37
1986–1989 USA 96 5.21
a
Only patients with shock
b
Only severe cases
c
Only AOSC
Table 5. Acute cholecystitis in patients with abdominal pain
Reports of all patients with abdominal pain
Telfer40
Eskelinen et al.38
Brewer et al.39
Under 50 50 years and
n = 1333 n = 1000 years old (n = 6317) over (n = 2406)
Nonspecific 618 Unknown cause 413 Nonspecific 39.5% Acute cholecystitis 20.9%
abdominal pain abdominal pain
Appendicitis 271 Gastroenteritis 69 Appendicitis 32.0% Nonspecific 15.7%
abdominal pain
Acute cholecystitis 124 Intrapelvic 67 Acute cholecystitis 6.3% Appendicitis 15.2%
infection
Ileus 53 Urinary tract 52 Ileus 2.5% Ileus 12.3%
infection
Dyspepsia 50 Ureterolith 43 Acute hepatitis 1.6% Acute hepatitis 7.3%
Ureterolith 57 Appendicitis 43 Diverticulitis <0.1% Diverticulitis 5.5%
Diverticulitis 19 Acute cholecystitis 25 Cancer <0.1% Cancer 4.1%
Mesenteric 11 Ileus 25 Hernia <0.1% Hernia 3.1%
lymphadenitis
Acute pancreatitis 22 Constipation 23 Vascular lesion <0.1% Vascular lesion 2.3%
Peptic ulcer 9 Duodenal ulcer 20
perforation
Urinary tract 22 Dysmenorrhea 18
infection
Gynecological 15 Pregnancy 18
diseases
Others 62 Pyelitis 17
Gastritis 14
Chronic 12
cholecystitis
Ovarian abscess 10
Dyspepsia 10
Risk factors. Acute cholecystitis is the most frequent
complication occurring in patients with cholelithiasis.
According to the Comprehensive Survey of Living Con-
ditions of the People on Health and Welfare conducted
by the Medical Statistics Bureau of the Japanese Min-
istry of Health and Welfare, the number of those with
acute cholecystitis has increased, from 3.9 million in
1979 to over 10 million in 1993 (Public Welfare Index
in Japan; 1933; level 4).
According to the review by Friedman,48
of the natural
history of cholelithiasis, serious symptoms or com-
plications (acute cholecystitis, acute cholangitis, clinical

jaundice, and pancreatitis) were observed in 1%–2% of
asymptomatic patients and in 1%–3% of patients with
mild symptoms per year (Table 6), and the risk of com-
plications increased in the first several years after the
discovery of gallbladder stones, but then decreased
(level 2c). Every year, 6%–8% of patients whose symp-
toms progress from minor to serious undergo cholecys-
tectomy, but this percentage decreases year by year.48
In a follow-up of cholelithiasis patients with mild or
nonspecific symptoms (n = 153), acute gallstone compli-
cation was observed in 15% (n = 23) and acute chole-
cystitis was seen in 12% (n = 18) (level 4).49
According
to another report, on the follow-up of the patients with
asymptomatic cholelithiasis (n = 600), 16% (96) of them
presented with some symptoms (average period of
observation until the manifestation of symptom, 29.8
months) during the follow-up period, while 3.8% (23
patients) presented with acute cholecystitis. The rate of
change from asymptomatic to symptomatic cholelithia-
sis is highest during the first 3 years after diagnosis
(15%–26%), but then declines (level 4). However, there
is a report suggesting that there is no difference in the
incidence of common symptoms such as heartburn and
upper abdominal pain, in cholelithiasis patients between
those patients with asymptomatic cholelithiasis and
controls without gallstones (level 2b).50
AIDS as a risk factor. Enlarged liver and/or abnormal
liver functions are observed in two/thirds of AIDS
patients, some of whom have biliary tract disease.
Biliary disease may occur by two mechanisms in AIDS
patients: via AIDS cholangiopathy (which is more fre-
quent) and via acute acalculous cholecystitis; AIDS
patients with sclerosing cholangitis are also seen.
AIDS cholangiopathy is often observed in middle-
aged male patients who have had AIDS for more than
1 year (average disease period, 15 ± 2.2 months; average
age, 37 years [range, 21 to 59 years]). Ninety percent of
the patients complain of upper abdominal pain and
have enlarged intra- and extrahepatic bile ducts on ab-
dominal ultrasonography. Abnormal findings on ab-
dominal ultrasonography and computed tomography
are seen in 81% and 78% of patients, respectively. Bio-
chemical tests show a marked increase in the level of
alkaline phosphatase (level 4).51
Acalculous cholecystitis in AIDS patients is charac-
terized by: (1) younger age than in non-AIDS patients,
(2) problems with oral ingestion (3), right upper ab-
dominal pain, (4) a marked increase in alkaline phos-
phatase and a mild increase in serum bilirubin level, and
(5) association with cytomegalovirus and cryptosporid-
ium infections (level 4).51
According to a review of ab-
dominal surgery for AIDS patients, acute cholecystitis
is the most frequent reason for performing open surgery
in AIDS patients.52
Drugs as etiologic agents. According to the review by
Michielsen et al.,53
regarding the association between
drugs and acute cholecystitis, 90%–95% of acute chole-
cystitis cases are caused by cholelithiasis, and drugs pro-
moting the formation of stones are indirectly associated
with a risk of acute cholecystitis (level 4). The etiologi-
cal mechanism of drug-associated gallbladder diseases,
as discussed in the review,53
is shown in Table 7.
Table 6. Natural history of asymptomatic, mildly symptomatic, and symptomatic cholelithiasis patients
Average Only those with
follow-up No. of acute remarkable
No. of period cholecystitis jaundice Gallbladder
Author Characteristic cases (years) cases (%) (%) Cholangitis Cholecystitis cancer
Comfort et al. Asymptomatic 112 15 0 0 0 0 0
Lund Asymptomatic 95 13 ? ? 1 (?) 0 0
Gracie et al. Asymptomatic 123 11 2 0 0 1 0
McSherry et al. Asymptomatic 135 5 3 0 0 0 0
Friedman et al. Asymptomatic 123 7 4 2 2 0 0
Thistle et al. Asymptomatic 305 2 ≥3 0 0 0 0
+ Symptomatic
Wenckert et al. Mildly 781 11 81 (10.4) <59a
0 <59a
3
symptomatic
Ralston et al. Mildly 116 22 ? ? ? ? 2
symptomatic
Friedman et al. Mildly 344 9 20 (5.8) 10 1 3 2
symptomatic
Newman et al. Symptomatic 332 10 38 (11.4) ? ? 1 2
McSherry et al. Symptomatic 556 7 47 (8.5) 19 0 0 1
Review by Friedman48
a
In this report, 59 cases were diagnosed as jaundice and/or acute pancreatitis, based on serum bilirubin and amylase values

It is reported that women taking oral conceptives
have a higher risk of having gallbladder disease, but
there also is a report which denies the association be-
tween the disease and these drugs (level 2a).54
Among
various drugs used for the treatment of hyperlipidemia,
only fibrate is shown to be associated with gallstone
diseases (level 2b).55
One report suggests that thiazides
induce acute cholecystitis (level 3b),56
and another re-
port denies this association (level 3b).57
The administra-
tion of a large dose of ceftriaxone, a third-generation
cephalosporin antimicrobial, in infants, precipitates cal-
cium salt in bile and forms a sludge in 25%–45% of
them, but these effects disappear when the medication
is discontinued (level 4).53
It is reported that the long-
term administration of octreotide causes cholestasis,
and that administration for a year causes cholelithiasis
in 50% of patients (level 4).53
Hepatic artery infusion
will cause chemical cholecystitis (level 4).53
Erythr-
omycin and ampicillin are reported to be a cause of
hypersensitive cholecystitis (level 4).53
According to a
meta-analysis of the risk of disease induced by hormone
replacement therapy, the relative risks (RRs) of chole-
cystitis were 1.8 (95% confidence interval [CI], 1.6–2.0)
and 2.5 (95% CI, 2.0–2.9) at less than 5 years of
treatment and at 5 and more years, respectively
(level 1a).58
Ascaris as an etiologic factor. The complications of as-
cariasis include hepatic, biliary, and pancreatic diseases.
Complications in the biliary tract include: (1) choleli-
thiasis with the ascarid as a nidus for stone formation,
(2) acalculous cholecystitis (3), acute cholangitis (4),
acute pancreatitis, and (5) hepatic abscess.59
Biliary
tract disease is caused by the obstruction of the hepatic
and biliary tracts by the entry of ascarids from the duo-
denum through the papilla. Ascarids entering the biliary
tract usually return to the duodenum in a week, but if
they stay over 10 days there, they will die and form a
nidus for stone formation.
Ascarid-associated biliary diseases occur more fre-
quently in women (male/female ratio, 1:3) and less fre-
quently in infants. The risk of biliary complications is
higher in pregnant than in non-pregnant women (level
4).59
In epidemic regions such as China and Southeast
Asia, ascariasis is a frequent cause of cholelithiasis.59
Role of pregnancy. The risk of cholelithiasis in women
begins to increase when adolescence begins and it de-
clines when the menopause begins. It is also said that
the use of oral conceptives is correlated with a risk of
gallbladder disease. It is considered, therefore, that
levels of estrogen and progesterone are involved in the
formation of gallstones.60
Cholecystitis is the second
most common cause of acute abdomen, following ap-
pendicitis, in pregnant women, and occurs in one of
1600 to 10000 pregnant women (level 4).60
Cholelithia-
sis is the most frequent cause of cholecystitis in preg-
nancy and accounts for 90% or more of all causes of
cholecystitis (level 4).60
Routine ultrasonography found
cholelithiasis in 3.5% of pregnant women (level 4),60
but
it is unknown whether pregnancy increases the risk of
cholecystitis. The frequency of cholecystectomy in preg-
nant women is lower than that in non-pregnant women.
This is not because of the lower incidence of cholecys-
tectomy in pregnant women, but because physicians
tend to refrain from performing any operation during
pregnancy. Though there are few reports of patients
undergoing cholecystectomy during pregnancy, there is
no evidence that laparoscopic surgery increases the
maternal or fetal risks (level 2c).61
Acute cholecystitis and four (or five) “Fs”. It has been
said that the patients with cholelithiasis have factors
such as “4F” and “5F” (fair, fat, female, fertile, and
Table 7. Etiological mechanisms of gallbladder diseases
Etiological mechanism Drug/Treatment
Direct chemical toxicity Hepatic artery infusion
Promotion of stone formation by bile
Inhibition of ACAT activity Progesterone, fibrate
Increased hepatic lipoprotein receptors Estrogen
Induction of acute cholecystitis in patients Thiazides (unconfirmed)
with cholelithiasis
Promotion of calcium salt precipitation in bile Ceftriaxone octreotide
Altered mobility of the gallbladder Narcoid
Anticholinergic drugs
Promotion of hemolysis Dapsone
Immunological mechanism Antimicrobial drugs (erythromycin,
ampicillin)
Immunotherapy
Review by Michielsen et al.53

forty). Common to all individuals with these “4/5Fs” are
high levels of estrogen and progesterone.
According to the Framingham Study, which exam-
ined the risk factors for cholelithiasis in a 10-year
follow-up study of 30- to 59-year-old subjects, the risk
of cholelithiasis within 10 years was highest among the
55- to 62-year-old age group, and most of the patients
were diagnosed with cholelithiasis in their fifties and
sixties. Although the incidence of cholelithiasis in fe-
male patients of all age groups is more than double that
of male patients, the difference between the incidence
in men and women tends to shrink with increasing age
(level 1b).62
Cholelithiasis is one of the main diseases associated
with obesity. The Framingham study also confirms that
cholelithiasis patients tend to be more obese than non-
cholelithiasis patients (level 2a).62
However, there is a
report that this tendency is much more prominent in
female than in male patients.63
Not only obesity but also
dieting is associated with the risk of cholelithiasis. Dras-
tic dieting increases the risk of cholelithiasis in obese
people (level 2b).64–67
The incidences of both cholelithia-
sis and cholecystitis in obese people (age, 37–60 years;
women with a body mass index [BMI] of 34 or higher
and men with a BMI of 38 or more) are significantly
higher that those in non-obese people (cholelithiasis,
5.8% vs 1.5%; Odds ratio [OR], 4.9; women 6.4% vs
22.6%; OR, 4.7; cholecystitis, 0.8% vs 3.4%; OR, 5.2;
women 4.0% vs 11.2%; OR, 3.4) (level 2b).68
The Framingham Study indicates that the number of
pregnancies in those patients who had cholelithiasis at
entry into a cohort or those in whom the symptoms of
cholelithiasis appeared within 10 years, was significantly
higher than the number of pregnancies in subjects not
fulfilling these criteria (level 2b).62
Though the association of “4F” and “5F” with chole-
lithiasis has been relatively closely examined, no study
has examined the association of factors other than
obesity and age with the risk of onset of acute
cholecystitis.
Pathophysiology
In the majority of patients, gallstones are the cause of
acute cholecystitis. The process is one of physical ob-
struction of the gallbladder by a gallstone, at the neck
or in the cystic duct. This obstruction results in increased
pressure in the gallbladder. There are two factors which
determine the progression to acute cholecystitis — the
degree of obstruction and the duration of the obstruc-
tion. If the obstruction is partial and of short duration
the patient experiences biliary colic. If the obstruction
is complete and of long duration the patient develops
acute cholecystitis. If the patient does not receive early
treatment, the disease becomes more serious and com-
plications occur.
Pathological classification
Edematous cholecystitis: first stage (2–4 days). The gall-
bladder has interstitial fluid with dilated capillaries and
lymphatics. The gallbladder wall is edematous. The gall-
bladder tissue is intact histologically, with edema in the
subserosal layer.
Necrotizing cholecystitis: second stage (3–5 days). The
gallbladder has edematous changes with areas of hem-
orrhage and necrosis. When the gallbladder wall is sub-
jected to elevated internal pressure, the blood flow is
obstructed, with histological evidence of vascular throm-
bosis and occlusion. There are areas of scattered necro-
sis, but it is superficial and does not involve the full
thickness of the gallbladder wall.
Suppurative cholecystitis: third stage (7–10 days). The
gallbladder wall has white blood cells present, with ar-
eas of necrosis and suppuration. In this stage, the active
repair process of inflammation is evident. The enlarged
gallbladder begins to contract and the wall is thickened
due to fibrous proliferation. Intrawall abscesses are
present and involve the entire thickness of the wall.
Pericholecystic abscesses are present.
Chronic cholecystitis. Chronic cholecystitis occurs after
the repeated occurrence of mild attacks of cholecystitis,
and is characterized by mucosal atrophy and fibrosis of
the gallbladder wall. It can also be caused by chronic
irritation by large gallstones and may often induce acute
cholecystitis.
Specific forms of acute cholecystitis. There are four
specific forms of acute cholecystitis: (1) acalculous cho-
lecystitis, which is acute cholecystitis without cholecys-
tolithiasis; (2) xanthogranulomatous cholecystitis, which
is characterized by the xanthogranulomatous thicken-
ing of the gallbladder wall and elevated intra-gallblad-
der pressure due to stones, with rupture of the the
Rokitansky-Achoff sinuses. This rupture causes leakage
and bile entry into the gallbladder wall. The bile is in-
gested by histocytes, forming granulomas consisting of
foamy histocytes. Patients usually have symptoms of
acute cholecystitis in the initial stage. (3) emphysema-
tous cholecystitis, in which air appears in the gallblad-
der wall due to infection with gas-forming anaerobes,
including Clostridium perfringens. This form is likely to
progress to sepsis and gangrenous cholecystitis; it is of-
ten seen in diabetic patients. (4) Torsion of the gallblad-
der.69
Torsion of the gallbladder is known to occur by
inherent, acquired, and other physical causes. An inher-
ent factor is a floating gallbladder, which is very mobile
because the gallbladder and cystic ducts are connected
with the liver by a fused ligament. Acquired factors in-

clude splanchnoptosis, senile humpback, scoliosis, and
weight loss. Physical factors causing torsion of the gall-
bladder include sudden changes of intraperitoneal pres-
sure, sudden changes of body position, a pendulum-like
movement in the anteflexion position, hyperperistalsis
of organs near the gallbladder, defecation, and trauma
to the abdomen.
Incidence of complications with advanced forms of
acute cholecystitis
The incidence of complications with advanced forms of
acute cholecystitis ranges widely, from 7.2% to 26%, in
reports published since 1990.70–74
In patients with acute
cholecystitis (n = 368), the incidence of morbidity was
17%, with the incidences of gangrenous, suppurative,
perforating, and emphysematous cholecystitis being
7.1%, 6.3%, 3.3%, and 0.5%, respectively.74
Types of complications. There are four types of compli-
cations. (1) Perforation of the gallbladder, which is
caused by acute cholecystitis, injury, or tumors, and oc-
curs most often as a result of ischemia and necrosis of
the gallbladder wall. (2) Biliary peritonitis, which occurs
with the entry into the peritoneal cavity of bile leaked
due to various causes, including cholecystitis-induced
gallbladder perforation, trauma, a catheter detached
during biliary drainage, and incomplete suture after bili-
ary operation. (3) Pericholecystic abscess, a morbid
condition in which a perforation of the gallbladder wall
is covered by the surrounding tissue, with the formation
of an abscess around the gallbladder. (4) Biliary fistula,
which can occur between the gallbladder and the duo-
denum following an episode of acute cholecystitis. The
fistula is usually caused by a large gallbladder stone
eroding through the wall of the gallbladder into the
duodenum. If the stone is large, the patient can develop
gallstone ileus, with the stone causing mechanical small-
bowel obstruction at the ileocecal valve.
Prognosis
The mortality in patients with acute cholecystitis is
0–10%75–81
(Table 8), whereas the mortality in patients
with postoperative cholecystitis and acalculous chole-
cystitis is as high as 23%–40%.82–84
The mortality of
elderly patients (75 years and older) tends to be higher
than that of younger patients,85,86
and a comorbidity
such as diabetes may increase the risk of death.75
Many reports of the mortality and morbidity of
acute cholecystitis are difficult to compare, because
there are significant variations in the diagnostic criteria,
timing and type of operation, presence of comorbidities,
and hospital support systems for critically ill patients,
as well as variations in available surgical expertise.
According to reports published in 1980 and before,
most of the causes of death after cholecystectomy were
related to postoperative infections, such as ascending
cholangitis, hepatic abscess, and sepsis.76,77
Since 1980,
postoperative mortality from infection has decreased
and the major causes of death include myocardial in-
farction, cardiac failure, and pulmonary infarction.78,79
Cholecystostomy was a common form of treatment in
1970 and before, and the most common cause of death
during that period was pneumonia and sepsis.87
Cur-
rently, the major causes of death following cholecystos-
tomy include malignant tumor, respiratory failure, and
cardiac failure.88,89
Recurrence rate of acute cholecystitis after
conservative treatment
Most patients with acute cholecystitis are treated with
a cholecystectomy, and it is difficult to anticipate wheth-
er the outcome will show recurrence. Recurrences of
clinical concern include the recurrence of (1) acute cho-
lecystitis after spontaneous recovery without the under-
going of any treatment; (2) acute cholecystitis while
waiting for cholecystectomy after conservative treat-
ment with diet modification and antibiotics; (3) acute
Table 8. Mortality of acute cholecystitis
Author Period Country Subjects No. of cases Mortality (%)
Meyer76
1958–1964 USA 245 4.49
Ranasohoff75
1960–1981 USA 298 3.36
Gagic77
1966–1971 USA 93 9.68
Girard and Moria78
1970–1986 Canada 1691 0.65
Addison and Finan79
1971–1990 UK 236 4.66
Bedirli80
1991–1994 Turkey 368 2.72
Gharaibeh81
1993–1900 Jordan 204 0
Hafif85
1952–1967 Israel Age, 70 years and older 131 3.82
Gingrich87
1976–1985 USA Only external biliary drainage 114 32
Glenn86
1977–1987 USA Age, 65 years old and older 655 9.92
Kalliafas82
1981–1987 USA Acalculous cases only 27 40.74
Inoue and Mishima83
1989–1993 Japan Postoperative cases only 494 23.08
Savoca84
1994–1999 USA Acalculous cases only 47 6.38

cholecystitis when cholecystectomy is not performed for
some reason, such as surgical risk or the patient’s deci-
sion (with or without biliary drainage); and (4) cholan-
gitis after cholecystectomy.
There are no data on the recurrence of acute chole-
cystitis after resolution of the initial symptoms. The re-
currence of acute cholecystitis while patients are waiting
for cholecystectomy following conservative treatment
ranges from 2.5% to 22%.75,90
In 311 patients with acute
calculous cholecystitis , 25 of 39 patients who did not
have a cholecystectomy during the acute stage were
scheduled to undergo delayed operation after being dis-
charged from hospital. Only 1 of the 25 patients (2.5%)
developed recurrent acute cholecystitis while waiting
for an operation.75
In non-severe cases, acute cholecys-
titis recurred in 2% of patients within an 8- to 10-week
waiting period, 6% of whom showed gallbladder
perforation.90
Long-term recurrence is reported to be 10%–50% in
6 months to several years of observation, though there
are few reports. According to a randomized controlled
trial comparing non-operative treatment and cholecys-
tectomy for patients with acute cholecystitis, excluding
those with severe cases (n = 56), 11% had a history of
acute cholecystitis, and 8 (24%) of 33 patients assigned
to non-operative treatment underwent cholecystectomy
during an observation period of 1.5–4 years.91
In pa-
tients with acute cholecystitis who were observed after
treatment with percutaneous drainage, acute cholecys-
titis recurred once or more in 28 of 60 patients (47%)
during an average observation period of 18 months,88
and it recurred once or more in 11 of 36 (31%) patients
who were observed for 37 months on average.89
In a
report of 114 patients who underwent only cholecystos-
tomy, among 585 patients who were hospitalized be-
cause of acute cholecystitis, acute cholecystitis recurred
in 5 of 23 patients observed for 6 months to 14 years
and 14 of the 23 patients remained asymptomatic.92
Cholangitis (H-15-Medicine-30), with a research subsi-
dy for fiscal 2003 and 2004 (Integrated Research Project
We also truly appreciate the panelists who cooperat-
ed with and contributed significantly to the Interna-
tional Consensus Meeting, held on April 1 and 2,
2006.
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DOI 10.1007/s00534-006-1153-x
Flowcharts for the diagnosis and treatment of acute
Fumihiko Miura1
, Tadahiro Takada1
, Yuji Nimura3
, Keita Wada1
, Masahiko Hirota4
,
Masato Nagino3
, Toshio Tsuyuguchi5
, Toshihiko Mayumi6
, Masahiro Yoshida1
, Steven M. Strasberg7
,
Henry A. Pitt8
, Jacques Belghiti9
, Dirk J. Gouma12
,
Sheung-Tat Fan13
, Miin-Fu Chen14
, Robert T. Padbury15
, Philippus C. Bornman16
, Sun-Whe Kim17
,
Kui-Hin Liau18
, Giulio Belli19
, and Christos Dervenis20
1
Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo 173-8605, Japan
2
3
4
5
6
7
8
9
10
11
12
13
Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
14
Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
15
Division of Surgical and Specialty Services, Flinders Medical Centre, Adelaide, Australia
16
Division of General Surgery, University of Cape Town, Cape Town, South Africa
17
18
19
Department of General and Hepato-Pancreato-Biliary Surgery, S.M. Loreto Nuovo Hospital, Naples, Italy
20
First Department of Surgery, Agia Olga Hospital, Athens, Greece
with severe (grade III) acute cholecystitis, multiorgan support
is a critical part of management. Biliary peritonitis due to
perforation of the gallbladder is an indication for urgent
cholecystectomy and/or drainage. Delayed elective cholecys-
tectomy may be performed after initial treatment with gall-
bladder drainage and improvement of the patient’s general
medical condition.
Key words Cholangitis · Acute cholecystitis · Cholecystec-
tomy · Laparoscopic cholecystectomy · Biliary · Drainage ·
Guidelines
Introduction
Acute biliary inflammation/infection is classified as ei-
ther acute cholangitis or acute cholecystitis, and ranges
from mild forms that improve with medical treatment
to severe forms that require intensive care and urgent
intervention. The medical condition of a patient with
biliary inflammation/infection is likely to deteriorate
rapidly and the condition can become life-threatening.
Early diagnosis should be made based on clinical signs/
symptoms and laboratory findings. The type and timing
of treatment should be based on the grade of severity
of the disease.
Abstract
Diagnostic and therapeutic strategies for acute biliary inflam-
mation/infection (acute cholangitis and acute cholecystitis),
according to severity grade, have not yet been established in
the world. Therefore we formulated flowcharts for the man-
agement of acute biliary inflammation/infection in accordance
with severity grade. For mild (grade I) acute cholangitis, medi-
cal treatment may be sufficient/appropriate. For moderate
(grade II) acute cholangitis, early biliary drainage should be
performed. For severe (grade III) acute cholangitis, appropri-
ate organ support such as ventilatory/circulatory management
is required. After hemodynamic stabilization is achieved, ur-
gent endoscopic or percutaneous transhepatic biliary drainage
should be performed. For patients with acute cholangitis of
any grade of severity, treatment for the underlying etiology,
including endoscopic, percutaneous, or surgical treatment
should be performed after the patient’s general condition has
improved. For patients with mild (grade I) cholecystitis, early
laparoscopic cholecystectomy is the preferred treatment. For
patients with moderate (grade II) acute cholecystitis, early
laparoscopic or open cholecystectomy is preferred. In patients
with extensive local inflammation, elective cholecystectomy is
recommended after initial management with percutaneous
gallbladder drainage and/or cholecystostomy. For the patient
Offprint requests to: F. Miura

28 F. Miura et al.: Management strategy for biliary inflammation/infection
Although endoscopic and laparoscopic techniques
have advanced recently (level 1b–2b),1,2
the treatment
of severe acute biliary inflammation/infection still re-
sults in fatalities and increased hospital costs. To our
knowledge, there are no definite diagnostic and thera-
peutic guidelines for acute biliary inflammation/infec-
tion according to the grade of severity of the disease.
This article describes the management strategy for bil-
iary inflammation/infection in accordance with the se-
verity of the biliary disease. Guidelines were developed,
based on best clinical evidence and discussions at the
International Consensus Meeting held in Tokyo on
April 1–2, 2006.
General guidance for the management of acute biliary
inflammation/infection
A flowchart showing general guidance for the man-
agement of acute biliary inflammation/infection is
presented in Fig. 1.
Clinical presentation
Clinical findings associated with acute cholangitis in-
clude abdominal pain, jaundice, fever (Charcot’s triad),
and rigor. The triad was already reported as an indicator
of hepatic fever by Charcot in 1877,3
and has been, his-
torically, used as the generally accepted clinical findings
of acute cholangitis. About 50%–70% of patients with
acute cholangitis develop all three symptoms (level
2b–4).4–7
Reynolds’ pentad (Charcot’s triad plus shock
and a decreased level of consciousness) was presented
in 1959, when Reynolds and Dargan8
defined acute ob-
structive cholangitis. The pentad is often used to indi-
cate severe (grade III) cholangitis, but shock and a
decreased level of consciousness are observed in
only 30% or fewer patients with acute cholangitis (level
2b–4).4–7
A history of biliary disease, such as gallstones,
previous biliary procedures, or the placement of a bil-
iary stent are factors that are very helpful to suggest a
diagnosis of acute cholangitis.
Clinical symptoms of acute cholecystitis include ab-
dominal pain (right upper abdominal pain), nausea,
vomiting, and fever (level 2b–4).9–11
The most typical
symptom is right epigastric pain. Tenderness in the right
upper abdomen, a palpable gallbladder, and Murphy’s
sign are the characteristic findings of acute cholecystitis.
A positive Murphy’s sign has a specificity of 79%–96%
(level 2b–3b)9,11
for acute cholecystitis.
Blood tests
The diagnosis of acute cholangitis requires a white
blood cell count; measurement of the C-reactive protein
level; and liver function tests, including alkaline phos-
phatase, gamma-glutamyltranspeptidase (GGT), aspar-
tate aminotransferase (AST), alanine aminotransferase
(ALT), and bilirubin. Assessment of the severity of the
illness requires knowledge of the platelet count, blood
urea nitrogen, creatinine, and prothrombin time (PT).
Blood cultures are also helpful for severity assessment,
as well as for the selection of antimicrobial drugs. Hy-
peramylasemia is a useful parameter to identify compli-
cations such as choledocholithiasis causing biliary
pancreatitis (level 1a).12
There is no specific blood test for acute cholecystitis;
however, the white blood cell count and the measure-
ment of C-reactive protein is very useful in confirming
an inflammatory process. Bilirubin, blood urea nitrogen,
creatinine, and PT are very useful in assessing the dis-
ease severity status of the patient.
Diagnostic imaging
Abdominal ultrasound (US) and abdominal computer-
ized tomography (CT) with intravenous contrast are
very helpful studies in evaluating patients with acute
Suspicion of acute biliary infection
Diagnostic criteria
Clinical presentations, blood test,
diagnostic imaging
Acute cholangitis Acute cholecystitis
Other diseases
Differential
diagnosis
Fig. 1. Flowchart showing general guid-
ance for the management of acute biliary
infection

F. Miura et al.: Management strategy for biliary inflammation/infection 29
biliary tract disease. Abdominal US should be per-
formed in all patients suspected of having acute biliary
inflammation/infection. Ultrasound examination has
satisfactory diagnostic capability when it is performed
not only by specialists but also by emergency physicians
(level 1b).13,14
The role of diagnostic imaging in acute cholangitis is
to determine the presence/absence of biliary obstruc-
tion, the level of the obstruction, and the cause of the
obstruction, such as gallstones and/or biliary strictures.
Assessment should include both US and CT. These stud-
ies complement each other and CT may better demon-
strate dilatation of the bile duct and pneumobilia.
Some of the characteristic finding of acute cholecys-
titis include an enlarged gallbladder, thickened gall-
bladder wall, gallbladder stones and/or debris in the
gallbladder, sonographic Murphy’s sign, pericholecystic
fluid, and pericholecystic abscess. Sonographic Mur-
phy’s sign is a very reliable finding of acute cholecystitis,
with a specificity exceeding 90% (level 3b,4).15,16
CT
scan or even plain X-ray may demonstrate free air,
pneumobilia, and ileus.
Differential diagnosis
Diseases which should be differentiated from acute
cholangitis are acute cholecystitis, gastric and duodenal
ulcer, acute pancreatitis, acute hepatitis, and septicemia
of other origins. Diseases which should be differentiated
from acute cholecystitis are gastric and duodenal ulcer,
hepatitis, pancreatitis, gallbladder cancer, hepatic ab-
scess, Fitz-Hugh-Curtis syndrome, right lower lobar
pneumonia, angina pectoris, myocardial infarction, and
urinary infection.
Flowchart for the management of acute cholangitis
A flowchart for the management of acute cholangitis is
shown in Fig. 2. The treatment of acute cholangitis
should be guided by the grade of severity of the disease.
Biliary drainage and antibiotics are the two most impor-
tant elements of treatment. When a diagnosis of acute
cholangitis is suspected, medical treatment, including nil
per os (NPO) and the use of intravenous fluids, antibiot-
ics, and analgesia, together with close monitoring of
blood pressure, pulse, and urinary output should be
initiated. Simultaneously, a severity assessment of the
cholangitis should be documented, even if it is mild.
Frequent reassessment is important, and patients may
need to be reclassified as having mild (grade I), moder-
ate (grade II), or severe (grade III) disease, based on
the response to medical treatment. Appropriate treat-
ment should be performed in accordance with the sever-
ity grade. Patients with concomitant diseases such as
acute pancreatitis or malignant tumor, and elderly pa-
tients are likely to progress to a severe level; therefore,
such patients should be monitored frequently.
Mild (grade I) acute cholangitis
Medical treatment may be sufficient. Biliary drainage is
not required in most cases. However, for non-
responders to medical treatment, the necessity of biliary
Diagnosis of acute cholangitis
Urgent
biliary
drainage
Treatment for etiology
(Endoscopic treatment,
percutaneous treatment,
or surgery)
Organsupport
forseverecases
Observation
Severe
(Grade III)
Early
biliary
drainage
Medicaltreatment
Moderate
(Grade II)
Severity assessment
Launch of medical treatment
Mild
(Grade I)
Fig. 2. Flowchart for the management of
acute cholangitis

drainage should be considered. Treatment options such
as endoscopic, percutaneous, or operative intervention
may be required, depending on the etiology. Some pa-
tients, such as those who develop postoperative cholan-
gitis, may only require antibiotics and generally do not
require intervention.
Moderate (grade II) acute cholangitis
Patients with acute cholangitis who do not respond to
medical treatment have moderate (grade II) acute
cholangitis. In these patients, early endoscopic or per-
cutaneous drainage or even emergent operative drain-
age with a T-tube should be performed. A definitive
procedure should be performed to remove the cause of
the obstruction once the patient is in a stable
condition.
Severe (grade III) acute cholangitis
Patients with acute cholangitis and organ failure are
classified as having severe (grade III) acute cholangitis.
These patients require organ support, such as ventila-
tory/circulatory management (e.g., endotracheal intu-
bation, artificial respiration management, and the use
of vasopressin), and treatment for disseminated
Yes
No
Yes
No
Panelists N=41 Audience N=67
100%
0%
97%
3%
Yes
No
Yes
No
98%
2%
99%
1%
Yes
No
Yes
No
93%
7%
97%
3%
Fig. 3. A Responses to the question “Do
you agree with the flowchart for the man-
agement of mild acute (grade I) cholangi-
tis?” The flowchart for the management
of mild acute (grade I) cholangitis was
agreed upon by 100% and 97% of the
panelists and the audience, respectively.
B Responses to the question “Do you
agree with the flowchart for the manage-
ment of moderate acute (grade II) cholan-
gitis?” The flowchart for the management
of moderate acute (grade II) cholangitis
was agreed upon by 93% and 97% of the
panelists and the audience, respectively.
C Responses to the question “Do you
agree with the flowchart for the manage-
ment of severe acute (grade III) cholan-
gitis?” The flowchart for the management
of severe acute (grade III) cholangitis was
agreed upon by 98% and 99% of the pan-
elists and the audience, respectively
A
B
C

intravascular coagulation (DIC) in addition to the gen-
eral medical management. Urgent biliary drainage must
be anticipated. When the patient is stabilized, urgent
(ASAP) endoscopic or percutaneous transhepatic bil-
iary drainage or an emergent operation with decom-
pression of the bile duct with a T-tube should be
performed. Definitive treatment of the cause of the ob-
struction, including endoscopic, percutaneous, or oper-
ative intervention, should be considered once the acute
illness has resolved.
Results of the Tokyo International Consensus Meeting
At the International Consensus Meeting, responses to
the flowcharts for the management of the different
grades of acute cholangitis were elicited and a consen-
sus was reached (Fig. 3).
Flowchart for the management of acute cholecystitis
A flowchart for the management of acute cholecystitis
is shown in Fig. 4. Early cholecystectomy is recommend-
ed for most patients, with laparoscopic cholecystectomy
as the preferred method. Among high-risk patients, per-
cutaneous gallbladder drainage is an alternative therapy
for those patients who cannot safely undergo urgent/
early cholecystectomy (level 4).17,18
When a diagnosis of acute cholecystitis is suspected,
medical treatment, including NPO, intravenous fluids,
antibiotics, and analgesia, together with close monitor-
ing of blood pressure, pulse, and urinary output should
be initiated. Simultaneously, the grade of severity needs
to be established. Appropriate treatment should be per-
formed in accordance with the severity grade. The as-
sessment of operative risk should also be evaluated
based on the severity grade.
After the acute inflammation has been resolved by
medical treatment and gallbladder drainage, it is
desirable to perform a cholecystectomy to prevent
recurrence. In surgically high-risk patients with chole-
cystolithasis, medical support after percutaneous chole-
cystolithotomy should be considered (level 4).19–21
For
patients with acalculous cholecystitis, cholecystectomy
is not required, because recurrence of acute acalculous
cholecystitis after gallbladder drainage is rare (level
4).17,22
Early laparoscopic cholecystectomy is the preferred
treatment. Elective cholecystectomy may be selected (if
early cholecystectomy is not performed) in order to
improve other medical problems.
Early laparoscopic or open cholecystectomy is pre-
ferred. If a patient has serious local inflammation mak-
ing early cholecystectomy difficult, then percutaneous
or operative drainage of the gallbladder is recom-
mended. Elective cholecystectomy can be performed
after improvement of the acute inflammatory process.
Severe (grade III) acute cholecystitis is accompanied by
organ dysfunction and/or severe local inflammation.
Appropriate organ support in addition to medical treat-
ment is necessary for patients with organ dysfunction.
Management of severe local inflammation by percuta-
neous gallbladder drainage and/or cholecystectomy is
needed. Biliary peritonitis due to perforation of the
gallbladder is an indication for urgent cholecystectomy
Diagnosis of acute cholecystitis
Urgent/ early
cholecystectomyEarly LC
Observation
Early/ elective
cholecystectomy Observation
Severity assessment
Medicaltreatment
Organsupport
forseverecases
Urgent/ early
GB drainage
Severe
(Grade III)
Mild
(Grade I)
Moderate
(Grade II)
Fig. 4. Flowchart for the management of
acute cholecystitis. GB, gallbladder; LC,
laparoscopic cholecystectomy

Yes
No
Yes
No
92%
8%
87%
13%
Yes
No
Yes
No
Japanese panelists N=19 Japanese audience N=65
89%
11%
83%
17%
Yes
No
Yes
No
97%
3%
95%
5%
Fig. 5. A Responses to the question “Do
you agree with the flowchart for the man-
agement of mild acute (grade I) cholecys-
titis?” The flowchart for the management
of mild acute (grade I) cholecystitis was
agreed upon by 92% and 87% of the pan-
elists and the audience, respectively. B
Responses to the question “Do you agree
with the flowchart for the management of
moderate acute (grade II) cholecystitis?”
The flowchart for the management of
moderate acute (grade II) cholecystitis
was agreed upon by 89% and 83% of the
Japanese panelists and the Japanese audi-
ence, respectively. C Responses to the
question “Do you agree with the flowchart
for the management of severe acute (grade
III) cholecystitis?” The flowchart for the
management of severe acute (grade III)
cholecystitis was agreed upon by 97%
and 95% of the panelists and audience,
respectively
A
B
C
and drainage. Elective cholecystectomy may be per-
formed after improvement of the acute illness by gall-
bladder drainage.
Results of the Tokyo International Consensus Meeting
At the International Consensus Meeting, flowcharts
for the management of mild (grade I) and severe (grade
III) acute cholecystitis were agreed upon by almost
all of the participants; however, the flowchart for
moderate (grade II) acute cholecystitis was agreed upon
by fewer than 90% of the participants (Fig. 5).
for Assessing Medical Technology), sponsored by the

We also truly appreciate the panelists who coope-
rated with and contributed significantly to the Interna-
tional Consensus Meeting held in Tokyo on April 1 and
2, 2006.
References
1. Lai EC, Mok FP, Tan ES, Lo CM, Fan ST, You KT, et al. Endo-
scopic biliary drainage for severe acute cholangitis. N Engl J Med
1992;326:1582–6. (level 2b)
2. Lo CM, Liu CL, Fan ST, Lai EC, Wong J. Prospective randomized
study of early versus delayed laparoscopic cholecystectomy for
acute cholecystitis. Ann Surg 1998;227:461–7. (level 1b)
3. Charcot M. De la fievre hepatique symptomatique Comparison
avec la fievre uroseptique. Paris: Bourneville et Sevestre, 1877.
(level 4)
4. Boey JH, Way LW. Acute cholangitis. Ann Surg 1980;191:264–70.
(level 4)
Surg 1992;79:655–8. (level 2b)
treatment of acute suppurative cholangitis. Am J Surg 1976;
131:527–32. (level 4)
Surg 1982;117:437–41. (level 4)
8. Reynolds BM, Dargan EL. Acute obstructive cholangitis; a
distinct clinical syndrome. Ann Surg 1959;150:299–303. (level 4)
abdominal pain. Theor Surg 1993;8:15–20. (level 2b)
10. Staniland JR, Ditchburn J, De Dombal FT. Clinical presentation
of acute abdomen: study of 600 patients. BMJ 1972;3:393–8. (level
4)
11. Trowbridge RL, Rutkowski NK, Shojania KG. Does this patient
have acute cholecystitis? JAMA 2003;289:80–6. (level 3b)
12. AbboudPA,MaletPF,BerlinJA,StaroscikR,CabanaMD,Clarke
JR, et al. Predictors of common bile duct stones prior to cholecys-
tectomy: a meta-analysis. Gastrointest Endosc 1996;44:450–5.
(level 1a)
13. Rosen CL, Brown DF, Chang Y, Moore C, Averill NJ, Arkoff LJ,
et al. Ultrasonography by emergency physicians in patients
with suspected cholecystitis. Am J Emerg Med 2001;19:32–6.
(level 1b)
14. Kendall JL, Shimp RJ. Performance and interpretation of focused
right upper quadrant ultrasound by emergency physicians. J
Emerg Med 2001;21:7–13. (level 1b)
15. Ralls PW, Halls J, Lapin SA, Quinn MF, Morris UL, Boswell W.
Prospective evaluation of the sonographic Murphy sign in sus-
pected acute cholecystitis. J Clin Ultrasound 1982;10:113–5. (level
4)
16. Soyer P, Brouland JP, Boudiaf M, Kardache M, Pelage JP, Panis Y,
et al. Color velocity imaging and power Doppler sonography
of the gallbladder wall: a new look at sonographic diagnosis of
acute cholecystitis. Am J Roentgenol AJR 1998;171:183–8. (level
3b)
17. Sugiyama M, Tokuhara M, Atomi Y. Is percutaneous cholecysto-
stomy the optimal treatment for acute cholecystitis in the very
elderly? World J Surg 1998;22:459–63. (level 4)
18. Chopra S, Dodd GD 3rd, Mumbower AL, Chintapalli KN,
Schwesinger WH, Sirinek KR, et al. Treatment of acute cholecys-
titis in non-critically ill patients at high surgical risk: comparison
of clinical outcomes after gallbladder aspiration and after percu-
taneous cholecystostomy. Am J Roentgenol AJR 2001;176:1025–
31. (level 4)
19. Inui K, Nakazawa S, Naito Y, Kimoto E, Yamao K. Nonsurgical
treatment of cholecystolithiasis with percutaneous transhepatic
cholecystoscopy. Am J Gastroenterol 1988;83:1124–7. (level 4)
20. Boland GW, Lee MJ, Mueller PR, Dawson SL, Gaa J, Lu DS,
et al. Gallstones in critically ill patients with acute calculous chole-
cystitis treated by percutaneous cholecystostomy: nonsurgical
therapeutic options. Am J Roentgenol AJR 1994;162:1101–3.
(level 4)
21. MajeedAW,ReedMW,RossB,PeacockJ,JohnsonAG.Gallstone
removal with a modified cholecystoscope: an alternative to chole-
cystectomy in the high-risk patient. J Am Coll Surg 1997;184:273–
80. (level 4)
22. Shirai Y, Tsukada K, Kawaguchi H, Ohtani T, Muto T, Hatakeya-
ma K. Percutaneous transhepatic cholecystostomy for acute acal-
culous cholecystitis. Br J Surg 1993;80:1440–2. (level 4)
Consensus Meeting
General guidance
Acute biliary inflammation/infection consists of acute
cholangitis and acute cholecystitis. In these infectious
diseases, bacterial contamination is an essential condi-
tion, but inflammation has a wider meaning and includes
not only infection but also other inflammation caused by
non-bacterial vectors (Sun-Whe Kim, Korea). It may be
difficult to initially determine whether the inflammation
is progressing to an bacterial infection (Thomas R.
Gadacz, USA); therefore, in this article, we adopted the
term “acute biliary inflammation/infection”.
As for general guidance for the management of acute
biliary inflammation/infection, most aspects were ac-
cepted with great concordance. During the initial evalu-
ation of a patient, information on a past history of biliary
disease (gallstone, previous biliary surgery, and biliary
stent placement) was emphasized (Jacques Belghiti,
France; Philippus C. Bornman, South Africa; and Ste-
ven M. Strasberg, USA). Jacques Belghiti added that
septicemia arising from other diseases needs to be dif-
ferentiated from acute cholangitis.
Flowchart for the management of acute cholangitis
Concerning the treatment of acute cholangitis, the par-
ticular importance of antibiotics as well as urgent biliary
drainage was confirmed (Jacques Belghiti; Joseph W.Y.
Lau, Hong Kong, and Steven M. Strasberg). There were
few controversial matters in the flowchart for the man-
agement of acute cholangitis. Joseph W.Y. Lau advocat-
ed that mild cholangitis and moderate cholangitis should
be combined, because many patients with moderate
cholangitis would easily revert to the mild grade within
12h after successful medical treatment, and he suggest-
ed that severity assessment should depend on whether
patients responded to the initial treatment. This
statement implies that severity assessment should be

DOI 10.1007/s00534-006-1154-9
Techniques of biliary drainage for acute cholangitis: Tokyo Guidelines
Toshio Tsuyuguchi1
, Tadahiro Takada2
, Yuji Nimura4
, Keita Wada2
,
Masato Nagino4
, Toshihiko Mayumi5
, Masahiro Yoshida2
, Fumihiko Miura2
, Atsushi Tanaka6
,
Yuichi Yamashita7
, Masahiko Hirota8
, Koichi Hirata9
, Hideki Yasuda10
, Yasutoshi Kimura9
,
Steven Strasberg11
, Henry Pitt12
, Markus W. Büchler13
, Horst Neuhaus14
,
, Sheung-Tat Fan17
, Kui-Hin Liau18
, and Vibul Sachakul19
1
Department of Medicine and Clinical Oncology, Graduate School of Medicine Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677,
Japan
2
3
4
5
6
7
8
9
10
Department of Surgery, Teikyo University Ichihara Hospital, Chiba, Japan
11
12
13
14
Department of Internal Medicine, Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany
15
16
17
18
Department of Surgery, Tan Tock Seng Hospital/Hepatobiliary Surgery, Medical Centre, Singapore, Singapore
19
Key words Cholangitis · Endoscopic sphincterotomy · Biliary
drainage · Percutaneous · Endoscopy · Endoscopic cholangio-
pancreatography · Guidelines
Introduction
Acute cholangitis may progress rapidly to a severe form,
particularly in the elderly, and the severe form often
results in a high mortality (level 4).1–3
When Reynolds
and Dargan1
published their report, surgical operation
was the only available treatment, and the mortality rate
was steep. Even now, when the mortality rate has de-
clined, due to the ubiquitous application of endoscopic
and percutaneous transhepatic biliary drainage, acute
cholangitis can be fatal unless it is treated in a timely
way. Although endoscopic drainage is less invasive than
other drainage techniques and should be considered as
the drainage technique of first choice (level 2b),4
details
of its procedures remain controversial. This article out-
lines various biliary drainage techniques, especially in
regard to endoscopic procedures.
Abstract
Biliary decompression and drainage done in a timely manner
is the cornerstone of acute cholangitis treatment. The morta-
lity rate of acute cholangitis was extremely high when no
interventional procedures, other than open drainage, were
available. At present, endoscopic drainage is the procedure of
first choice, in view of its safety and effectiveness. In patients
with severe (grade III) disease, defined according to the
severity assessment criteria in the Guidelines, biliary drainage
should be done promptly with respiration management, while
patients with moderate (grade II) disease also need to under-
go drainage promptly with close monitoring of their responses
to the primary care. For endoscopic drainage, endoscopic naso-
biliary drainage (ENBD) or stent placement procedures are
performed. Randomized controlled trials (RCTs) have
reported no difference in the drainage effect of these two
procedures, but case-series studies have indicated the fre-
quent occurrence of hemorrhage associated with endoscopic
sphincterotomy (EST), and complications such as pancreati-
tis. Although the usefulness of percutaneous transhepatic
drainage is supported by the case-series studies, its lower suc-
cess rate and higher complication rates makes it a second-
option procedure.
Offprint requests to: T. Tsuyuguchi

36 T. Tsuyuguchi et al.: Drainage methods for acute cholangitis
Techniques of endoscopic biliary drainage
Transpapillary biliary drainage for acute cholangitis is
based on selective cannulation into the bile duct with
endoscopic retrograde cholangiopancreatography
(ERCP). However, as these drainage procedures
are different in regard to: (i) the additional application
of endoscopic sphincterotomy (EST), and (ii) the
selection of either endoscopic nasobiliary drainage
(ENBD) or stent placement, they are explained below
in detail.
ERCP
ERCP is a procedure to insert a contrast test catheter
into the papilla, using a duodenal scope to visualize the
bile duct. To secure a drainage route (for ENBD or
stent placement), successful selective cannulation into
the bile duct is essential. If cannulation deep into the
bile duct is difﬁcult, replacement of the catheter, the use
of a guidewire, and precutting (by EST, explained be-
low), are necessary. If the cannulation into the bile duct
fails, other drainage, such as percutaneous transhepatic
biliary drainage, is necessary. Also, the quantity of con-
Fig. 1a,b. Pull-type sphincterotome. a A pull-type sphinctero-
tome is shown; it has various applications, and is useful for
opening the bile duct. b The direction of the tip of the blade
Fig. 2. Push-type sphincterotome. The direction of the blade
cannot be altered, but its length and form can be changed. It
can be used for precutting
Fig. 3. Needle-type sphincterotome. Because of the needle
point, opening of the bile duct can be performed
can be manipulated by pulling. The direction can usually be
changed by using a guidewire
a b

T. Tsuyuguchi et al.: Drainage methods for acute cholangitis 37
and the incidence of acute pancreatitis, known to be-
come fatal once it progresses severely, depends on the
skills of the endoscopist (level 1b, level 4)6,7
(Table 1).
Precutting techniques
Precutting is an incision of the papilla to facilitate can-
nulation into the bile duct when selective cannulation is
impossible. EST can be completed by a common proce-
dure after selective cannulation into the bile duct
becomes possible. The method using a needle-type
sphincterotome for probing in the opening of the bile
duct is common (Fig. 6), but there is also a method to
incise the tips of the bile duct with a push-type or shark’s
fin-type sphincterotome. The types of sphincterotome
and the detailed procedures used differ depending on
the medical institution. It is also known that precutting
is likely to cause serious complications such as acute
pancreatitis and perforation, and therefore it can
be used only by skilled endoscopic surgeons (level 1b,
level 4).6,7
Significance of EST in endoscopic biliary drainage
According to some case-series studies, the reasons that
additional EST are not necessary in acute cholangitis
are that:
(i) The application of additional EST to drainage pro-
duces no difference in effect
Fig. 4a,b. Standard techniques for endoscopic sphincterotomy (EST). a Selective cannulation of the bile duct. b A high-
frequency electric surgical incision of the papilla of Vater is made with the blade
trast medium should be minimized to avoid the infusion
of an excessive amount, which may exacerbate the
cholangitis.
EST
Standard techniques
EST is a procedure used widely not only in the
treatment of choledocholithiasis but also as a drainage
procedure for malignant biliary obstruction. Sphincter-
otomes used for incision include several types such as:
the pull-type (Fig. 1a,b), push-type (Fig. 2), needle type
(Fig. 3) and, the shark’s fin-type, and others, each
of which has a different length of exposed wire and dif-
ferent tip shape. The most common sphincterotome is
the pull type. The pull-type sphincterotome is useful
when ERCP is difficult, because the direction of the tip
of the sphincterotome can be changed by adjusting
the tension of the blade (Fig. 1b). The push-type and
needle-type are used for difficult cases.
A common EST technique is to perform a high-
frequency electric surgical incision of the duodenal pa-
pilla, using a sphincterotome selectively cannulated in
the bile duct (Figs. 4 and 5). In EST for drainage pur-
poses, unlike that for stone removal, only a limited inci-
sion is necessary (level 4).5
Acute pancreatitis and
cholangitis are common complications caused by EST,
Table 1. Complications caused by EST
Author n Pancreatitis Hemorrhage Cholangitis Cholecystitis Perforation Mortality
Freeman (1996)6
2347 5.4% 2.0% 1.0% 0.5% 0.3% 0.4%
Cotton (1991)7
7729 1.9% 3.0% 1.7% 1.0% 1.3%
a b

(ii) the additional EST causes complications such as
hemorrhage.
Acute cholangitis is one of the risk factors for post-
EST hemorrhage (level 1b),6
and the use of EST in
patients with severe (grade III) disease complicated by
coagulopathy should be avoided. On the other hand,
EST has advantages such as:
(a) Not only drainage but also single-stage lithotomy
can be employed in patients with choledocholithi-
asis (not complicated by severe cholangitis)
(b) Precutting can ensure a drainage route into the bile
duct in patients in whom selective cannulation
is difﬁcult.
Endoscopic drainage employed for acute cholangitis
does not always require EST (level 4).8,9
However, pre-
cutting may be indispensable in performing drainage in
some patients with impacted stones in the papilla of
Vater, and whether or not additional EST should be
conducted depends on the condition of the patient and
the skills of the endoscopist. In the Guidelines, readers
are reminded to be cautious when additional EST
is employed.
Endoscopic biliary drainage (EBD)
Endoscopic drainage includes not only endoscopic bi-
liary drainage (EBD) but also EST without stent
Fig. 5a–c. Example of EST procedure. a Gallstones are visible
via the duodenal papilla. b In this patient, cannulation with an
endoscopic catheter resulted in resolution of the debris-like
Fig. 6a,b. Precutting EST techniques with a needle-type
sphincterotome. a Needle-knife sphincterotomy was per-
formed, starting from the papillary oriﬁce, cutting upward. b
Incising through the wall of the major papilla is performed
with the needle-knife until achieving access into the bile
duct
stones. c The catheter was replaced by a high-frequency elec-
tric sphincterotome
a b,c
a b

insertion, which means that calculus removal can be
performed with only one endoscopic procedure. EBD
is of two types endoscopic nasobiliary drainage (ENBD;
external drainage) and stent placement (internal drain-
age). No difference between these two methods was
proven by past RCTs (level 2b),10,11
and the Guidelines
suggest that either drainage procedure may be chosen.
Internal drainage does, however, confer less electrolyte
disturbance as there is no external loss of bile and its
contents.
Endoscopic nasobiliary drainage (ENBD)
ENBD is an external drainage procedure done by plac-
ing a 5- to 7-Fr tube, using a guidewire technique, after
selective cannulation into the bile duct, and it is used to
complete nasobiliary drainage (Fig. 7–10). ENBD has
these advantages:
(i) No additional EST is required
(ii) Clogging in the tube (external drain) can be washed
out
(iii) Bile cultures can be done
However, because of the patient’s discomfort from
the transnasal tube placement, self-extraction and dis-
location of the tube are likely to occur, especially in
elderly patients. Loss of electrolytes and ﬂuid as well as
collapse of tubes by twisting, may also occur.
Additional EST must be considered for the removal
of concomitant bile duct stones and viscous bile or pus
in patients with suppurative cholangitis.
Fig. 7a,b. Endoscopic nasobiliary
drainage (ENBD) tubes. a Straight-tip
tube. The leading portion of the tube is
straight. A “duodenal loop” of the tube
(arrow) is formed to prevent disloca-
tion. b Pigtail-tip tube (arrow). To pre-
vent dislodgement, the leading portion
of the tube has a “pigtail”
Fig. 8. Cholangiography through ENBD tube. Many stones
are seen in the bile duct. Attention should be paid: cholangi-
ography should be performed after improvement of
inﬂammation
a b

Fig. 9a–f. ENBD procedure:
part 1. a An endoscopic cath-
eter is cannulated into the
bile duct. b A guidewire is
passed through the catheter
into the bile duct. c The cath-
eter is withdrawn. d The
ENBD tube is passed along
the guidewire. e The guide-
wire is withdrawn. f The en-
doscope is removed while
applying pushing pressure on
the ENBD tube to keep it in
place
a b
c d
e
f

Fig. 10a–f. ENBD procedure: part 2. a The ENBD tube is
inserted transorally. b A short plastic tube is inserted transna-
sally in order to engage the ENBD tube. c Surgical forceps
are used to pull the leading end of the short plastic tube out
orally. d The tubes are connected by inserting the end of the
ENBD tube into the short plastic tube. e The short plastic
tube and the connected ENBD tube are then pulled back out
nasally. f A 5- to 7-French tube is used for biliary drainage via
the nasal route
a b
c d
e
f

Plastic stent placement
Plastic stent placement is an internal drainage proce-
dure done to place a 7- to 10-Fr plastic stent in the bile
duct, using a guidewire after selective cannulation into
the bile duct (Figs. 11 and 12). There are two different
stent shapes, a straight type with flaps on both sides, and
a pig tail type, to prevent dislocation (Fig. 13). Absence
of discomfort and no loss of electrolytes or fluid relative
to transnasal biliary drainage are advantages. However,
as it cannot be known in real time whether the stent
is patent, there is a risk of dislodgement or clogging of
the stent. The other disadvantage is that when a stent
with a diameter larger than 7-Fr is inserted, EST is
necessary.
EST without stent insertion
EST without stent insertion can be used to remove bile
duct calculi as well as for drainage. This method can
shorten the hospital stay because both calculus removal
and drainage are completed with only one endoscopic
procedure. However, caution should be exercised, with
monitoring for cholangitis due to residual calculi or
sludge.
Fig. 11a–f. Plastic stent placement (7-Fr straight plastic stent).
a An endoscopic catheter is cannulated into the bile duct. b
A guidewire is passed through the catheter into the bile duct.
c The catheter is withdrawn. d A plastic stent is inserted along
the guidewire into the bile duct by using a pusher tube. e The
guidewire is removed while pushing on the pusher tube (care
should be taken not to deviate from the bile duct). f The
endoscope is removed, leaving the plastic stent in place
Techniques of percutaneous transhepatic
cholangial drainage (PTCD)
Though there are no studies comparing percutaneous
transhepatic cholangial drainage PTCD; also known as
percutaneous transhepatic biliary drainage; PTBD, and
endoscopic drainage, PTCD should applied, in princi-
ple, to those patients who cannot undergo endoscopic
drainage because of the possible serious complications
of PTCD, including intraperitoneal hemorrhage and
biliary peritonitis (level 4) (Table 212
) and a long hospi-
tal stay. A propensity for hemorrhage is a relative con-
traindication, but if there is no other lifesaving method,
Table 2. Serious complications caused by PTCD12
Complication Rate
Sepsis 2.5%
Hemorrhage 2.5%
Localized inflammation/infection (abscess, 1.2%
peritonitis, cholecystitis, pancreatitis)
Pleural effusion 0.5%
Death 1.7%
a,b
d,e
c
f

Fig. 12a,b. Leaving the stent in place (acute cholangitis, aris-
ing from chronic pancreatitis caused by bile duct stricture). a
Endoscopic cholangiography (ERC) shows the stent in place.
Fig. 13a,b. Types of plastic stent. a
Straight stent : the stent has two ﬂaps
to prevent dislocation or deviation.
Should EST be required, a 10-Fr or
larger stent can be used. b Pigtail stent:
both ends of the stent have a “pigtail”
form to prevent dislocation or devia-
tion. Maximum stent size is 7Fr
b Endoscopic view immediately following stent placement.
Bile ﬂows to the duodenum via the stent
a b
a
b

Fig. 14a–h. Percutaneous tran-
shepatic cholangial drainage
(PTCD or PTBD [biliary])
procedure. a Under ultrasound
guidance, the intrahepatic bile
duct is punctured by the use of
a hollow needle (external cyl-
inder with a mandolin). b Only
the mandolin is removed, and
the cylinder remains. After
confirming the backflow of
bile, bile duct imaging is per-
formed. c A steel wire is in-
serted through the cylinder. d
After confirming sufficient in-
sertion of the wire into the bile
duct, the hollow needle (cylin-
der with the mandolin) is re-
moved. e An elastic needle is
passed over the wire. f Back-
flow of bile is confirmed after
withdrawing the inner tube
from the elastic needle. A
guidewire is then inserted. g A
PTCD (or PTBD) tube is
passed over the guidewire. h
The guidewire is withdrawn
and the tube is left and fixed in
place
PTCD is indicated. In view of this, the Guidelines give
recommendation grades A and B to endoscopic drain-
age and PTCD, respectively.
Before the widespread application of ultrasono-
graphy, a procedure to puncture the bile duct under fluo-
roscopic control following PCTD (level 4)13
was
employed. But because it caused complications in many
cases, puncture under ultrasonography is more common
now (level 4).14
After ultrasound-guided transhepatic puncture of the
intrahepatic bile duct is done with an 18- to 22-G needle
to confirm backflow of bile, a 7- to 10-Fr catheter is
placed in the bile duct under fluoroscopic control, using
a guidewire (Seldinger technique). As a guidewire
a
b
c d
e f
g h

cannot be inserted directly when a 22-G needle is used,
it is necessary to insert the guide-wire after dilating the
bile duct with an elastic needle, using a steel wire. This
procedure, requiring another step, is a little complicated
(see Fig. 14), but puncture with a small-gauge (22-G)
needle is safer in those patients without biliary dilata-
tion. According to the Quality Improvement Guidelines
produced by American radiologists, the success rates of
drainage are 95% in patients with biliary dilatation and
70% in those without biliary dilatation (level 4).13
Techniques of open drainage
Patients with acute cholangitis are preferentially treated
with a noninvasive drainage procedure such as endo-
scopic drainage and PTCD, and only a few undergo
open drainage. However, open drainage may be indi-
cated for patients who cannot undergo such noninvasive
drainage procedures, for anatomical and structural rea-
sons, including patients after Roux-en-Y choledochoje-
junostomy with a propensity for hemorrhage. In open
drainage, the goal is to decompress the biliary system.
Simple procedures such as T-tube placement without
choledocholithotomy should be recommended, because
prolonged operations should be avoided in such ill
patients (level 4).15
ducted as part of the Project on the Preparation and
Cholangitis (H-15-Medicine-30), with a research sub-
sidy for fiscal 2003 and 2004 (Integrated Research
Project for Assessing Medical Technology) sponsored
Welfare.
We also truly appreciate the panelists who cooper
2, 2006.
References
tinct syndrome. Ann Surg 1959;150:299–303. (level 4)
Surg 1982;117:437–41. (level 4)
treatment of acute suppurative cholangitis. Am J Surg 1976;131:
527–32. (level 4)
4. Lai EC, Mok FP, Tan ES, Lo CM, Fan ST, You KT, et al. Endo-
scopic biliary drainage for severe acute cholangitis. N Engl J Med
1992;24;1582–6. (level 2b)
5. Boender J, Nix GA, de Ridder MA, Dees J, Schutte HE, van
Buuren HR, et al. Endoscopic sphincterotomy and biliary drain-
age in patients with cholangitis due to common bile duct stones.
Am J Gastroenterol 1995;90:233–8. (level 4)
6. Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME,
Dorsher PJ, et al. Complications of endoscopic biliary sphincter-
otomy. N Engl J Med 1996;335:909–18. (level 1b)
7. Cotton PB, Lehman G, Vennes JA, Geenen JE, Russell RCG,
Meyers WC, et al. Endoscopic sphincterotomy complications and
their management : an attempt at consensus. Gastrointest Endosc
1991;37:255–8. (level 4)
8. Sugiyama M, Atomi Y. The benefits of endoscopic nasobiliary
drainage without sphincterotomy for acute cholangitis. Am J Gas-
troenterol 1998;93:2065–8. (level 4)
9. Hui CK, Lai KC, Yuen MF, Ng M, Chan CK, Hu W, et al. Does
the addition of endoscopic sphincterotomy to stent insertion
improve drainage of the bile duct in acute suppurative cholangi-
tis? Gastrointest Endosc 2003;58:500–4. (level 4)
10. Lee DW, Chan AC, Lam YH, Ng EK, Lau JY, Law BK, et al. Bili-
ary decompression by nasobiliary catheter or biliary stent in acute
suppurative cholangitis: a prospective randomized trial. Gastroin-
test Endosc 2002;56:361–5. (level 2b)
11. Sharma BC, Kumar R, Agarwal N, Sarin SK. Endoscopic biliary
drainage by nasobiliary drain or by stent placement in patients
with acute cholangitis. Endoscopy 2005;37:439–43. (level 2b)
12. Burke DR, Lewis CA, Cardella JF, Citron SJ, Drooz AT, Haskal
ZJ, et al. Society of Interventional Radiology Standards of Prac-
tice Committee Quality improvement guidelines for percutan-
eous transhepatic cholangiography and biliary drainage. J Vasc
Interv Radiol 2003;14:243–6. (level 4)
13. TakadaT,HanyuF,KobayashiS,UchidaY.Percutaneoustranshe-
patic cholangial drainage: direct approach under fluoroscopic
control. J Surg Oncol 1976;8:83–97. (level 4)
14. Takada T, Yasuda H, Hanyu F. Technique and management
of percutaneous transhepatic cholangial drainage for treating an
obstructive jaundice. Hepatogastroenterology 1995;42:317–22.
(level 4)
15. Saltzstein EC, Peacock JB, Mercer LC. Early operation for acute
biliary tract stone disease. Surgery 1983;94:704–8. (level 4)

repeated after the initiation of treatment for acute
cholangitis.
Flowchart for the management of acute cholecystitis
There were several controversies over the treatment of
acute cholecystitis. Early cholecystectomy is indicated
for most patients with acute cholecystitis, and laparo-
scopic cholecystectomy is preferred for experienced
surgeons. Several randomized controlled trials compar-
ing early and delayed operation conducted in the 1970s
to 1980s found that early surgery had the advantages of
less blood loss, shorter operation time, a lower compli-
cation rate, and a shorter hospital stay. Some Japanese
doctors advocated that early cholecystectomy should
not be recommended because early cholecystectomy
was not prevalent in Japan. Steven M. Strasberg men-
tioned: “We have to be willing to accept the fact that
we may need to change our practice based upon the
evidence”. Results of randomized controlled trials com-
paring early laparoscopic cholecystectomy with delayed
laparoscopic cholecystectomy have also shown that
early laparoscopic surgery is superior to delayed sur-
gery in terms of the conversion rate to open surgery,
complication rate, and total hospital stay. Toshihiko
Mayumi (Japan) mentioned that because laparoscopic
cholecystectomy by inexperienced surgeons resulted in
more frequent intraoperative complications than open
cholecystectomy, the laparoscopic procedure should
not be overemphasized.
There was more discussion to determine the treat-
ment strategy for acute moderate (grade II) cholecysti-
tis. Before the start of the international symposium it
was considered that urgent/early cholecystectomy
should be performed for these patients. Steven M. Stras-
berg mentioned: “For patients with acute moderate
cholecystitis (patients who have a white [cell] count
over 18000; patients who have cholecystitis for more
than 72h; patients who have a palpable inflammatory
mass), early cholecystectomy is going to be maybe very
difficult. Therefore do we really want to say to the gen-
eral surgeon in a small hospital that we recommend that
when the white [cell] count is over 18000 that he takes
the patient to the operating room? I do not think so.”
After the statement of his opinion, delayed elective
cholecystectomy was recommended for acute moderate
(grade II) cholecystitis with severe local inflammation.
On the other hand, Eduardo de Santibanes (Argentina)
advocated that early laparoscopic cholecystectomy
could be performed for patients with acute moderate
cholecystitis.
The treatment courses for mild (grade I) and severe
(grade III) cholecystitis were accepted without major
adverse opinions. The recommendation of early laparo-
scopic cholecystectomy for mild (grade I) cases and
gallbladder drainage for severe (grade III) cases ob-
tained consensus. Some Japanese doctors suggested that
endoscopic gallbladder drainage as well as percutaneous
gallbladder drainage should be recommended. Howev-
er, Jacques Belghiti rejected this suggestion, because
there was poor evidence for efficacy, and because endo-
scopic gallbladder drainage needed a special technique.
Thomas R. Gadacz added surgical cholecystostomy to
one of the methods for gallbladder drainage.

DOI 10.1007/s00534-006-1161-x
Surgical treatment of patients with acute cholecystitis:
Tokyo Guidelines
Yuichi Yamashita1
, Tadahiro Takada2
, Yuji Nimura4
, Masahiko Hirota5
,
Fumihiko Miura2
, Toshihiko Mayumi6
, Masahiro Yoshida2
, Steven Strasberg7
, Henry A. Pitt8
,
, Markus W. Büchler11
, Dirk J. Gouma12
, Sheung-Tat Fan13
,
Serafin C. Hilvano14
, Joseph W.Y. Lau15
, Sun-Whe Kim16
, Giulio Belli17
, John A. Windsor18
, Kui-Hin Liau19
,
and Vibul Sachakul20
1
Department of Surgery, Fukuoka University Hospital, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku,
Fukuoka 814-0180, Japan
2
3
4
5
6
7
Washington University in St Louis and Barnes-Jewish Hospital, St Louis, USA
8
9
10
Hepatobiliopancreatic Surgery and Liver Transplantation, Hospital Beaujon, Clichy, France
11
12
G4-116, Academic Medical Center, Amsterdam, The Netherlands
13
Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
14
15
Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
16
17
18
Department of Surgery, The University of Auckland, Auckland, New Zealand
19
Department of Surgery, Tan Tock Seng Hospital / Hepatobiliary Surgery, Medical Centre, Singapore, Singapore
20
treatment of acute cholecystitis in a question-and-answer
format.
Key words Acute cholecystitis · Cholecystectomy · Laparo-
scopic cholecystectomy · Open surgery · Cholecystostomy ·
Guidelines
Introduction
Cholecystectomy has been widely accepted as an effec-
tive treatment for acute cholecystitis. Several studies
conducted during the era of open cholecystectomy
demonstrated the advantages of early cholecystectomy
for patients with acute cholecystitis — its safety, cost-
effectiveness, and the rapid return of the patient to
normal activity (level 1b).1–3
Although acute cholecysti-
tis had initially been considered a contraindication to
laparoscopic cholecystectomy because of the higher in-
cidence of complications than in non-acute cholecystitis
(level 2b),4
as a result of the mastery of the required
skills by surgeons and the improvements in laparoscopic
instruments, laparoscopic cholecystectomy is now ac-
cepted as safe when surgeons who are expert in laparo-
scopic techniques perform it. Some recent randomized
Abstract
Cholecystectomy has been widely performed in the treatment
of acute cholecystitis, and laparoscopic cholecystectomy has
been increasingly adopted as the method of surgery over the
past 15 years. Despite the success of laparoscopic cholecystec-
tomy as an elective treatment for symptomatic gallstones,
acute cholecystitis was initially considered a contraindication
for laparoscopic cholecystectomy. The reasons for it being
considered a contraindication were the technical difﬁculty of
performing it in acute cholecystitis and the development of
complications, including bile duct injury, bowel injury, and
hepatic injury. However, laparoscopic cholecystectomy is now
accepted as being safe for acute cholecystitis, when surgeons
who are expert at the laparoscopic technique perform it. Lap-
aroscopic cholecystectomy has been found to be superior to
open cholecystectomy as a treatment for acute cholecystitis
because of a lower incidence of complications, shorter length
of postoperative hospital stay, quicker recuperation, and ear-
lier return to work. However, laparoscopic cholecystectomy
for acute cholecystitis has not become routine, because the
timing and approach to the surgical management in patients
with acute cholecystitis is still a matter of controversy. These
Guidelines describe the timing of and the optimal surgical
Offprint requests to: Y. Yamashita

92 Y. Yamashita et al.: Surgical treatment for acute cholecystitis
clinical trials (level 1b)5–9
have addressed the timing and
surgical approach to the gallbladder in patients with
acute cholecystitis, and the results have indicated
that laparoscopic cholecystectomy was associated with
a shorter hospital stay, more rapid recovery, and a re-
duction in the overall cost of treatment, and that early
laparoscopic cholecystectomy was sufficiently safe to be
performed routinely.
Nevertheless, urgent or early laparoscopic cholecys-
tectomy for acute cholecystits seems to remain unpopu-
lar, and the reasons for its unpopularity include a lack
of availability of surgeons who have mastered the neces-
sary skills, as well as the limited availability of operating
room space (level 2c).10,11
Critically ill patients with acute cholecystitis often
present a difficult therapeutic dilemma. Although they
require emergency surgical intervention, many such pa-
tients have a serious medical or surgical complication
and may be too ill to undergo open or laparoscopic
cholecystectomy under general anesthesia. By avoiding
the risks of cholecystectomy, drainage by cholecyst-
ostomy offers a distinct advantage in such critically ill
patients, but the optimal timing of subsequent surgery
has not been examined. These Guidelines describe the
timing and optimal type of surgical treatment for acute
cholecystitis in a question-and-answer format.
Q1. When is the optimal time for cholecystectomy in
acute cholecystitis?
the gallbladder in patients with acute cholecystitis, and
the results have indicated that laparoscopic cholecystec-
tomy performed during the first admission was associ-
ated with a shorter hospital stay, quicker recovery, and
reduction in overall cost of treatment compared to open
cholecystectomy. Early laparoscopic cholecystectomy
is now accepted to be sufficiently safe for routine use,
because earlier reports of increased risk of bile duct
injury (level 4)14
have not been substantiated by more
recent experience (level 1b).5,7,8,15
The results of a randomized controlled trial compar-
ing early laparoscopic cholecystectomy after admission
with delayed laparoscopic cholecystectomy showed that
performing the surgery early was superior in terms of a
lower conversion rate to open surgery and shorter total
hospital stay (Table 1). These results indicate that early
laparoscopic cholecystectomy is preferable in patients
with acute cholecystitis.
However, the fact that the above trials excluded pa-
tients with pan-peritonitis caused by perforation of the
gallbladder, patients with common bile duct stones, and
those with concomitant severe cardiopulmonary disease
should be borne in mind when evaluating the results.
After evaluation of patients’ overall condition and
confirmation of the diagnosis by ultrasonography, com-
puted tomography (CT), and/or magnetic resonance
cholargio-parcreatography (MRCP), the timing of the
surgical management of acute cholecystitis patients
should be immediately decided by experienced sur-
geons (level 5).16
Outcome of the Tokyo Consensus Meeting
The panelists voted on the timing of cholecystectomy in
patients with grade 1 (mild) and 2 (moderate) acute
cholecystitis. The results showed that 72% of doctors
from abroad and 33% of Japanese doctors agreed with
early cholecystectomy, but 28% of the doctors from
abroad and 41% of the Japanese doctors voted that
minor modification of the guideline was needed, and
none of the doctors from abroad and 26% of Japanese
doctors disagreed with early timing (Fig. 1).
Table 1. Comparisons of early and delayed laparoscopic cholecystectomy for acute cholecystitis
Length of Length of
Conversion Conversion Postoperative Postoperative hospital stay hospital stay
Number rate of rate of complications complications (days) Early (days) Delayed
Author of patients early LC delayed LC of early LC of delayed LC surgery surgery
Lo et al.5
86 11% 23% 13% 29% 6 11
Lai et al.6
91 21% 24% 9% 8% 7.6 11.6
Chandler et al.7
43 24% 36% 4% 9% 5.4 7.1
Johansson et al.15
143 31% 29% 18% 10% 5 8
LC, laparoscopic cholecystectomy; conversion rate, conversion rate to open surgery
Cholecystectomy is preferable early after admis-
sion (recommendation A).
Randomized controlled trials in the open cholecystec-
tomy era, comparing early surgery with delayed surgery
in the 1970s–1980s, found that early surgery had the
advantages of less blood loss, a shorter operation time,
a lower complication rate, and a briefer hospital stay
(level 1b)1–3,12
(level 3b).13
Some recent randomized clinical trials (level 1b)5–9
have addressed the timing of and surgical approach to

Y. Yamashita et al.: Surgical treatment for acute cholecystitis 93
Yes
Yes, but needs minor modification
No
Japanese panelists
72%
28%
33%
41%
26%
Panelists from abroad
Fig. 1. Timing of cholecystectomy for
acute cholecystitis. Votes on the
proposed guideline: cholecystectomy is
preferable early after admission
Q2. Which surgical procedure should be adopted,
laparoscopic cholecystectomy or open
cholecystectomy?
laparoscopic surgery has led to laparoscopic cholecys-
tectomy becoming as good as, or safer than, open cho-
lecystectomy for the treatment of acute cholecystitis
(level 1b).8
Although early cholecystectomy for acute
cholecystitis has remained unpopular (level 2c),10,11
if
early cholecystectomy is performed early laparoscopic
cholecystectomy is the preferable procedure.
Because the set of skills required for laparoscopic
cholecystectomy is different from the set required for
conventional open cholecystectomy, only surgeons who
possess that set of skills in laparoscopic cholecystectomy
should perform it. The surgeon should be aware of the
complications (described later in Q4) that have been
associated with the laparoscopic procedure and should
take maximum care to prevent bile duct injury, which
sometimes lead to serious complications. The surgeon
should never hesitate to convert to open cholecystec-
tomy to prevent severe complications, if the anatomy
Laparoscopic cholecystectomy is preferable to
open cholecystectomy (recommendation A).
Cholecystectomy has been widely performed to treat
acute cholecystitis, with laparoscopic cholecystectomy
having been increasingly adopted over the past 10 years.
Several reports of complications associated with early
laparoscopic cholecystectomy caused a transient wane
in the enthusiasm for early laparoscopic cholecystec-
tomy (level 4),14
(level 2b),17
(level 4),18,19
but such con-
cerns were allayed by evidence indicating that early
laparoscopic cholecystectomy for patients with acute
cholecystitis was safe and effective, and required a
shorter hospitalization time (level 1b)8,9
(level 2b)20,21
(level 3b)22
(level 4).23
Thus, increased experience with
Yes
Yes, but needs minor modification
No
Japanese panelistsPanelists from abroad
63%
30%
61%
31%
8%7%
Fig. 2. Surgical procedure for the treat-
ment of acute cholecystitis. Votes on
the proposed guideline: laparoscopic
cholecystectomy is preferable to open
cholecystectomy

Treatment of acute cholecystitis essentially consists of
early cholecystectomy, and the optimal surgical treat-
ment for each grade of severity of acute cholecystitis
is required. Early laparoscopic cholecystectomy is indi-
cated for patients with mild (grade I) acute cholecysti-
tis, because laparoscopic cholecystectomy can be
performed in most these patients. Early laparoscopic
or open cholecystectomy (within 72h of the onset of
acute cholecystitis) is generally required for patients
with moderate (grade II) acute cholecystitis, but in
some patients with moderate (grade II) acute cholecys-
titis, it is difficult to remove the gallbladder surgically,
because of severe inflammation limited to the gallblad-
der. The severe local inflammation of the gallbladder
is evaluated according to factors such as more than 72h
from the onset, wall thickness of the gallbladder of
more than 8mm, and a WBC count of more than 18000.
Continuous medical treatment or drainage of the con-
tents of a swollen gallbladder by percutaneous transhe-
patic gallbladder drainage (PTGBD) or surgical
cholecystostomy is the optimal treatment, with delayed
cholecystectomy indicated after the inflammation of
the gallbladder resolves. Urgent management of severe
(grade III) acute cholecystitis is always necessary, be-
cause the patients have organ dysfunction, and drain-
age of the gallbladder contents and/or cholecystectomy
is required to treat the severe inflammation of the gall-
bladder. Urgent or early cholecystectomy is required
after improvement of patient’s general condition.
Q4. What are the complications of laparoscopic
cholecystectomy to be avoided?
Mild (grade I) acute cholecystitis: early laparo-
scopic cholecystectomy is the preferred
procedure.
Moderate (grade II) acute cholecystitis: early
cholecystectomy is performed. However, if pa-
tients have severe local inflammation, early gall-
bladder drainage (percutaneous or surgical) is
indicated. Because early cholecystectomy may be
difficult, medical treatment and delayed cholecys-
tectomy are necessary.
Severe (grade III) acute cholecystitis: urgent
management of organ dysfunction and manage-
ment of severe local inflammation by gallbladder
drainage and/or cholecystectomy should be car-
ried out. Delayed elective cholecystectomy should
be performed later, when cholecystectomy is
indicated.
Bile duct injury and injury of other organs.
Complications of laparoscopic cholecystectomy were
reported soon after its introduction, and consist of bile
duct injury, bowel injury, and hepatic injury, as well
as the common complications of conventional open
cholecystectomy, such as wound infection, ileus, intra-
peritoneal hemorrhage, atelectasis, deep vein thrombo-
sis, and urinary tract infection. Bile duct injury is
considered a serious complication. Bowel and hepatic
injuries should be avoided as they are also serious com-
plications (level 2b).25
These injuries have been attribut-
able to the limitations of laparoscopy, such as the narrow
view and the lack of tactile manipulation. Laparoscopic
cholecystectomy has not always been associated with a
higher incidence of complications than open cholecys-
tectomy, but any serious complication that requires re-
operation and prolonged hospitalization may become a
serious problem for patients who firmly believe that
laparoscopic cholecystectomy is less invasive. The inci-
dence of biliary injury has recently decreased in associa-
tion with the acquisition of greater surgical skills and
the improvements in laparoscopic instruments.
Q5. When is the optimal time for conversion from
laparoscopic to open cholecystectomy?
To prevent injuries, surgeons should never hesi-
tate to convert to open surgery when they
experience difficulty in performing laparoscopic
cholecystectomy.
of Calot’s triangle remains unclear despite accurate
dissection.
Decompression of an acutely inflamed gallbladder
may not only allow the patient time to recover from the
acute illness prior to surgery, but may decrease the tech-
nical difficulty of cholecystectomy. Open cholecystos-
tomy under local anesthesia is a traditional practice that
provides an alternative to cholecystectomy in critically
ill patients with acute cholecystitis (level 4),24
but per-
cutaneous cholecystostomy has now become a valuable
alternative procedure for decompressing an acutely in-
flamed gallbladder.
Out come of the Tokyo Consensus Meeting
Voting for “laparoscopic cholecystectomy is preferable
to open cholecystectomy” showed that 63% of the doc-
tors from abroad and 61% of the Japanese doctors
agreed with this; 30% of the doctors from abroad and
31% of the Japanese doctors voted that they agreed, but
that minor modification of the guideline was needed;
while 7% of the doctors from abroad and 8% of the
Japanese doctors disagreed (Fig. 2).
Q3. What is the optimal surgical treatment for acute
cholecystitis according to grade of severity?

There is a relatively high rate of conversion from lapa-
roscopic cholecystectomy to open cholecystectomy
for acute cholecystitis because of technical difficulties,
and laparoscopic cholecystectomy is associated with a
high complication rate (level 3b).22
Although certain
preoperative factors, such as male sex, previous
abdominal surgery, presence or history of jaundice,
advanced cholecystitis, and infectious complications
are associated with a need for conversion from laparo-
scopic to open cholecystectomy, they have limited
predictive ability (level 3b).22,26,27
Surgeons find factors
that lead them to decide whether to convert to
open cholecystectomy mostly during the laparoscopic
cholecystectomy. Not only the experience of the sur-
geon but also the experience of the institution with
laparoscopic cholecystectomy is a prerequisite for suc-
cessful cholecystectomy for all patients with acute
cholecystitis.
Because conversion to open cholecystectomy is not
disadvantageous for patients, to prevent intraoperative
accidents and postoperative complications, surgeons
should never hesitate to convert when they experience
difficulty in performing laparoscopic cholecystectomy.
A low threshold for conversion to open cholecys-
tectomy is important to minimize the risk of major
complications.
Q6. When is the optimal time for cholecystectomy
following PTGBD?
Q7. When is the optimal time for laparoscopic chole-
cystectomy after endoscopic stone extraction in
patients with cholecysto-choledocholithiasis?
Early cholecystectomy during the initial hospital
stay is preferable (recommendation B).
There have been no randomized controlled trials of
surgical management in patients with acute cholecystitis
after PTGBD. However, PTGBD is known to be an
effective option in critically ill patients, especially in
elderly patients and patients with complications (level
4).28
Cholecystectomy is often performed at an interval
of several days following PTGBD. Early cholecystecto-
my following PTGBD is preferable when the patient’s
condition improves, and if the patient has no complica-
tions. Complications of PTGBD, such as intrahepatic
hematoma, pericholecystic abscess, biliary pleural effu-
sion, and biliary peritonitis (which may be caused by
puncture of the liver and migration of the catheter)
sometimes occur (level4)29
and efforts should be made
to prevent such occurrences. More case-series studies
are required.
Early cholecystectomy following endoscopic stone
extraction during the same hospital stay is prefer-
able (recommendation B).
Combining endoscopic stone extraction during endo-
scopic retrograde cholangiography with laparoscopic
cholecystectomy has been found to be a useful means
of treating patients with cholecysto-choledocholithiasis.
However, the optimal time for laparoscopic cholecys-
tectomy following endoscopic stone extraction (ESE) is
still a matter of controversy. There have been several
reports of combinations of ESE and laparoscopic cho-
lecystectomy (level 2b),30
(level4),31–33
and in most of
them, the interval between the two procedures was a
few days. Actually, the interval between ESE and lapa-
roscopic cholecystectomy was left to the individual sur-
geon. At present, early laparoscopic cholecystectomy
following ESE during the same hospital stay is regarded
as preferable in most patients without complications
related to ESE.
who provided us with great support and guidance in
the preparation of the Guidelines. This process was
conducted as part of the Project on the Preparation
and Diffusion of Guidelines for the Management of
Acute Cholangitis (H-15-Medicine-30), with a research
subsidy for fiscal 2003 and 2004 (Integrated Research
Welfare.
2, 2006.
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early and delayed surgery. A controlled clinical trial. Scand J
Gastroenterol 1978;13:673–8. (level 1b)
2. Jarvinen HJ, Hastbacka J. Early cholecystectomy for acute cho-
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501–5. (level 1b)
3. Norrby S, Herlin P, Holmin T, Sjodahl R, Tagesson C. Early or
delayed cholecystectomy in acute cholecystitis? A clinical trial. Br
J Surg 1983;70:163–5. (level 1b)
4. Cushieri A, Dubois F, Mouiel J, Mouiel P, Becker H, Buess G,
et al. The European experience with laparoscopic cholecystec-
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5. Lo CM, Liu Cl, Fan ST, Lai EC, Wong J. Prospective randomized
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6. Lai PB, Kwong KH, Leung KL, Kwok SP, Chan AC, Chung SC.
Randomized trial of early versus delayed laparoscopic cholecys-
tectomy for acute cholecystitis. Br J Surg 1998;85:764–7.
(level 1b)
7. Chandler CF, Lane JS, Ferguson P, Thonpson JE. Prospective
evaluation of early versus delayed laparoscopic cholecystectomy
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(level 1b)
8. Kiviluoto T, Siren J, Luukkonen P, Kivilaakso E. Randomized
trial of laparoscopic versus open cholecystectomy for acute and
gangrenous cholecystitis. Lancet 1998;351:321–325. (level 1b)
9. Berrgren U, Gordh T, Grama D, Haglund U, Rastad J, Arvidsson
D. Laparoscopic versus open cholecystectomy: hospitalization,
sick leave, analgesia and trauma responses. Br J Surg 1994;81:
1362–5. (level 1b)
10. Senapati PSP, Bhattarcharya D, Harinath G, Ammori BJ. A sur-
vey of the timing and approach to the surgical management of
cholelithiasis in patients with acute biliary pancreatitis and acute
cholecystitis in the UK. Ann R Coll Surg Engl 2003;85:306–12.
(level 2c)
11. Cameron IC, Chadwick C, Phillips J, Johnson AG. Management
of acute cholecystitis in UK hospitals: time for a charge. Postgrad
Med J 2004;80:292–4. (level 2c)
12. van der Linden W, Sunzel H. Early versus delayed operation
for acute cholecystitis. A controlled clinical trial. Am J Surg
1970;120:7–13. (level 1b)
13. van der Linden W, Edlund G. Early versus delayed cholecystec-
tomy: the effect of a change in management. Br J Surg 1981;68:
753–7. (level 3b)
14. Kum CK, Eypasch E, Lefering R, Math D, Paul A, Neugebauer
E, et al. Laparoscopic cholecystectomy for acute cholecystitis: is
it really safe? World J Surg 1996;20:43–9. (level 4)
15. Johansson M, Tbune A, Blomqvist A, Nelvin L, Lundell L. Man-
agement of acute cholecystitis in the laparoscopic era: results of
a prospective, randomized clinical trial. J Gastrointest Surg
2003;7:642–5. (level 1b)
16. Mason GR. Acute cholecystitis; surgical aspects. In: Berk JE, edi-
tor. 4th ed. Philadelphia: WB Saunders; 1985. p.3616–18. (level
5)
17. Russell JC, WaIsh SJ, Mattie AS, Lynch JT. Bile duct injuries,
1989–1993. A statewide experience. Arch Surg 1996;131:382–8.
(level 2b)
18. Branum G, Schmtt C, Baillie J. Management of major biliary
complications after laparoscopic cholecystectomy. Ann Surg
1993;217:532–40. (level 4)
19. Bender JS, Zenilman ME. Immediate laparoscopic cholecystec-
tomy as definitive therapy for acute cholecystitis. Surg Endosc
1995;9:1081–8. (level 4)
20. Zacks SL, Sandler RS, Rutledge R, Brown RS. A population-
based cohort study comparing laparoscopic cholecystectomy and
open cholecystectomy. Am J Gastroenterol 2002;97:334–40. (level
2b)
21. Flowers JL, Bailey RW, Scovill WA, Zucker KA. The Baltimore
experience with laparoscopic management of acute cholecystitis.
Am J Surg 1991;161:388–92. (level 2b)
22. Eldar S, Sabo E, Nash E, Abrahamson J, Matter I. Laparoscopic
cholecystectomy for acute cholecystitis: prospective trial. World
J Surg 1997;21:540–5. (level 3b)
23. Cox MR, Wilson TG, Luck AJ, Leans PL, Padbury RTA, Toouli
J. Laparoscopic cholecystectomy for acute inflammation of the
gallbladder. Ann Surg 1993;218:630–4. (level 4)
24. Glenn F. Cholecystostomy in the high risk patient with biliary
tract disease. Ann Surg 1977;185:185–91. (level 4)
25. The Southern Surgeons Club. A prospective analysis of 1518
laparoscopic cholecystectomies. N Engl J Med 1991;324:1073–8.
(level 2b)
26. Brodsky A, Matter I, Sabo E, Cohen A, Abrahamson J, Eldar S.
Laparoscopic cholecystectomy for acute cholecystitis: can the
need for conversion and the probability of complications be
predicted? Surg Endosc 2000;14:755–60. (level 3b)
27. Kama NA, Doganay M, Dolapci E, Reis E, Ati M, Kologlu M.
Risk factors resulting in conversion of laparoscopic cholecystec-
tomy to open surgery. Surg Endosc 2001;15:965–8. (level 3b)
28. Tseng LJ, Tsai CC, Mo LR, Lin RC, Kuo JY, Chang KK, et al.
Palliative percutaneous transhepatic gallbladder drainage of gall-
bladder empyema before laparoscopic cholecystectomy. Hepato
gastroenterology 2000;47:932–6. (level 4)
29. Kivinen H, Makela JT, Autio R, Tikkakoski T, Leinonen S,
Siniluoto T, et al. Percutaneous cholecystostomy in acute chole-
cystitis in high-risk patients: an analysis of 69 patients. Int Surg
1998;83:299–302. (level 4)
30. Cuschieri A, Crose E, Faggioni A, Jakimowicz J, Lacy A, Lezoche
E, et al. EAES ductal stone study. Preliminary findings of multi-
center prospective randomized trial comparing two-stage vs
single-stage management. Surg Endosc 1996;10:1130–5. (level
2b)
31. Sarli L, Iusco DR, Roncoroni L. Preoperative endoscopic sphinc-
terotomy and laparoscopic cholecystectomy for the management
of cholecystocholedocholithiasis: 10-year experience. World J
Surg 2003;27:180–6. (level 4)
32. Basso N, Pizzuto G, Surgo D, Materia A, Silecchia G, Fantini A,
et al. Laparoscopic cholecystectomy and intraoperative endo-
scopic sphincterotomy in the treatment of cholecysto-choledo-
cholithiasis. Gastrointest Endosc 1999;50:532–5. (level 4)
33. Cemachovic I, Letard JC, Begin GF, Rousseau D, Nivet LM.
Intraoperative endoscopic sphincterotomy is a reasonable option
for complete single-stage minimally invasive biliary stone treat-
ment: short-term experience with 57 patients. Endoscopy
2000;32:956–62. (level 4)
Discussion at the Tokyo Consensus Meeting
Severity of acute cholecystitis
There has been some high-quality evidences obtained
by randomized controlled trials (RCTs) in the field of
surgical treatment for acute cholecystitis. However, no
RCTs have examined the optimal surgical treatment
for acute cholecystitis according to grade of severity.
The need for surgical treatment according to grade of
severity was suggested by panelists, and surgical treat-
ment strategies were discussed.
Steven Strasberg (USA) proposed grading the
severity of acute cholecystitis as mild (grade I),
moderate (grade II), and severe (grade III).
Early cholecystectomy for acute cholecystitis
There were some important remarks in the discussion
of the concept that early cholecystectomy during the
first admission is preferable. These remarks were that:
(a) it is necessary to know whether the numbers of pa-
tients in the RCTs were sufficient to evaluate the inci-
dence of serious complications such as bile duct injury,
(b) it is important to know whether all of the surgeons
who performed cholecystectomy in the RCTs possessed
the skills for laparoscopic surgery, (c) “early cholecys-

tectomy” was not defined in any of the RCTs, (d) sur-
gical treatments for acute cholecystitis of each grade
of severity should be stated individually in these
Guidelines.
On the basis of these remarks, the panelists voted
on the timing of cholecystectomy in patients with mild
(grade I) and moderate (grade II) acute cholecystitis.
None of the doctors from abroad disagreed with early
cholecystectomy. In contrast, 26% of the Japanese doc-
tors disagreed with it. Thus, the results of the votes of
the doctors from abroad and the Japanese doctors
differed.
Laparoscopic cholecystectomy for acute cholecystitis
There were some important remarks in the discussion
of the concept that laparoscopic cholecystectomy was
superior to open cholecystectomy. They were: (a) lapa-
roscopic cholecystectomy is associated with a greater
risk of bile duct injury, (b) laparoscopic cholecystecto-
my should be performed by experienced surgeons, and
(c) the majority of acute cholecystitis patients treated
surgically have mild (grade I) acute cholecystitis.
The vote on the cholecystectomy procedure was per-
formed on the basis of the above remarks. Voting for
“laparoscopic cholecystectomy is preferable to open
cholecystectomy” showed that approximately 60% of
both Japanese and overseas doctors agreed, and ap-
proximately 30% of both groups of doctors voted that
they agreed, but that minor modification of the guide-
line was needed; only a few percent of both groups of
doctors disagreed. Thus, laparoscopic cholecystectomy
for mild (grade I) and moderate (grade II) acute chole-
cystitis, except in patients with localized severe inflam-
mation of the gallbladder, was approved of by many
doctors in both groups.
Cholecystectomy for acute cholecystitis
The results of the voting on the timing and surgical
procedure for mild (grade I) and moderate (grade II)
acute cholecystitis are described above. There was an
important remark during the discussion, that patients
in whom it is difficult to remove the gallbladder are
frequently encountered among patients with moderate
(grade II) acute cholecystitis, and that removal of the
gallbladder, especially by laparoscopic cholecystecto-
my, is difficult in such patients. This remark was agreed
with by many panelists at the Meeting, and it was con-
cluded that if patients have severe local inflammation
of the gallbladder, early gallbladder drainage (percuta-
neous or surgical) is the initial treatment of choice.
Because early cholecystectomy may be difficult,
medical treatment and delayed cholecystectomy are
performed.
The fact that there was a consensus among the doc-
tors from abroad and Japanese doctors concerning the
surgical treatment strategy for moderate (grade II)
acute cholecystitis facilitated the drafting of the
Guideline.

DOI 10.1007/s00534-006-1160-y
Antimicrobial therapy for acute cholecystitis: Tokyo Guidelines
Masahiro Yoshida1
, Tadahiro Takada1
, Atsushi Tanaka3
, Yuji Nimura4
,
Harumi Gomi5
, Masahiko Hirota6
, Fumihiko Miura1
, Keita Wada1
, Toshihiko Mayumi7
, Joseph S. Solomkin8
,
Steven Strasberg9
, Henry A. Pitt10
, Sheung-Tat Fan13
,
Miin-Fu Chen14
, Giulio Belli15
, Serafin C. Hilvano16
, Sun-Whe Kim17
, and Chen-Guo Ker18
1
Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
2
3
4
5
Division of Infection Control and Prevention, Jichi Medical University Hospital, Tochigi, Japan
6
7
8
Department of Surgery, Division of Trauma and Critical Care, University of Cincinnati College of Medicine, Cincinnati, USA
9
10
11
12
13
14
Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
15
Department of General and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy
16
17
18
Division of HPB Surgery, Yuan’s General Hospital, Taoyuan, Taiwan
Introduction
Acute cholecystitis consists of various morbid condi-
tions, ranging from mild cases that are relieved by
the oral administration of antimicrobial drugs or that
resolve even without antimicrobials to severe cases
complicated by biliary peritonitis, each of which re-
quires a different treatment strategy. Decisions on an-
timicrobial therapy must be based upon knowledge of
the likely infecting microorganisms, the pharmacokinet-
ics/pharmacodynamics and adverse reactions/effects of
available agents, and the results of local antimicrobial
susceptibility testing (local antibiogram). The severity
of illness and history of exposure to antimicrobials are
also key factors in determining appropriate therapy.
Once presumptive antimicrobial agents are selected and
administered, they should be changed for more appro-
priate agents, based on the organisms identified and
their susceptibility testing results. Continuous use of
unnecessarily broader-spectrum agents should be avoid-
ed to prevent the emergence of antimicrobial resistance.
Furthermore, the duration of therapy should be strictly
evaluated periodically to avoid unnecessarily prolonged
use of antimicrobial agents.
In this article we discuss the medical treatment stra-
tegy, including antimicrobial therapy, for acute chole-
cystitis. In an extensive literature search, we were
faced with the fact that there were very few, if any,
randomized controlled trials (RCTs) of antimicrobial
therapy for acute cholecystitis. Therefore, we propose
Abstract
Acute cholecystitis consists of various morbid conditions,
ranging from mild cases that are relieved by the oral admin-
istration of antimicrobial drugs or that resolve even without
antimicrobials to severe cases complicated by biliary peritoni-
tis. Microbial cultures should be performed by collecting bile
at all available opportunities to identify both aerobic and
anaerobic organisms. Empirically selected antimicrobials
should be administered. Antimicrobial activity against poten-
tial causative organisms, the severity of the cholecystitis, the
patient’s past history of antimicrobial therapy, and local sus-
ceptibility patterns (antibiogram) must be taken into consid-
eration in the choice of antimicrobial drugs. In mild cases
which closely mimic biliary colic, the administration of nons-
teroidal anti-inflammatory drugs (NSAIDs) is recommended
to prevent the progression of inflammation (recommendation
grade A). When causative organisms are identified, the anti-
microbial drug should be changed for a narrower-spectrum
antimicrobial agent on the basis of the species and their sus-
ceptibility testing results.
Key words Acute cholecystitis · Anti-infective agents · Guide-
lines · Infection · Biliary
Offprint requests to: M. Yoshida

84 M. Yoshida et al.: Antimicrobial therapy for acute cholecystitis
consensus-based and in vitro activities-based guidelines
for empirical antimicrobial therapy for acute cholecys-
titis. The text is organized in a question and recommen-
dation format.
Q1. What microbiological studies should be performed
in acute cholecystitis?
Patients with mild case of disease, with little abdominal
pain and mild inflammatory findings, (closely mimick-
ing biliary colic), may be observed and treated with oral
antimicrobial drugs or even observed without anti-
microbials. In these patients, the administration of
nonsteroidal anti-inflammatory drugs (NSAIDs) is
recommended, as described below.
When early cholecystectomy is performed, antimicro-
bial therapy may be considered prophylactic in that the
infection itself is surgically removed.
Q3. Is the administration of NSAIDs to patients
suffering from an attack of biliary colic effective to
prevent the development of acute cholecystitis?
Table 1. Bacterial culture positive rates in bile (%) in various biliary diseases
Choledo-
Non-biliary Chole- Acute cholithiasis Hepatolithiasis
Bile disease lithiasis cholecystitis (+cholangitis) (+cholangitis)
Chang (2002)3
Gallbladder 17.0 47.0 63.0 70.0
Csendes (1996)4, 5
Gallbladder 0 22.2 46.1
Csendes (1994)6
Gallbladder 0 32.0 41.0 58.0
Maluenda (1989)2
Gallbladder 0 43.0
Csendes (1975)7
(Gallbladder wall) 47.0 (Chronic; 33)
Kune (1974)8
Gallbladder 0 13.0 54.0 59.0
Bile and blood culture should be performed at all
available opportunities, especially in severe cases
(recommendation B).
The clinical significance of microbial examination in
acute cholecystitis depends on the severity of the dis-
ease. Although most mild and moderate cases are cur-
able without microbial information, biliary infection is
associated with postoperative complications and higher
mortality rates in patients with severe cases or biliary
stones. A positive bile culture is correlated with the
progression of the cholecystitis to a severe form (level
2b–3b).1,2
Therefore, especially in severe cases, gall-
bladder bile should be collected at the time of operative,
laparoscopic, or percutaneous intervention for culture
and susceptibility testing. A sample of the gallbladder
wall should be sent separately for culture, and for his-
topathology if needed. Aerobic cultures only should
be obtained. Positive rates for bacterial culture in
acute cholecystitis and other biliary diseases are listed
in Table 1 (level 2b–3b).3–8
The importance of blood culture results is relatively
limited in acute cholecystitis and the presence of posi-
tive blood cultures does not alter the agents to be used
or the duration of treatment.
Q2. How should antimicrobial agents be used in
patients with acute cholecystitis?
Antimicrobial agents should be administered to
patients diagnosed with acute cholecystitis, except
for those with mild cases (recommendation A).
Administration of NSAIDs to patients with an
attack of biliary colic is recommended, to prevent
the onset of acute cholecystitis (recommendation
A).
NSAIDs such as diclofenac or indomethacin should be
used in the medical treatment for their analgesic effects
and their inhibition of prostaglandin release from the
gallbladder wall. An RCT of NSAID administration
(75mg diclofenac; intramuscular injection) in patients
with biliary colic attack showed that the NSAID had the
effect of relieving the patients’ pain and preventing the
progression of the disease to acute cholecystitis (level
1b).9
Although it has been reported that NSAIDs ef-
fectively improve gallbladder function in patients with
chronic cholangitis (level 3a),10
there is no report to date
showing that NSAID administration after the onset of
acute cholecystitis alleviates the disease.
Q4. What are the important factors for consideration
in antimicrobial drug selection?
(1) Antimicrobial activity against causative
bacteria
(2) Severity of acute cholecystitis

M. Yoshida et al.: Antimicrobial therapy for acute cholecystitis 85
The dose of antimicrobial agents should be reduced for
patients with reduced renal function. Because most
cephalosporins, penicillins, aminoglycosides, and car-
bapenems are excreted by the kidneys, the dose is to be
reduced for patients with decreased renal function. The
Sanford guide to antimicrobial therapy (2006)11
and
Goodman and Gilman’s The pharmacological basis of
therapeutics12
recommend that renal function be esti-
mated by the following formula:
Predicted creatinine clearance from serum creatinine
(×0.85 for females) = (140 − age)(optimum body
weight kg)/(72 × serum creatinine mg/dl)
where male optimum body weight is 50.0kg + 0.9kg/cm
(150cm and taller) and female optimum body weight is
45.5kg + 0.91kg/cm (150cm and taller)
Drug dosage adjustment for ceftriaxone is not necessary
in patients with renal dysfunction. By contrast, dose
adjustment of ceftriaxone may be indicated in patients
with severe hepatic impairment.11
If patients have a biliary obstruction that blocks the
enterohepatic circulation of bile, in view of the fact that
the administration of wider-spectrum antimicrobials
such as third- and fourth-generation cephalosporins
may replace intestinal microorganisms and disturb vita-
min K absorption, which could lead to hemorrhage,
vitamin K is administered intravenously as required.
Q5. Should penetration into the bile or gallbladder
wall be considered important in the selection of
therapeutic antimicrobials in acute cholecystitis?
There is a common belief, particularly in Japan, that
antimicrobial agents with excellent penetration into
the gallbladder wall should be chosen for antimicrobial
therapy. There was some debate on whether penetra-
tion into the gallbladder should be considered in choos-
ing antimicrobial agents. However, there are no clinical
or experimental data to support this. For reference,
Table 2 shows antimicrobial agents with good penetra-
tion of the gallbladder wall (level 3b–4).13–16
The usefulness of biliary wall penetration for the
selection of therapeutic antimicrobials in acute
Table 2. Intravenous antimicrobial drugs with good penetration into the gallbladder
wall5
Penicillins Ampicillin, piperacillin, piperacillin/tazobactam
Cephalosporins
1st generation Cefazoline
2nd generation Cefmetazole, flomoxef, cefotiam,
3rd, 4th generation Cefoperazone/sulbactam,13
ceftriaxone,14
ceftazidime,
cefpirome, cefozopran
Fluoroquinolones Ciprofloxacin,13
pazufloxacin
Monobactams Aztreonam15
Carbapenems Meropenem, panipenem/betamipron
Lincosamides Clindamycin16
<Japanese panelists> < Panelists from abroad>
YES 39% (9/23)
NO
NO
YES 78% (21/27)
Fig. 1. Clinical question, “Should the
biliary penetration of antimicrobial
agents be considered important in their
selection in moderate or severe acute
cholecystitis?” Responses at the Interna-
tional Consensus Meeting. Responses
from Japanese panelists and panelists
from abroad showed that 78% (21/27)
and 39% (9/23), respectively, answered
“Yes” to the question
(3) Presence/absence of renal and hepatic
dysfunction
(4) Patient’s past history of antimicrobial
administration
(5) Local susceptibility patterns (antibiogram)
Drug dosage should be adjusted in patients with
decreased renal function. The Sanford guide to
antimicrobial therapy and Goodman and Gil-
man’s the pharmacological basis of therapeutics
should be consulted (recommendation A).

cholecystitis is still controversial. At the Tokyo Inter-
national Consensus Meeting, consensus was not ob-
tained on this question (Fig. 1). See “Discussion” for
details.
Q6. What are the results of clinical trials regarding
antimicrobial therapy for acute cholecystitis?
Three RCTs have evaluated the effect of antimicrobial
agents in patients with acute cholecystitis (Table 3)
(level 2b),17–19
and all of them demonstrated that re-
cently developed antimicrobial drugs had effectiveness
and usefulness equivalent to that of ampicillin and an
aminoglycoside, which was regarded as a standard
regimen for cholecystitis in the 1980s (level 4–5).20,21
Therefore, according to the clinical trials available so
far, piperacillin, ampicillin and an aminoglycoside, as
well as several cephalosporins, are recommended for
the treatment of acute cholecystitis (recommendation
A).
However, only one RCT focused only on acute chole-
cystitis. In addition, the antimicrobial agents widely used
at present for acute cholecystitis, including penicillin/
β-lactamase inhibitors, carbapenems, and the third- and
fourth-generation cephalosporins, were not tested in
these RCTs. In this regard, in the Tokyo Guidelines,
we recommend alternative regimens of antimicrobial
agents, as given below. A consensus on these recom-
mendations was reacted at the International Consensus
Meeting.
Q7. What are the current recommendations for
antimicrobial therapy in acute cholecystitis?
Table 3. Comparative clinical tests of antimicrobial drugs in cholecystitis
Authors Subjects Antimicrobial Clinical cure rate Significant difference
Muller (1987)17
Cholecystitis ABPC+TOB 11/13 (85%)
Piperacillin 18/19 (95%) NS
Cefoperazone 19/20 (95%) NS
Chacon (1990)18
Cholecystitis + Pefloxacin 49/50 (98%) NS
cholangitis ABPC+GM 45/47 (95.7%)
Thompson (1993)19
Cholecystitis + Cefepime 78/80 (97.5%) NS
cholangitis Mezlocillin+GM 40/40 (100%)
ABPC, ampicillin; TOB, tobramycin; GM, gentamicin
<Japanese panelists> < Panelists from abroad >
YES 100% (28/28) YES 87% (20/23)
Fig. 2. Clinical question: “Should empirically adminis-
tered antimicrobial drugs be changed for more appr-
opriate agents according to the identified causative
microorganisms and their sensitivity to antimicrobials?”
Responses at the International Consensus Meeting. Re-
sponses from Japanese panelists and panelists from abroad
showed that 100% (28/28) and 39% (20/23), respectively,
answered “Yes” to the question
• Antimicrobial drugs should be selected accord-
ing to the severity assessment.
• Empirically administered antimicrobial drugs
should be changed for more appropriate agents,
according to the identified causative microor-
ganisms and their susceptibility testing results.
Antimicrobial drugs should be selected on the basis
of the severity assessment, according to the Infectious
Diseases Society of America (IDSA) guidelines (level
4)22
for complicated intraabdominal infections. But
there is very little evidence that supports this notion.
Adequate dosages of antimicrobial drugs should be de-
termined in each country; the issue of cost is not ad-
dressed in the Tokyo Guidelines. See “Discussion at the
Tokyo International Consensus Meeting” for details.
Empirically administered antimicrobial drugs should
be changed for more appropriate agents according to
the identified causative microorganisms and their sus-
ceptibility testing results. There is very little evidence
that supports this notion; however, at the Tokyo Inter-
national Consensus Meeting, consensus in support of
this notion was obtained with Japanese and overseas
panelists (Fig. 2).
Mild (Grade I) acute cholecystitis is often caused by a
single intestinal organism, such as Escherichia coli, and

therefore monotherapy with one of the antimicrobial
drugs listed in Table 4 is recommended. Because intes-
tinal organisms producing β-lactamase, which are resis-
tant to penicillins, and cefazoline, are likely to be
detected, the use of penicillin/β-lactamase inhibitors,
suchaspiperacillin/tazobactam,23
orampicillin/sulbactam
is recommended.
Patients with mild acute cholecystitis, with relatively
mild abdominal pain and mild inflammatory findings on
laboratory data and imaging studies, closely mimicking
biliary colic, may be observed with oral antimicrobial
drugs, or even without antimicrobials.
Moderate (grade II) and severe (grade III) acute
cholecystitis (Table 5)
For moderate (grade II) acute cholecystitis, wider-
spectrum penicillins, second-generation cephalosporins,
and oxacephems are recommended empirically as the
drug of first choice. For patients with severe (grade III)
acute cholecystitis, who are often infected with multiple
and/or resistant organisms (level 2b–3b),24–26
third- and
fourth-generation cephalosporins with a wider antimi-
crobial spectrum are recommended as the drug of first
choice. Depending on the local susceptibility patterns
(antibiogram), if the drug of first choice is ineffective,
fluoroquinolones and carbapenems can be used.
It should be emphasized that the inappropriate use
or overuse of third- and fourth-generation cephalospo-
rins and carbapenems would likely result in the emer-
gence of resistant bacteria.
Of note, the ratio of piperacillin to tazobactam in
Japan (4:1) is different vs. from that used in the United
States (8:1).
In each country, antimicrobials should be chosen
from the available agents that meet the concepts and
criteria discussed above and agreed on at this Consen-
sus Meeting.
Q8. What is the appropriate antimicrobial
dosing regimen?
On the basis of pharmacokinetics and pharmacody-
namics, there is a significant difference between the
United States and Japan in antimicrobial dosing regi-
mens. To provide practical recommendations on anti-
microbial therapy, this issue, even though it is a domestic
one in Japan, needed to be discussed here as well as at
the Consensus Meeting.
Regarding Japanese domestic issues about antimicro-
bial dosing regimens, the basic principles of antimicro-
bial therapy will be discussed first.
Antimicrobial therapy is classified into three types
according to the purpose of the antimicrobial use. These
are, presumptive or empirical therapy, definitive or spe-
cific therapy, and prophylaxis. Presumptive therapy is
the antimicrobial usage when infection is suspected and
causative organisms are not yet identified or when the
results of microbiological studies are pending. After
the microbiological testing results come back, therapy
should be changed accordingly, to what is called “defini-
tive therapy or specific therapy.” Lastly, “prophylaxis”
includes either primary or secondary prevention for
expected infections in the future. Of note, in our Guide-
lines, presumptive or empirical therapy for biliary tract
infection is discussed and provided.
After the appropriate antimicrobial agents are
selected, dosing regimens should be determined, on the
basis of their pharmacokinetics and pharmacodynamics,
to achieve the best clinical outcomes and to avoid the
emergence of antimicrobial resistance. Andes et al.27
classified antimicrobial agents by their bactericidal pat-
terns.Theseareeithertime-dependentorconcentration-
dependent. Time-dependent agents are the ones whose
Table 4. Antibacterials for mild (grade I) acute cholecystitis
Oral fluoroquinolones Levofloxacin, ciprofloxacin
Oral cephalosporins Cefotiam, cefcapene
First-generation cephalosporins cefazolin
Wide-spectrum penicillin/ Ampicillin/sulbactam
β-lactamase inhibitor
Table 5. Antibacterials for moderate (grade II) and severe (grade III) acute cholecystitis
First options for moderate cases
Wide-spectrum penicillin/β-lactamase Piperacillin/tazobactam, ampicillin/sulbactam
inhibitors
Second-generation cephalosporins Cefmetazole, cefotiam, oxacephem, flomoxef
First options for severe cases
Third- and fourth-generation cephalosporins Cefoperazon/sulbactam, ceftriaxone, ceftazidime, cefepime, cefozopran
Monobactams Aztreonam
One of above + metronidazole (when anaerobic bacteria are detected or are expected to co-exist)
Second options for severe cases
Fluoroquinolones Ciprofloxacin, levofloxacin, pazufloxacin + metronidazole (when
anaerobic bacteria are detected or are expected to co-exist)
Carbapanems Meropenem, impenem/cilastatin, panipenem/betamipron

bactericidal activities are affected by the time above the
minimum inhibitory concentration (time > MIC), i.e.,
the duration of time that bacteria are exposed to an
antimicrobial concentration above the MIC. For these
agents, the time intervals of antimicrobial administra-
tion are critical for gaining an appropriate clinical re-
sponse. On the other hand, for concentration-dependent
agents, the peak concentration at the site of infection is
important for achieving an appropriate clinical response
or bactericidal activity. Time-dependent agents include
β-lactams, and concentration-dependent agents with a
prolonged persistent effect include fluoroquinolones,
ketolides, and aminoglycosides. Concentration-
dependent agents with a moderate to prolonged
persistent effect include the macrolides.
In Japan, in general, for most of the available agents,
significantly fewer doses per day are approved
compared with practice in the Unite States. Morever, in
Japan, the time intervals of administration of time-
dependent agents such as β-lactams do not seem to be
determined by their half-life.
These facts suggest that, in Japan, antimicrobial
dosing regimens should be re-considered and/or re-
examined to provide the best available therapy to
achieve the best clinical outcomes for the patients. To
provide appropriate dosing regimens, body size differ-
ences among Asians, Caucasians, and other ethnic
groups should be addressed. At the Consensus Meeting,
it was agreed that doses per kilogram (body size) should
be provided, instead of the absolute number of total
doses of each agent. For details see “Discussion at the
Tokyo International Consensus Meeting.”
Cholangitis (H-15-Medicine-30), with a research sub-
sidy for fiscal 2003 and 2004 (Integrated Research
Welfare.
We also truly appreciate the panelists who cooperat-
ed with and contributed significantly to the Interna-
tional Consensus Meeting, held on April 1 and 2, 2006.
References
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spective randomized comparison of pefloxacin and ampicillin plus
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S. Cefepime for infections of the biliary tract. Surg Gynecol
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21. Thompson JJ, Tompkins R, Longmire WJ. Factors in manage-
ment of acute cholangitis. Ann Surg 1982;195:137–45. (level 4)

22. Solomkin J, Mazuski J, Baron E, Sawyer R, Nathens A, DiPiro
J, et al. Guidelines for the selection of anti-infective agents for
complicated intra-abdominal infections. Clin Infect Dis 2003;37:
997–1005. (level 4)
23. Investigators of the Piperacillin/Tazobactam Intra-abdominal
Infection Study Group. Results of the North American trial of
piperacillin/tazobactam compared with clindamycin and gentami-
cin in the treatment of severe intra-abdominal infections. Eur J
Surg 1994;573 (Suppl):61–6. (level 2b)
24. Marne C, Pallares R, Martin R, Sitges-Serra A. Gangrenous cho-
lecystitis and acute cholangitis associated with anaerobic bacteria
in bile. Eur J Clin Microbiol 1986;5:35–9. (level 3b)
25. Claesson B, Holmlund D, Matzsch T. Microﬂora of the gall-
bladder related to duration of acute cholecystitis. Surg Gynecol
Obstet 1986;162:531–5. (level 2b)
26. Nielsen M, Justesen T. Anaerobic and aerobic bacteriological
studies in biliary tract disease. Scand J Gastroenterol 1976;11:437–
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27. Andes D, Anon J, Jacobs MR, Craig WA. Application of phar-
macokinetics and pharmacodynamics to antimicrobial therapy
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(level 4)
Consensus Meeting
Community-acquired or hospital-acquired
biliary infections
Henry Pitt (USA): We should talk about community-
acquired or hospital-acquired infections. The bacteriol-
ogy of a de novo cholecystitis/cholangitis patient with
the latter, most likely to have stones, is one spectrum
that is typically the E. coli, Klebsiella Enterococcus, En-
terobacter, but it was clear that that subset of patients
had a different bacteriology with much more resistant
organisms, more yeast and more methicillin-resistant
Staphylococcus aureus (MRSA) and the kinds of things
that are like vancomycin-resistant Enterococcus (VRE)
now, that are likely to cause trouble. So we have to take
that into account here as well; that there may be de
novo cholangitis/cholecystitis, and then there is another
group of patients that have hospital-acquired type
infections.
Duration of antimicrobial therapy
Henry Pitt: I think in particular, for the acute cholecys-
titis, if you do a cholecystectomy, that you can often get
away with a very short course, especially if it is a mild
case, which meant most of the cases.
Joseph S. Solomkin (USA): The other point I will
make, just to relay our experience in North America, is
that there is increasing emphasis on shortened duration
of therapy and the i.v. to oral switch is very helpful if
you are interested in sending patients home more
rapidly; it does reduce, also, the problem of needing to
have an i.v. in place, and a nurse to give the infusion.
Biliary penetration
At the International Consensus Meeting, 78% (21/27)
and 39% (9/23), respectively, of the Japanese panelists
and the panelists from abroad answered “yes” to the
clinical question: “Should the biliary penetration of
antimicrobial agents be considered to be important in
their selection in moderate or severe acute cholecysti-
tis?” (see Fig. 1).
Steven Strasberg (USA): The reason why the im-
portance of biliary penetration in Japan and overseas
(especially the United States) is signiﬁcantly different
seems to be derived from treatment strategies in both
countries. In the United States, cholecystectomy tends
to be performed after diagnosis immediately, so that
you can often get away with a very short course, and
biliary penetration is not so important for them.
Nagai (Japan): With acute cholecystitis, the good
penetration of the antimicrobial selection is nonsense;
that is what I am telling to my residents.
Drug selection on the basis of severity assessment
Joseph S. Solomkin: The notion that more seriously ill
patients should get different antibiotics, and that is the
notion that we put into the IDSA guidelines, and I think
is suggested here also; one has to realize that there is
very little real evidence that works. I think it is very
important to know that there really is very little, if any,
evidence that that is the case. It is very reasonable to
simply take an approach that targets the organism sepa-
rate from the severity of illness, and I think that is one
issue that might be put to this group to respond to
whether these guidelines should be based on severity
or not.
Drug dosage and cost
Joseph S. Solomkin: If you are making a recommenda-
tion that these guidelines should include what I would
call North American dosing; or what would be your
recommendation? Also, realizing the regulatory issues
about drug dosing.
Harumi Gomi (Japan): That is the critical point; dos-
ing regimens are the critical point of microbial therapy
and I personally think that doses should be included in
the Guidelines. Then for legal issues, I think that this is
our domestic issue, and we need to ask the government
or we need to make some actions to make those anti-
microbial agents available for Japanese patients.
Sheung-Tat Fan (China): I wondered if dosage should
be expressed in terms of the body weight — kilograms
— rather than absolute amount. I see that there is a
difference in body size between Asians and Americans,
so there may be a difference. We have to be more real-

istic; that means we have to talk about the body weight,
rather than absolute amount.
Harumi Gomi: For example, 30kg — for these
low-body-weight patients, we may have to use FDA-
approved pediatric dosage.
Henry Pitt: I think that the issue of cost should be in
our guidelines as well.
Harumi Gomi: The major reasons for proposals on
appropriate dosing regimens are as follows:
(a) Best available medical treatment with appropriate
antimicrobial dosing regimens should be provided
to patients, when possibile, to avoid inadequate
clinical response
(b) Overuse or unnecessary use of broader-spectrum
antimicrobial agents, such as carbapenems, should
be avoided in Japan.
(c) Medical professionals in Japan should be aware of
scientiﬁcally sound or appropriate antimicrobial
dosing regimens on the basis of pharmacokinetics
and pharmacodynamics of the agents
(d) To make the appropriate dosing regimens available
in Japan, legal action or policy-making is
required.

DOI 10.1007/s00534-006-1163-8
Results of the Tokyo Consensus Meeting Tokyo Guidelines
Toshihiko Mayumi1
, Tadahiro Takada2
, Yuji Nimura4
, Masahiro Yoshida2
,
Miho Sekimoto5
, Fumihiko Miura2
, Keita Wada2
, Masahiko Hirota6
, Yuichi Yamashita7
, Masato Nagino4
,
Toshio Tsuyuguchi8
, Atsushi Tanaka9
, Harumi Gomi10
, and Henry A. Pitt11
1
Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku,
Nagoya 466-8550, Japan
2
3
4
5
Kyoto, Japan
6
7
8
Department of Medicine and Clinical Oncology, Graduate School of Medicine Chiba University, Chiba, Japan
9
10
Division of Infection Control and Prevention, Jichi Medical University Hospital, Tochigi, Japan
11
back at open symposia and conferences, was essential
during the development of the Guidelines.
As one of the Integrated Research Projects for As-
sessing Medical Technology, sponsored by the Japanese
Ministry of Health, Labour, and Welfare, a Research
Group for the Preparation and Diffusion of Guidelines
for the Management of Acute Biliary Tract Infection
was established. With support from the Japanese Soci-
ety for Abdominal Emergency Medicine, the Japan
Biliary Association, and the Japanese Society of Hepato-
Biliary-Pancreatic Surgery, development of the Guide-
lines for the Management of Acute Cholangitis and
Cholecystitis has been underway since 2003.
After several open consensus conferences and open
symposia to obtain feedback from members of these
societies, a Japanese-language version of “Evidence-
Based Practice Guidelines for the Management of
Acute Cholangitis and Cholecystitis” was prepared and
published.
An English-language version of these Guidelines
(draft) was discussed, via e-mail, with worldwide ex-
perts on acute cholangitis and cholecystitis, with the aim
of publishing International Guidelines for the Manage-
ment of Acute Cholangitis and Cholecystitis. Much
spirited debate, which changed many areas of diagnosis
criteria, severity assessment, etc, then took place at the
International Consensus Meeting, held in Tokyo on
April 1 and 2, 2006, attended by experts from Japan and
many other parts of the world. After several modifica-
tions by the Organizing Committee, the final version is
published here as the International Guidelines for the
Management of Acute Cholangitis and Cholecystitis.
In this article, we outlined comments and opinions
given at the International Consensus Meeting,
Abstract
A systematic review of references conducted in the process of
developing the Guidelines for the Management of Acute
Cholangitis and Cholecystitis did not find many high-quality
research reports. There were no criteria for diagnosis, severity
assessment, or patient transfer, and no established principles
of clinical practice guidelines for acute cholangitis and chole-
cystitis. In order to develop guidelines that would be useful
in clinical practice, an understanding of the current status of
clinical practice for acute cholangitis and cholecystitis was
considered essential. After several open symposia and a
survey of these two diseases, we developed and published a
Japanese-language version of Evidence-Based Practice Guide-
lines for the Management of Acute Cholangitis and Cholecys-
titis. In order to prepare international Guidelines, we had
repeated discussions about the draft Guidelines together with
international experts, and, following the Consensus Meeting,
held on April 1–2, 2006, in Tokyo, with the attendance of 300
world experts in the field, the International Guidelines for the
Management of Acute Cholangitis and Cholecystitis were de-
veloped. In this article, we outline the comments and opinions
given at the International Meeting and how they are reflected
in the final version of the Guidelines.
Key words Guidelines · Consensus development meeting ·
Evidence-based medicine · Cholangitis · Acute cholecystitis
Introduction
Guidelines should not only be based on evidence but
should also meet the needs of current medical practice.
We thought that adequate discussion, to receive feed-
Offprint requests to: T. Mayumi

T. Mayumi et al.: Results of the Tokyo Consensus Meeting 115
and how they are reflected in final version of the
Guidelines.
Changes made in the Guidelines at the International
Consensus Meeting for the Management of Acute
Cholangitis and Cholecystitis (Tokyo, April 1–2, 2006)
In order to prepare international guidelines based on
the “Evidence-Based Practice Guidelines for the Man-
agement of Acute Cholangitis and Cholecystitis”, draft
guidelines were modified several times by the Organiz-
ing Committee, and discussion was carried out, via e-
mail, with worldwide experts on acute cholangitis and
acute cholecystitis before the International Consensus
Meeting.
The discussions were followed by the 2-day Interna-
tional Consensus Meeting, held in Tokyo on April 1–2,
2006, with the attendance of about 300 world experts
specializing in acute cholangitis and acute cholecystitis,
in order to prepare evidence-based guidelines. Attend-
ees from abroad are listed (Page 8–10). Discussions at
the Meeting are outlined below.
Diagnostic criteria for acute cholangitis
Some panelists proposed that “History of biliary dis-
ease” should be included in the diagnostic criteria for
acute cholangitis (Table 1B). A history of biliary dis-
ease, such as gallstones, a history of previous biliary
surgery, and having an indwelling biliary stent play an
important role in making the diagnosis, as agreed upon
by many participants at the Consensus Meeting. But
other panelists disagreed and proposed different crite-
ria (Table 1C).
Because not only an increase but also a decrease in
the WBC count indicates inflammation, “leukocytosis”
was changed to “abnormal WBC count”. Because C-
reactive protein (CRP) is sometimes not elevated, “or
other evidence of inflammatory response” was added.
“WBC count” and “elevation of CRP level or other evi-
dence of inflammatory response” are separate items.
As aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) sometimes increase in acute
cholangitis, “abnormal liver function tests, alkaline
phosphatase (ALP), γ-GTP, AST, ALT)” was added.
Imaging findings of inflammatory changes in acute
cholangitis are also useful for diagnosis. “Biliary dilata-
tion or etiology (stricture, tumor, stones)” (Table 1A)
was changed to “biliary dilatation, inflammatory find-
ings, or etiology (stricture, tumor, stones)” (Table 1B,
C).
Two ways of making a definite diagnosis were
proposed; in revision 1 (Table 1B), these were: (1)
three or four items in A (Charcot’s triad) and (2)
any item in A + two items in B + C, and in Revision 2
(Table 1C), these were: Any item in A + two items in
B + C.
As more than 90% of the participants at the Tokyo
Consensus Meeting agreed on four criteria in revision
1 (Table 1B), a history of biliary disease was included,
and abnormal WBC count and elevation of CRP or
other evidence of inflammatory response were included
in the final version of the diagnostic criteria for acute
cholangitis (Table 1D).
In Table 1D, two or more items in A were defined as
a suspected diagnosis, and either: (1) Charcot’s triad
(items 2 + 3 + 4 in A) or (2) two or more items in A plus
both items in B + C, were defined as a definite diagnosis
of acute cholangitis.
Severity assessment criteria for acute cholangitis
(Table 2)
More than 70% of the participants at the Tokyo Con-
sensus Meeting agreed that the severity of acute chol-
angitis should be divided into three grades, severe (grade
III), moderate (grade II), and mild (grade I). To stratify
acute cholangitis into three grades, two different criteria
were necessary, and it was decided to use “onset of
organ dysfunction” and “response to the initial medical
treatment” as criteria for the severity assessment of
acute cholangitis.
“Severe (grade III)” acute cholangitis was defined as
that associated with any one of the categories of organ/
system dysfunction or severe local inflammation listed
in Table 2. This was supported by more than 90% of the
panelists at the International Consensus Meeting. But
the thresholds of these categories were not discussed at
the Summary session.
There was some argument about whether the score
on an acute physiology scoring system, such as acute
physiology and chronic health evaluation (APACHE)
II, or a multiple organ dysfunction scoring system, such
as Marshall’s system or the sepsis-related organ failure
assessment (SOFA) system should be used as a criterion
for severe (grade III) acute cholangitis. The principal
advantage of these scoring systems is that they provide
gradations of severity. The APACHE II system has
been validated, especially for critical care patients, in-
cluding patients with sepsis, and acute cholangitis can
be interpreted as a subset of sepsis. The disadvantage
of these scoring systems is that the scores are some-
times troublesome to calculate, and critically speaking,
they have not been satisfactory validated in patients
with acute cholangitis. The vote on this argument
showed that 37.8% of the panelists supported the use
of APACHE II and 62.2% did not. As a result of this
vote, the chairmen of this session, Drs. Yoshifumi
Kawarada (Japan) and Henry Pitt (United States),
had proposed to remit the final decision of whether or

116 T. Mayumi et al.: Results of the Tokyo Consensus Meeting
Table 1. Diagnostic criteria for acute cholangitis
(A) Original
A. Clinical signs 1. Fever and/or chills
2. Jaundice
3. Abd. pain (RUQ, epigastric)
B. Laboratory data 4. Leukocytosis or elevation of CRP level
5. Elevation of ALP or γ-GTP level
C. Imaging findings 6. Biliary dilatation or etiology (stricture, tumor, stones)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
Definite diagnosis (1) All items in A (Charcot’s triad)
(2) One or two items in A + all items in B + C
Note: acute hepatitis and other causes of acute abdomen should be excluded
(B) Proposed revision 1 at International Meeting
A. Clinical context and manifestations 1. History of biliary disease
2. Fever and/or chills
3. Jaundice
B. Laboratory data 5. Abnormal WBC count
6. Elevation of CRP level or other evidence of inflammatory response
7. Abnormal liver function tests (ALP, γ-GTP, AST, ALT)
C. Imaging findings 8. Biliary dilatation, inflammatory findings, or etiology (stricture, tumor, stones)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
Definite diagnosis (1) Three or 4 items in A (Charcot’s triad)
(2) Any item in A + 2 items in B + C
(C) Proposed revision 2 at International Meeting
A. Clinical context and manifestations 1. Fever and/or chills
2. Jaundice
B. Laboratory data 4. Abnormal WBC count
5. Elevation of CRP level or other evidence of inflammatory response
6. Abnormal liver function tests (ALP, γ-GTP, AST, ALT)
C. Imaging findings 7. Biliary dilatation, inflammatory findings, or etiology (stricture, tumor, stones)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
Definite diagnosis (1) Any item in A + 2 items in B + C
(D) Final version of diagnostic criteria for acute cholangitis
A. Clinical context and clinical 1. History of biliary disease
manifestations 2. Fever and/or chills
3. Jaundice
4. Abdominal pain (RUQ or upper abdominal)
B. Laboratory data 5. Evidence of inflammatory responsea
6. Abnormal liver function testsb
C. Imaging findings 7. Biliary dilatation, or evidence of an etiology (stricture, stone, stent, etc)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
Suspected diagnosis Two or more items in A
Definite diagnosis (1) Charcot’s triad (2 + 3 + 4)
(2) Two or more items in A + both items in B + C
a
Abnormal WBC count, increased serum CRP level, and other changes indicating inflammation
b
Increased serum ALP, γ-GTP (GGT), AST, and ALT levels
not APACHE II should be included as a criterion for
severe (grade III) acute cholangitis to the Organizing
Committee, and this proposal was approved by the
audience.
Neither “recurrent symptom” nor “malignancy as eti-
ology” always shows moderate (grade II) acute cholan-
gitis. Therefore, both of these were deleted from the
criteria for “moderate (grade II)” acute cholangitis. The
thresholds of high fever and WBC counts were not
decided.
After the International Meeting, all the criteria and
thresholds of severity of acute cholangitis were dis-

Table 2. Severity assess ment criteria for acute cholangitis
(A) Proposed severity assessment criteria at International Meeting
“Severe (grade III)” acute cholangitis
“Severe (grade III)” acute cholangitis is that associated with dysfunctions of at least one of the following organs/systems
1. Cardiovascular Hypotension
2. Neurologic Disturbance of consciousness
3. Respiratory PaO2/FiO2 ratio <300, SpO2 decrease: (not decided)
4. Renal Oliguria, creatinine >2.0mg/dl
5. Hepatic PT > 15?, 20? Seconds? or INR > 1.5?, or PT prolongation?: (not decided)
6. Hematologic Platelets < 100000/mm3
?
7. APACHE II? To be included or not included? If yes, Score?
“Moderate (grade II)” acute cholangitis
“Moderate (grade II)” acute cholangitis is that associated with at least one of the following factors
High fever >39°C?: (threshold level was not decided)
WBC > 20000/mm3
? (threshold level was not decided)
No remission for 48–72h
Recurrent symptom
Malignancy as etiology
Note: elderly patients (>75 years) and patients with medical comorbidities should be closely monitored
“Mild (grade I)” acute cholangitis
“Mild (grade I)” acute cholangitis is that which does not meet the criteria for “severe” or “moderate” acute cholangitis.
(i.e., neither organ dysfunction nor risk factors)
(B) Final version of severity assessment criteria for acute cholangitis
Mild (grade I) acute cholangitis
“Mild (grade I)” acute cholangitis is defined as acute cholangitis that responds to the initial medical treatmenta
Moderate (grade II) acute cholangitis
“Moderate (grade II)” acute cholangitis is defined as acute cholangitis that does not respond to the initial medical
treatmenta
and is not associated with organ dysfunction
Severe (grade III) acute cholangitis
“Severe (grade III)” acute cholangitis is defined as acute cholangitis that is associated with the onset of dysfunction at least
in any one of the following organs/systems:
1. Cardiovascular system Hypotension requiring dopamine м5µg/kg per min, or any dose of dobutamine
2. Nervous system Disturbance of consciousness
3. Respiratory system PaO2/FiO2 ratio <300
4. Kidney Serum creatinine >2.0mg/dl
5. Liver PT-INR > 1.5
6. Hematological system Platelet count <100000/µl
Note: compromised patients, e.g., elderly (>75 years old) and patients with medical comorbidities, should be closely monitored
a
General supportive care and antibiotics
cussed and decided or by the Organizing Committee
(Table 2B). The definition of moderate (grade II) acute
cholangitis was changed to: “acute cholangitis that does
not respond to the initial medical treatment and is not
associated with organ dysfunction (Table 2B).
Diagnostic criteria for acute cholecystitis (Table 3)
After the discussion during the Tokyo International
Consensus Meeting, almost unanimous agreement was
achieved (Table 3B). However, 19% of the panelists
from abroad expressed the necessity for minor mo-
difications, because the diagnostic criteria did not in-
clude technetium hepatobiliary iminodiacetic acid
(Tc-HIDA) scans as an item in the provisional version.
Some panelists insisted that “suspected diagnosis”
was not necessary, and that only “definite diagnosis”
should be included in the diagnostic criteria for acute
cholecystitis. There was no discussion on whether, if
“suspected diagnosis” was deleted, how the definition
of definite diagnosis should be modified.
After the International Meeting, “A. Local signs of
inflammation”; “B. Systemic signs of inflammation” and
“C. Imaging findings” were clearly specified in the diag-
nostic criteria for acute cholecystitis (Table 3B). Tc-
HIDA scan was included in “C. Imaging findings”.
“Suspected diagnosis” was deleted from the criteria.
Severity assessment criteria for acute cholecystitis
(Table 4)
Before the International Meeting, “Severe (grade III)”
acute cholecystitis was defined as that associated with
dysfunction in any one of the organs/systems or any one
of the severe local inflammation categories listed in
Table 4A.

118 T. Mayumi et al.: Results of the Tokyo Consensus Meeting
Table 3. Diagnostic criteria for acute cholecystitis
(A) Proposed at International Meeting
1. (1) Murphy’s sign, (2) RUQ, mass/pain/tenderness, (3) rigidity/muscle guarding, (4) rebound tenderness
2. (1) Fever, (2) abnormal WBC count, (3) elevated CRP
3. Imaging findings characteristic of acute cholecystitis
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
Suspected diagnosis: one item in 1. and one item in 2. are positive. (Suspected diagnosis may be deleted? If so, definition of
definite diagnosis?)
Definite diagnosis: 3. is positive in patients who fulfill the criteria for suspected diagnosis
Note: acute hepatitis, other causes of acute abdomen, and chronic cholecystitis should be excluded
(B) Final version of diagnostic criteria for acute cholecystitis
A. Local signs of inflammation (1) Murphy’s sign, (2) RUQ mass/pain/tenderness
B. Systemic signs of inflammation (1) Fever, (2) elevated CRP, (3) elevated WBC count
C. Imaging findingsa
Imaging findings characteristic of acute cholecystitis
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
Definite diagnosis
(1) One item in A and one item in B are positive
(2) C confirms the diagnosis when acute cholecystitis is suspected clinically
Note: acute hepatitis, other acute abdominal disease, and chronic cholecystitis should be excluded
a
Imaging findings of acute cholecystitis
Ultrasonography
• Sonographic Murphy sign (tenderness elicited by pressing the gallbladder with the ultrasound probe)
• Thickened gallbladder wall (>4mm, if the patient does not have chronic liver disease and/or ascites or right heart failure)
• Enlarged gallbladder (long axis diameter >8cm, short axis diameter >4cm)
• Incarcerated gallstone, debris echo, pericholecystic fluid collection
• Sonolucent layer in the gallbladder wall, striated intramural lucencies, and Doppler signals
MRI
• Pericholecystic high signal
• Enlarged gallbladder
• Thickened gallbladder wall
CT
• Thickened gallbladder wall
• Pericholecystic fluid collection
• Enlarged gallbladder
• Linear high-density areas in the pericholecystic fat tissue
Tc-HIDA scan (technetium hepatobiliary iminodiacetic acid scan)
• Non-visualized gallbladder with normal uptake and excretion of radioactivity
• Rim sign (augmentation of radioactivity around the gallbladder fossa)
At the Meeting, concepts of the severity of acute
cholecystitis were discussed and changed as shown
below. The concept of the final version of the severity
assessment of acute cholecystitis, “severe (grade III)”
acute cholecystitis was defined as that associated with
organ dysfunction, “moderate (grade II)” acute chole-
cystitis was defined as that associated with difficulty to
perform cholecystectomy due to local inflammation,
and “mild (grade I)” acute cholecystitis was defined as
that which does not meet the criteria of “severe” or
“moderate” acute cholecystitis.
In the severity assessment initially proposed at the
Meeting “moderate (grade II)” acute cholecystitis was
associated with any of the following conditions: (1) ab-
normal WBC (>15000, >18000? threshold was not de-
cided), (2) palpable inflammatory mass, (3) onset more
than 72–96h and (4) Serious wall thickening and fluid
collection around the gallbladder.
Some panelists insisted that “serious” should be
changed to “thickening” or deleted. Whether threshold
of wall thickening should be included was not discussed.
If included, the extent of the thickness, whether 6–7mm
or 8mm, or twice that of the normal gallbladder wall,
also remained as questions. Also, it was queried wheth-
er both the thickness of the gallbladder wall and fluid
collection around the gallbladder were necessary for the
diagnosis of moderate acute cholecystitis?
Panelists suggested that liver cirrhosis should be de-
scribed in a Note.
After the International Meeting, each item and its
threshold were discussed and decided on by the Orga-
nizing Committee. “Severe local inflammation” was
deleted from the criteria for severe (grade III) acute
cholecystitis (Table 4B). “Onset more than 72–96h” was
changed to “prolonged local signs of inflammation” in
the criteria for moderate (grade II) acute cholangitis.
Flowcharts
Flow charts for the management of acute cholangitis
and acute cholecystitis according to severity were also
discussed and modified at the Meeting.

Table 4. Severity assessment criteria for acute cholecystitis
(A) Proposed at International Meeting
“Severe (grade III)” acute cholecystitis
“Severe (grade III)” acute cholecystitis is associated with any one of the following categories. Organ/System dysfunction
(Note: Thresholds were not discussed at the Summary session)
• Cardiovascular Hypotension
• Neurologic (Disturbance of consciousness)
• Respiratory (PaO2/FiO2 ratio <300)
• Renal (Oliguria, creatinine >2.0mg/dl)
• Hepatic (T. bilirubin >5.0mg/dl)
• DIC (Platelets <100000/mm3
)
Severe local inflammation
Biliary peritonitis, pericholecystic abscess, hepatic abscess, gangrenous cholecystitis, emphysematous cholecystitis
“Moderate (grade II)” acute cholecystitis
“Moderate (grade II)” acute cholecystitis is associated with any of the following conditions.
• WBC > 15000, 18000 (Threshold?)
• Palpable inflammatory mass
• Onset > 72–96h
• Serious thickening? (or “serious” deleted?), thickening of wall (include threshold?, if so, what thickness — 6–7mm or
8mm? or twice normal gallbladder wall?) and fluid collection around the gallbladder. (Is both thickness of gallbladder wall
and fluid collection around the gallbladder necessary?)
Liver cirrhosis should be described in a Note.
“Mild (grade I)” acute cholecystitis
“Mild (grade I)” acute cholecystitis does not meet the criteria of “severe” or “moderate” acute cholecystitis
(B) Final version of severity assessment criteria for acute cholecystitis
“Mild (grade I)” acute cholecystitis does not meet the criteria of “severe (grade III)” or “moderate (grade II)” acute
cholecystitis. It can also be defined as acute cholecystitis in a healthy patient with no organ dysfunction and mild
inflammatory changes in the gallbladder, making cholecystectomy a safe and low-risk operative procedure.
“Moderate” acute cholecystitis is associated with any one of the following conditions:
1. Elevated WBC count (>18000/mm3
)
2. Palpable tender mass in the right upper abdominal quadrant
3. Duration of complaints >72ha
4. Marked local inflammation (biliary peritonitis, pericholecystic abscess, hepatic abscess, gangrenous cholecystitis,
emphysematous cholecystitis)
a
Laparoscopic surgery should be performed within 96h of the onset of acute cholecystitis
“Severe” acute cholecystitis is associated with dysfunction of any one of the following organs/systems
1. Cardiovascular dysfunction (hypotension requiring treatment with dopamine м5µg/kg per min, or any dose of dobutamine)
2. Neurological dysfunction (decreased level of consciousness)
3. Respiratory dysfunction (PaO2/FiO2 ratio <300)
4. Renal dysfunction (oliguria, creatinine >2.0mg/dl)
5. Hepatic dysfunction (PT-INR > 1.5)
6. Hematological dysfunction (platelet count <100000/mm3
)
Almost all panelists agreed with the flowchart for
“General guidance for the management of acute biliary
infection” (Fig. 1). But in the flowchart for the manage-
ment of acute cholangitis (Fig. 2a), panelists suggested
that medical treatment should be begun before assess-
ment of the severity of acute cholangitis. Therefore, the
flowchart was changed, as shown in Fig. 2b.
In the flowchart for the management of acute chole-
cystitis (Fig. 3a), because the concept of severity of
cholecystitis was changed, this flowchart was also modi-
fied (Fig. 3b). As “severe (grade III)” acute cholecystitis
is associated with organ dysfunction, urgent/early drain-
age was preferred to urgent/early cholecystectomy for
“severe (grade III)” cholecystitis. Similarly, as “moder-
ate (grade II)” acute cholecystitis is associated with
difficulty to perform cholecystectomy due to local
inflammation, urgent/early drainage was preferred to
early/elective cholecystectomy for “moderate (grade
II)” cholecystitis also.
Definitions of severity: mild to severe (grades I–III)
Before the Meeting, the severity of both acute cholangi-
tis and acute cholecystitis was classified as mild,

Suspicion of acute biliary infection
Diagnostic criteria
Clinical presentations, blood test,
diagnostic imaging
Acute cholangitis Acute cholecystitis
Other diseases
Differential
diagnosis
Fig. 1. Flowchart for general guidance
for the management of acute biliary
infection
Urgent
biliary
drainage
(Endoscopic treatment and surgery)
Organsupport
forseverecases
Observation
Severe
(Grade III)
Early
biliary
drainage
Medicaltreatment
Moderate
(Grade II)
Severity assessment
Mild
(Grade I)
Urgent
biliary
drainage
(Endoscopic treatment,
percutaneous treatment,
or surgery)
Organsupport
forseverecases
Observation
Severe
(Grade III)
Early
biliary
drainage
Medicaltreatment
Moderate
(Grade II)
Severity assessment
Launch of medical treatment
Mild
(Grade I)
Fig. 2a,b. Flowcharts for the manage-
ment of acute cholangitis. a Original;
b modiﬁed at the Meeting
a
b

moderate, and severe. But, with these criteria, even
“moderate” acute cholangitis and “moderate” acute
cholecystitis sometimes cause organ failure and even
death. This definition could have confused users of these
Guidelines, as “moderate” diseases are usually regarded
as those having a good course without high morbidity or
mortality. Therefore, instead of using the categories
“mild”,“moderate”,and“severe”,thecategories“grades
I, II, and III” were used as the severity classifications for
both acute cholangitis and acute cholecystitis.
Conclusion
In the preparation of the Guidelines for Acute Biliary
Tract Infections (Acute Cholangitis and Cholecystitis),
we found that there was not a sufficient volume of high-
quality research. In this article, we have reported the
process of developing the Guidelines, ranging from the
identification of current clinical practice for acute bili-
ary tract infection, to the proposals for the Guidelines
and the improvements based on consensus. The Guide-
lines are the world’s first international guidelines for the
clinical management of acute biliary tract infections
(acute cholangitis and cholecystitis), and it is strongly
expected that they may be used broadly in everyday
medical practice throughout the world as Guidelines
that fully reflect local and regional conditions.
We also truly appreciate the panelists who cooperated
with and contributed significantly to the International
Consensus Meeting, held in Tokyo on April 1 and 2,
2006.
Observation Early/elective
cholecystectomy
Observation
Severity assessment
Medicaltreatment
Organsupport
forseverecases
Urgent/ early
cholecystectomy
SevereMild
(Grade I)
Moderate
(Grade II)
Urgent/ early
GB drainage
Early/elective
cholecystectomy
Urgent/ early
cholecystectomyEarly LC
Observation
Early/ elective
cholecystectomy Observation
Severity assessment
Medicaltreatment
Organsupport
forseverecases
Urgent/ early
GB drainage
Severe
(Grade III)
Mild
(Grade I)
Moderate
(Grade II)
(Grade III)
Fig. 3a,b. Flowcharts for the manage-
ment of acute cholecystitis. a Original; b
modified at the Meeting. GB, gallbladder;
LC, laparoscopic cholecystectomyb
a

Tokyo guidelines for cholangitis and cholecystitis

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